@article {pmid38748774,
year = {2024},
author = {Luk, IS and Bridgwater, CM and Yu, A and Boila, LD and Yáñez-Bartolomé, M and Lampano, AE and Hulahan, TS and Boukhali, M and Kathiresan, M and Macarulla, T and Kenerson, HL and Yamamoto, N and Sokolov, D and Engstrom, IA and Sullivan, LB and Lampe, PD and Cooper, JA and Yeung, RS and Tian, TV and Haas, W and Saha, SK and Kugel, S},
title = {SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.},
journal = {Science translational medicine},
volume = {16},
number = {747},
pages = {eadj7685},
doi = {10.1126/scitranslmed.adj7685},
pmid = {38748774},
issn = {1946-6242},
mesh = {*Cholangiocarcinoma/drug therapy/pathology/metabolism/genetics ; Humans ; *Dasatinib/pharmacology ; *Mutation/genetics ; *src-Family Kinases/metabolism/antagonists & inhibitors ; *Adaptor Proteins, Signal Transducing/metabolism ; Cell Line, Tumor ; *Isocitrate Dehydrogenase/metabolism/genetics ; Animals ; Cell Adhesion Molecules/metabolism ; Cell Proliferation/drug effects ; Phosphorylation/drug effects ; Signal Transduction/drug effects ; Mice ; Bile Duct Neoplasms/pathology/metabolism/genetics/drug therapy ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; },
abstract = {Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.},
}

*Cholangiocarcinoma/drug therapy/pathology/metabolism/genetics
Humans
*Dasatinib/pharmacology
*Mutation/genetics
*src-Family Kinases/metabolism/antagonists & inhibitors
*Adaptor Proteins, Signal Transducing/metabolism
Cell Line, Tumor
*Isocitrate Dehydrogenase/metabolism/genetics
Animals
Cell Adhesion Molecules/metabolism
Cell Proliferation/drug effects
Phosphorylation/drug effects
Signal Transduction/drug effects
Mice
Bile Duct Neoplasms/pathology/metabolism/genetics/drug therapy
Ribosomal Protein S6 Kinases, 70-kDa/metabolism

@article {pmid38747556,
year = {2024},
author = {Jiang, MZ and Gaynor, SM and Li, X and Van Buren, E and Stilp, A and Buth, E and Wang, FF and Manansala, R and Gogarten, SM and Li, Z and Polfus, LM and Salimi, S and Bis, JC and Pankratz, N and Yanek, LR and Durda, P and Tracy, RP and Rich, SS and Rotter, JI and Mitchell, BD and Lewis, JP and Psaty, BM and Pratte, KA and Silverman, EK and Kaplan, RC and Avery, C and North, KE and Mathias, RA and Faraday, N and Lin, H and Wang, B and Carson, AP and Norwood, AF and Gibbs, RA and Kooperberg, C and Lundin, J and Peters, U and Dupuis, J and Hou, L and Fornage, M and Benjamin, EJ and Reiner, AP and Bowler, RP and Lin, X and Auer, PL and Raffield, LM and , },
title = {Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddae050},
pmid = {38747556},
issn = {1460-2083},
support = {/NH/NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; 1OT3HL142479-01//BioData Catalyst/ ; //NHLBI BioData Catalyst Fellowship/ ; //NHLBI TOPMed Fellowship/ ; R01HL163560/HB/NHLBI NIH HHS/United States ; U01 HG009088/HG/NHGRI NIH HHS/United States ; /TR/NCATS NIH HHS/United States ; KL2TR002490/NH/NIH HHS/United States ; /NH/NIH HHS/United States ; //NCI/ ; //NHGRI/ ; //NHLBI/ ; //NIDA/ ; //NIMH/ ; //NINDS/ ; },
abstract = {Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.},
}

@article {pmid38747505,
year = {2024},
author = {Mo, G and Lee, SY and Coffey, DG and Voillet, V and Kirsch, IR and Gottardo, R and Smythe, KS and Yeung, CCS and Greenbaum, A and Green, DJ and Maloney, DG and Till, BG},
title = {Long-term Remissions Following CD20-directed Chimeric Antigen Receptor Adoptive T cell Therapy.},
journal = {Blood cancer discovery},
volume = {},
number = {},
pages = {},
doi = {10.1158/2643-3230.BCD-23-0263},
pmid = {38747505},
issn = {2643-3249},
abstract = {Chimeric antigen receptor (CAR) T cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma (NHL), but long-term data are minimal to date. Here, we present long-term follow-up of a pilot trial testing a CD20-targeting 3rd generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the 3 patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B cell aplasia in both patients suggested a lack of functional CAR T cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular anti-tumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas.},
}

@article {pmid38744973,
year = {2024},
author = {Zhou, T and Zhang, R and Jia, D and Doty, RT and Munday, AD and Gao, D and Xin, L and Abkowitz, JL and Duan, Z and Ma, J},
title = {GAGE-seq concurrently profiles multiscale 3D genome organization and gene expression in single cells.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {38744973},
issn = {1546-1718},
support = {R01HG012303//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01HG012303//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {The organization of mammalian genomes features a complex, multiscale three-dimensional (3D) architecture, whose functional significance remains elusive because of limited single-cell technologies that can concurrently profile genome organization and transcriptional activities. Here, we introduce genome architecture and gene expression by sequencing (GAGE-seq), a scalable, robust single-cell co-assay measuring 3D genome structure and transcriptome simultaneously within the same cell. Applied to mouse brain cortex and human bone marrow CD34[+] cells, GAGE-seq characterized the intricate relationships between 3D genome and gene expression, showing that multiscale 3D genome features inform cell-type-specific gene expression and link regulatory elements to target genes. Integration with spatial transcriptomic data revealed in situ 3D genome variations in mouse cortex. Observations in human hematopoiesis unveiled discordant changes between 3D genome organization and gene expression, underscoring a complex, temporal interplay at the single-cell level. GAGE-seq provides a powerful, cost-effective approach for exploring genome structure and gene expression relationships at the single-cell level across diverse biological contexts.},
}

@article {pmid38743457,
year = {2024},
author = {Boonyaratanakornkit, J and Wang, Q and Nader, A and Kimball, L and Stevens-Ayers, T and Levkova, M and Blazevic, R and Nguyen, J and Wright, J and Castor, J and Greninger, AL and Ford, E and Mielcarek, M and Fordred, S and Han, J and Boeckh, M and Waghmare, A},
title = {The effect of gastrointestinal graft-versus-host disease and diarrhea on the pharmacokinetic profile of sotrovimab in hematopoietic stem cell transplant recipients.},
journal = {The Journal of infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1093/infdis/jiae236},
pmid = {38743457},
issn = {1537-6613},
abstract = {BACKGROUND: Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics (PK) of the long-acting mAb sotrovimab targeting SARS-CoV-2 in hematopoietic cell transplant (HCT) recipients.

METHODS: All participants received an intravenous infusion of sotrovimab within one week prior to initiating the pre-transplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks post-transplant.

RESULTS: Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal (GI) graft-versus-host disease (GVHD) post-transplant.

CONCLUSIONS: These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased GI clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations.},
}

@article {pmid38742743,
year = {2024},
author = {Epplein, M and McCall, SJ and Wang, F and Alagesan, P and Brown, H and Wawrzynski, J and Labriola, C and Zuzul, R and Cook, C and Dillon, M and Hyslop, T and Patierno, SR and Salama, NR and Garman, KS},
title = {Prevalence of the cagA Virulence Factor Varies by Race among H. pylori-infected Patients Undergoing Upper Endoscopy.},
journal = {Clinical and translational gastroenterology},
volume = {},
number = {},
pages = {},
doi = {10.14309/ctg.0000000000000713},
pmid = {38742743},
issn = {2155-384X},
support = {DK135169/DK/NIDDK NIH HHS/United States ; CA251657/CA/NCI NIH HHS/United States ; },
abstract = {INTRODUCTION: We designed a race-conscious study to assess the presence of Helicobacter pylori (Hp) virulence factor cagA in a retrospective cohort of patients with active Hp infection.

METHODS: We compared cagA status by race in gastric tissue samples from 473 patients diagnosed with active Hp infection from 2015-2019.

RESULTS: Hp+ Black patients were two times more likely to be cagA+ than Hp+ White patients (82% vs. 36%, P < .0001).

DISCUSSION: Presence of cagA is common among endoscopy patients with active Hp infection; appropriate testing and treatment of Hp can both reduce gastric cancer risk and address health disparities.},
}

@article {pmid38741226,
year = {2024},
author = {Kirchhoff, AC and Waters, AR and Liu, Q and Ji, X and Yasui, Y and Yabroff, KR and Conti, RM and Huang, IC and Henderson, T and Leisenring, WM and Armstrong, GT and Nathan, PC and Park, ER},
title = {Health insurance among survivors of childhood cancer following affordable care act implementation.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djae111},
pmid = {38741226},
issn = {1460-2105},
abstract = {BACKGROUND: The Affordable Care Act (ACA) increased private non-employer health insurance options, expanded Medicaid eligibility, and provided pre-existing health conditions protections. We evaluated insurance coverage among long-term adult survivors of childhood cancer pre/post-ACA implementation.

METHODS: Using the multicenter Childhood Cancer Survivor Study, we included participants from two cross-sectional surveys: pre-ACA (2007-2009; survivors: N = 7,505; siblings: N = 2,175) and post-ACA (2017-2019; survivors: N = 4,030; siblings: N = 987). A subset completed both surveys (1,840 survivors; 646 siblings). Multivariable regression models compared post-ACA insurance coverage and type (private/public/uninsured) between survivors and siblings and identified associated demographic and clinical factors. Multinomial models compared gaining and losing insurance vs staying the same among survivors and siblings who participated in both surveys.

RESULTS: The proportion with insurance was higher post-ACA (survivors pre-ACA 89.1% to post-ACA 92.0% [+2.9%]; siblings pre-ACA 90.9% to post-ACA 95.3% [+4.4%]). Post-ACA insurance coverage was greater among those age 18-25 (survivors: 15.8% vs < 2.3% ages 26+; siblings +17.8% vs < 4.2% ages 26+). Survivors were more likely to have public insurance than siblings post-ACA (18.4% vs 6.9%; odds ratios [OR]=1.7, 95%CI 1.1-2.6). Survivors with severe chronic conditions (OR = 4.7, 95%CI 3.0-7.3) and those living in Medicaid expansion states (OR = 2.4, 95%CI 1.7-3.4) had increased odds of public insurance coverage post-ACA. Among the subset completing both surveys, low/mid income survivors (<$60,000) experienced both insurance losses and gains in reference to highest household income survivors (≥$100,000), relative to odds of keeping the same insurance status.

CONCLUSIONS: Post-ACA, more childhood cancer survivors and siblings had health insurance, although disparities remain in coverage.},
}

@article {pmid38741126,
year = {2024},
author = {Blanco-Melo, D and Campbell, MA and Zhu, H and Dennis, TPW and Modha, S and Lytras, S and Hughes, J and Gatseva, A and Gifford, RJ},
title = {A novel approach to exploring the dark genome and its application to mapping of the vertebrate virus fossil record.},
journal = {Genome biology},
volume = {25},
number = {1},
pages = {120},
pmid = {38741126},
issn = {1474-760X},
support = {MC_UU_12014/12/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; *Vertebrates/genetics/virology ; *Genome ; *Fossils ; *Phylogeny ; Evolution, Molecular ; Humans ; Gene Transfer, Horizontal ; Viruses/genetics ; Genomics/methods ; Endogenous Retroviruses/genetics ; DNA Transposable Elements ; },
abstract = {BACKGROUND: Genomic regions that remain poorly understood, often referred to as the dark genome, contain a variety of functionally relevant and biologically informative features. These include endogenous viral elements (EVEs)-virus-derived sequences that can dramatically impact host biology and serve as a virus fossil record. In this study, we introduce a database-integrated genome screening (DIGS) approach to investigate the dark genome in silico, focusing on EVEs found within vertebrate genomes.

RESULTS: Using DIGS on 874 vertebrate genomes, we uncover approximately 1.1 million EVE sequences, with over 99% originating from endogenous retroviruses or transposable elements that contain EVE DNA. We show that the remaining 6038 sequences represent over a thousand distinct horizontal gene transfer events across 10 virus families, including some that have not previously been reported as EVEs. We explore the genomic and phylogenetic characteristics of non-retroviral EVEs and determine their rates of acquisition during vertebrate evolution. Our study uncovers novel virus diversity, broadens knowledge of virus distribution among vertebrate hosts, and provides new insights into the ecology and evolution of vertebrate viruses.

CONCLUSIONS: We comprehensively catalog and analyze EVEs within 874 vertebrate genomes, shedding light on the distribution, diversity, and long-term evolution of viruses and reveal their extensive impact on vertebrate genome evolution. Our results demonstrate the power of linking a relational database management system to a similarity search-based screening pipeline for in silico exploration of the dark genome.},
}

Animals
*Vertebrates/genetics/virology
*Genome
*Fossils
*Phylogeny
Evolution, Molecular
Humans
Gene Transfer, Horizontal
Viruses/genetics
Genomics/methods
Endogenous Retroviruses/genetics
DNA Transposable Elements

@article {pmid38712065,
year = {2024},
author = {Jones, DC and Elz, AE and Hadadianpour, A and Ryu, H and Glass, DR and Newell, EW},
title = {Cell Simulation as Cell Segmentation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38712065},
support = {P01 CA225517/CA/NCI NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; },
abstract = {Single-cell spatial transcriptomics promises a highly detailed view of a cell's transcriptional state and microenvironment, yet inaccurate cell segmentation can render this data murky by misattributing large numbers of transcripts to nearby cells or conjuring nonexistent cells. We adopt methods from ab initio cell simulation to rapidly infer morphologically plausible cell boundaries that preserve cell type heterogeneity. Benchmarking applied to datasets generated by three commercial platforms show superior performance and computational efficiency of this approach compared with existing methods. We show that improved accuracy in cell segmentation aids greatly in detection of difficult to accurately segment tumor infiltrating immune cells such as neutrophils and T cells. Lastly, through improvements in our ability to delineate subsets of tumor infiltrating T cells, we show that CXCL13-expressing CD8+ T cells tend to be more closely associated with tumor cells than their CXCL13-negative counterparts in data generated from renal cell carcinoma patient samples. Proseg is available under at open source license at https://github.com/dcjones/proseg.},
}

@article {pmid38741014,
year = {2024},
author = {Jia, G and Ping, J and Guo, X and Yang, Y and Tao, R and Li, B and Ambs, S and Barnard, ME and Chen, Y and Garcia-Closas, M and Gu, J and Hu, JJ and Huo, D and John, EM and Li, CI and Li, JL and Nathanson, KL and Nemesure, B and Olopade, OI and Pal, T and Press, MF and Sanderson, M and Sandler, DP and Shu, XO and Troester, MA and Yao, S and Adejumo, PO and Ahearn, T and Brewster, AM and Hennis, AJM and Makumbi, T and Ndom, P and O'Brien, KM and Olshan, AF and Oluwasanu, MM and Reid, S and Butler, EN and Huang, M and Ntekim, A and Qian, H and Zhang, H and Ambrosone, CB and Cai, Q and Long, J and Palmer, JR and Haiman, CA and Zheng, W},
title = {Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.},
journal = {Nature genetics},
volume = {56},
number = {5},
pages = {819-826},
pmid = {38741014},
issn = {1546-1718},
abstract = {We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10[-8]), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.},
}

@article {pmid38740820,
year = {2024},
author = {Aubert, M and Haick, AK and Strongin, DE and Klouser, LM and Loprieno, MA and Stensland, L and Santo, TK and Huang, ML and Hyrien, O and Stone, D and Jerome, KR},
title = {Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {4018},
pmid = {38740820},
issn = {2041-1723},
mesh = {Animals ; *Gene Editing/methods ; Female ; *Dependovirus/genetics ; Mice ; *Herpesvirus 1, Human/genetics/physiology ; *Herpes Simplex/genetics/virology/therapy ; *Viral Load ; *Virus Shedding ; Disease Models, Animal ; Virus Latency/genetics ; Humans ; Genetic Vectors/genetics ; Vero Cells ; Genetic Therapy/methods ; Herpes Genitalis/therapy/virology ; DNA, Viral/genetics ; },
abstract = {Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.},
}

Animals
*Gene Editing/methods
Female
*Dependovirus/genetics
Mice
*Herpesvirus 1, Human/genetics/physiology
*Herpes Simplex/genetics/virology/therapy
*Viral Load
*Virus Shedding
Disease Models, Animal
Virus Latency/genetics
Humans
Genetic Vectors/genetics
Vero Cells
Genetic Therapy/methods
Herpes Genitalis/therapy/virology
DNA, Viral/genetics

@article {pmid38740628,
year = {2024},
author = {Giguere, R and Balán, IC and Kutner, BA and Choi, SK and Tingler, R and Johnson, S and Macagna, N and Webster, J and Liu, A and Chariyalertsak, S and Hoesley, C and Gonzales, P and Ho, K and Kayange, N and Palanee-Phillips, T and Brown, E and Zemanek, J and Jacobson, CE and Doncel, GF and Piper, J and Bauermeister, JA and , },
title = {History of Rectal Product Use and Country of Residence Influence Preference for Rectal Microbicide Dosage Forms Among Young Sexual and Gender Minorities: A Multi-country Trial Comparing Placebo Douche, Suppository, and Insert Products.},
journal = {AIDS and behavior},
volume = {},
number = {},
pages = {},
pmid = {38740628},
issn = {1573-3254},
support = {K23MH124569/MH/NIMH NIH HHS/United States ; P30MH043520/MH/NIMH NIH HHS/United States ; },
abstract = {The DESIRE Study (MTN-035) explored product preference among three placebo rectal microbicide (RM) formulations, a rectal douche (RD), a suppository, and an insert, among 210 sexually active transgender people and men who have sex with men in five counties: the United States, Peru, Thailand, South Africa, and Malawi. Participants used each product prior to receptive anal sex (RAS) for 1 month, following a randomly assigned sequence, then selected their preferred product via computer assisted self-interview. In-depth interviews examined reasons for preference. We compared product preference and prior product use by country to explore whether geographic location and experience with the similar products impacted preference. A majority in the United States (56%) and Peru (58%) and nearly half in South Africa (48%) preferred the douche. Most in Malawi (59%) preferred the suppository, while half in Thailand (50%) and nearly half in South Africa (47%) preferred the insert. Participants who preferred the douche described it as quick and easy, already routinized, and serving a dual purpose of cleansing and protecting. Those who preferred the insert found it small, portable, discreet, with quick dissolution. Those who preferred the suppository found the size and shape acceptable and liked the added lubrication it provided. Experience with product use varied by country. Participants with RD experience were significantly more likely to prefer the douche (p = 0.03). Diversifying availability of multiple RM dosage forms can increase uptake and improve HIV prevention efforts globally.},
}

@article {pmid38740030,
year = {2024},
author = {Necchi, A and Roumiguié, M and Kamat, AM and Shore, ND and Boormans, JL and Esen, AA and Lebret, T and Kandori, S and Bajorin, DF and Krieger, LEM and Niglio, SA and Uchio, EM and Seo, HK and de Wit, R and Singer, EA and Grivas, P and Nishiyama, H and Li, H and Baranwal, P and Van den Sigtenhorst-Fijlstra, M and Kapadia, E and Kulkarni, GS},
title = {Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial.},
journal = {The Lancet. Oncology},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1470-2045(24)00178-5},
pmid = {38740030},
issn = {1474-5488},
abstract = {BACKGROUND: The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ.

METHODS: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing.

FINDINGS: Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred.

INTERPRETATION: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial.

FUNDING: Merck Sharp & Dohme.},
}

@article {pmid38738881,
year = {2024},
author = {Schwartz, LF and Stratton, KL and Leisenring, WM and Marron Rodriguez, S and Alston, S and McDonald, A and Vukadinovich, C and Rinehart, D and Oeffinger, KC and Chow, EJ and Krull, KR and Brinkman, TM and Nathan, PC and Tan, MM and McCrae, JS and Burkhardt, T and Ness, KK and Armstrong, GT and Henderson, TO},
title = {Adverse Childhood Experiences, Resilience, and Cardiovascular Disease in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.},
journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
volume = {},
number = {},
pages = {},
doi = {10.1158/1055-9965.EPI-24-0249},
pmid = {38738881},
issn = {1538-7755},
abstract = {BACKGROUND: The impact of Adverse Childhood Experiences (ACEs: e.g., abuse, neglect and/or household dysfunction experienced before age 18) and resilience on risk for cardiovascular disease (CVD) has not previously been investigated in adult survivors of childhood cancer.

METHODS: We conducted a nested case-control study among long-term, adult-aged survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS). Self-report questionnaires ascertained ACEs and resilience, and scores were compared between cases with serious/life-threatening CVD and controls without CVD matched on demographic and cardiotoxic treatment factors.

RESULTS: Among 95 cases and 261 controls, the mean ACE score was 1.4 for both groups; 53.4% of survivors endorsed ≥1 ACE. There was no association between ACEs or resilience and CVD in adjusted models.

CONCLUSIONS: ACEs and resilience do not appear to contribute to CVD risk for adult survivors of childhood cancer with cardiotoxic treatment exposures.

IMPACT: Although not associated with CVD in this population, ACEs are associated with serious health issues in other populations. Therefore, future studies could investigate effects of ACEs on other health outcomes affecting childhood cancer survivors.},
}

@article {pmid38736375,
year = {2024},
author = {Pholsena, TN and Lewis, FM and Phillips, F and Loggers, ET and Yockel, MR and Zahlis, EH and Shands, ME},
title = {Advanced parental cancer and adolescents: Parenting issues and challenges.},
journal = {Palliative & supportive care},
volume = {},
number = {},
pages = {1-6},
doi = {10.1017/S1478951524000774},
pmid = {38736375},
issn = {1478-9523},
abstract = {BACKGROUND: An estimated 609,820 child-rearing adults in 2023 died from advanced cancer, affecting 153,675 dependent children. Although children are known to suffer significant distress when a parent is diagnosed with cancer, few studies have described parents' views of their adolescent's behavioral response to their advanced cancer or what the parent did to interpret or manage that response.

OBJECTIVES: To describe patient-reported concerns about their adolescent and how they responded to their adolescent's behavior.

METHODS: Single occasion interviews were administered to 6 adolescent-rearing parents with Stage IV cancer. Interviews were analyzed using inductive content analysis by trained coders. Trustworthiness of results was protected through peer debriefing, coding to consensus, and maintaining an audit trail.

RESULTS: The core construct that explained study data was Being There without Taking Over, comprised of 4 domains: Struggling to Read My Child, Attempting to Talk with My Child about My Cancer, Trying to Maintain Optimism, and Understanding My Child.

CONCLUSIONS: Parents were deeply concerned about the impact of their advanced cancer on their adolescent but were unable to distinguish between cancer-related distress and adolescent angst. They feared initiating cancer-related discussions and struggled with their own feelings of guilt and parental inadequacy but did not turn to professionals for help.

SIGNIFICANCE OF RESULTS: Adolescent-rearing patients with advanced disease need to be triaged into services that offer a framework from which parents can interpret their child's behavior and learn ways to have adolescent-appropriate conversations about the cancer. Such services should also help parents gain skills to manage feelings of parental inadequacy and guilt. In the absence of services, parents struggle and do not know how to interpret and respond to their adolescent's cancer-related behavior.},
}

@article {pmid38736319,
year = {2024},
author = {Chlebowski, RT and Aragaki, AK and Pan, K and Simon, MS and Neuhouser, ML and Haque, R and Rohan, TE and Wactawski-Wende, J and Orchard, TS and Mortimer, JE and Lane, D and Kaunitz, AM and Desai, P and Wild, RA and Barac, A and Manson, JE},
title = {Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.},
journal = {Cancer},
volume = {},
number = {},
pages = {},
doi = {10.1002/cncr.35318},
pmid = {38736319},
issn = {1097-0142},
support = {R01 CA10921/CA/NCI NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; },
abstract = {BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials.

METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status.

RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m[2]; p < .001).

CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.},
}

@article {pmid38734236,
year = {2024},
author = {Miranda, RN and Amador, C and Chan, JKC and Guitart, J and Rech, KL and Medeiros, LJ and Naresh, KN and , },
title = {5TH EDITION OF THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF TUMORS OF THE HEMATOPOIETIC AND LYMPHOID TISSUES.},
journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},
volume = {},
number = {},
pages = {100512},
doi = {10.1016/j.modpat.2024.100512},
pmid = {38734236},
issn = {1530-0285},
abstract = {This review focuses on mature T-cell, NK cell, and stroma-derived neoplasms in the 5[th] edition of the World Health Organization (WHO) classification of hematolymphoid tumors (WHO-HEM5), including changes from the revised 4[th] edition (WHO-HEM4R). Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, EBV-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the WHO-HEM5 can be applied in routine clinical practice.},
}

@article {pmid38732035,
year = {2024},
author = {Watanabe, R and Miura, N and Kurata, M and Kitazawa, R and Kikugawa, T and Saika, T},
title = {Unveiling the Genomic Landscape of Intraductal Carcinoma of the Prostate Using Spatial Gene Expression Analysis.},
journal = {International journal of molecular sciences},
volume = {25},
number = {9},
pages = {},
pmid = {38732035},
issn = {1422-0067},
support = {22K09449//Japan Society for the Promotion of Science/ ; Medical Research Grants//Takeda Science Foundation/ ; N/A//Japanese Foundation for Prostate Research/ ; Young Research Grant//Japanese Urological Association/ ; N/A//Takahashi Industrial and Economic Research Foundation/ ; },
mesh = {Male ; Humans ; *Prostatic Neoplasms/genetics/pathology/metabolism ; *Gene Expression Regulation, Neoplastic ; *Tumor Microenvironment/genetics ; Biomarkers, Tumor/genetics ; Gene Expression Profiling/methods ; Carcinoma, Ductal/genetics/pathology/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Transcriptome ; Receptors, CCR5 ; },
abstract = {Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced recruitment of fibroblasts and immune cells, which reflect morphological features of IDCP, may influence the aggressiveness of high-grade prostate cancer.},
}

Male
Humans
*Prostatic Neoplasms/genetics/pathology/metabolism
*Gene Expression Regulation, Neoplastic
*Tumor Microenvironment/genetics
Biomarkers, Tumor/genetics
Gene Expression Profiling/methods
Carcinoma, Ductal/genetics/pathology/metabolism
Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
Transcriptome
Receptors, CCR5

@article {pmid38731931,
year = {2024},
author = {Wakabayashi, N and Yagishita, Y and Joshi, T and Kensler, TW},
title = {Dual Deletion of Keap1 and Rbpjκ Genes in Liver Leads to Hepatomegaly and Hypercholesterolemia.},
journal = {International journal of molecular sciences},
volume = {25},
number = {9},
pages = {},
pmid = {38731931},
issn = {1422-0067},
support = {1R35CA197222-21A7/NH/NIH HHS/United States ; },
mesh = {Animals ; *Kelch-Like ECH-Associated Protein 1/metabolism/genetics ; Mice ; *Hypercholesterolemia/genetics/metabolism/pathology ; *Liver/metabolism/pathology ; *Hepatomegaly/genetics/metabolism/pathology ; *Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics/metabolism ; NF-E2-Related Factor 2/metabolism/genetics ; Lipid Metabolism/genetics ; Gene Deletion ; Signal Transduction ; Cholesterol/metabolism ; Mice, Knockout ; Male ; Bile Acids and Salts/metabolism ; },
abstract = {The hepatic deletion of Rbpjκ (Rbpj[F/F]::AlbCre) in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the Rbpj[F/F]::AlbCre mouse by hepatic deletion of Keap1 in compound Keap1[F/F]::Rbpj[F/F]::AlbCre mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the Rbpj[F/F]::AlbCre mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the Rbpj[F/F]::AlbCre mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of Cyp1A7 and Abcb11 genes involved in bile acid homeostasis was significantly reduced in Keap1[F/F]::Rbpj[F/F]::AlbCre compared to Rbpj[F/F]::AlbCre mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the Keap1[F/F]::Rbpj[F/F]::AlbCre mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth.},
}

Animals
*Kelch-Like ECH-Associated Protein 1/metabolism/genetics
Mice
*Hypercholesterolemia/genetics/metabolism/pathology
*Liver/metabolism/pathology
*Hepatomegaly/genetics/metabolism/pathology
*Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics/metabolism
NF-E2-Related Factor 2/metabolism/genetics
Lipid Metabolism/genetics
Gene Deletion
Signal Transduction
Cholesterol/metabolism
Mice, Knockout
Male
Bile Acids and Salts/metabolism

@article {pmid38730407,
year = {2024},
author = {Johnson, AM and Zhou, C and Haviland, M and Mendoza, JA},
title = {Evaluation of a walking school bus program: a cluster randomized controlled trial.},
journal = {The international journal of behavioral nutrition and physical activity},
volume = {21},
number = {1},
pages = {55},
pmid = {38730407},
issn = {1479-5868},
support = {R01CA16314601//Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Walking/statistics & numerical data ; Female ; Male ; Child ; *Schools ; *Transportation/methods ; Health Promotion/methods ; Washington ; Texas ; Students ; Exercise ; Motor Vehicles ; Accelerometry ; Poverty ; Program Evaluation ; Cluster Analysis ; },
abstract = {BACKGROUND: The purpose of this study was to investigate the effects of a walking school bus intervention on children's active commuting to school.

METHODS: We conducted a randomized controlled trial (RCT) in Houston, Texas (Year 1) and Seattle, Washington (Years 2-4) from 2012 to 2016. The study had a two-arm, cluster randomized design comparing the intervention (walking school bus and education materials) to the control (education materials) over one school year October/November - May/June). Twenty-two schools that served lower income families participated. Outcomes included percentage of days students' active commuting to school (primary, measured via survey) and moderate-to-vigorous physical activity (MVPA, measured via accelerometry). Follow-up took place in May or June. We used linear mixed-effects models to estimate the association between the intervention and outcomes of interest.

RESULTS: Total sample was 418 students [Mage=9.2 (SD = 0.9) years; 46% female], 197 (47%) in the intervention group. The intervention group showed a significant increase compared with the control group over time in percentage of days active commuting (β = 9.04; 95% CI: 1.10, 16.98; p = 0.015) and MVPA minutes/day (β = 4.31; 95% CI: 0.70, 7.91; p = 0.02).

CONCLUSIONS: These findings support implementation of walking school bus programs that are inclusive of school-age children from lower income families to support active commuting to school and improve physical activity.

TRAIL REGISTRATION: This RCT is registered at clinicaltrials.gov (NCT01626807).},
}

Humans
*Walking/statistics & numerical data
Female
Male
Child
*Schools
*Transportation/methods
Health Promotion/methods
Washington
Texas
Students
Exercise
Motor Vehicles
Accelerometry
Poverty
Program Evaluation
Cluster Analysis

@article {pmid38730398,
year = {2024},
author = {Ortblad, KF and Kuo, AP and Mogere, P and Roche, SD and Kiptinness, C and Wairimu, N and Gakuo, S and Baeten, JM and Ngure, K},
title = {Low selection of HIV PrEP refills at private pharmacies among clients who initiated PrEP at public clinics: findings from a mixed-methods study in Kenya.},
journal = {BMC health services research},
volume = {24},
number = {1},
pages = {618},
pmid = {38730398},
issn = {1472-6963},
mesh = {Humans ; Kenya ; *HIV Infections/prevention & control ; Male ; Female ; *Pre-Exposure Prophylaxis/methods ; Adult ; *Pharmacies/statistics & numerical data ; Anti-HIV Agents/therapeutic use ; Young Adult ; },
abstract = {BACKGROUND: In Africa, the delivery of HIV pre-exposure prophylaxis (PrEP) at public healthcare clinics is challenged by understaffing, overcrowding, and HIV-associated stigma, often resulting in low PrEP uptake and continuation among clients. Giving clients the option to refill PrEP at nearby private pharmacies, which are often more convenient and have shorter wait times, may address these challenges and improve PrEP continuation.

METHODS: This mixed methods study used an explanatory sequential design. At two public clinics in Kiambu County, Kenya, clients ≥ 18 years initiating PrEP were given the option to refill PrEP at the clinic where they initiated for free or at one of three nearby private pharmacies for 300 Kenyan Shillings (~ $3 US Dollars). The providers at these pharmacies (pharmacists and pharmaceutical technologists) were trained in PrEP service delivery using a prescribing checklist and provider-assisted HIV self-testing, both with remote clinician oversight. Clients were followed up to seven months, with scheduled refill visits at one, four, and seven months. The primary outcomes were selection of pharmacy-based PrEP refills and PrEP continuation. Following pilot completion, 15 in-depth interviews (IDIs) with clients who refilled PrEP were completed. We used descriptive statistics and thematic analysis to assess study outcomes.

RESULTS: From November 2020 to November 2021, 125 PrEP clients were screened and 106 enrolled. The majority (59%, 63/106) of clients were women and the median age was 31 years (IQR 26-38 years). Over 292 client-months of follow-up, 41 clients (39%) refilled PrEP; only three (3%) at a participating pharmacy. All clients who completed IDIs refilled PrEP at clinics. The reasons why clients did not refill PrEP at pharmacies included: a preference for clinic-delivered PrEP services (i.e., pre-existing relationships, access to other services), concerns about pharmacy-delivered PrEP services (i.e., mistrust, lower quality care, costs), and lack of knowledge of this refill location.

CONCLUSIONS: These findings suggest that clients who initiate PrEP at public clinics in Kenya may have already overcome barriers to clinic-delivered PrEP services and prefer PrEP access there. To reach new populations that could benefit from PrEP, a stand-alone model of pharmacy-delivered PrEP services may be needed.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT04558554 [registered: June 5, 2020].},
}

Humans
Kenya
*HIV Infections/prevention & control
Male
Female
*Pre-Exposure Prophylaxis/methods
Adult
*Pharmacies/statistics & numerical data
Anti-HIV Agents/therapeutic use
Young Adult

@article {pmid38729566,
year = {2024},
author = {Goetz, MP and Toi, M and Huober, J and Sohn, J and Trédan, O and Park, IH and Campone, M and Chen, SC and Manso, LM and Paluch-Shimon, S and Freedman, OC and O'Shaughnessy, J and Pivot, X and Tolaney, SM and Hurvitz, S and Llombart-Cussac, A and André, V and Saha, A and van Hal, G and Shahir, A and Iwata, H and Johnston, SRD},
title = {Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: Final overall survival results of MONARCH 3.},
journal = {Annals of oncology : official journal of the European Society for Medical Oncology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.annonc.2024.04.013},
pmid = {38729566},
issn = {1569-8041},
abstract = {BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- advanced breast cancer (ABC) with disease progression on prior endocrine therapy (ET). In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3.

PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase 3 study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival (CFS) was an exploratory endpoint.

RESULTS: A total of 493 women were randomized 2:1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval [CI], 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease (sVD), there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% CI, 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and CFS numerically improved with the addition of abemaciclib. No new safety signals were observed.

CONCLUSION: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (ITT: 13.1 months; sVD: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.},
}

@article {pmid38728385,
year = {2024},
author = {Andrews, JS and Boonyaratanakornkit, JB and Krusinska, E and Allen, S and Posada, JA},
title = {Assessment of the Impact of RNase in Patients With Severe Fatigue Related to Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): A Randomized Phase 2 Trial of RSLV-132.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {},
number = {},
pages = {},
doi = {10.1093/cid/ciae205},
pmid = {38728385},
issn = {1537-6591},
support = {//Resolve Therapeutics/ ; },
abstract = {BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC).

METHODS: This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a).

RESULTS: A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men.

CONCLUSION: While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.},
}

@article {pmid38728375,
year = {2024},
author = {Muffly, L and Liang, EC and Dolan, JG and Pulsipher, MA},
title = {How I Use Next Generation Sequencing-MRD to Plan Approach and Prevent Relapse after HCT for Children and Adults with ALL.},
journal = {Blood},
volume = {},
number = {},
pages = {},
doi = {10.1182/blood.2023023699},
pmid = {38728375},
issn = {1528-0020},
abstract = {Measurable residual disease (MRD) evaluation by multiparameter flow cytometry (MFC) or quantitative PCR methods is an established standard of care for assessing risk of relapse prior to or after hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL). Next generation sequencing (NGS)-MRD has emerged as a highly effective approach that allows detection of lymphoblasts at a level of fewer than 1 in 106 nucleated cells, increasing sensitivity of ALL detection by 2-3 logs. Early studies have shown superior results compared with MFC and suggest that NGS-MRD may allow determination of patients in whom reduced toxicity transplant preparative approaches could be deployed without sacrificing outcomes. Many centers/study groups have implemented immune modulation approaches based on MRD measurements that have resulted in improved outcomes. Challenges remain with NGS-MRD, as it is not commercially available in many countries and interpretation of results can be complex. Through patient case review, discussion of relevant studies, and detailed expert opinion we share our approach to NGS-MRD testing prior to and after HCT in pediatric and adult ALL. Improved pre-HCT risk classification and post-HCT monitoring for relapse in bone marrow and less invasive peripheral blood monitoring by NGS-MRD may lead to alternative approaches to prevent relapse in patients undergoing this challenging procedure.},
}

@article {pmid38728244,
year = {2024},
author = {Anderson, LJ and Paulsen, L and Miranda, G and Syrjala, KL and Graf, SA and Chauncey, TR and Garcia, JM},
title = {Neuromuscular electrical stimulation for physical function maintenance during hematopoietic stem cell transplantation: Study protocol.},
journal = {PloS one},
volume = {19},
number = {5},
pages = {e0302970},
pmid = {38728244},
issn = {1932-6203},
mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Quality of Life ; *Electric Stimulation Therapy/methods ; Male ; Female ; Adult ; Electric Stimulation/methods ; Fatigue/therapy ; Middle Aged ; Hematologic Neoplasms/therapy ; Transplantation, Autologous ; Body Composition ; },
abstract = {Hematopoietic stem cell transplantation is a common life-saving treatment for hematologic malignancies, though can lead to long-term functional impairment, fatigue, muscle atrophy, with decreased quality of life. Although traditional exercise has helped reduce these effects, it is inconsistently recommended and infrequently maintained, and most patients remain sedentary during and after treatment. There is need for alternative rehabilitation strategies, like neuromuscular electrical stimulation, that may be more amenable to the capabilities of hematopoietic stem cell transplant recipients. Patients receiving autologous HCT are being enroled in a randomized controlled trial with 1:1 (neuromuscular electrical stimulation:sham) design stratified by diagnosis and sex. Physical function, body composition, quality of life, and fatigue are assessed prior to hematopoietic stem cell transplant (prior to initiating preparatory treatment) and 24±5 days post hematopoietic stem cell transplant (Follow-up 1); physical function and quality of life are also assessed 6-months post hematopoietic stem cell transplant (Follow-up 2). The primary outcome is between-group difference in the 6-minute walk test change scores (Follow-up 1-Pre-transplant; final enrolment goal N = 23/group). We hypothesize that 1) neuromuscular electrical stimulation will attenuate hematopoietic stem cell transplant-induced adverse effects on physical function, muscle mass, quality of life, and fatigue compared to sham at Follow-up 1, and 2) Pre-transplant physical function will significantly predict fatigue and quality of life at Follow-up 2. We will also describe feasibility and acceptability of neuromuscular electrical stimulation during hematopoietic stem cell transplant. This proposal will improve rehabilitative patient care and quality of life by determining efficacy and feasibility of a currently underutilized therapeutic strategy aimed at maintaining daily function and reducing the impact of a potent and widely used cancer treatment. This trial is registered with clinicaltrials.gov (NCT04364256).},
}

Humans
*Hematopoietic Stem Cell Transplantation/methods
*Quality of Life
*Electric Stimulation Therapy/methods
Male
Female
Adult
Electric Stimulation/methods
Fatigue/therapy
Middle Aged
Hematologic Neoplasms/therapy
Transplantation, Autologous
Body Composition

@article {pmid38728140,
year = {2024},
author = {Stjepić, V and Nakamura, M and Hui, J and Parkhurst, SM},
title = {Two Septin complexes mediate actin dynamics during cell wound repair.},
journal = {Cell reports},
volume = {43},
number = {5},
pages = {114215},
doi = {10.1016/j.celrep.2024.114215},
pmid = {38728140},
issn = {2211-1247},
abstract = {Cells have robust wound repair systems to prevent further damage or infection and to quickly restore cell cortex integrity when exposed to mechanical and chemical stress. Actomyosin ring formation and contraction at the wound edge are major events during closure of the plasma membrane and underlying cytoskeleton during cell wound repair. Here, we show that all five Drosophila Septins are required for efficient cell wound repair. Based on their different recruitment patterns and knockdown/mutant phenotypes, two distinct Septin complexes, Sep1/Sep2/Pnut and Sep4/Sep5/Pnut, are assembled to regulate actin ring assembly, contraction, and remodeling during the repair process. Intriguingly, we find that these two Septin complexes have different F-actin bending activities. In addition, we find that Anillin regulates the recruitment of only one of two Septin complexes upon wounding. Our results demonstrate that two functionally distinct Septin complexes work side by side to discretely regulate actomyosin ring dynamics during cell wound repair.},
}

@article {pmid38728029,
year = {2024},
author = {Bhatt, NS and Goodman, P and Leisenring, WM and Armstrong, GT and Chow, EJ and Hudson, MM and Krull, KR and Nathan, PC and Oeffinger, KC and Robison, LL and Kirchhoff, AC and Mulrooney, DA},
title = {Chronic Health Conditions and Longitudinal Employment in Survivors of Childhood Cancer.},
journal = {JAMA network open},
volume = {7},
number = {5},
pages = {e2410731},
pmid = {38728029},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; *Cancer Survivors/statistics & numerical data/psychology ; *Employment/statistics & numerical data ; Adult ; Chronic Disease/epidemiology ; Retrospective Studies ; Longitudinal Studies ; *Neoplasms/epidemiology/psychology ; Adolescent ; Child ; Young Adult ; Middle Aged ; United States/epidemiology ; },
abstract = {IMPORTANCE: Employment is an important factor in quality of life and provides social and economic support. Longitudinal data on employment and associations with chronic health conditions for adult survivors of childhood cancer are lacking.

OBJECTIVE: To evaluate longitudinal trends in employment among survivors of childhood cancer.

Retrospective cohort study of 5-year cancer survivors diagnosed at age 20 years or younger between 1970 and 1986 enrolled in the multi-institutional Childhood Cancer Survivor Study (CCSS). Sex-stratified employment status at baseline (2002 to 2004) and follow-up (2014 to 2016) was compared with general population rates from the Behavioral Risk Factor Surveillance System cohort. Data were analyzed from July 2021 to June 2022.

EXPOSURES: Cancer therapy and preexisting and newly developed chronic health conditions.

MAIN OUTCOMES AND MEASURES: Standardized prevalence ratios of employment (full-time or part-time, health-related unemployment, unemployed, not in labor force) among adult (aged ≥25 years) survivors between baseline and follow-up compared with the general population. Longitudinal assessment of negative employment transitions (full-time to part-time or unemployed at follow-up).

RESULTS: Female participants (3076 participants at baseline; 2852 at follow-up) were a median (range) age of 33 (25-53) years at baseline and 42 (27-65) years at follow-up; male participants (3196 participants at baseline; 2557 at follow-up) were 33 (25-54) and 43 (28-64) years, respectively. The prevalence of full-time or part-time employment at baseline and follow-up was 2215 of 3076 (71.3%) and 1933 of 2852 (64.8%) for female participants and 2753 of 3196 (85.3%) and 2079 of 2557 (77.3%) for male participants, respectively, with declining standardized prevalence ratios over time (female participant baseline, 1.01; 95% CI, 0.98-1.03; follow-up, 0.94; 95% CI, 0.90-0.98; P < .001; male participant baseline, 0.96; 95% CI, 0.94-0.97; follow-up, 0.92; 95% CI, 0.89-0.95; P = .02). While the prevalence of health-related unemployment increased (female participants, 11.6% to 17.2%; male participants, 8.1% to 17.1%), the standardized prevalence ratio remained higher than the general population and declined over time (female participant baseline, 3.78; 95% CI, 3.37-4.23; follow-up, 2.23; 95% CI, 1.97-2.51; P < .001; male participant baseline, 3.12; 95% CI, 2.71-3.60; follow-up, 2.61; 95% CI, 2.24-3.03; P = .002). Among survivors employed full-time at baseline (1488 female participants; 1933 male participants), 285 female participants (19.2%) and 248 male participants (12.8%) experienced a negative employment transition (median [range] follow-up, 11.5 [9.4-13.8] years). Higher numbers and grades of chronic health conditions were significantly associated with these transitions.

CONCLUSIONS AND RELEVANCE: In this retrospective analysis of adult survivors of childhood cancer, significant declines in employment and increases in health-related unemployment among cancer survivors compared with the general population were identified. A substantial portion of survivors in the midcareer age range fell out of the workforce. Awareness among clinicians, caregivers, and employers may facilitate clinical counseling and occupational provisions for supportive work accommodations.},
}

Humans
Female
Male
*Cancer Survivors/statistics & numerical data/psychology
*Employment/statistics & numerical data
Adult
Chronic Disease/epidemiology
Retrospective Studies
Longitudinal Studies
*Neoplasms/epidemiology/psychology
Adolescent
Child
Young Adult
Middle Aged
United States/epidemiology

@article {pmid38712232,
year = {2024},
author = {Crook, ZR and Sevilla, GP and Young, P and Girard, EJ and Phi, TD and Howard, M and Price, J and Olson, JM and Nairn, NW},
title = {CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38712232},
support = {R01 CA223674/CA/NCI NIH HHS/United States ; },
abstract = {Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a novel catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal target delivery while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.},
}

@article {pmid38712102,
year = {2024},
author = {Belmont, L and Contreras, M and Cartwright-Acar, CH and Marceau, CD and Agrawal, A and Levoir, LM and Lubow, J and Goo, L},
title = {Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38712102},
support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; },
abstract = {Dengue virus (DENV) can hijack non-neutralizing IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR) - a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this non-canonical infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout screens in an in vitro system permissive to infection only in the presence of IgG antibodies. Validating our approach, a top hit was FcgRIIa, which facilitates binding and internalization of IgG-bound DENV but is not required for canonical infection. Additionally, we identified host factors with no previously described role in DENV infection, including TBC1D24 and SV2B, both of which have known functions in regulated secretion. Using genetic knockout and trans-complemented cells, we validated a functional requirement for these host factors in ADE assays performed with monoclonal antibodies and polyclonal sera in multiple cell lines and using all four DENV serotypes. We show that knockout of TBC1D24 or SV2B impaired binding of IgG-DENV complexes to cells without affecting FcgRIIa expression levels. Thus, we identify cellular factors beyond FcgR that are required for ADE of DENV infection. Our findings represent a first step towards advancing fundamental knowledge behind the biology of ADE that can ultimately be exploited to inform vaccination and therapeutic approaches.},
}

@article {pmid38726844,
year = {2024},
author = {Cohen, M and Graf, SA},
title = {Could protein kinase inhibitors become a next generation pharmacotherapy for non-Hodgkin's lymphoma?.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14656566.2024.2354915},
pmid = {38726844},
issn = {1744-7666},
}

@article {pmid38726832,
year = {2024},
author = {Kampouri, E and Little, JS and Crocchiolo, R and Hill, JA},
title = {Human herpesvirus-6, HHV-8 and parvovirus B19 after allogeneic hematopoietic cell transplant: the lesser-known viral complications.},
journal = {Current opinion in infectious diseases},
volume = {},
number = {},
pages = {},
pmid = {38726832},
issn = {1473-6527},
abstract = {PURPOSE OF REVIEW: Viral infections continue to burden allogeneic hematopoietic cell transplant (HCT) recipients. We review the epidemiology, diagnosis, and management of human herpesvirus (HHV)-6, HHV-8 and parvovirus B19 following HCT.

RECENT FINDINGS: Advances in HCT practices significantly improved outcomes but impact viral epidemiology: post-transplant cyclophosphamide for graft-versus-host disease prevention increases HHV-6 reactivation risk while the impact of letermovir for CMV prophylaxis - and resulting decrease in broad-spectrum antivirals - is more complex. Beyond the well established HHV-6 encephalitis, recent evidence implicates HHV-6 in pneumonitis. Novel less toxic therapeutic approaches (brincidofovir, virus-specific T-cells) may enable preventive strategies in the future. HHV-8 is the causal agent of Kaposi's sarcoma, which is only sporadically reported after HCT, but other manifestations are possible and not well elucidated. Parvovirus B19 can cause severe disease post-HCT, frequently manifesting with anemia, but can also be easily overlooked due to lack of routine screening and ambiguity of manifestations.

SUMMARY: Studies should establish the contemporary epidemiology of HHV-6, and other more insidious viruses, such as HHV-8 and parvovirus B19 following HCT and should encompass novel cellular therapies. Standardized and readily available diagnostic methods are key to elucidate epidemiology and optimize preventive and therapeutic strategies to mitigate the burden of infection.},
}

@article {pmid38726320,
year = {2024},
author = {Xu, Y and Miller, CP and Tykodi, SS and Akilesh, S and Warren, EH},
title = {Signaling crosstalk between tumor endothelial cells and immune cells in the microenvironment of solid tumors.},
journal = {Frontiers in cell and developmental biology},
volume = {12},
number = {},
pages = {1387198},
pmid = {38726320},
issn = {2296-634X},
abstract = {Tumor-associated endothelial cells (TECs) are crucial mediators of immune surveillance and immune escape in the tumor microenvironment (TME). TECs driven by angiogenic growth factors form an abnormal vasculature which deploys molecular machinery to selectively promote the function and recruitment of immunosuppressive cells while simultaneously blocking the entry and function of anti-tumor immune cells. TECs also utilize a similar set of signaling regulators to promote the metastasis of tumor cells. Meanwhile, the tumor-infiltrating immune cells further induce the TEC anergy by secreting pro-angiogenic factors and prevents further immune cell penetration into the TME. Understanding the complex interactions between TECs and immune cells will be needed to successfully treat cancer patients with combined therapy to achieve vasculature normalization while augmenting antitumor immunity. In this review, we will discuss what is known about the signaling crosstalk between TECs and tumor-infiltrating immune cells to reveal insights and strategies for therapeutic targeting.},
}

@article {pmid38725300,
year = {2024},
author = {Bouras, E and Gill, D and Zuber, V and Murphy, N and Dimou, N and Aleksandrova, K and Lewis, SJ and Martin, RM and Yarmolinsky, J and Albanes, D and Brenner, H and Castellví-Bel, S and Chan, AT and Cheng, I and Gruber, S and Van Guelpen, B and Li, CI and Le Marchand, L and Newcomb, PA and Ogino, S and Pellatt, A and Schmit, SL and Wolk, A and Wu, AH and Peters, U and Gunter, MJ and Tsilidis, KK},
title = {Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.},
journal = {International journal of epidemiology},
volume = {53},
number = {3},
pages = {},
pmid = {38725300},
issn = {1464-3685},
support = {/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; *Mendelian Randomization Analysis ; *Body Mass Index ; Risk Factors ; *Obesity/genetics/epidemiology ; Insulin-Like Growth Factor I/metabolism ; Alcohol Drinking/epidemiology ; },
abstract = {BACKGROUND: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC.

METHODS: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses.

RESULTS: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA.

CONCLUSIONS: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.},
}

Humans
*Colorectal Neoplasms/genetics/epidemiology
*Mendelian Randomization Analysis
*Body Mass Index
Risk Factors
*Obesity/genetics/epidemiology
Insulin-Like Growth Factor I/metabolism
Alcohol Drinking/epidemiology

@article {pmid38725043,
year = {2024},
author = {Luo, K and Taryn, A and Moon, EH and Peters, BA and Solomon, SD and Daviglus, ML and Kansal, MM and Thyagarajan, B and Gellman, MD and Cai, J and Burk, RD and Knight, R and Kaplan, RC and Cheng, S and Rodriguez, CJ and Qi, Q and Yu, B},
title = {Gut microbiota, blood metabolites, and left ventricular diastolic dysfunction in US Hispanics/Latinos.},
journal = {Microbiome},
volume = {12},
number = {1},
pages = {85},
pmid = {38725043},
issn = {2049-2618},
support = {R01 HL141824/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Gastrointestinal Microbiome ; Female ; Middle Aged ; Male ; *Hispanic or Latino ; *Ventricular Dysfunction, Left/microbiology/blood ; United States ; Dysbiosis/microbiology ; Aged ; Bacteria/classification/isolation & purification ; Metabolome ; Echocardiography ; },
abstract = {BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is an important precursor of heart failure (HF), but little is known about its relationship with gut dysbiosis and microbial-related metabolites. By leveraging the multi-omics data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a study with population at high burden of LVDD, we aimed to characterize gut microbiota associated with LVDD and identify metabolite signatures of gut dysbiosis and incident LVDD.

RESULTS: We included up to 1996 Hispanic/Latino adults (mean age: 59.4 years; 67.1% female) with comprehensive echocardiography assessments, gut microbiome, and blood metabolome data. LVDD was defined through a composite criterion involving tissue Doppler assessment and left atrial volume index measurements. Among 1996 participants, 916 (45.9%) had prevalent LVDD, and 212 out of 594 participants without LVDD at baseline developed incident LVDD over a median 4.3 years of follow-up. Using multivariable-adjusted analysis of compositions of microbiomes (ANCOM-II) method, we identified 7 out of 512 dominant gut bacterial species (prevalence > 20%) associated with prevalent LVDD (FDR-q < 0.1), with inverse associations being found for Intestinimonas_massiliensis, Clostridium_phoceensis, and Bacteroide_coprocola and positive associations for Gardnerella_vaginali, Acidaminococcus_fermentans, Pseudomonas_aeruginosa, and Necropsobacter_massiliensis. Using multivariable adjusted linear regression, 220 out of 669 circulating metabolites with detection rate > 75% were associated with the identified LVDD-related bacterial species (FDR-q < 0.1), with the majority being linked to Intestinimonas_massiliensis, Clostridium_phoceensis, and Acidaminococcus_fermentans. Furthermore, 46 of these bacteria-associated metabolites, mostly glycerophospholipids, secondary bile acids, and amino acids, were associated with prevalent LVDD (FDR-q < 0.1), 21 of which were associated with incident LVDD (relative risk ranging from 0.81 [p = 0.001, for guanidinoacetate] to 1.25 [p = 9 × 10[-5], for 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4)]). The inclusion of these 21 bacterial-related metabolites significantly improved the prediction of incident LVDD compared with a traditional risk factor model (the area under the receiver operating characteristic curve [AUC] = 0.73 vs 0.70, p = 0.001). Metabolite-based proxy association analyses revealed the inverse associations of Intestinimonas_massilliensis and Clostridium_phoceensis and the positive association of Acidaminococcus_fermentans with incident LVDD.

CONCLUSION: In this study of US Hispanics/Latinos, we identified multiple gut bacteria and related metabolites linked to LVDD, suggesting their potential roles in this preclinical HF entity. Video Abstract.},
}

Humans
*Gastrointestinal Microbiome
Female
Middle Aged
Male
*Hispanic or Latino
*Ventricular Dysfunction, Left/microbiology/blood
United States
Dysbiosis/microbiology
Aged
Bacteria/classification/isolation & purification
Metabolome
Echocardiography

@article {pmid38724463,
year = {2024},
author = {Grauwet, K and Berger, T and Kann, MC and Silva, H and Larson, R and Leick, MB and Bailey, SR and Bouffard, AA and Millar, D and Gallagher, K and Turtle, CJ and Frigault, MJ and Maus, MV},
title = {Stealth transgenes enable CAR-T cells to evade host immune responses.},
journal = {Journal for immunotherapy of cancer},
volume = {12},
number = {5},
pages = {},
pmid = {38724463},
issn = {2051-1426},
mesh = {Animals ; Humans ; Mice ; *Receptors, Chimeric Antigen/immunology/genetics ; *Immunotherapy, Adoptive/methods ; Transgenes ; T-Lymphocytes/immunology ; },
abstract = {BACKGROUND: Adoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, as the extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to the non-self CAR components of autologous CAR-T cells or donor-specific antigens of allogeneic CAR-T cells, which is thought to potentially limit CAR-T cell persistence and the success of repeated dosing.

METHODS: In this study, we implemented a one-shot approach to prevent rejection of engineered T cells by simultaneously reducing antigen presentation and the surface expression of both Classes of the major histocompatibility complex (MHC) via expression of the viral inhibitors of transporter associated with antigen processing (TAPi) in combination with a transgene coding for shRNA targeting class II MHC transactivator (CIITA). The optimal combination was screened in vitro by flow cytometric analysis and mixed lymphocyte reaction assays and was validated in vivo in mouse models of leukemia and lymphoma. Functionality was assessed in an autologous setting using patient samples and in an allogeneic setting using an allogeneic mouse model.

RESULTS: The combination of the Epstein-Barr virus TAPi and an shRNA targeting CIITA was efficient and effective at reducing cell surface MHC classes I and II in αCD19 'stealth' CAR-T cells while retaining in vitro and in vivo antitumor functionality. Mixed lymphocyte reaction assays and IFNγ ELISpot assays performed with T cells from patients previously treated with autologous αCD19 CAR-T cells confirm that CAR T cells expressing the stealth transgenes evade allogeneic and autologous anti-CAR responses, which was further validated in vivo. Importantly, we noted anti-CAR-T cell responses in patients who had received multiple CAR-T cell infusions, and this response was reduced on in vitro restimulation with autologous CARs containing the stealth transgenes.

CONCLUSIONS: Together, these data suggest that the proposed stealth transgenes may reduce the immunogenicity of autologous and allogeneic cellular therapeutics. Moreover, patient data indicate that repeated doses of autologous FMC63-based αCD19 CAR-T cells significantly increased the anti-CAR T cell responses in these patients.},
}

Animals
Humans
Mice
*Receptors, Chimeric Antigen/immunology/genetics
*Immunotherapy, Adoptive/methods
Transgenes
T-Lymphocytes/immunology

@article {pmid38723650,
year = {2024},
author = {Juraska, M and Early, AM and Li, L and Schaffner, SF and Lievens, M and Khorgade, A and Simpkins, B and Hejazi, NS and Benkeser, D and Wang, Q and Mercer, LD and Adjei, S and Agbenyega, T and Anderson, S and Ansong, D and Bii, DK and Buabeng, PBY and English, S and Fitzgerald, N and Grimsby, J and Kariuki, SK and Otieno, K and Roman, F and Samuels, AM and Westercamp, N and Ockenhouse, CF and Ofori-Anyinam, O and Lee, CK and MacInnis, BL and Wirth, DF and Gilbert, PB and Neafsey, DE},
title = {Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial.},
journal = {The Lancet. Infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1473-3099(24)00179-8},
pmid = {38723650},
issn = {1474-4457},
abstract = {BACKGROUND: The first licensed malaria vaccine, RTS,S/AS01E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy.

METHODS: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01E regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291.

FINDINGS: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01E regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1-1·6 infections (95% CI union 0·6-2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0·0053).

INTERPRETATION: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation.

FUNDING: GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research.},
}

@article {pmid38723638,
year = {2024},
author = {Verma, S and Dufort, MJ and Olsen, TM and Kimmel, S and Labuda, JC and Scharffenberger, S and McGuire, AT and Harrison, OJ},
title = {Antigen-level resolution of commensal-specific B cell responses can be enabled by phage display screening coupled with B cell tetramers.},
journal = {Immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.immuni.2024.04.014},
pmid = {38723638},
issn = {1097-4180},
abstract = {Induction of commensal-specific immunity contributes to tissue homeostasis, yet the mechanisms underlying induction of commensal-specific B cells remain poorly understood in part due to a lack of tools to identify these cells. Using phage display, we identified segmented filamentous bacteria (SFB) antigens targeted by serum and intestinal antibodies and generated B cell tetramers to track SFB-specific B cells in gut-associated lymphoid tissues. We revealed a compartmentalized response in SFB-specific B cell activation, with a gradient of immunoglobulin A (IgA), IgG1, and IgG2b isotype production along Peyer's patches contrasted by selective production of IgG2b within mesenteric lymph nodes. V(D)J sequencing and monoclonal antibody generation identified somatic hypermutation driven affinity maturation to SFB antigens under homeostatic conditions. Combining phage display and B cell tetramers will enable investigation of the ontogeny and function of commensal-specific B cell responses in tissue immunity, inflammation, and repair.},
}

@article {pmid38723632,
year = {2024},
author = {Dareng, EO and Coetzee, SG and Tyrer, JP and Peng, PC and Rosenow, W and Chen, S and Davis, BD and Dezem, FS and Seo, JH and Nameki, R and Reyes, AL and Aben, KKH and Anton-Culver, H and Antonenkova, NN and Aravantinos, G and Bandera, EV and Beane Freeman, LE and Beckmann, MW and Beeghly-Fadiel, A and Benitez, J and Bernardini, MQ and Bjorge, L and Black, A and Bogdanova, NV and Bolton, KL and Brenton, JD and Budzilowska, A and Butzow, R and Cai, H and Campbell, I and Cannioto, R and Chang-Claude, J and Chanock, SJ and Chen, K and Chenevix-Trench, G and , and Chiew, YE and Cook, LS and DeFazio, A and Dennis, J and Doherty, JA and Dörk, T and du Bois, A and Dürst, M and Eccles, DM and Ene, G and Fasching, PA and Flanagan, JM and Fortner, RT and Fostira, F and Gentry-Maharaj, A and Giles, GG and Goodman, MT and Gronwald, J and Haiman, CA and Håkansson, N and Heitz, F and Hildebrandt, MAT and Høgdall, E and Høgdall, CK and Huang, RY and Jensen, A and Jones, ME and Kang, D and Karlan, BY and Karnezis, AN and Kelemen, LE and Kennedy, CJ and Khusnutdinova, EK and Kiemeney, LA and Kjaer, SK and Kupryjanczyk, J and Labrie, M and Lambrechts, D and Larson, MC and Le, ND and Lester, J and Li, L and Lubiński, J and Lush, M and Marks, JR and Matsuo, K and May, T and McLaughlin, JR and McNeish, IA and Menon, U and Missmer, S and Modugno, F and Moffitt, M and Monteiro, AN and Moysich, KB and Narod, SA and Nguyen-Dumont, T and Odunsi, K and Olsson, H and Onland-Moret, NC and Park, SK and Pejovic, T and Permuth, JB and Piskorz, A and Prokofyeva, D and Riggan, MJ and Risch, HA and Rodríguez-Antona, C and Rossing, MA and Sandler, DP and Setiawan, VW and Shan, K and Song, H and Southey, MC and Steed, H and Sutphen, R and Swerdlow, AJ and Teo, SH and Terry, KL and Thompson, PJ and Vestrheim Thomsen, LC and Titus, L and Trabert, B and Travis, R and Tworoger, SS and Valen, E and Van Nieuwenhuysen, E and Edwards, DV and Vierkant, RA and Webb, PM and , and Weinberg, CR and Weise, RM and Wentzensen, N and White, E and Winham, SJ and Wolk, A and Woo, YL and Wu, AH and Yan, L and Yannoukakos, D and Zeinomar, N and Zheng, W and Ziogas, A and Berchuck, A and Goode, EL and Huntsman, DG and Pearce, CL and Ramus, SJ and Sellers, TA and , and Freedman, ML and Lawrenson, K and Schildkraut, JM and Hazelett, D and Plummer, JT and Kar, S and Jones, MR and Pharoah, PDP and Gayther, SA},
title = {Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2024.04.011},
pmid = {38723632},
issn = {1537-6605},
abstract = {To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10[-8]) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10[-5]). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.},
}

@article {pmid38722664,
year = {2024},
author = {Kopmar, NE and Quach, K and Gooley, TA and Martino, CH and Cherian, S and Percival, MM and Halpern, AB and Ghiuzeli, CM and Oehler, VG and Abkowitz, JL and Walter, RB and Cassaday, RD},
title = {Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.},
journal = {JAMA oncology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaoncol.2024.0967},
pmid = {38722664},
issn = {2374-2445},
abstract = {IMPORTANCE: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL.

OBJECTIVE: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL.

This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment.

INTERVENTIONS: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design.

MAIN OUTCOMES AND MEASURES: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects.

RESULTS: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively.

CONCLUSIONS: In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03991884.},
}

@article {pmid38721745,
year = {2024},
author = {Tarantelli, C and Wald, D and Munz, N and Spriano, F and Bruscaggin, A and Cannas, E and Cascione, L and Gaudio, E and Arribas, AJ and Manjappa, S and Golino, G and Scalise, L and Cacciapuoti, MT and Zucca, E and Stathis, A and Inghirami, G and Van Berkel, PH and Rossi, D and Caimi, PF and Zammarchi, F and Bertoni, F},
title = {Targeting CD19-positive lymphomas with the antibody-drug conjugate loncastuximab tesirine: preclinical evidence as single agent and in combination therapy.},
journal = {Haematologica},
volume = {},
number = {},
pages = {},
doi = {10.3324/haematol.2023.284197},
pmid = {38721745},
issn = {1592-8721},
abstract = {Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels, and identified combination partners providing synergy with loncastuximab tesirine. Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with CD19 expression level and intrinsic sensitivity of cell lines to the ADC's warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.},
}

@article {pmid38721740,
year = {2024},
author = {Rashidi, A},
title = {Cachexia during anti-leukemia chemotherapy: it is not "just" the chemo.},
journal = {Haematologica},
volume = {},
number = {},
pages = {},
doi = {10.3324/haematol.2024.285455},
pmid = {38721740},
issn = {1592-8721},
abstract = {Not available.},
}

@article {pmid38720547,
year = {2024},
author = {Ruplin, A and Segal, E and McFarlane, T},
title = {Review of drug-drug interactions in patients with prostate cancer.},
journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners},
volume = {},
number = {},
pages = {10781552241238198},
doi = {10.1177/10781552241238198},
pmid = {38720547},
issn = {1477-092X},
abstract = {OBJECTIVE: The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for managing polypharmacy.

DATA SOURCES: A literature search of PubMed, Embase, and CINAHL was carried out to identify pharmacokinetic and pharmacodynamic changes caused by DDIs that are relevant for prostate cancer patients, DDIs between prostate cancer therapies and co-administered medications (both prescription and over-the-counter), and measures to prevent DDIs. Medication package inserts were used to identify the impact of DDI on the prostate cancer therapy and suggested interventions.

DATA SUMMARY: No DDIs are expected for the LHRH agonists leuprolide acetate, histrelin, goserelin, or leuprolide mesylate. However, DDIs have been reported for GnRH antagonists, anti-androgens, PARP inhibitors, and taxanes. Although there are no confirmed DDIs for sipuleucel-T to date, it is not generally recommended to use sipuleucel-T concurrently with immunosuppressive medications. Interventions to prevent DDIs include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education.

CONCLUSIONS: Prostate cancer patients have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, and patient/caregiver education will aid the development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.},
}

@article {pmid38720086,
year = {2024},
author = {Desautels, TA and Arrildt, KT and Zemla, AT and Lau, EY and Zhu, F and Ricci, D and Cronin, S and Zost, SJ and Binshtein, E and Scheaffer, SM and Dadonaite, B and Petersen, BK and Engdahl, TB and Chen, E and Handal, LS and Hall, L and Goforth, JW and Vashchenko, D and Nguyen, S and Weilhammer, DR and Lo, JK and Rubinfeld, B and Saada, EA and Weisenberger, T and Lee, TH and Whitener, B and Case, JB and Ladd, A and Silva, MS and Haluska, RM and Grzesiak, EA and Earnhart, CG and Hopkins, S and Bates, TW and Thackray, LB and Segelke, BW and , and Lillo, AM and Sundaram, S and Bloom, JD and Diamond, MS and Crowe, JE and Carnahan, RH and Faissol, DM},
title = {Computationally restoring the potency of a clinical antibody against Omicron.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {38720086},
issn = {1476-4687},
abstract = {The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs[1-3] and revealed how quickly viral escape can curtail effective options[4,5]. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab[4-6]. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination[4] and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.},
}

@article {pmid38718133,
year = {2024},
author = {Olayiwola, O and Castillejo, A and Louella, M and Supercharger, M and Harlow, E and Dee, L and Abdallah, K and Kityo-Mutuluuza, C and Adair, JE and Orentas, R and Dubé, K},
title = {Nothing about us without us: Advocacy and engagement in genetic medicine.},
journal = {Science translational medicine},
volume = {16},
number = {746},
pages = {eadn2401},
doi = {10.1126/scitranslmed.adn2401},
pmid = {38718133},
issn = {1946-6242},
mesh = {Humans ; *Patient Advocacy ; *Anemia, Sickle Cell/genetics ; Genetic Therapy ; },
abstract = {The development of new genetic medicines to treat sickle cell disease highlights the need for greater collaboration between researchers and people with lived experiences. Drawing on the adage "Nothing about us, without us," we call for increased investments in community advocacy and engagement.},
}

Humans
*Patient Advocacy
*Anemia, Sickle Cell/genetics
Genetic Therapy

@article {pmid38718130,
year = {2024},
author = {Doxzen, KW and Adair, JE and Fonseca Bazzo, YM and Bukini, D and Cornetta, K and Dalal, V and Guerino-Cunha, RL and Hongeng, S and Jotwani, G and Kityo-Mutuluuza, C and Lakshmanan, K and Mahlangu, J and Makani, J and Mathews, V and Ozelo, MC and Rangarajan, S and Scholefield, J and Batista Silva Júnior, J and McCune, JM},
title = {The translational gap for gene therapies in low- and middle-income countries.},
journal = {Science translational medicine},
volume = {16},
number = {746},
pages = {eadn1902},
doi = {10.1126/scitranslmed.adn1902},
pmid = {38718130},
issn = {1946-6242},
mesh = {Humans ; *Genetic Therapy ; *Developing Countries ; *Translational Research, Biomedical ; },
abstract = {Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must be given to those who will benefit and what proactive steps must be taken to widen development and access potential, particularly in regions carrying a high disease burden.},
}

Humans
*Genetic Therapy
*Developing Countries
*Translational Research, Biomedical

@article {pmid38716804,
year = {2024},
author = {Nakasone, ES and Zemla, TJ and Yu, M and Lin, SY and Ou, FS and Carter, K and Innocenti, F and Saltz, L and Grady, WM and Cohen, SA},
title = {Evaluating the utility of ZNF331 promoter methylation as a prognostic and predictive marker in stage III colon cancer: results from CALGB 89803 (Alliance).},
journal = {Epigenetics},
volume = {19},
number = {1},
pages = {2349980},
doi = {10.1080/15592294.2024.2349980},
pmid = {38716804},
issn = {1559-2308},
mesh = {Humans ; *DNA Methylation ; Female ; *Promoter Regions, Genetic ; *Colonic Neoplasms/genetics/pathology ; Male ; Middle Aged ; *Biomarkers, Tumor/genetics/metabolism ; Aged ; Prognosis ; Neoplasm Staging ; Transcription Factors/genetics/metabolism ; Adult ; Trefoil Factor-3 ; },
abstract = {While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of ZNF331 promoter hypermethylation (mZNF331) as a prognostic and predictive marker in colon cancer. We examined the association of mZNF331 with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients. ZNF331 promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of mZNF331 in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. mZNF331 was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with mZNF331 compared to unmethylated ZNF331 (unmZNFF31). There was no significant difference in disease-free or overall survival between patients with mZNF331 versus unmZNF331 colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by ZNF331 methylation status. While ZNF331 promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of mZNF331 as a prognostic and predictive marker.},
}

Humans
*DNA Methylation
Female
*Promoter Regions, Genetic
*Colonic Neoplasms/genetics/pathology
Male
Middle Aged
*Biomarkers, Tumor/genetics/metabolism
Aged
Prognosis
Neoplasm Staging
Transcription Factors/genetics/metabolism
Adult
Trefoil Factor-3

@article {pmid38716731,
year = {2024},
author = {Cross, DL and Layton, ED and Yu, KK and Smith, MT and Aguilar, MS and Li, S and Wilcox, EC and Chapuis, AG and Mayanja-Kizza, H and Stein, CM and Boom, WH and Hawn, TR and Bradley, P and Newell, EW and Seshadri, C},
title = {MR1-restricted T cell clonotypes are associated with "resistance" to Mycobacterium tuberculosis infection.},
journal = {JCI insight},
volume = {9},
number = {9},
pages = {},
doi = {10.1172/jci.insight.166505},
pmid = {38716731},
issn = {2379-3708},
mesh = {Humans ; *Mycobacterium tuberculosis/immunology ; Uganda ; Adult ; Male ; Minor Histocompatibility Antigens/immunology/genetics ; Female ; Tuberculosis/immunology/microbiology ; T-Lymphocytes/immunology ; Latent Tuberculosis/immunology/microbiology ; Clone Cells/immunology ; Disease Resistance/immunology/genetics ; Young Adult ; Histocompatibility Antigens Class I ; },
abstract = {T cells are required for protective immunity against Mycobacterium tuberculosis. We recently described a cohort of Ugandan household contacts of tuberculosis cases who appear to "resist" M. tuberculosis infection (resisters; RSTRs) and showed that these individuals harbor IFN-γ-independent T cell responses to M. tuberculosis-specific peptide antigens. However, T cells also recognize nonprotein antigens via antigen-presenting systems that are independent of genetic background, known as donor-unrestricted T cells (DURTs). We used tetramer staining and flow cytometry to characterize the association between DURTs and "resistance" to M. tuberculosis infection. Peripheral blood frequencies of most DURT subsets were comparable between RSTRs and latently infected controls (LTBIs). However, we observed a 1.65-fold increase in frequency of MR1-restricted T (MR1T) cells among RSTRs in comparison with LTBIs. Single-cell RNA sequencing of 18,251 MR1T cells sorted from 8 donors revealed 5,150 clonotypes that expressed a common transcriptional program, the majority of which were private. Sequencing of the T cell receptor α/T cell receptor δ (TCRα/δ) repertoire revealed several DURT clonotypes were expanded among RSTRs, including 2 MR1T clonotypes that recognized mycobacteria-infected cells in a TCR-dependent manner. Overall, our data reveal unexpected donor-specific diversity in the TCR repertoire of human MR1T cells as well as associations between mycobacteria-reactive MR1T clonotypes and resistance to M. tuberculosis infection.},
}

Humans
*Mycobacterium tuberculosis/immunology
Uganda
Adult
Male
Minor Histocompatibility Antigens/immunology/genetics
Female
Tuberculosis/immunology/microbiology
T-Lymphocytes/immunology
Latent Tuberculosis/immunology/microbiology
Clone Cells/immunology
Disease Resistance/immunology/genetics
Young Adult
Histocompatibility Antigens Class I

@article {pmid38714703,
year = {2024},
author = {Pershad, Y and Mack, T and Poisner, H and Jakubek, YA and Stilp, AM and Mitchell, BD and Lewis, JP and Boerwinkle, E and Loos, RJF and Chami, N and Wang, Z and Barnes, K and Pankratz, N and Fornage, M and Redline, S and Psaty, BM and Bis, JC and Shojaie, A and Silverman, EK and Cho, MH and Yun, JH and DeMeo, D and Levy, D and Johnson, AD and Mathias, RA and Taub, MA and Arnett, D and North, KE and Raffield, LM and Carson, AP and Doyle, MF and Rich, SS and Rotter, JI and Guo, X and Cox, NJ and Roden, DM and Franceschini, N and Desai, P and Reiner, AP and Auer, PL and Scheet, PA and Jaiswal, S and Weinstock, JS and Bick, AG},
title = {Determinants of mosaic chromosomal alteration fitness.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {3800},
pmid = {38714703},
issn = {2041-1723},
support = {R01 DK117445/DK/NIDDK NIH HHS/United States ; R01 MD012765/MD/NIMHD NIH HHS/United States ; },
mesh = {Humans ; *Mosaicism ; *Chromosome Aberrations ; *Clonal Hematopoiesis/genetics ; Male ; Female ; Genome-Wide Association Study ; Janus Kinase 2/genetics ; Telomerase/genetics/metabolism ; Loss of Heterozygosity ; Cross-Sectional Studies ; Mutation ; Middle Aged ; Hematopoietic Stem Cells/metabolism ; Polymorphism, Single Nucleotide ; Aged ; },
abstract = {Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R[2] = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.},
}

Humans
*Mosaicism
*Chromosome Aberrations
*Clonal Hematopoiesis/genetics
Male
Female
Genome-Wide Association Study
Janus Kinase 2/genetics
Telomerase/genetics/metabolism
Loss of Heterozygosity
Cross-Sectional Studies
Mutation
Middle Aged
Hematopoietic Stem Cells/metabolism
Polymorphism, Single Nucleotide
Aged

@article {pmid38714193,
year = {2024},
author = {Chakrabarti, R and Gillespie, K and Walke, JT and Fernandes, M and Almeida, A and Chery-Karschney, L and Kanjee, U and Skillman, KM and White, J and Babar, PH and Pereira, L and Mascarenhas, A and Vaz, M and Khandeparkar, A and Gomes, E and Janes, H and Rathod, PK and Duraisingh, MT},
title = {Descriptive, Hospital-Based, 10-Year Study of Malaria Transmission in Goa, a Southwest Indian State in the Malaria Elimination Phase.},
journal = {The American journal of tropical medicine and hygiene},
volume = {},
number = {},
pages = {},
doi = {10.4269/ajtmh.23-0828},
pmid = {38714193},
issn = {1476-1645},
abstract = {The South Asia International Center of Excellence for Malaria Research, an NIH-funded collaborative program, investigated the epidemiology of malaria in the Indian state of Goa through health facility-based data collected from the Goa Medical College and Hospital (GMC), the state's largest tertiary healthcare facility, between 2012 and 2021. Our study investigated region-specific spatial and temporal patterns of malaria transmission in Goa and the factors driving such patterns. Over the past decade, the number of malaria cases, inpatients, and deaths at the GMC decreased significantly after a peak in 2014-2015. However, the proportion of severe malaria cases increased over the study period. Also, a trend of decreasing average parasitemia and increasing average gametocyte density suggests a shift toward submicroscopic infections and an increase in transmission commitment characteristic of low-transmission regions. Although transmission occurred throughout the year, 75% of the cases occurred between June and December, overlapping with the monsoon (June-October), which featured rainfall above yearly average, minimal diurnal temperature variation, and high relative humidity. Sociodemographic factors also had a significant association with malaria cases, with cases being more frequent in the 15-50-year-old age group, men, construction workers, and people living in urban areas within the GMC catchment region. Our environmental model of malaria transmission projects almost negligible transmission at the beginning of 2025 (annual parasitic index: 0.0095, 95% CI: 0.0075-0.0114) if the current control measures continue undisrupted.},
}

@article {pmid38714104,
year = {2024},
author = {Bantjes, J and Hunt, X and Cuijpers, P and Kazdin, AE and Kennedy, CJ and Luedtke, A and Malenica, I and Petukhova, M and Sampson, N and Zainal, NH and Davids, C and Dunn-Coetzee, M and Gerber, R and Stein, DJ and Kessler, RC},
title = {Comparative effectiveness of remote digital gamified and group CBT skills training interventions for anxiety and depression among college students: Results of a three-arm randomised controlled trial.},
journal = {Behaviour research and therapy},
volume = {178},
number = {},
pages = {104554},
doi = {10.1016/j.brat.2024.104554},
pmid = {38714104},
issn = {1873-622X},
abstract = {Digital interventions can enhance access to healthcare in under-resourced settings. However, guided digital interventions may be costly for low- and middle-income countries, despite their effectiveness. In this randomised control trial, we evaluated the effectiveness of two digital interventions designed to address this issue: (1) a Cognitive Behavioral Therapy Skills Training (CST) intervention that increased scalability by using remote online group administration; and (2) the SuperBetter gamified self-guided CBT skills training app, which uses other participants rather than paid staff as guides. The study was implemented among anxious and/or depressed South African undergraduates (n = 371) randomised with equal allocation to Remote Group CST, SuperBetter, or a MoodFlow mood monitoring control. Symptoms were assessed with the Generalized Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9). Intention-to-treat analysis found effect sizes at the high end of prior digital intervention trials, including significantly higher adjusted risk differences (ARD; primary outcome) in joint anxiety/depression remission at 3-months and 6-months for Remote Group CST (ARD = 23.3-18.9%, p = 0.001-0.035) and SuperBetter (ARD = 12.7-22.2%, p = 0.047-0.006) than MoodFlow and mean combined PHQ-9/GAD-7 scores (secondary outcome) significantly lower for Remote Group CST and SuperBetter than MoodFlow. These results illustrate how innovative delivery methods can increase the scalability of standard one-on-one guided digital interventions. PREREGISTRATION INTERNATIONAL STANDARD RANDOMISED CONTROLLED TRIAL NUMBER (ISRTCN) SUBMISSION #: 47,089,643.},
}

@article {pmid38713891,
year = {2024},
author = {Byrne, EH and Song, H and Srinivasan, S and Fredricks, DN and Reed, SD and Guthrie, KA and Wu, M and Mitchell, CM},
title = {Association between vaginal microbiota and vaginal inflammatory immune markers in postmenopausal women.},
journal = {Menopause (New York, N.Y.)},
volume = {},
number = {},
pages = {},
pmid = {38713891},
issn = {1530-0374},
abstract = {OBJECTIVE: In premenopausal individuals, vaginal microbiota diversity and lack of Lactobacillus dominance are associated with greater mucosal inflammation, which is linked to a higher risk of cervical dysplasia and infections. It is not known if the association between the vaginal microbiota and inflammation is present after menopause, when the vaginal microbiota is generally higher-diversity and fewer people have Lactobacillus dominance.

METHODS: This is a post hoc analysis of a subset of postmenopausal individuals enrolled in a randomized trial for treatment of moderate-severe vulvovaginal discomfort that compared vaginal moisturizer, estradiol, or placebo. Vaginal fluid samples from 0, 4, and 12 weeks were characterized using 16S rRNA gene sequencing (microbiota) and MesoScale Discovery (vaginal fluid immune markers: IL-1b, IL-1a, IL-2, IL-6, IL-18, IL-10, IL-9, IL-13, IL-8, IP10, MIP1a, MIP1b, MIP3a). Global associations between cytokines and microbiota (assessed by relative abundance of individual taxa and Shannon index for alpha, or community, diversity) were explored, adjusting for treatment arm, using linear mixed models, principal component analysis, and Generalized Linear Mixed Model + Microbiome Regression-based Kernel Association Test (GLMM-MiRKAT).

RESULTS: A total of 119 individuals with mean age of 61 years were included. At baseline, 29.5% of participants had a Lactobacillus-dominant vaginal microbiota. Across all timepoints, alpha diversity (Shannon index, P = 0.003) was highly associated with immune markers. Individual markers that were associated with Lactobacillus dominance were similar to those observed in premenopausal people: IL-10, IL-1b, IL-6, IL-8 (false discovery rate [FDR] < 0.01), IL-13 (FDR = 0.02), and IL-2 (FDR = 0.09). Over 12 weeks, change in alpha diversity was associated with change in cytokine concentration (Shannon, P = 0.018), with decreased proinflammatory cytokine concentrations observed with decreasing alpha diversity.

CONCLUSIONS: In this cohort of postmenopausal individuals, Lactobacillus dominance and lower alpha diversity were associated with lower concentrations of inflammatory immune markers, as has been reported in premenopausal people. This suggests that after menopause lactobacilli continue to have beneficial effects on vaginal immune homeostasis, despite lower prevalence.},
}

@article {pmid38713408,
year = {2024},
author = {Moser, JC and Bhatia, S and Amin, A and Pavlick, AC and Betts, KA and Du, EX and Poretta, T and Shelley, K and Srinivasan, S and Sakkal, LA and Palaia, J and Lobo, M and Pe Benito, M and Linton, JA and Chen, Y and Xu, C and Yin, L and Sundar, M and Weber, J},
title = {Clinical outcomes of adjuvant nivolumab in resected stage III melanoma: comparison of CheckMate 238 trial and real-world data.},
journal = {Cancer immunology, immunotherapy : CII},
volume = {73},
number = {7},
pages = {116},
pmid = {38713408},
issn = {1432-0851},
mesh = {Humans ; *Melanoma/drug therapy/mortality/pathology/surgery ; *Nivolumab/therapeutic use ; Female ; Male ; Middle Aged ; *Neoplasm Staging ; Chemotherapy, Adjuvant/methods ; Aged ; Skin Neoplasms/drug therapy/mortality/pathology/surgery ; Treatment Outcome ; Antineoplastic Agents, Immunological/therapeutic use ; Adult ; },
abstract = {OBJECTIVES: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab.

MATERIALS: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies.

RESULTS: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0 years; median follow-up, 61.4 vs. 25.5 months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64).

CONCLUSIONS: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results.},
}

Humans
*Melanoma/drug therapy/mortality/pathology/surgery
*Nivolumab/therapeutic use
Female
Male
Middle Aged
*Neoplasm Staging
Chemotherapy, Adjuvant/methods
Aged
Skin Neoplasms/drug therapy/mortality/pathology/surgery
Treatment Outcome
Antineoplastic Agents, Immunological/therapeutic use
Adult

@article {pmid38699359,
year = {2024},
author = {Žuštra, A and Leonard, VR and Holland, LA and Hu, JC and Mu, T and Holland, SC and Wu, LI and Begnel, ER and Ojee, E and Chohan, BH and Richardson, BA and Kinuthia, J and Wamalwa, D and Slyker, J and Lehman, DA and Gantt, S and Lim, ES},
title = {Longitudinal dynamics of the nasopharyngal microbiome in response to SARS-CoV-2 Omicron variant and HIV infection in Kenyan women and their infants.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {38699359},
support = {R01 HD092311/HD/NICHD NIH HHS/United States ; },
abstract = {The nasopharynx and its microbiota are implicated in respiratory health and disease. The interplay between viral infection and the nasopharyngeal microbiome is an area of increased interest and of clinical relevance. The impact of SARS-CoV-2, the etiological agent of the Coronavirus Disease 2019 (COVID-19) pandemic, on the nasopharyngeal microbiome, particularly among individuals living with HIV, is not fully characterized. Here we describe the nasopharyngeal microbiome before, during and after SARS-CoV-2 infection in a longitudinal cohort of Kenyan women (21 living with HIV and 14 HIV-uninfected) and their infants (18 HIV-exposed, uninfected and 18 HIV-unexposed, uninfected), followed between September 2021 through March 2022. We show using genomic epidemiology that mother and infant dyads were infected with the same strain of the SARS-CoV-2 Omicron variant that spread rapidly across Kenya. Additionally, we used metagenomic sequencing to characterize the nasopharyngeal microbiome of 20 women and infants infected with SARS-CoV-2, 6 infants negative for SARS-CoV-2 but experiencing respiratory symptoms, and 34 timepoint matched SARS-CoV-2 negative mothers and infants. Since individuals were sampled longitudinally before and after SARS-CoV-2 infection, we could characterize the short- and long-term impact of SARS-CoV-2 infection on the nasopharyngeal microbiome. We found that mothers and infants had significantly different microbiome composition and bacterial load (p-values <.0001). However, in both mothers and infants, the nasopharyngeal microbiome did not differ before and after SARS-CoV-2 infection, regardless of HIV-exposure status. Our results indicate that the nasopharyngeal microbiome is resilient to SARS-CoV-2 infection and was not significantly modified by HIV.},
}

@article {pmid38699305,
year = {2024},
author = {Maqsood, R and Holland, LA and Wu, LI and Begnel, ER and Adhiambo, J and Owiti, P and Chohan, BH and Gantt, S and Kinuthia, J and Wamalwa, D and Ojee, E and Richardson, BA and Slyker, J and Lehman, DA and Lim, ES},
title = {Gut virome and microbiome dynamics before and after SARS-CoV-2 infection in women living with HIV and their infants.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {38699305},
support = {R01 HD092311/HD/NICHD NIH HHS/United States ; },
abstract = {Microbiome perturbations can have long-term effects on health. The dynamics of the gut microbiome and virome in women living with HIV (WLHIV) and their newborn infants is poorly understood. Here, we performed metagenomic sequencing analyses on longitudinal stool samples including 23 mothers (13 WLHIV, 10 HIV-negative) and 12 infants that experienced SARS-CoV-2 infection with mild disease, as well as 40 mothers (18 WLHIV, 22 HIV-negative) and 60 infants that remained SARS-CoV-2 seronegative throughout the study follow-up. Regardless of HIV or SARS-CoV-2 status, maternal bacterial and viral profiles were distinct from infants. Using linear mixed effects models, we showed that while the microbiome alpha diversity trajectory was not significantly different between SARS-CoV-2 seropositive and seronegative women. However, seropositive women's positive trajectory while uninfected was abruptly reversed after SARS-CoV-2 infection (p = 0.015). However, gut virome signatures of women were not associated with SARS-CoV-2. Alterations in infant microbiome and virome diversities were generally not impacted by SARS-CoV-2 but were rather driven by development. We did not find statistically significant interactions between HIV and SARS-CoV-2 on the gut microbiome and virome. Overall, our study provides insights into the complex interplay between maternal and infant bacterial microbiome, virome, and the influence of SARS-CoV-2 and HIV status.},
}

@article {pmid38712673,
year = {2024},
author = {Ravandi, F and Subklewe, M and Walter, RB and Vachhani, P and Ossenkoppele, G and Buecklein, V and Döhner, H and Jongen-Lavrencic, M and Baldus, CD and Fransecky, L and Pardee, TS and Kantarjian, H and Yen, PK and Mukundan, L and Panwar, B and Yago, MR and Agarwal, S and Khaldoyanidi, SK and Stein, A},
title = {Safety and tolerability of AMG 330 in adults with relapsed/refractory AML: a phase 1a dose-escalation study.},
journal = {Leukemia & lymphoma},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/10428194.2024.2346755},
pmid = {38712673},
issn = {1029-2403},
abstract = {AMG 330, a bispecific T-cell engager (BiTE®) that binds CD33 and CD3 on T cells facilitates T-cell-mediated cytotoxicity against CD33+ cells. This first-in-human, open-label, dose-escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AMG 330 in adults with relapsed/refractory acute myeloid leukemia (R/R AML). Amongst 77 patients treated with AMG 330 (0.5 µg/day-1.6 mg/day) on 14-day or 28-day cycles, maximum tolerated dose was not reached; median duration of treatment was 29 days. The most frequent treatment-related adverse events were cytokine release syndrome (CRS; 78%) and rash (30%); 10% of patients experienced grade 3/4 CRS. CRS was mitigated with stepwise dosing of AMG 330, prophylactic dexamethasone, and early treatment with tocilizumab. Among 60 evaluable patients, eight achieved complete remission or morphologic leukemia-free state; of the 52 non-responders, 37% had ≥50% reduction in AML bone marrow blasts. AMG 330 is a promising CD33-targeted therapeutic strategy for R/R AML.},
}

@article {pmid38712512,
year = {2024},
author = {Magee, AF and Holbrook, AJ and Pekar, JE and Caviedes-Solis, IW and Matsen Iv, FA and Baele, G and Wertheim, JO and Ji, X and Lemey, P and Suchard, MA},
title = {Random-effects substitution models for phylogenetics via scalable gradient approximations.},
journal = {Systematic biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/sysbio/syae019},
pmid = {38712512},
issn = {1076-836X},
abstract = {Phylogenetic and discrete-trait evolutionary inference depend heavily on an appropriate characterization of the underlying character substitution process. In this paper, we present random-effects substitution models that extend common continuous-time Markov chain models into a richer class of processes capable of capturing a wider variety of substitution dynamics. As these random-effects substitution models often require many more parameters than their usual counterparts, inference can be both statistically and computationally challenging. Thus, we also propose an efficient approach to compute an approximation to the gradient of the data likelihood with respect to all unknown substitution model parameters. We demonstrate that this approximate gradient enables scaling of sampling-based inference, namely Bayesian inference via Hamiltonian Monte Carlo, under random-effects substitution models across large trees and state-spaces. Applied to a dataset of 583 SARS-CoV-2 sequences, an HKY model with random-effects shows strong signals of nonreversibility in the substitution process, and posterior predictive model checks clearly show that it is a more adequate model than a reversible model. When analyzing the pattern of phylogeographic spread of 1441 influenza A virus (H3N2) sequences between 14 regions, a random-effects phylogeographic substitution model infers that air travel volume adequately predicts almost all dispersal rates. A random-effects state-dependent substitution model reveals no evidence for an effect of arboreality on the swimming mode in the tree frog subfamily Hylinae. Simulations reveal that random-effects substitution models can accommodate both negligible and radical departures from the underlying base substitution model. We show that our gradient-based inference approach is over an order of magnitude more time efficient than conventional approaches.},
}

@article {pmid38711498,
year = {2024},
author = {Schreiber, S and Dressler, LS and Loffredo-Verde, E and Asen, T and Färber, S and Wang, W and Groll, T and Chakraborty, A and Kolbe, F and Kreer, C and Kosinska, AD and Simon, S and Urban, S and Klein, F and Riddell, SR and Protzer, U},
title = {CARs derived from broadly neutralizing, human monoclonal antibodies identified by single B cell sorting target hepatitis B virus-positive cells.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1340619},
pmid = {38711498},
issn = {1664-3224},
mesh = {Humans ; *Hepatitis B virus/immunology/genetics ; Animals ; Mice ; *Hepatitis B Surface Antigens/immunology ; Receptors, Chimeric Antigen/immunology/genetics/metabolism ; Antibodies, Monoclonal/immunology ; Immunotherapy, Adoptive ; Hepatitis B/immunology/virology ; Broadly Neutralizing Antibodies/immunology ; B-Lymphocytes/immunology ; T-Lymphocytes/immunology ; },
abstract = {To design new CARs targeting hepatitis B virus (HBV), we isolated human monoclonal antibodies recognizing the HBV envelope proteins from single B cells of a patient with a resolved infection. HBV-specific memory B cells were isolated by incubating peripheral blood mononuclear cells with biotinylated hepatitis B surface antigen (HBsAg), followed by single-cell flow cytometry-based sorting of live, CD19[+] IgG[+] HBsAg[+] cells. Amplification and sequencing of immunoglobulin genes from single memory B cells identified variable heavy and light chain sequences. Corresponding immunoglobulin chains were cloned into IgG1 expression vectors and expressed in mammalian cells. Two antibodies named 4D06 and 4D08 were found to be highly specific for HBsAg, recognized a conformational and a linear epitope, respectively, and showed broad reactivity and neutralization capacity against all major HBV genotypes. 4D06 and 4D08 variable chain fragments were cloned into a 2[nd] generation CAR format with CD28 and CD3zeta intracellular signaling domains. The new CAR constructs displayed a high functional avidity when expressed on primary human T cells. CAR-grafted T cells proved to be polyfunctional regarding cytokine secretion and killed HBV-positive target cells. Interestingly, background activation of the 4D08-CAR recognizing a linear instead of a conformational epitope was consistently low. In a preclinical model of chronic HBV infection, murine T cells grafted with the 4D06 and the 4D08 CAR showed on target activity indicated by a transient increase in serum transaminases, and a lower number of HBV-positive hepatocytes in the mice treated. This study demonstrates an efficient and fast approach to identifying pathogen-specific monoclonal human antibodies from small donor cell numbers for the subsequent generation of new CARs.},
}

Humans
*Hepatitis B virus/immunology/genetics
Animals
Mice
*Hepatitis B Surface Antigens/immunology
Receptors, Chimeric Antigen/immunology/genetics/metabolism
Antibodies, Monoclonal/immunology
Immunotherapy, Adoptive
Hepatitis B/immunology/virology
Broadly Neutralizing Antibodies/immunology
B-Lymphocytes/immunology
T-Lymphocytes/immunology

@article {pmid38710906,
year = {2024},
author = {Prentice, RL},
title = {Competing risks and multivariate outcomes in epidemiological and clinical trial research.},
journal = {Lifetime data analysis},
volume = {},
number = {},
pages = {},
pmid = {38710906},
issn = {1572-9249},
support = {P30CA015704/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; },
abstract = {Data analysis methods for the study of treatments or exposures in relation to a clinical outcome in the presence of competing risks have a long history, often with inference targets that are hypothetical, thereby requiring strong assumptions for identifiability with available data. Here data analysis methods are considered that are based on single and higher dimensional marginal hazard rates, quantities that are identifiable under standard independent censoring assumptions. These lead naturally to joint survival function estimators for outcomes of interest, including competing risk outcomes, and provide the basis for addressing a variety of data analysis questions. These methods will be illustrated using simulations and Women's Health Initiative cohort and clinical trial data sets, and additional research needs will be described.},
}

@article {pmid38710483,
year = {2024},
author = {Li, CI and Rogers, SC and Bult, CJ and Guerra, CE and Talton, A and Williams, LB and Law, W},
title = {Executing plans to enhance diversity across cancer centers in the United States: Opportunities and challenges.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djae100},
pmid = {38710483},
issn = {1460-2105},
abstract = {BACKGROUND: Lack of diversity in the cancer research workforce persists which the new requirement for all NCI-designated cancer centers to have a Plan to Enhance Diversity (PED) seeks to address. However, it is not well understood how different cancer centers are approaching the development and execution of these plans. Our objective was to assess how cancer centers are establishing and pursuing their PED.

METHODS: We conducted a cross-sectional survey of members of the Cancer Center DEI Network which includes all NCI-designated cancer centers and several emerging centers. 62 cancer centers (75% of those invited), including 58 NCI-designated cancer centers (81% of those with this designation), participated and completed a questionnaire that assessed PED leadership, major challenges, implementation strategies, and approach to evaluate PED progress.

RESULTS: The most common PED challenge identified is recruiting diverse faculty (68% of centers) and the most common strategy currently used to address this is reviewing and revising faculty recruitment practices (67%). The most common approach centers are using to measure PED progress are shifts in demographics (68%), and data on the demographics of faculty, leadership, and trainees are available at 79%, 81%, and 75% of centers, respectively.

CONCLUSION(S): While almost all centers have established a PED leadership structure, there is considerable variation in the approaches used to realize PED goals, and in the resources provided to support PED work. Realizing opportunities to share and implement common best practices and exemplar programs has the potential to elevate the impact of PED efforts nationally.},
}

@article {pmid38710302,
year = {2024},
author = {Kopmar, NE and Othus, M and Quach, K and Rasmussen, A and Schonhoff, K and Becker, PS and Walter, RB and Halpern, AB and Salit, R and Cassaday, RD and Shustov, A and Stewart, FM and Oehler, VG and Scott, BL and Sandmaier, BM and Lee, SJ and Estey, EH and Percival, MM},
title = {Intensive Re-Induction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplant for Relapsed/Refractory High-Grade Myeloid Neoplasms.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2024.05.002},
pmid = {38710302},
issn = {2666-6367},
abstract = {Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplant (HCT) the only therapy likely to result in cure. Therefore, we conducted a study to determine the feasibility of early HCT - within 60 days of beginning reinduction chemotherapy - to see if getting patients to HCT in an expeditious manner would facilitate a larger number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults 18-75 with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis, who were eligible for a reduced-intensity HCT. Subjects received reinducton chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/melphalan). We enrolled 30 patients: all received CLAG-M reinduction, although only 9 received HCT within 60 days (< 15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range 42-60). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplant of 83 days (range 53-367). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit real-world uptake of such early-to-transplant protocols.},
}

@article {pmid38709898,
year = {2024},
author = {Guo, H and Malone, KE and Heckbert, SR and Li, CI},
title = {Statin use and risks of breast cancer recurrence and mortality.},
journal = {Cancer},
volume = {},
number = {},
pages = {},
doi = {10.1002/cncr.35362},
pmid = {38709898},
issn = {1097-0142},
support = {T32CA09168/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients.

METHODS: In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality.

RESULTS: Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88).

CONCLUSIONS: These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.},
}

@article {pmid38709726,
year = {2024},
author = {Balasingam, S and Dheda, K and Fortune, S and Gordon, SB and Hoft, D and Kublin, JG and Loynachan, CN and McShane, H and Morton, B and Nambiar, S and Sharma, NR and Robertson, B and Schrager, LK and Weller, CL},
title = {Review of the current TB human infection studies for use in accelerating TB vaccine development: A meeting report.},
journal = {The Journal of infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1093/infdis/jiae238},
pmid = {38709726},
issn = {1537-6613},
abstract = {Tools to evaluate and accelerate tuberculosis (TB) vaccine development are needed to advance global TB control strategies. Validated human infection studies for TB have the potential to facilitate breakthroughs in understanding disease pathogenesis, identify correlates of protection, develop diagnostic tools, and accelerate and de-risk vaccine and drug development. However, key challenges remain for realizing the clinical utility of these models, which require further discussion and alignment amongst key stakeholders. In March 2023, the Wellcome Trust and the International AIDS Vaccine Initiative (IAVI) convened international experts involved in developing both TB and Bacillus Calmette-Guerin (BCG) human infection studies (including mucosal and intradermal challenge routes) to discuss the status of each of the models and the key enablers to move the field forward. This report provides a summary of the presentations and discussion from the meeting. Discussions identified key issues, including demonstrating model validity, to provide confidence for vaccine developers, which may be addressed through demonstration of known vaccine effects, e.g. BCG vaccination in specific populations, and by comparing results from field efficacy and human infection studies. The workshop underscored the importance of establishing safe and acceptable studies in high-burden settings, and the need to validate more than one model to allow for different scientific questions to be addressed as well as to provide confidence to vaccine developers and regulators around use of human infection study data in vaccine development and licensure pathways.},
}

@article {pmid38704119,
year = {2024},
author = {Crew, KD and Anderson, GL and Arnold, KB and Stieb, AP and Amenta, JN and Collins, N and Law, CW and Pruthi, S and Sandoval-Leon, A and Bertoni, D and Grosse Perdekamp, MT and Colonna, S and Krisher, S and King, T and Yee, LD and Ballinger, TJ and Braun-Inglis, C and Mangino, D and Wisinski, KB and DeYoung, CA and Ross, M and Floyd, J and Kaster, A and Vander Walde, L and Saphner, T and Zarwan, C and Lo, S and Graham, C and Conlin, A and Yost, K and Agnese, D and Jernigan, C and Hershman, DL and Neuhouser, ML and Arun, B and Kukafka, R},
title = {Making informed choices on incorporating chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial.},
journal = {Contemporary clinical trials},
volume = {},
number = {},
pages = {107564},
doi = {10.1016/j.cct.2024.107564},
pmid = {38704119},
issn = {1559-2030},
abstract = {INTRODUCTION: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy.

METHODS/DESIGN: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation.

RESULTS/DISCUSSION: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S.

TRIAL REGISTRATION: NCT04496739.},
}

@article {pmid38703890,
year = {2024},
author = {Zhang, X and Schenk, JM and Perrigue, M and Drewnowski, A and Wang, CY and Beatty, SJ and Neuhouser, ML},
title = {No effect of high eating frequency compared to low eating frequency on appetite and inflammation biomarkers: results from a randomized cross-over clinical trial.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tjnut.2024.04.029},
pmid = {38703890},
issn = {1541-6100},
abstract = {BACKGROUND: Eating frequency (EF) focuses on the total number of eating occasions per day and may influence metabolic health.

OBJECTIVE: We sought to examine the effect of high vs. low EF on appetite regulation and inflammatory biomarkers among healthy adults.

METHODS: Data are from a randomized, cross-over trial (the Frequency of Eating and Satiety Hormones (FRESH) Study). Participants (n=50) completed two isocaloric 21-day study periods of low EF (three eating occasions/day) and high EF (six eating occasions/day) in random order with a 14-day wash-out period in-between. Participants were free-living and consumed their own food, using study-directed, structured meal plans with identical foods and total energy in both study periods. On days 1 and 21 of each EF period, fasting blood was collected during in-person clinic visits to assess plasma concentrations of ghrelin, leptin, adiponectin, and high-sensitive C-reactive protein (hs-CRP). Linear mixed models with EF, diet order, and period as fixed effects; and participant as random effect estimated the intervention effect. Interaction effects between EF and % body fat were examined.

RESULTS: Among the 50 participants who completed the trial, 39 (78%) were women, 30 (60%) were Non-Hispanic White, 40 (80%) had a BMI<25 kg/m[2], and the mean age was 32.1years. The differences between high vs. low EF in fasting ghrelin (geometric mean difference: 17.76 ng/ml, p=0.60), leptin (geometric mean difference: 2.09 ng/ml, p=0.14), adiponectin (geometric mean difference: 381.7 ng/ml, p=0.32), and hs-CRP (geometric mean difference: -0.018 mg/dl, p=0.08) were not statistically significant. No EF x % body fat interaction was observed on appetite regulation and inflammatory biomarkers.

CONCLUSIONS: No differences was observed in fasting ghrelin, leptin, adiponectin, and hs-CRP, comparing high vs. low EF. Future studies are needed to understand the physiology of eating frequency and appetite as they relate to metabolic health.},
}

@article {pmid38703776,
year = {2024},
author = {Rupert, PB and Buerger, M and Friend, DJ and Strong, RK},
title = {Structural elucidation of the mesothelin-mucin-16/CA125 interaction.},
journal = {Structure (London, England : 1993)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.str.2024.04.011},
pmid = {38703776},
issn = {1878-4186},
abstract = {Mesothelin (MSLN) is a cell-surface glycoprotein expressed at low levels on normal mesothelium but overexpressed in many cancers. Mesothelin has been implicated to play role/s in cell adhesion and multiple signaling pathways. Mucin-16/CA125 is an enormous cell-surface glycoprotein, also normally expressed on mesothelium and implicated in the progression and metastasis of several cancers, and directly binds mesothelin. However, the precise biological function/s of mesothelin and mucin-16/CA125 remain mysterious. We report protein engineering and recombinant production, qualitative and quantitative binding studies, and a crystal structure determination elucidating the molecular-level details governing recognition of mesothelin by mucin-16/CA125. The interface is small, consistent with the ∼micromolar binding constant and is free of glycan-mediated interactions. Sequence comparisons and modeling suggest that multiple mucin-16/CA125 modules can interact with mesothelin through comparable interactions, potentially generating a high degree of avidity at the cell surface to overcome the weak affinity, with implications for functioning and therapeutic interventions.},
}

@article {pmid38703010,
year = {2024},
author = {Loggers, ET and Chugh, R and Federman, N and Hartner, L and Riedel, RF and Cho, S and Hyslop, D and Lim, A and Oton, AB and Oktay, KH},
title = {Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study.},
journal = {Cancer},
volume = {},
number = {},
pages = {},
doi = {10.1002/cncr.35324},
pmid = {38703010},
issn = {1097-0142},
support = {//Springworks Therapeutics, Inc/ ; },
abstract = {INTRODUCTION: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT.

METHODS: Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL).

RESULTS: Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up.

CONCLUSION: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient.},
}

@article {pmid38702775,
year = {2024},
author = {Tian, X and Janes, HE and Kublin, JG},
title = {Statistical design and analysis of controlled human malaria infection trials.},
journal = {Malaria journal},
volume = {23},
number = {1},
pages = {133},
pmid = {38702775},
issn = {1475-2875},
support = {R01CA15208/NH/NIH HHS/United States ; },
mesh = {Humans ; *Malaria/prevention & control ; Animals ; Research Design ; Controlled Clinical Trials as Topic ; Models, Statistical ; Anopheles/parasitology ; },
abstract = {BACKGROUND: Malaria is a potentially life-threatening disease caused by Plasmodium protozoa transmitted by infected Anopheles mosquitoes. Controlled human malaria infection (CHMI) trials are used to assess the efficacy of interventions for malaria elimination. The operating characteristics of statistical methods for assessing the ability of interventions to protect individuals from malaria is uncertain in small CHMI studies. This paper presents simulation studies comparing the performance of a variety of statistical methods for assessing efficacy of intervention in CHMI trials.

METHODS: Two types of CHMI designs were investigated: the commonly used single high-dose design (SHD) and the repeated low-dose design (RLD), motivated by simian immunodeficiency virus (SIV) challenge studies. In the context of SHD, the primary efficacy endpoint is typically time to infection. Using a continuous time survival model, five statistical tests for assessing the extent to which an intervention confers partial or full protection under single dose CHMI designs were evaluated. For RLD, the primary efficacy endpoint is typically the binary infection status after a specific number of challenges. A discrete time survival model was used to study the characteristics of RLD versus SHD challenge studies.

RESULTS: In a SHD study with the continuous time survival model, log-rank test and t-test are the most powerful and provide more interpretable results than Wilcoxon rank-sum tests and Lachenbruch tests, while the likelihood ratio test is uniformly most powerful but requires knowledge of the underlying probability model. In the discrete time survival model setting, SHDs are more powerful for assessing the efficacy of an intervention to prevent infection than RLDs. However, additional information can be inferred from RLD challenge designs, particularly using a likelihood ratio test.

CONCLUSIONS: Different statistical methods can be used to analyze controlled human malaria infection (CHMI) experiments, and the choice of method depends on the specific characteristics of the experiment, such as the sample size allocation between the control and intervention groups, and the nature of the intervention. The simulation results provide guidance for the trade off in statistical power when choosing between different statistical methods and study designs.},
}

Humans
*Malaria/prevention & control
Animals
Research Design
Controlled Clinical Trials as Topic
Models, Statistical
Anopheles/parasitology

@article {pmid38699315,
year = {2024},
author = {Langelier, C and Chu, V and Glascock, A and Donnell, D and Grabow, C and Brown, C and Ward, R and Love, C and Kalantar, K and Cohen, S and Cannon, C and Woodworth, M and Kelley, C and Celum, C and Luetkemeyer, A},
title = {Doxycycline post-exposure prophylaxis for sexually transmitted infections impacts the gut antimicrobial resistome.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {38699315},
support = {K23 AI144036/AI/NIAID NIH HHS/United States ; R01 AI143439/AI/NIAID NIH HHS/United States ; },
abstract = {Doxycycline post-exposure prophylaxis (doxy-PEP) reduces bacterial sexually transmitted infections (STIs) among men who have sex with men and transgender women. While poised for widespread clinical implementation, the impact of doxy-PEP on antimicrobial resistance remains a primary concern as its effects on the gut microbiome and resistome, or the antimicrobial resistance genes (ARGs) present in the gut microbiome, are unknown. To investigate these effects, we studied participants from a randomized clinical trial who either received doxy-PEP as a one-time doxycycline 200 mg taken after condomless sex (DP arm, n = 100) or standard of care treatment (SOC arm, n = 50). From self-collected rectal swabs at enrollment (day-0) and after 6 months (month-6), we performed metagenomic DNA sequencing (DNA-seq) or metatranscriptomic RNA sequencing (RNA-seq). DNA-seq data was analyzable from 127 samples derived from 89 participants, and RNA-seq data from 86 samples derived from 70 participants. We compared the bacterial microbiome and resistome between the two study arms and over time. Tetracycline ARGs were detected in all day-0 DNA-seq samples and 85% of day-0 RNA-seq samples. The proportional mass of tetracycline ARGs in the resistome increased between day-0 and month-6 in DP participants from 46-51% in the metagenome (p = 0.02) and 4-15% in the metatranscriptome (p < 0.01), but no changes in other ARG classes were observed. Exposure to a higher number of doxycycline doses correlated with proportional enrichment of tetracycline ARGs in the metagenome (Spearman's ρ = 0.23, p < 0.01) and metatranscriptome (Spearman's ρ = 0.55, p < 0.01). Bacterial microbiome alpha diversity, beta diversity, and total bacterial mass did not differ between day-0 and month-6 samples from DP participants when assessed by either DNA-seq or RNA-seq. In an abundance-based correlation analysis, we observed an increase over time in the strength of the correlation between tetracycline ARGs and specific bacterial taxa, including some common human pathogens. In sum, doxy-PEP use over a 6-month period was associated with an increase in the proportion of tetracycline ARGs comprising the gut resistome, and an increase in the expression of tetracycline ARGs. Notably, doxy-PEP did not significantly alter alpha diversity or taxonomic composition of the gut microbiome, and did not demonstrate significant increases in non-tetracycline ARG classes. Further studies and population level surveillance are needed to understand the implications of these findings as doxy-PEP is implemented as a public health strategy.},
}

@article {pmid38701912,
year = {2024},
author = {Donlan, AN and Leslie, JL and Simpson, ME and Petri, WA and Allen, JE and Petri, WA},
title = {IL-13 protects from C. difficile Colitis.},
journal = {Anaerobe},
volume = {},
number = {},
pages = {102860},
doi = {10.1016/j.anaerobe.2024.102860},
pmid = {38701912},
issn = {1095-8274},
abstract = {OBJECTIVES: Clostridioides difficile infection (CDI) is the leading hospital-acquired infection in North America. We have previously discovered that antibiotic disruption of the gut microbiota decreases intestinal IL-33 and IL-25 and increases susceptibility to CDI. We further found that IL-33 promotes protection through type 2 Innate Lymphoid Cells (ILC2s), which produce IL-13. However, the contribution of IL-13 to disease has never been explored.

METHODS: We used a validated model of CDI in mice, in which we neutralized via blocking antibodies, or administered recombinant protein, IL-13 to assess the role of this cytokine during infection using weight and clinical scores. Fluorescent activated cell sorting (FACS) was used to characterize myeloid cell population changes in response to IL-13 manipulation.

RESULTS: We found that administration of IL-13 protected, and anti-IL-13 exacerbated CDI. Additionally, we observe alterations to the monocyte/macrophage cells following neutralization of IL-13 as early as day three post infection. We also observed elevated accumulation of myeloid cells by day four post-infection following IL-13 neutralization. Neutralization of the decoy receptor, IL-13Rα2, resulted in protection from disease, likely through increased available endogenous IL-13.

CONCLUSIONS: Our data highlight the protective role of IL-13 in protecting from more severe CDI and the association of poor responses with a dysregulated monocyte-macrophage compartment. These results increase our understanding of type 2 immunity in CDI and may have implications for treating disease in patients.},
}

@article {pmid38701405,
year = {2024},
author = {Ahmed, G and Alsouqi, A and Szabo, A and Samples, L and Shadman, M and Awan, FT and Rojek, AE and Riedell, PA and Iqbal, M and Fenske, TS and Kharfan-Dabaja, MA and Ito, S and Hamadani, M},
title = {CAR T-cell Therapy in Mantle Cell Lymphoma with Secondary CNS Involvement - a multicenter experience.},
journal = {Blood advances},
volume = {},
number = {},
pages = {},
doi = {10.1182/bloodadvances.2023012255},
pmid = {38701405},
issn = {2473-9537},
}

@article {pmid38700798,
year = {2024},
author = {Mogal, H and Shen, P},
title = {Top Peritoneal Surface Malignancy Articles from 2022 to Inform your Cancer Practice.},
journal = {Annals of surgical oncology},
volume = {},
number = {},
pages = {},
pmid = {38700798},
issn = {1534-4681},
abstract = {Over the last few decades, the role of cytoreductive surgery (CRS) with or without regional-based peritoneal therapies such as hyperthermic intraperitoneal chemotherapy (HIPEC) has evolved in the management of patients with peritoneal surface malignances (PSMs). Despite the benefit of CRS in improving oncologic outcomes, significant challenges remain in the treatment of patients with advanced PSMs, and the role of HIPEC continues to be questioned. Additionally, while there has been improvement in perioperative outcomes, long-term survival remains poor. As a result, there is much need to improve our understanding of the processes that drive tumor biology, thereby improving patient selection for various treatment approaches. Additionally, newer therapies are needed for patients who remain poor surgical candidates and who progress on systemic therapy. This article highlights recently published studies that we consider impactful in the care of patients with PSMs.},
}

@article {pmid38700620,
year = {2024},
author = {Merkel, EC and Vandeleur, DM and Cheng, X and Littman, AJ and Baker, KS},
title = {Association between adverse childhood experiences and health related quality of life in adult cancer survivors in the United States.},
journal = {Journal of cancer survivorship : research and practice},
volume = {},
number = {},
pages = {},
pmid = {38700620},
issn = {1932-2267},
support = {CA009351/NH/NIH HHS/United States ; GM086270/NH/NIH HHS/United States ; },
abstract = {PURPOSE: The impact of adverse childhood experiences (ACEs) on health-related quality of life (HRQOL) is increasingly recognized, however, this has not been studied in cancer survivors in the United States. This study investigates if ACEs are associated with HRQOL in cancer survivors.

METHODS: We conducted a cross-sectional analysis of the 2020 Behavioral Risk Factor Surveillance System from states that administered ACEs and Cancer Survivorship modules. Eligibility criteria included being a cancer survivor and not currently receiving cancer treatment. Primary exposure was number of ACEs (categorized as 0, 1-2, 3, or ≥ 4). Primary outcomes were self-reported measures of HRQOL including worse overall health and ≥ 14 unhealthy days (mentally or physically) per month. Mantel-Haenszel stratified analyses were performed and prevalence ratios were adjusted for age.

RESULTS: Of 5,780 participants, 62.0% were female and 67.8% were ≥ 65 years. Prevalence of worse overall health was 22.5% for individuals with no ACEs compared to 30.2% for 2-3 ACEs (aPR = 1.4, 95% CI 1.2, 1.5) and 38.5% for ≥ 4 ACEs (aPR = 1.7, 95% CI 1.5, 2.0). Prevalence of ≥ 14 unhealthy days was 18.1% with no ACEs compared to 21.0% for 1 ACE (aPR = 1.3, 95% CI 1, 1.3), 29.0% for 2-3 ACEs (aPR = 1.6, 95% CI 1.4, 1.8), and 44.8% for ≥ 4 ACEs (aPR = 2.2, 95% CI 2.0, 2.5).

CONCLUSIONS: Our study provides novel evidence of the association of multiple ACEs with higher prevalence of poor HRQOL in cancer survivors.

Screening for ACEs is warranted in all patients to guide targeted interventions to improve HRQOL and mitigate the impact of ACEs on HRQoL in cancer survivors.},
}

@article {pmid38700521,
year = {2024},
author = {Gulleen, EA and Lubwama, M},
title = {How Should We Manage Antimicrobial Resistance in Resource-Limited Settings?.},
journal = {AMA journal of ethics},
volume = {26},
number = {5},
pages = {E373-379},
doi = {10.1001/amajethics.2024.373},
pmid = {38700521},
issn = {2376-6980},
mesh = {Humans ; *Developing Countries ; *Health Resources ; Anti-Bacterial Agents/therapeutic use ; Health Services Accessibility ; Drug Resistance, Bacterial ; Drug Resistance, Microbial ; Anti-Infective Agents/therapeutic use ; Resource-Limited Settings ; },
abstract = {Patients living in low- and middle-income countries (LMICs) shoulder the greatest burden of infections caused by antimicrobial-resistant pathogens. Speedy access to appropriate broad-spectrum antimicrobials significantly improves health outcomes and reduces transmission of antimicrobial-resistant pathogens, but persons living in LMICs have compromised access to these antimicrobials. This article considers how inequities in microbiology diagnostics, antimicrobial access, and antimicrobial affordability influence outcomes for patients infected with antimicrobial-resistant pathogens who live in resource-limited settings.},
}

Humans
*Developing Countries
*Health Resources
Anti-Bacterial Agents/therapeutic use
Health Services Accessibility
Drug Resistance, Bacterial
Drug Resistance, Microbial
Anti-Infective Agents/therapeutic use
Resource-Limited Settings

@article {pmid38700354,
year = {2024},
author = {Ouwendijk, WJD and Roychoudhury, P and Cunningham, AL and Jerome, KR and Koelle, DM and Kinchington, PR and Mohr, I and Wilson, AC and Verjans, GMGM and Depledge, DP},
title = {Reply to Wang et al., "Ample evidence for the presence of HSV-1 LAT in non-neuronal ganglionic cells of mice and humans".},
journal = {Journal of virology},
volume = {},
number = {},
pages = {e0052024},
doi = {10.1128/jvi.00520-24},
pmid = {38700354},
issn = {1098-5514},
}

@article {pmid38699999,
year = {2024},
author = {Schumacher, BT and LaMonte, MJ and Di, C and Parada, H and Hooker, SP and Bellettiere, J and Simonsick, EM and Liles, S and LaCroix, AZ},
title = {Associations of Relative Intensity of Physical Activity with Incident Cardiovascular Events and All-Cause Mortality.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glae113},
pmid = {38699999},
issn = {1758-535X},
abstract = {BACKGROUND: The relative intensity of a physical activity (PA) can be estimated as the percent of one's maximal effort required.

METHODS: We compared associations of relative and absolute intensity PA with incident major cardiovascular disease (CVD) and all-cause mortality in 5,633 women from the Objective Physical Activity and Cardiovascular Health Study (mean age 78.5±6.7). Absolute intensity was measured by accelerometry. Relative intensity was estimated by dividing accelerometer-estimated metabolic equivalents (METs) by maximal MET capacity. Both were aggregated into mean daily hours of light intensity PA (LPA) and moderate-to-vigorous PA (MVPA). Cox proportional hazards models estimated hazard ratios (HRs) for one-hour higher amounts of PA on outcomes.

RESULTS: During follow-up (median=7.4 years), there were 748 incident CVD events and 1,312 deaths. Greater LPA and MVPA, on either scale, was associated with reduced risk of both outcomes. HRs for a one-hour increment of absolute LPA were 0.88 (95% CI:0.83-0.93) and 0.88 (95% CI:0.84-0.92) for incident CVD and mortality, respectively. HRs for a one-hour increment of absolute MPVA were 0.73 (95% CI:0.61-0.87) and 0.55 (95% CI:0.48-0.64) for the same outcomes. HRs for a one-hour increment of relative LPA were 0.70 (95% CI:0.59-0.84) and 0.78 (95% CI:0.68-0.89) for incident CVD and mortality, respectively. HRs for a one-hour increment of relative MPVA were 0.89 (95% CI:0.83-0.96) and 0.82 (95% CI:0.77-0.87) for the same outcomes. On the relative scale, LPA was more strongly, inversely associated with both outcomes than relative MVPA. Absolute MVPA was more strongly inversely associated with the outcomes than relative MVPA.

CONCLUSION: Findings support the continued shift in the PA intensity paradigm towards recommendation of more movement, regardless of intensity. Relative LPA--a modifiable, more easily achieved behavioral target, particularly among ambulatory older adults--was associated with reduced risk of incident major CVD and death.},
}

@article {pmid38698683,
year = {2024},
author = {Kuczmarski, TM and Lynch, RC},
title = {Managing common toxicities associated with checkpoint inhibitor and chemotherapy combinations for untreated classic Hodgkin lymphoma.},
journal = {British journal of haematology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bjh.19478},
pmid = {38698683},
issn = {1365-2141},
abstract = {Combination checkpoint inhibitor (CPI) and chemotherapy is an effective and safe treatment strategy for patients with untreated classic Hodgkin lymphoma. Recent studies of programmed cell death protein 1 inhibitors combined with doxorubicin, vinblastine and dacarbazine have demonstrated high overall and complete response rates. This combination has a unique toxicity profile that should be managed appropriately so as not to compromise treatment efficacy. Common toxicities include rash, hepatoxicity, neutropenia and thyroid dysfunction. Here, we present four cases and the management strategies around such toxicities. In addition, we highlight key clinical decision-making around the administration of subsequent doses of CPI and chemotherapy.},
}

@article {pmid38698170,
year = {2024},
author = {Baik, C and Cheng, ML and Dietrich, M and Gray, JE and Karim, NA},
title = {A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.},
journal = {Advances in therapy},
volume = {},
number = {},
pages = {},
pmid = {38698170},
issn = {1865-8652},
abstract = {According to current guidelines, targeted therapy with a combination of BRAF plus MEK inhibitors is the preferred first-line treatment for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC). In the open-label, single-arm, phase 2 PHAROS trial (NCT03915951), the combination of encorafenib, a potent BRAF inhibitor, and binimetinib, a potent MEK inhibitor, demonstrated durable antitumor activity with a manageable safety profile in this patient population. On the basis of the results of this study, the combination of encorafenib plus binimetinib was approved by the US Food and Drug Administration on October 11, 2023, for patients with BRAF V600E-mutant metastatic NSCLC. In this review, we summarize the efficacy and safety of encorafenib plus binimetinib from the PHAROS study. In addition, we discuss strategies to manage adverse reactions with this combination therapy with the intent of minimizing unnecessary treatment discontinuations in these patients.},
}

@article {pmid38698071,
year = {2024},
author = {Ramdial, J and Kebriaei, P and Champlin, RE and Popat, U and Rezvani, K and Shpall, EJ and Mehta, RS},
title = {Improved survival with younger HLA-matched unrelated donors versus older matched sibling donor HCT with PTCy-prophylaxis.},
journal = {Leukemia},
volume = {},
number = {},
pages = {},
pmid = {38698071},
issn = {1476-5551},
}

@article {pmid38697998,
year = {2024},
author = {Ping, J and Jia, G and Cai, Q and Guo, X and Tao, R and Ambrosone, C and Huo, D and Ambs, S and Barnard, ME and Chen, Y and Garcia-Closas, M and Gu, J and Hu, JJ and John, EM and Li, CI and Nathanson, K and Nemesure, B and Olopade, OI and Pal, T and Press, MF and Sanderson, M and Sandler, DP and Yoshimatsu, T and Adejumo, PO and Ahearn, T and Brewster, AM and Hennis, AJM and Makumbi, T and Ndom, P and O'Brien, KM and Olshan, AF and Oluwasanu, MM and Reid, S and Yao, S and Butler, EN and Huang, M and Ntekim, A and Li, B and Troester, MA and Palmer, JR and Haiman, CA and Long, J and Zheng, W},
title = {Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {3718},
pmid = {38697998},
issn = {2041-1723},
support = {R01CA202981//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01CA235553//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
mesh = {Humans ; Female ; *Genetic Predisposition to Disease ; *Breast Neoplasms/genetics ; *Transcriptome ; Middle Aged ; Genome-Wide Association Study ; Adult ; Polymorphism, Single Nucleotide ; Case-Control Studies ; Receptors, Estrogen/genetics/metabolism ; Black People/genetics ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Aged ; },
abstract = {African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.},
}

Humans
Female
*Genetic Predisposition to Disease
*Breast Neoplasms/genetics
*Transcriptome
Middle Aged
Genome-Wide Association Study
Adult
Polymorphism, Single Nucleotide
Case-Control Studies
Receptors, Estrogen/genetics/metabolism
Black People/genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Aged

@article {pmid38697986,
year = {2024},
author = {Shadman, M and Tedeschi, A and Mohseninejad, L and Yang, K and Lamanna, N and Xu, S and Cohen, A and Challagulla, S and Xue, M and Williams, R and O'Brien, SM and Brown, JR and Tam, C},
title = {Similar efficacy of ibrutinib arms across ALPINE and ELEVATE-RR trials in relapsed/refractory chronic lymphocytic leukemia: a matching-adjusted indirect comparison.},
journal = {Blood cancer journal},
volume = {14},
number = {1},
pages = {77},
pmid = {38697986},
issn = {2044-5385},
mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality ; *Adenine/*analogs & derivatives/therapeutic use ; *Piperidines/therapeutic use ; Male ; Pyrazoles/therapeutic use ; Female ; Pyrimidines/therapeutic use ; Aged ; Treatment Outcome ; Middle Aged ; },
}

Humans
*Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality
*Adenine/*analogs & derivatives/therapeutic use
*Piperidines/therapeutic use
Male
Pyrazoles/therapeutic use
Female
Pyrimidines/therapeutic use
Aged
Treatment Outcome
Middle Aged

@article {pmid38697164,
year = {2024},
author = {Webb, AB and Berg, CD and Castle, PE and Crosby, D and Etzioni, R and Kessler, LG and Menon, U and Parmar, M and Steele, RJC and Sasieni, PD},
title = {Considerations for using potential surrogate endpoints in cancer screening trials.},
journal = {The Lancet. Oncology},
volume = {25},
number = {5},
pages = {e183-e192},
doi = {10.1016/S1470-2045(24)00015-9},
pmid = {38697164},
issn = {1474-5488},
mesh = {Humans ; *Early Detection of Cancer/methods ; *Neoplasms/diagnosis ; Biomarkers, Tumor/analysis ; Clinical Trials as Topic ; Research Design/standards ; Biomarkers/analysis ; Endpoint Determination ; },
abstract = {The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.},
}

Humans
*Early Detection of Cancer/methods
*Neoplasms/diagnosis
Biomarkers, Tumor/analysis
Clinical Trials as Topic
Research Design/standards
Biomarkers/analysis
Endpoint Determination

@article {pmid38696256,
year = {2024},
author = {Peralta, J and DuPriest, B and Orozco, D and Pacheco, JR and Martins, L and Soriano, RA and Wong, A and Wong, R and Grillo-Hill, B},
title = {Drosophila Nhe2 Over-expression Induces Autophagic Cell Death.},
journal = {Molecular biology of the cell},
volume = {},
number = {},
pages = {mbcE24020058},
doi = {10.1091/mbc.E24-02-0058},
pmid = {38696256},
issn = {1939-4586},
abstract = {Autophagy is a conserved catabolic process where double membrane-bound structures form around macromolecules or organelles targeted for degradation. Autophagosomes fuse with lysosomes to facilitate degradation and macromolecule recycling for homeostasis or growth in a cell autonomous fashion. In cancer cells, autophagy is often upregulated and helps cancer cells survive nutrient deprivation and stressful growth conditions. Here, we propose that the increased intracellular pH (pHi) common to cancer cells is sufficient to induce autophagic cell death. We previously developed tools to increase pHi in the Drosophila eye via over-expression of DNhe2, resulting in aberrant patterning and reduced tissue size. We examined fly eyes at earlier stages of development and found fewer interommatidial cells. We next tested whether this decrease in cell number was due to increased cell death. We found that the DNhe2-induced cell death was caspase-independent, which is inconsistent with apoptosis. However, this cell death required autophagy genes, which supports autophagy as the mode of cell death. We also found that expression of molecular markers supports increased autophagy. Together, our findings suggest new roles for ion transport proteins in regulating conserved, critical developmental processes and provide evidence for new paradigms in growth control.},
}

@article {pmid38695668,
year = {2024},
author = {Lyman, GH and Kuderer, NM},
title = {Artificial Intelligence in Cancer Clinical Research: I. Introduction.},
journal = {Cancer investigation},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/07357907.2024.2347784},
pmid = {38695668},
issn = {1532-4192},
}

@article {pmid38695123,
year = {2024},
author = {Cortes, JE and Jiang, Q and Wang, J and Weng, J and Zhu, H and Liu, X and Hochhaus, A and Kim, DW and Radich, J and Savona, M and Martin-Regueira, P and Sy, O and Saglio, G},
title = {Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN.},
journal = {Haematologica},
volume = {},
number = {},
pages = {},
doi = {10.3324/haematol.2023.283428},
pmid = {38695123},
issn = {1592-8721},
abstract = {Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.},
}

@article {pmid38692824,
year = {2024},
author = {Frank, I and Li, SS and Grunenberg, N and Overton, ET and Robinson, ST and Zheng, H and Seaton, KE and Heptinstall, JR and Allen, MA and Mayer, KH and Culver, DA and Keefer, MC and Edupuganti, S and Pensiero, MN and Mehra, VL and De Rosa, SC and Morris, DE and Wang, S and Seaman, MS and Montefiori, DC and Ferrari, G and Tomaras, GD and Kublin, JG and Corey, L and Lu, S and , },
title = {Safety and immunogenicity of a polyvalent DNA-protein HIV vaccine with matched Env immunogens delivered as a prime-boost regimen or coadministered in HIV-uninfected adults in the USA (HVTN 124): a phase 1, placebo-controlled, double-blind randomised controlled trial.},
journal = {The lancet. HIV},
volume = {11},
number = {5},
pages = {e285-e299},
doi = {10.1016/S2352-3018(24)00036-5},
pmid = {38692824},
issn = {2352-3018},
mesh = {Humans ; *AIDS Vaccines/administration & dosage/immunology/adverse effects ; Adult ; Male ; Female ; Double-Blind Method ; *Vaccines, DNA/administration & dosage/immunology/adverse effects ; *HIV Infections/prevention & control/immunology ; Middle Aged ; Young Adult ; *HIV Antibodies/blood ; Adolescent ; *HIV-1/immunology ; United States ; Immunization, Secondary ; Immunogenicity, Vaccine ; HIV Envelope Protein gp120/immunology/genetics ; Antibodies, Neutralizing/blood ; },
abstract = {BACKGROUND: An effective HIV vaccine will most likely need to have potent immunogenicity and broad cross-subtype coverage. The aim of the HIV Vaccine Trials Network (HVTN) 124 was to evaluate safety and immunogenicity of a unique polyvalent DNA-protein HIV vaccine with matching envelope (Env) immunogens.

METHODS: HVTN 124 was a randomised, phase 1, placebo-controlled, double-blind study, including participants who were HIV seronegative and aged 18-50 years at low risk for infection. The DNA vaccine comprised five plasmids: four copies expressing Env gp120 (clades A, B, C, and AE) and one gag p55 (clade C). The protein vaccine included four DNA vaccine-matched GLA-SE-adjuvanted recombinant gp120 proteins. Participants were enrolled across six clinical sites in the USA and were randomly assigned to placebo or one of two vaccine groups (ie, prime-boost or coadministration) in a 5:1 ratio in part A and a 7:1 ratio in part B. Vaccines were delivered via intramuscular needle injection. The primary outcomes were safety and tolerability, assessed via frequency, severity, and attributability of local and systemic reactogenicity and adverse events, laboratory safety measures, and early discontinuations. Part A evaluated safety. Part B evaluated safety and immunogenicity of two regimens: DNA prime (administered at months 0, 1, and 3) with protein boost (months 6 and 8), and DNA-protein coadministration (months 0, 1, 3, 6, and 8). All randomly assigned participants who received at least one dose were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT03409276) and is closed to new participants.

FINDINGS: Between April 19, 2018 and Feb 13, 2019, 60 participants (12 in part A [five men and seven women] and 48 in part B [21 men and 27 women]) were enrolled. All 60 participants received at least one dose, and 14 did not complete follow-up (six of 21 in the prime-boost group and eight of 21 in the coadminstration group). 11 clinical adverse events deemed by investigators as study-related occurred in seven of 48 participants in part B (eight of 21 in the prime-boost group and three of 21 in the coadministration group). Local reactogenicity in the vaccine groups was common, but the frequency and severity of reactogenicity signs or symptoms did not differ between the prime-boost and coadministration groups (eg, 20 [95%] of 21 in the prime-boost group vs 21 [100%] of 21 in the coadministration group had either local pain or tenderness of any severity [p=1·00], and seven [33%] vs nine [43%] had either erythema or induration [p=0·97]), nor did laboratory safety measures. There were no delayed-type hypersensitivity reactions or vasculitis or any severe clinical adverse events related to vaccination. The most frequently reported systemic reactogenicity symptoms in the active vaccine groups were malaise or fatigue (five [50%] of ten in part A and 17 [81%] of 21 in the prime-boost group vs 15 [71%] of 21 in the coadministration group in part B), headache (five [50%] and 18 [86%] vs 12 [57%]), and myalgia (four [40%] and 13 [62%] vs ten [48%]), mostly of mild or moderate severity.

INTERPRETATION: Both vaccine regimens were safe, warranting evaluation in larger trials.

FUNDING: US National Institutes of Health and US National Institute of Allergy and Infectious Diseases.},
}

Humans
*AIDS Vaccines/administration & dosage/immunology/adverse effects
Adult
Male
Female
Double-Blind Method
*Vaccines, DNA/administration & dosage/immunology/adverse effects
*HIV Infections/prevention & control/immunology
Middle Aged
Young Adult
*HIV Antibodies/blood
Adolescent
*HIV-1/immunology
United States
Immunization, Secondary
Immunogenicity, Vaccine
HIV Envelope Protein gp120/immunology/genetics
Antibodies, Neutralizing/blood

@article {pmid38692470,
year = {2024},
author = {Dougan, MM and Fest, S and Cushing-Haugen, K and Farland, LV and Chavarro, J and Harris, HR and Missmer, SA},
title = {A prospective study of dietary patterns and the incidence of endometriosis diagnosis.},
journal = {American journal of obstetrics and gynecology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajog.2024.04.030},
pmid = {38692470},
issn = {1097-6868},
support = {P30 DK046200/DK/NIDDK NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: Although endometriosis is a common condition-affecting ∼10% of premenopausal individuals-its etiology is unknown. Diet receives large patient attention, but studies of the role of diet are limited. Examining dietary patterns is essential to provide new insight.

OBJECTIVE: We sought to determine whether dietary patterns are associated with laparoscopically-confirmed endometriosis diagnosis.

STUDY DESIGN: We conducted a prospective cohort study among 81,997 premenopausal participants of the Nurses' Health Study II, who were followed from 1991-2015. Diet was assessed with validated food frequency questionnaires every four years. We examined six dietary patterns: Western, Prudent, Alternative Healthy Eating Index (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH), an estrogen-associated pattern, and a pro-inflammatory pattern. Cox proportional hazard ratios (HR) and 95% confidence intervals (CI) were used to quantify the association between each of these patterns and laparoscopically-confirmed endometriosis diagnosis.

RESULTS: 3,810 incident cases of endometriosis were diagnosed during 24 years of follow-up. Adherence to the AHEI-2010, reflecting a healthier dietary pattern, was associated with a 13% lower risk of endometriosis diagnosis (5[th] vs 1[st] quintile 95% CI=0.78-0.96; ptrend=0.02). Participants in the highest quintile of the Western dietary pattern, characterized by high intake of red meat, processed meat, refined grains, and desserts, had a 27% higher risk of endometriosis diagnosis compared to those in the lowest quintile (95% CI=1.09-1.47; ptrend=0.004). The Prudent, DASH, and estrogen-associated dietary patterns did not demonstrate clear associations with endometriosis risk, and there was the suggestion of higher risk of endometriosis diagnosis among those with a higher pro-inflammatory diet score (HR for 5[th] vs 1[st] quintile=1.10; 95% CI=0.99-1.23; ptrend=0.01).

CONCLUSION: Our results suggest that consuming a dietary pattern that adheres to the AHEI-2010 recommendations lowers the risk of endometriosis diagnosis, potentially through a beneficial impact on pelvic pain. In addition, consuming a less healthy diet high in red/processed meats and refined grains may have a detrimental impact on endometriosis symptoms.},
}

@article {pmid38691368,
year = {2024},
author = {Manson, JE and Crandall, CJ and Rossouw, JE and Chlebowski, RT and Anderson, GL and Stefanick, ML and Aragaki, AK and Cauley, JA and Wells, GL and LaCroix, AZ and Thomson, CA and Neuhouser, ML and Van Horn, L and Kooperberg, C and Howard, BV and Tinker, LF and Wactawski-Wende, J and Shumaker, SA and Prentice, RL},
title = {The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2024.6542},
pmid = {38691368},
issn = {1538-3598},
abstract = {IMPORTANCE: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.

OBSERVATIONS: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.

CONCLUSIONS AND RELEVANCE: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.},
}

@article {pmid38659838,
year = {2024},
author = {O'Connor, SA and Garcia, L and Patel, AP and Hugnot, JP and Paddison, PJ and Plaisier, CL},
title = {Breaking out of the cycle: Including quiescence in cell cycle classification.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38659838},
support = {R01 CA190957/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 NS123038/NS/NINDS NIH HHS/United States ; R01 NS119650/NS/NINDS NIH HHS/United States ; R21 CA170722/CA/NCI NIH HHS/United States ; },
abstract = {Single-cell transcriptomics has unveiled a vast landscape of cellular heterogeneity in which the cell cycle is a significant component. We trained a high-resolution cell cycle classifier (ccAFv2) using single cell RNA-seq (scRNA-seq) characterized human neural stem cells. The ccAFv2 classifies six cell cycle states (G1, Late G1, S, S/G2, G2/M, and M/Early G1) and a quiescent-like G0 state, and it incorporates a tunable parameter to filter out less certain classifications. The ccAFv2 classifier performed better than or equivalent to other state-of-the-art methods even while classifying more cell cycle states, including G0. We showcased the versatility of ccAFv2 by successfully applying it to classify cells, nuclei, and spatial transcriptomics data in humans and mice, using various normalization methods and gene identifiers. We provide methods to regress the cell cycle expression patterns out of single cell or nuclei data to uncover underlying biological signals. The classifier can be used either as an R package integrated with Seurat (https://github.com/plaisier-lab/ccafv2_R) or a PyPI package integrated with scanpy (https://pypi.org/project/ccAFv2/). We proved that ccAFv2 has enhanced accuracy, flexibility, and adaptability across various experimental conditions, establishing ccAFv2 as a powerful tool for dissecting complex biological systems, unraveling cellular heterogeneity, and deciphering the molecular mechanisms by which proliferation and quiescence affect cellular processes.},
}

@article {pmid38689544,
year = {2024},
author = {Yun, J and Baek, G and Indorf, A and Duong, A},
title = {Incidence of port site complications in relation to timing of bevacizumab infusion.},
journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners},
volume = {},
number = {},
pages = {10781552241245037},
doi = {10.1177/10781552241245037},
pmid = {38689544},
issn = {1477-092X},
abstract = {INTRODUCTION: Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor, with a serious complication of wound healing complications. The package insert currently does not have recommendations on the management of bevacizumab administration around minor procedures, including port placements. Currently, there are only two trials that have examined the optimal timing of bevacizumab after port placement.

METHODS: This is a single-center retrospective trial aiming to evaluate the rate of wound dehiscence and other port site complications depending on the time between port placement and bevacizumab infusion. Eligible patients who have had at least one port place and have received bevacizumab for an oncologic indication were identified in a study period of 1/1/2016-3/31/2021. The primary outcome of this study was the incidence of wound dehiscence in relation to the timing of bevacizumab infusion.

RESULTS: A total of 243 patients met the inclusion criteria, and 116 port placements had a port site complication. For wound dehiscence, 6% was observed 0 days from port placement, 10% was observed 1 day from port placement, 0% was observed 2 days from port placement, 0% was observed 3-7 days from port placement, 3% was observed 8-14 days from port placement, and 3% was observed 15-30 days from port placement.

CONCLUSIONS: The results of this study show an inverse relationship between the risk of wound dehiscence and port site complication and the timing of bevacizumab infusion to port placement, with an increase in absolute risk of wound dehiscence when bevacizumab is given within 2 days of port placement.},
}

@article {pmid38689480,
year = {2024},
author = {Chambers, M and Andre, AT and Wright, JL and Vakar-Lopez, F and Tretiakova, M and Reder, NP and Haffner, MC and True, LD},
title = {Outcome Analysis of a Series of Mixed-Grade, Non-muscle Invasive, Papillary Carcinomas of the Bladder.},
journal = {International journal of surgical pathology},
volume = {},
number = {},
pages = {10668969241246492},
doi = {10.1177/10668969241246492},
pmid = {38689480},
issn = {1940-2465},
abstract = {Introduction. Papillary urothelial carcinomas are currently graded as either low- or high-grade tumors based on World Health Organization (WHO) 2022 guidelines for genitourinary tumors. However, a minority of tumors are mixed-grade tumors, composed predominantly of low-grade cancer with a minor high-grade component. In the 2022 WHO these cancers are recognized as having outcomes comparable to low-grade cancers, although data to date has been limited. Methods. The pathology records of a large academic institution were searched for mixed-grade, non-muscle invasive papillary carcinomas of the bladder and ureter in order to characterize prognosis of these cancers. Results. Of 136 cancers, the majority (n = 104, 76.5%) were solitary, mixed-grade tumors, while 21 (15.4%) had a concurrent low-grade cancer and 11 (8.1%) had multiple mixed-grade tumors at the time of diagnosis. At follow-up (median 48.3 months, range = 1.3 months-18.1 years), 71 cancers recurred (52.2%): 52 (38.2%) as low- or mixed-grade cancers and 18 (13.2%) as high-grade cancers. There were no instances of stage-progression to >pT2. Conclusions. The clinical outcome of mixed-grade carcinomas was similar to what has been reported for low-grade carcinomas. Based on our results, and prior congruent studies of mixed-grade lesions, these lesions may be regarded as a distinct sub-category with a better prognosis than high-grade tumors.},
}

@article {pmid38688309,
year = {2024},
author = {Cloyd, JM and Colby, S and Guthrie, KA and Lowy, AM and Chiorean, EG and Philip, P and Sohal, D and Ahmad, S},
title = {Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.},
journal = {Journal of the National Comprehensive Cancer Network : JNCCN},
volume = {},
number = {},
pages = {1-6},
doi = {10.6004/jnccn.2023.7099},
pmid = {38688309},
issn = {1540-1413},
abstract = {BACKGROUND: Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC.

METHODS: SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models.

RESULTS: Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95).

CONCLUSIONS: Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.},
}

@article {pmid38688280,
year = {2024},
author = {Benbarche, S and Pineda, JMB and Galvis, LB and Biswas, J and Liu, B and Wang, E and Zhang, Q and Hogg, SJ and Lyttle, K and Dahi, A and Lewis, AM and Sarchi, M and Rahman, J and Fox, N and Ai, Y and Mehta, S and Garippa, R and Ortiz-Pacheco, J and Li, Z and Monetti, M and Stanley, RF and Doulatov, S and Bradley, RK and Abdel-Wahab, O},
title = {GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2024.04.006},
pmid = {38688280},
issn = {1097-4164},
abstract = {Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.},
}

@article {pmid38687617,
year = {2024},
author = {Han, D and Labaf, M and Zhao, Y and Owiredu, J and Zhang, S and Patel, K and Venkataramani, K and Steinfeld, JS and Han, W and Li, M and Liu, M and Wang, Z and Besschetnova, A and Patalano, S and Mulhearn, MJ and Macoska, JA and Yuan, X and Balk, SP and Nelson, PS and Plymate, SR and Gao, S and Siegfried, KR and Liu, R and Stangis, MM and Foxa, G and Czernik, PJ and Williams, BO and Zarringhalam, K and Li, X and Cai, C},
title = {Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI168649},
pmid = {38687617},
issn = {1558-8238},
abstract = {One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared to the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remains unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.},
}

@article {pmid38687474,
year = {2024},
author = {Elmore, JG and Lee, CI},
title = {Toward More Equitable Breast Cancer Outcomes.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2024.6052},
pmid = {38687474},
issn = {1538-3598},
}

@article {pmid38687020,
year = {2024},
author = {Crawford, KHD and Selke, S and Pepper, G and Goecker, E and Sobel, A and Wald, A and Johnston, C and Greninger, AL},
title = {Performance characteristics of highly automated HSV-1 and HSV-2 IgG testing.},
journal = {Journal of clinical microbiology},
volume = {},
number = {},
pages = {e0026324},
doi = {10.1128/jcm.00263-24},
pmid = {38687020},
issn = {1098-660X},
abstract = {Herpes simplex virus (HSV) infections are one of the most common and stigmatized infections of humankind, affecting more than 4 billion people around the world and more than 100 million Americans. Yet, most people do not know their infection status, and antibody testing is not recommended, partly due to poor test performance. Here, we compared the test performance of the Roche Elecsys HSV-1 IgG and HSV-2 IgG, DiaSorin LIAISON HSV-1/2 IgG, and Bio-Rad BioPlex 2200 HSV-1 and HSV-2 IgG assays with the gold-standard HSV western blot in 1,994 persons, including 1,017 persons with PCR or culture-confirmed HSV-1 and/or HSV-2 infection. Across all samples, the Bio-Rad and Roche assays had similar performance metrics with low sensitivity (<85%) but high specificity (>97%) for detecting HSV-1 IgG and both high sensitivity (>97%) and high specificity (>98%) for detecting HSV-2 IgG. The DiaSorin assay had a higher sensitivity (92.1%) but much lower specificity (88.7%) for detecting HSV-1 IgG and comparatively poor sensitivity (94.5%) and specificity (94.2%) for detecting HSV-2 IgG. The DiaSorin assay performed poorly at low-positive index values with 60.9% of DiaSorin HSV-1 results and 20.8% of DiaSorin HSV-2 results with positive index values <3.0 yielding false positive results. Based on an estimated HSV-2 seroprevalence of 12% in the United States, positive predictive values for HSV-2 IgG were 96.1% for Roche, 87.4% for Bio-Rad, and 69.0% for DiaSorin, meaning nearly one of every three positive DiaSorin HSV-2 IgG results would be falsely positive. Further development in HSV antibody diagnostics is needed to provide appropriate patient care.IMPORTANCESerological screening for HSV infections is currently not recommended in part due to the poor performance metrics of widely used commercial HSV-1 and HSV-2 IgG assays. Here, we compare three Food and Drug Administration (FDA)-cleared automated HSV-1 and HSV-2 IgG assays to the gold-standard western blot across nearly 2,000 samples. We find that not all commercially available HSV assays are created equal, with comparably low sensitivities for HSV-1 IgG across platforms and high false positivity rates for DiaSorin on HSV-2 IgG. This study is the first large-scale comparison of performance metrics for the Bio-Rad and Roche assays in over 10 years. Our study confirms that there remains room for improvement in HSV serological diagnostic testing-especially in regard to low sensitivities for HSV-1 IgG detection-and highlights that some previously less-studied assays may have better performance metrics than previously considered typical of commercially available HSV-2 IgG assays.},
}

@article {pmid38684898,
year = {2024},
author = {Madden, EB and Hindorff, LA and Bonham, VL and Akintobi, TH and Burchard, EG and Baker, KE and Begay, RL and Carpten, JD and Cox, NJ and Di Francesco, V and Dillard, DA and Fletcher, FE and Fullerton, SM and Garrison, NA and Hammack-Aviran, CM and Hiratsuka, VY and Hildreth, JEK and Horowitz, CR and Hughes Halbert, CA and Inouye, M and Jackson, A and Landry, LG and Kittles, RA and Leek, JT and Limdi, NA and Lockhart, NC and Ofili, EO and Pérez-Stable, EJ and Sabatello, M and Saulsberry, L and Schools, LE and Troyer, JL and Wilfond, BS and Wojcik, GL and Cho, JH and Lee, SS and Green, ED},
title = {Advancing genomics to improve health equity.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {38684898},
issn = {1546-1718},
abstract = {Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.},
}

@article {pmid38659968,
year = {2024},
author = {Valint, DJ and Fiedler, TL and Liu, C and Srinivasan, S and Fredricks, DN},
title = {Effect of Metronidazole on Concentrations of Vaginal Bacteria Associated with Risk of HIV Acquisition.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {38659968},
support = {R01 AI061628/AI/NIAID NIH HHS/United States ; },
abstract = {Several bacterial vaginosis (BV)-associated bacteria have been associated with elevated risk of HIV acquisition, however susceptibility of these bacteria to antibiotics is poorly understood. Vaginal samples were collected from 22 persons daily for two weeks following BV diagnosis. Metronidazole treatment was prescribed for 5-7 days. Changes in bacterial concentrations were measured with taxon-specific 16S rRNA gene quantitative PCR (qPCR) assays. A culture-based antimicrobial assay confirmed presence of antibiotics in vaginal swab samples. Bacterial DNA concentrations decreased during antibiotic administration for all thirteen bacterial taxa tested. Comparison of bacterial DNA concentrations in samples before administration of antibiotics to samples taken on the last day of antimicrobial assay-confirmed antibiotic presence showed a 2.3-4.5 log10-fold decrease across all taxa. Concentrations were frequently reduced to the qPCR assay's limit of detection, suggesting eradication of bacteria. Mean clearance time varied across taxa (1.2-8.6 days), with several bacteria (e.g., Gemella asaccharolytica, Sneathia spp., Eggerthella-like sp.) taking >7 days to suppress. Metronidazole reduces quantities of bacterial taxa associated with increased HIV acquisition risk. Eradication of high-risk vaginal bacteria using metronidazole is one promising avenue for reducing HIV acquisition risk. A 5-7-day treatment course may not be sufficient to suppress all bacteria.},
}

@article {pmid38684813,
year = {2024},
author = {Radko-Juettner, S and Yue, H and Myers, JA and Carter, RD and Robertson, AN and Mittal, P and Zhu, Z and Hansen, BS and Donovan, KA and Hunkeler, M and Rosikiewicz, W and Wu, Z and McReynolds, MG and Roy Burman, SS and Schmoker, AM and Mageed, N and Brown, SA and Mobley, RJ and Partridge, JF and Stewart, EA and Pruett-Miller, SM and Nabet, B and Peng, J and Gray, NS and Fischer, ES and Roberts, CWM},
title = {Author Correction: Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.},
journal = {Nature},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41586-024-07402-3},
pmid = {38684813},
issn = {1476-4687},
}

@article {pmid38684704,
year = {2024},
author = {King, DF and Groves, H and Weller, C and Jones, I and Cramer, JP and Gilbert, PB and Goldblatt, D and Gruber, MF and Kampmann, B and Maïga, D and Pasetti, MF and Plotkin, SA and Precioso, A and Wassie, L and Wittke, F and Kaslow, DC},
title = {Realising the potential of correlates of protection for vaccine development, licensure and use: short summary.},
journal = {NPJ vaccines},
volume = {9},
number = {1},
pages = {82},
pmid = {38684704},
issn = {2059-0105},
abstract = {On 27–29[th] of September 2022, Wellcome convened an international multi-stakeholder workshop to discuss the use of Correlates of Protection (CoP) to accelerate vaccine development, the hybrid format meeting was attended by 80 delegates including developers, manufacturers, regulators, public health officials and policy-makers from 17 countries, including 7 LMIC’s.},
}

@article {pmid38684633,
year = {2024},
author = {Greywoode, R and Larson, J and Peraza, J and Clark, R and Allison, MA and Chaudhry, NA and Schnatz, PF and Shadyab, AH and Wallace, RB and Wassertheil-Smoller, S},
title = {Risk of Adverse Cardiovascular Outcomes in Postmenopausal Women with Inflammatory Bowel Disease.},
journal = {Digestive diseases and sciences},
volume = {},
number = {},
pages = {},
pmid = {38684633},
issn = {1573-2568},
support = {UL1TR001073/TR/NCATS NIH HHS/United States ; },
abstract = {BACKGROUND: Individuals with inflammatory bowel disease (IBD) who lack traditional cardiovascular disease (CVD) risk factors, such as young females, are observed to experience adverse CVD outcomes. Whether women with IBD have increased CVD risk after the menopause transition is unclear.

METHODS: We conducted a survival analysis of Women's Health Initiative (WHI) participants and excluded those with missing IBD diagnosis, model covariate data, follow-up data, or a baseline history of the following CVD outcomes: coronary heart disease (CHD), ischemic stroke, venous thromboembolism (VTE), peripheral arterial disease (PAD). Risk of outcomes between IBD and non-IBD women was performed using Cox proportional hazard models, stratified by WHI trial and follow-up. Models were adjusted for age, socio-demographics, comorbidities (e.g., hypertension, diabetes, hypercholesterolemia, etc.), family history, and lifestyle factors (e.g., smoking, alcohol, physical activity, body mass index, etc.).

RESULTS: Of 134,022 WHI participants meeting inclusion criteria, 1367 (1.0%) reported IBD at baseline. Mean baseline age was 63.4 years. After adjusting for age and other confounders, no significant difference was observed between IBD and non-IBD women for the risk of CHD (HR 0.96, 95% CI 0.73-1.24), VTE (HR 1.11, 95% CI 0.81-1.52) or PAD (HR 0.64, 95% CI 0.28-1.42). After adjusting for age, risk of ischemic stroke was significantly higher (HR 1.41, 95% CI 1.06-1.88) in IBD than non-IBD women. With further adjustment, the excess risk of ischemic stroke among IBD women was attenuated and no longer statistically significant (HR 1.31, 95% CI 0.98-1.76).

CONCLUSIONS: Among postmenopausal women with IBD, risk of ischemic stroke may be higher than in non-IBD women.},
}