tbuckley/cabot-search huggingface dataset:
Disparities in relapsed or refractory multiple myeloma: recommendations from an interprofessional consensus panel
Authors: Rahul Banerjee, Yelak Biru, Craig E. Cole, Beth Faiman, Shonali Midha, Sikander Ailawadhi
Journal: Blood Cancer Journal (2024)

Many studies have documented racial, socioeconomic, geographic, and other disparities for United States (US) patients with multiple myeloma pertaining to diagnosis and frontline management. In contrast, very little is known about disparities in the management of relapsed/refractory multiple myeloma (RRMM) despite a plethora of novel treatment options. In this review, we discuss the manifestations of disparities in RRMM and strategies to mitigate their impact. Immunomodulatory drugs can create disparities on many axes, for example inappropriately low dosing due to Duffy-null status as well as time toxicity and financial toxicity from logistical hurdles for socioeconomically vulnerable patients. Access to myeloma expertise at high-volume centers is a critical consideration given the disconnect between how drugs like carfilzomib and dexamethasone are prescribed in trials versus optimized in real-world practice to lower toxicities. Disparities in chimeric antigen receptor T-cell therapy and bispecific antibody therapy span across racial, ethnic, and socioeconomic lines in large part due to their limited availability outside of high-volume centers. Another insidious source of disparities is supportive care in RRMM, ranging from inadequate pain control in Black patients to limited primary care provider access in rural settings. We discuss the rationales and evidence base for several solutions aimed at mitigating these disparities: for example, (1) bidirectional co-management with community-based oncologists, (2) screening for risk factors based on social determinants of health, (3) strategies to build patient trust with regard to clinical trials, and (4) longitudinal access to a primary care provider. As the treatment landscape for RRMM continues to expand, these types of efforts by the field will help ensure that this landscape is equally accessible and traversable for all US patients.
Regional Heterogeneity of the Results of Glucagon-Like Peptide 1 Receptor Agonist Trials in Type 2 Diabetes: A Reanalysis of Individual Participant Data
Authors: Ariane Jullien, Clément Jambon-Barbara, Jean-Luc Cracowski, Brian L. Claggett, Anne-Laure Borel, Charles Khouri, Matthieu Roustit
Journal: Diabetes Care (2024)

OBJECTIVE Multiregional trials are designed under the assumption that treatment effect applies to the entire target population, yet several factors may introduce geographic heterogeneity in treatment effect. We explored whether such variations exist in trials assessing the efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in major cardiovascular events (MACE) in type 2 diabetes. RESEARCH DESIGN AND METHODS A systematic search of Medline and the Cochrane Library was conducted from inception until 30 June 2020. We included international randomized controlled trials comparing any GLP-1RA versus placebo, with MACE as a primary end point. Individual participant data were subsequently requested from the sponsor or through data sharing platforms. For each trial, we calculated hazard ratios (HRs) and their 95% CIs for MACE, subgrouped by region. We then performed a random-effects meta-analysis and conducted meta-regressions to assess the influence of predetermined variables of interest on treatment effect. RESULTS We included six trials including 45,426 patients. Baseline risk of MACE ranged from 2.9 per 100 patient-years in Southern Asia to 7.4 per 100 patient-years in Sub-Saharan Africa. HRs for MACE ranged between 0.25 (95% CI 0.05, 1.12) in Northern Africa to 0.98 (0.79, 1.22) in Western Europe. There was no significant subgroup difference across regions (P = 0.70). Baseline risk of MACE and indexes of development status (i.e., Human Development Index, gross domestic product) were independently associated with GLP-1RA efficacy. CONCLUSIONS This study does not suggest any regional heterogeneity of GLP-1RA efficacy in MACE. However, a higher baseline risk and lower development status were associated with a greater benefit of these drugs.
YAP1 regulates thrombopoiesis by binding to MYH9 in immune thrombocytopenia
Authors: Shuhong Hu, Yifei Liu, Xiang Zhang, Xiaoqi Wang, Yanting Li, Mengqian Chu, Jie Yin, Yanglan Fang, Changgeng Ruan, Li Zhu, Depei Wu, Yang Xu
Journal: Blood (2024)
Antimetabolite Dose Intensity and Adverse Outcomes in Children with Acute Lymphoblastic Leukemia: A COG-AALL03N1 Report
Authors: Aman Wadhwa, Yanjun Chen, Lindsey Hageman, Anne Angiolillo, David S. Dickens, Joseph P. Neglia, Yaddanapudi Ravindranath, Amanda Termuhlen, F. Lennie Wong, Wendy Landier, Smita Bhatia
Journal: Blood (2024)
Genetic Engineering of Transfusable Platelets with mRNA-Lipid Nanoparticles is Compatible with Blood Banking Practices
Authors: Colton Strong, Jerry Leung, Emma Kang, Katherine E. Badior, Madelaine Robertson, Nicolas Pereyra, Elyn M. Rowe, Amanda Wietrzny, Brenda Ma, Zechariah Noronha, Deaglan Arnold, Marco A. Ciufolini, Dana V. Devine, Eric Jan, Pieter R. Cullis, Christian J. Kastrup
Journal: Blood (2024)
Quantifying variant contributions in cystic kidney disease using national-scale whole genome sequencing
Authors: Omid Sadeghi-Alavijeh, Melanie M.Y. Chan, Gabriel T. Doctor, Catalin D. Voinescu, Alexander Stuckey, Athanasios Kousathanas, Alexander T. Ho, Horia C. Stanescu, Detlef Bockenhauer, Richard N. Sandford, Adam P. Levine, Daniel P. Gale
Journal: Journal of Clinical Investigation (2024)

BACKGROUNDCystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases.METHODSUsing whole-genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies.RESULTSIn 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with statistically significant gene-based signals in COL4A3 and (monoallelic) PKHD1. Quantification of disease risk for each gene (with replication in the separate UK Biobank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations, but suggested this category of variation contributes 3%-9% to the heritability of CyKD across European ancestries.CONCLUSIONBy providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counseling in the clinic.
Spatiotemporal transcriptomic mapping of regenerative inflammation in skeletal muscle reveals a dynamic multilayered tissue architecture
Authors: Andreas Patsalos, Laszlo Halasz, Darby Oleksak, Xiaoyan Wei, Gergely Nagy, Petros Tzerpos, Thomas Conrad, David W. Hammers, H. Lee Sweeney, Laszlo Nagy
Journal: Journal of Clinical Investigation (2024)

Tissue regeneration is orchestrated by macrophages that clear damaged cells and promote regenerative inflammation. How macrophages spatially adapt and diversify their functions to support the architectural requirements of actively regenerating tissue remains unknown. In this study, we reconstructed the dynamic trajectories of myeloid cells isolated from acutely injured and early-stage dystrophic muscles. We identified divergent subsets of monocytes/macrophages and dendritic cells (DCs) and validated markers (e.g., GPNMB) and transcriptional regulators associated with defined functional states. In dystrophic muscle, specialized repair-associated subsets exhibited distinct macrophage diversity and reduced DC heterogeneity. Integrating spatial transcriptomics analyses with immunofluorescence uncovered the ordered distribution of subpopulations and multilayered regenerative inflammation zones (RIZs) where distinct macrophage subsets are organized in functional zones around damaged myofibers supporting all phases of regeneration. Importantly, intermittent glucocorticoid treatment disrupted the RIZs. Our findings suggest that macrophage subtypes mediated the development of the highly ordered architecture of regenerative tissues, unveiling the principles of the structured yet dynamic nature of regenerative inflammation supporting effective tissue repair.
Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma
Authors: Baoyan Bai, Jillian F. Wise, Daniel Vodák, Sigve Nakken, Ankush Sharma, Yngvild Nuvin Blaker, Marianne Brodtkorb, Vera Hilden, Gunhild Trøen, Weicheng Ren, Susanne Lorenz, Michael S. Lawrence, Ola Myklebost, Eva Kimby, Qiang Pan-Hammarström, Chloé B. Steen, Leonardo A. Meza-Zepeda, Klaus Beiske, Erlend B. Smeland, Eivind Hovig, Ole Christian Lingjærde, Harald Holte, June Helen Myklebust
Journal: Blood Cancer Journal (2024)

Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL.
Longitudinal assessment of established risk stratification models in patients with monoclonal gammopathy of undetermined significance
Authors: Kosima Zuern, Thomas Hielscher, Annika Werly, Iris Breitkreutz, Sandra Sauer, Marc S. Raab, Carsten Müller-Tidow, Hartmut Goldschmidt, Elias K. Mai
Journal: Blood Cancer Journal (2024)

Abstract Risk of progression of monoclonal gammopathy of undetermined significance (MGUS) into multiple myeloma and related plasma cell disorders can be determined by three major risk stratification models, namely Mayo2005, Sweden2014, and NCI2019. This retrospective study of 427 patients with MGUS diagnosed according to the 2014 International Myeloma Working Group criteria aimed to describe and analyze the longitudinal applicability of these risk models. In all three models, the majority of patients remained at their baseline risk group, whereas small numbers of patients migrated to a different risk group. Proportions of patients among risk groups remained stable over time (e.g. Mayo2005 model, low-risk group, at baseline: 43%, after 1, 2, 3, 4, 5, and 8 years: 40%, 37%, 37%, 43%, 44%, and 43%). All three risk models reliably distinguished risk of progression at baseline, upon yearly reassessment (e.g. 1 year from diagnosis) and in time-dependent analyses. Upstaging to a high-risk category was associated with an increased risk of progression in all three models (Mayo2005: hazard ratio [HR] = 5.43, 95% confidence interval [95% CI] 1.21–24.39, p = 0.027; Sweden2014: HR = 13.02, 95% CI 5.25–32.28, p &lt; 0.001; NCI2019: HR = 5.85, 95% CI 2.49–13.74, p &lt; 0.001). Our study shows that MGUS risk stratification models can be applied longitudinally to repeatedly determine and improve individual risk of progression. Patient migration to higher risk categories during follow up should prompt more frequent monitoring in clinical routine.
Immunologic signatures of response and resistance to nivolumab with ipilimumab in advanced metastatic cancer
Authors: Apostolia M. Tsimberidou, Farah A. Alayli, Kwame Okrah, Alexandra Drakaki, Danny N. Khalil, Shivaani Kummar, Saad A. Khan, F. Stephen Hodi, David Y. Oh, Christopher R. Cabanski, Shikha Gautam, Stefanie L. Meier, Meelad Amouzgar, Shannon M. Pfeiffer, Robin Kageyama, EnJun Yang, Marko Spasic, Michael T. Tetzlaff, Wai Chin Foo, Travis J. Hollmann, Yanyun Li, Matthew Adamow, Phillip Wong, Jonni S. Moore, Sharlene Velichko, Richard O. Chen, Dinesh Kumar, Samantha Bucktrout, Ramy Ibrahim, Ute Dugan, Lisa Salvador, Vanessa M. Hubbard-Lucey, Jill O’Donnell-Tormey, Sandra Santulli-Marotto, Lisa H. Butterfield, Diane M. Da Silva, Justin Fairchild, Theresa M. LaVallee, Lacey J. Padrón, Padmanee Sharma
Journal: The Journal of Experimental Medicine (2024)

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 &amp;lt;15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8–35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1–43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8–51.4) of patients converted from CD8 &amp;lt;15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.
5-α Reductase Inhibitors and Prostate Cancer Mortality
Authors: Robert J. Hamilton, Julian Chavarriaga, Najia Khurram, Cindy Lau, Jin Luo, Ning Liu, Maria Komisarenko, Girish Kulkarni, Christopher Wallis, David N. Juurlink, Neil Fleshner, Antonio Finelli
Journal: JAMA Network Open (2024)

Importance 5-alpha-reductase-inhibitors (5-ARIs) are approved for treating benign prostatic hyperplasia (BPH) and have been found to reduce prostate cancer (PCa) risk by 25%. However, trials also have shown 5-ARIs to be associated with high-grade PCa. Whether 5-ARIs increase mortality among those with a diagnosis of PCa remains unclear. Objective To determine long-term outcomes of clinically localized PCa arising in individuals taking 5-ARIs compared with nonusers. Design, Setting, and Participants This population-based cohort study was conducted between January 2003 and October 2017. Eligible participants were men aged 65 years or older in Ontario, Canada, who developed clinically localized PCa with complete pathological abstraction from the Ontario Health Administrative Databases. Data analysis occurred from November 2017 to November 2022. Exposure 5-ARIs before PCa diagnosis. Main Outcomes and Measures The primary outcomes were overall mortality and PCa-specific mortality. Cause-specific hazard models with inverse probability treatment weights (IPTW) were used to examine associations of 5-ARI use with mortality outcomes. Sensitivity analyses based on prediagnostic 5-ARI use, Gleason score, comorbidity, 5-ARI indication, prostate-specific antigen modeling, and statin use were also performed. Results The cohort included 19 938 patients with PCa. Of these, 2112 (10.6%; median [IQR] age, 74 [70-79] years) were 5-ARI users and 17 826 (89.4%; median [IQR] age, 71 [68-76] years) were nonusers. During a median (IQR) follow-up of 8.96 (6.28-12.17) years, 6053 (30.4%) died, including 1047 (5.3%) from PCa. 5-ARI use appeared to be associated with increased overall and PCa specific mortality in crude analyses; however, after IPTW, 5-ARI use was not associated with overall mortality (hazard ratio, 0.98; 95% CI, 0.90-1.07; P = .77) or PCa-specific mortality (hazard ratio, 1.02; 95% CI, 0.83-1.25; P = .84). Conclusions and Relevance In this population-based cohort study of 5-ARI use prior to PCa diagnosis including long-term follow-up and clinicopathologic details, prediagnostic 5-ARI use was not associated with PCa-specific or all-cause mortality. This study offers reassuring safety data for patients using 5-ARIs before PCa diagnosis for both BPH and chemopreventive reasons.
Integrative multi-omics characterization of hepatocellular carcinoma in hispanic patients
Authors: Debodipta Das, Xiaojing Wang, Yu-Chiao Chiu, Hakim Bouamar, Francis E Sharkey, Jorge E Lopera, Zhao Lai, Susan T Weintraub, Xianlin Han, Yi Zou, Hung-I H Chen, Carla R Zeballos Torrez, Xiang Gu, Matyas Cserhati, Joel E Michalek, Glenn A Halff, Yidong Chen, Siyuan Zheng, Francisco G Cigarroa, Lu-Zhe Sun
Journal: JNCI Journal of the National Cancer Institute (2024)

The incidence and mortality rates of hepatocellular carcinoma among Hispanic individuals in the United States are much higher than in non-Hispanic White people. We conducted multi-omics analyses to elucidate molecular alterations in hepatocellular carcinoma among Hispanic patients.
Contribution of homoeologous exchange to domestication of polyploid Brassica
Authors: Tianpeng Wang, Aalt D. J. van Dijk, Ranze Zhao, Guusje Bonnema, Xiaowu Wang
Journal: Genome biology (2024)

Polyploidy is widely recognized as a significant evolutionary force in the plant kingdom, contributing to the diversification of plants. One of the notable features of allopolyploidy is the occurrence of homoeologous exchange (HE) events between the subgenomes, causing changes in genomic composition, gene expression, and phenotypic variations. However, the role of HE in plant adaptation and domestication remains unclear. Here we analyze the whole-genome resequencing data from Brassica napus accessions representing the different morphotypes and ecotypes, to investigate the role of HE in domestication. Our findings demonstrate frequent occurrence of HEs in Brassica napus, with substantial HE patterns shared across populations, indicating their potential role in promoting crop domestication. HE events are asymmetric, with the A genome more frequently replacing C genome segments. These events show a preference for specific genomic regions and vary among populations. We also identify candidate genes in HE regions specific to certain populations, which likely contribute to flowering-time diversification across diverse morphotypes and ecotypes. In addition, we assemble a new genome of a swede accession, confirming the HE signals on the genome and their potential involvement in root tuber development. By analyzing HE in another allopolyploid species, Brassica juncea, we characterize a potential broader role of HE in allopolyploid crop domestication. Our results provide novel insights into the domestication of polyploid Brassica species and highlight homoeologous exchange as a crucial mechanism for generating variations that are selected for crop improvement in polyploid species.
Errors in Figure Labels
Journal: JAMA Network Open (2024)

Aging and Racialized, Economic, and Environmental Injustice: NIMHD Social Epigenomics Program," 1 published July 29, 2024, there were errors introduced in the production process in the x-axis labels and data column headings in Figures 1 through 4. Instead of "OR (95% CI)," the x-axis labels should have been "Standardized effect estimate" and the data column headings should have been "Standardized effect estimate (95% CI)."In addition, the first sentence of all figure captions should be replaced with "Whiskers indicate 95%CIs."This article has been corrected.
Pediatric cancer screening in hereditary gastrointestinal cancer risk syndromes: An update from the AACR Childhood Cancer Predisposition Working Group
Authors: Suzanne P. MacFarland, Kerri Becktell, Kami Wolfe Schneider, Roland P. Kuiper, Harry Lesmana, Julia Meade, Kim E. Nichols, Christopher C. Porter, Sharon A. Savage, Kris Ann Schultz, Hamish Scott, Lisa States, Uri Tabori, Chieko Tamura, Gail Tomlinson, Kristin Zelley, Carol Durno, Andrew Bauer, Sharon E. Plon
Journal: Clinical Cancer Research (2024)

Gastrointestinal (GI) polyposis and cancer in pediatric patients is frequently due to an underlying hereditary cancer risk syndrome requiring ongoing cancer screening. Identification of at-risk patients through family history, clinical features of a syndrome, or symptom onset ensures appropriate cancer risk assessment and management in childhood and beyond. In this 2024 perspective, we outline updates to the hereditary GI cancer screening guidelines first published by the American Association of Cancer Research Pediatric Cancer Predisposition Workshop in 2017. These guidelines consider existing recommendations by pediatric and adult gastroenterology consortia to ensure alignment with gastroenterology practices in managing polyposis conditions. We specifically address the recommendations for pediatric screening in familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Further, we emphasize the importance of multidisciplinary care and partnership with gastroenterology, as it is crucial in management of children and families with these conditions.