tbuckley/cabot-search huggingface dataset:
Bayesian modeling for analyzing heterogeneous response in preclinical mouse tumor models
Authors: Bairu Zhang, Lukasz Magiera, Juliana Candido, Olga Muraeva, Jane Coates Ulrichsen, Jim Eyles, Elena Galvani, Natasha A. Karp
Journal: Science Translational Medicine (2024)

In anticancer research, tumor growth measured in mouse models is important for assessing treatment efficacy for a treatment to progress to human clinical trials. Statistical analysis of time-to-event tumor volume data is complex because of heterogeneity in response and welfare-related data loss. Traditional statistical methods of testing the mean difference between groups are not robust because they assume common responses across a population. Heterogeneity in response is also seen in the clinic, and consequently, the assessment of the treatment considers the diversity through classification of the individual’s response using the RECIST (Response Evaluation Criteria in Solid Tumors). To provide a comparable and translatable assessment of in vivo tumor response, we developed a statistical method called INSPECT (IN vivo reSPonsE Classification of Tumors) for analyzing heterogeneous responses through Bayesian modeling. This method can classify individual tumor behaviors into the categories of nonresponder, modest responder, stable responder, and regressing responder. Using both published and simulated data, we show that INSPECT methodology is more accurate and sensitive than existing methods with respect to balancing false-negative and false-positive rates. A case study demonstrates the value of INSPECT in drug projects for supporting the translation of drug efficacy from the preclinical phase into clinical trials. We also provide a package, “INSPECTumours,” that launches a web interface to enable users to conduct the analysis and generate reports.
The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma
Authors: Praneeth Reddy Sudalagunta, Rafael R. Canevarolo, Mark B. Meads, Maria Silva, Xiaohong Zhao, Christopher L. Cubitt, Samer S. Sansil, Gabriel DeAvila, Raghunandan Reddy Alugubelli, Ryan T. Bishop, Alexandre Tungesvik, Qi Zhang, Oliver Hampton, Jamie K. Teer, Eric A. Welsh, Sean J. Yoder, Bijal D. Shah, Lori Hazlehurst, Robert A. Gatenby, Dane R. Van Domelen, Yi Chai, Feng Wang, Andrew DeCastro, Amanda M. Bloomer, Erin M. Siegel, Conor C. Lynch, Daniel M. Sullivan, Melissa Alsina, Taiga Nishihori, Jason Brayer, John L. Cleveland, William Dalton, Christopher J. Walker, Yosef Landesman, Rachid Baz, Ariosto S. Silva, Kenneth H. Shain
Journal: Cancer Research (2024)

Abstract Several therapeutic agents have been approved for treating multiple myeloma (MM), a cancer of bone marrow resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. Here, we present an integrated functional genomic analysis of tumor samples from MM patients that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes. This analysis revealed a MM transcriptomic topology that generates “footprints” in association with ex vivo drug sensitivity that have both predictive and mechanistic applications. Validation of the transcriptomic footprints for the anti-CD38 monoclonal antibody daratumumab and the nuclear export inhibitor selinexor demonstrated that these footprints can accurately classify clinical responses. The analysis further revealed that daratumumab and selinexor have anti-correlated mechanisms of resistance, and treatment with a selinexor-based regimen immediately after a daratumumab-containing regimen was associated with improved survival in three independent clinical trials, supporting an evolutionary-based strategy involving sequential therapy. These findings suggest that this unique repository and computational framework can be leveraged to inform underlying biology and to identify therapeutic strategies to improve treatment of MM.
Contribution of health insurance to racial and ethnic disparities in advanced stage diagnosis of 10 cancers
Authors: Parichoy Pal Choudhury, Helmneh M Sineshaw, Rachel A Freedman, Michael T Halpern, Leticia Nogueira, Ahmedin Jemal, Farhad Islami
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract For many cancer sites, it is unclear to what extent differences in health insurance coverage contribute to racial and ethnic disparities in stage III-IV diagnoses. Using the National Cancer Database (1,893,026 patients aged 18-64 years, diagnosed between 2013-2019), we investigated a potential mediating role of health insurance (privately insured vs uninsured) in explaining racial and ethnic disparities in stage at diagnosis of 10 cancers (ie, breast, prostate, colorectal, lung, cervical, uterine, bladder, head and neck, skin melanoma), detectable early through screening, physical examination, or clinical symptoms. The analyses provided evidence of mediation of non-Hispanic Black vs White disparities in eight cancers (range of proportions mediated: 4.5%-29.1%); Hispanic vs non-Hispanic White disparities in six cancers (13.2%-68.8%); non-Hispanic Asian/Pacific Islander vs White disparities in three cancers (5.8%-11.3%). To summarize, health insurance accounts for a significant proportion of the racial and ethnic disparities in stage III-IV diagnoses across a wide range of cancers.
Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis
Authors: Edward D. Esplin, Casey Hanson, Si Wu, Aaron M. Horning, Nasim Barapour, Stephanie A. Nevins, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K. Guha, Zheng Hu, Rozelle Laquindanum, Meredith A. Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Joanne Chan, Mathew Ellenberger, Winston R. Becker, Bahareh Bahmani, Aziz Khan, Basil Michael, Annika K. Weimer, D. Glen Esplin, Jeanne Shen, Samuel Lancaster, Emma Monte, Thomas V. Karathanos, Uri Ladabaum, Teri A. Longacre, Anshul Kundaje, Christina Curtis, William J. Greenleaf, James M. Ford, Michael P. Snyder
Journal: Nature Cancer (2024)

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis.
Global loss of promoter–enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis
Authors: Yizhou Zhu, Hayan Lee, Shannon White, Annika K. Weimer, Emma Monte, Aaron Horning, Stephanie A. Nevins, Edward D. Esplin, Kristina Paul, Gat Krieger, Zohar Shipony, Roxanne Chiu, Rozelle Laquindanum, Thomas V. Karathanos, Melissa W. Y. Chua, Meredith Mills, Uri Ladabaum, Teri Longacre, Jeanne Shen, Ariel Jaimovich, Doron Lipson, Anshul Kundaje, William J. Greenleaf, Christina Curtis, James M. Ford, Michael P. Snyder
Journal: Nature Cancer (2024)

Abstract Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter–enhancer (P–E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P–E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.
Differential chromatin accessibility and transcriptional dynamics define breast cancer subtypes and their lineages
Authors: Michael D. Iglesia, Reyka G. Jayasinghe, Siqi Chen, Nadezhda V. Terekhanova, John M. Herndon, Erik Storrs, Alla Karpova, Daniel Cui Zhou, Nataly Naser Al Deen, Andrew T. Shinkle, Rita Jui-Hsien Lu, Wagma Caravan, Andrew Houston, Yanyan Zhao, Kazuhito Sato, Preet Lal, Cherease Street, Fernanda Martins Rodrigues, Austin N. Southard-Smith, André Luiz N. Targino da Costa, Houxiang Zhu, Chia-Kuei Mo, Lisa Crowson, Robert S. Fulton, Matthew A. Wyczalkowski, Catrina C. Fronick, Lucinda A. Fulton, Hua Sun, Sherri R. Davies, Elizabeth L. Appelbaum, Sara E. Chasnoff, Madelyn Carmody, Candace Brooks, Ruiyang Liu, Michael C. Wendl, Clara Oh, Diane Bender, Carlos Cruchaga, Oscar Harari, Andrea Bredemeyer, Kory Lavine, Ron Bose, Julie Margenthaler, Jason M. Held, Samuel Achilefu, Foluso Ademuyiwa, Rebecca Aft, Cynthia Ma, Graham A. Colditz, Tao Ju, Stephen T. Oh, James Fitzpatrick, E. Shelley Hwang, Kooresh I. Shoghi, Milan G. Chheda, Deborah J. Veis, Feng Chen, Ryan C. Fields, William E. Gillanders, Li Ding
Journal: Nature Cancer (2024)

Abstract Breast cancer (BC) is defined by distinct molecular subtypes with different cells of origin. The transcriptional networks that characterize the subtype-specific tumor-normal lineages are not established. In this work, we applied bulk, single-cell and single-nucleus multi-omic techniques as well as spatial transcriptomics and multiplex imaging on 61 samples from 37 patients with BC to show characteristic links in gene expression and chromatin accessibility between BC subtypes and their putative cells of origin. Regulatory network analysis of transcription factors underscored the importance of BHLHE40 in luminal BC and luminal mature cells and KLF5 in basal-like tumors and luminal progenitor cells. Furthermore, we identify key genes defining the basal-like ( SOX6 and KCNQ3 ) and luminal A/B ( FAM155A and LRP1B ) lineages. Exhausted CTLA4-expressing CD8 + T cells were enriched in basal-like BC, suggesting an altered means of immune dysfunction. These findings demonstrate analysis of paired transcription and chromatin accessibility at the single-cell level is a powerful tool for investigating cancer lineage and highlight transcriptional networks that define basal and luminal BC lineages.
Words Matter: Reflective Science Communication and Tradeoffs in Environmental Health Research
Authors: Kevin C. Elliott, Heather B. Patisaul, Robert M. Sargis, Laura N. Vandenberg
Journal: Environmental Health Perspectives (2024)

Scientists who communicate societally relevant information face challenging contexts in which misinformation, disinformation, hype, and spin are prevalent. As a result, they often face difficult decisions about how to frame their work in a socially responsible manner.
Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARα signaling in renal tubular epithelial cells
Authors: Hongyu Li, Yuying Ouyang, Haoran Lv, Hanzhi Liang, Siweier Luo, Yating Zhang, Haiping Mao, Tianfeng Chen, Wei Chen, Yiming Zhou, Qinghua Liu
Journal: Biomaterials (2024)

Klotho is an anti-aging protein produced primarily by tubular epithelial cells (TECs). Down-regulated expression of Klotho in injured TECs plays a key pathogenic role in promoting acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet therapeutic approaches targeting the restoration of renal Klotho levels remain challenging for clinical application. Here, we synthesize polydopamine-polyethylenimine-l-serine-Klotho plasmid nanoparticles (PPSK NPs), which can safely and selectively deliver the Klotho gene to the injured TECs through binding kidney injury molecule-1 and maintain the expression of Klotho protein. In vitro, PPSK NPs effectively reduce the hypoxia-reoxygenation-induced reactive oxygen species production and fibrotic gene expression. In the unilateral ischemia-reperfusion injury- and folic acid-induced AKI-CKD transition mouse models, a single low-dose injection of PPSK NPs is sufficient to preserve the normal kidney architecture and prevent renal fibrosis. Mechanismly, the protective effect of PPSK NPs relies on upregulating a key molecule peroxisome proliferator-activated receptor alpha (PPARα) via the inhibition of p38 and JNK phosphorylation, which in turn improves tubular fatty acid beta-oxidation and reduces renal lipid accumulation, thereby protecting against kidney fibrosis. In conclusion, our results highlight the translational potential of nanoparticle-based Klotho gene therapy in preventing the AKI-CKD transition.
A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features
Authors: Johanna Klughammer, Daniel L. Abravanel, Åsa Segerstolpe, Timothy R. Blosser, Yury Goltsev, Yi Cui, Daniel R. Goodwin, Anubhav Sinha, Orr Ashenberg, Michal Slyper, Sébastien Vigneau, Judit Jané‐Valbuena, Shahar Alon, Chiara Caraccio, Judy Chen, Ofir Cohen, Nicole Cullen, Laura K. DelloStritto, Danielle Dionne, Janet Files, Allison Frangieh, Karla Helvie, Melissa E. Hughes, Stephanie Inga, Abhay Kanodia, Ana Lako, Colin MacKichan, Simon Mages, Noa Moriel, Evan Murray, Sara Napolitano, Kyleen Nguyen, Mor Nitzan, Rebecca Ortiz, Miraj Patel, Kathleen L. Pfaff, Caroline B. M. Porter, Asaf Rotem, Sarah Strauss, Robert Strasser, Aaron R. Thorner, Madison Turner, Isaac Wakiro, Julia Waldman, Jingyi Wu, Jorge Gómez Tejeda Zañudo, Diane Zhang, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Edward S. Boyden, Fei Chen, Garry P. Nolan, Scott J. Rodig, Xiaowei Zhuang, Orit Rozenblatt-Rosen, Bruce E. Johnson, Aviv Regev, Nikhil Wagle
Journal: Nature Medicine (2024)

Abstract Although metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&amp;E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps.
Correction: Precursor central memory versus effector cell fate and naïve CD4+ T cell heterogeneity
Authors: Deeksha Deep, Herman Gudjonson, Chrysothemis C. Brown, Samuel A. Rose, Roshan Sharma, Yoselin A. Paucar Iza, Seunghee Hong, Saskia Hemmers, Michail Schizas, Zhong-Min Wang, Yuezhou Chen, Duane R. Wesemann, Virginia Pascual, Dana Pe’er, Alexander Y. Rudensky
Journal: The Journal of Experimental Medicine (2024)
Vascular occlusion for optimising the functional improvement in patients with knee osteoarthritis: a randomised controlled trial
Authors: Ewoud Jacobs, Lenka Stroobant, Jan Victor, Dirk Elewaut, Thomas Tampere, Steven Wallaert, Erik Witvrouw, Joke Schuermans, Evi Wezenbeek
Journal: Annals of the Rheumatic Diseases (2024)

Knee osteoarthritis (KOA) is a leading cause of global disability with conventional exercise yielding only modest improvements. Here we aimed to investigate the benefits of integrating blood flow restriction (BFR) into traditional exercise programmes to enhance treatment outcomes. The Vascular Occlusion for optimizing the Functional Improvement in patients with Knee Osteoarthritis randomised controlled trial enrolled 120 patients with KOA at Ghent University Hospital, randomly assigning them to either a traditional exercise programme or a BFR-enhanced programme over 24 sessions in 12 weeks. Assessments were conducted at baseline, 6 weeks, 12 weeks and 3 months postintervention using linear mixed models with Dunn-Sidak corrections for multiple comparisons. Primary outcome was the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire at 3 months follow-up with knee strength, Pain Catastrophizing Scale questionnaire and functional tests as secondary outcomes. Analysis followed an intention-to-treat approach (NCT04996680). The BFR group showed greater improvements in KOOS pain subscale (effect size (ES)=0.58; p=0.0009), quadriceps strength (ES=0.81; p<0.0001) and functional tests compared with the control group at 12 weeks. At 3 months follow-up, the BFR group continued to exhibit superior improvements in KOOS pain (ES=0.55; p=0.0008), symptoms (ES=0.59; p=0.0004) and quality of life (QoL) (ES=0.66; p=0.0001) with sustained benefits in secondary outcomes. Drop-out rates were similar in both groups. Incorporating BFR into traditional exercise programmes significantly enhances short-term and long-term outcomes for patients with KOA demonstrating persistent improvements in pain, symptoms, QoL and functional measures compared with conventional exercise alone. These findings suggest that BFR can provide the metabolic stimulus needed to achieve muscle strength and functional gains with lower mechanical loads. Reduced pain and increased strength support a more active lifestyle, potentially maintaining muscle mass, functionality and QoL even beyond the supervised intervention period. NCT04996680.
Comments on “Predictors of persistent pain after extracorporeal shockwave lithotripsy for painful chronic calcific pancreatitis”
Authors: Jiankun Wang, Li Liu, Zhining Fan
Journal: Endoscopy (2024)

Letter to: Predictors of persistent pain after extracorporeal shockwave lithotripsy for painful chronic calcific pancreatitisEndoscopy 2024; 56(06): 406-411DOI: 10.1055/a-2252-9920
Reply to Saito et al.
Authors: David M. de Jong, Rogier P. Voermans, Pieter Jan F. de Jonge
Journal: Endoscopy (2024)

Letter to: Who benefits from long-term plastic stents after walled-off necrosis treatment: prix fixe for all or à la carte?Endoscopy 2024; 56(11): 889-890DOI: 10.1055/a-2343-5778
Effect of apremilast on hand and whole-body MRI assessments of inflammation in patients with psoriatic arthritis (MOSAIC): a phase 4, multicentre, single-arm, open-label study
Authors: Mikkel Østergaard, Mikael Boesen, Walter P Maksymowych, Robert G Lambert, Michael R Bubb, Olga Kubassova, Guillermo Valenzuela, Jyotsna Reddy, Stephen Colgan, Yuri Klyachkin, Cynthia Deignan, Zhenwei Zhou, Hamid Amouzadeh, Philip J Mease
Journal: The Lancet Rheumatology (2024)
GPRASP protein deficiency triggers lymphoproliferative disease by affecting B‐cell differentiation
Authors: Antonio Morales‐Hernández, Emilia Kooienga, Heather Sheppard, Gabriela Gheorghe, Claire Caprio, Ashley Chabot, Shannon McKinney‐Freeman
Journal: HemaSphere (2024)

Abstract Gprasp1 and Gprasp2 encode proteins that control the stability and cellular trafficking of CXCR4, a master regulator of hematopoiesis whose dynamic regulation is required for appropriate trafficking of B‐cells in the germinal center (GC). Here, we report that Gprasp1 and Gprasp2 ‐deficient B‐cells accumulate in the GC and show transcriptional abnormalities, affecting the mechanisms controlling Aicda expression and exposing them to excessive somatic hypermutation. Consequently, about 30% of mice transplanted with Gprasp ‐deficient hematopoietic stem and progenitor cells developed a biologically aggressive and fatal B‐cell hyperproliferative disease by 20–50 weeks posttransplant. Histological and molecular profiling reveal that Gprasp1‐ and Gprasp2‐ deficient neoplasms morphologically resemble human high‐grade B‐cell lymphomas of germinal center origin with shared morphologic features of both Burkitt Lymphoma (BL) and diffuse large B‐cell lymphoma (DLBCL), and molecular features consistent with DLBCL, as well as elevated mutational burden and heterogenous transcriptional and mutational signature. Thus, reduced Gprasp1 and Gprasp2 gene expression perturbs B‐cell maturation and increases the risk of B‐cell neoplasms of germinal center origin. As this model recapitulates the essential features of the heterogenous group of human hematopoietic malignancies, it could be a powerful tool to interrogate the mechanisms of lymphomagenesis for these cancers.
Artificial intelligence-enabled reconstruction of the right ventricular pressure curve using the peak pressure value: a proof-of-concept study
Authors: Ádám Szijártó, Alina Nicoara, Mihai Podgoreanu, Márton Tokodi, Alexandra Fábián, Béla Merkely, András Sárkány, Zoltán Tősér, Sergio Caravita, Claudia Baratto, Michele Tomaselli, Denisa Muraru, Luigi Paolo Badano, Bálint Lakatos, Attila Kovács
Journal:  (2024)

Conventional echocardiographic parameters of right ventricular (RV) function are afterload-dependent. Therefore, incorporating RV pressures may enable the formulation of new parameters that reflect intrinsic RV function accurately. Accordingly, we sought to develop an artificial intelligence-based method to reconstruct the RV pressure curve based on the peak RV pressure. We invasively acquired RV pressure in 29 heart failure patients before and after implanting a left ventricular (LV) assist device. Using these tracings, we trained various machine learning models to reconstruct the RV pressure curve of the entire cardiac cycle based on the peak value of the curve. The best-performing model was compared with two other methods that estimated RV pressures based on a reference LV and RV pressure curve, respectively. Seventeen consecutive patients from another centre who underwent right heart catheterization and simultaneous echocardiography served as an external validation cohort. Among the evaluated algorithms, multilayer perceptron (MLP) achieved the best performance with an R 2 of 0.887 (0.834-0.941). The RV and LV reference curve-based methods achieved R 2 values of 0.879 (0.815-0.943) and 0.636 (0.500-0.771), respectively. During external validation, MLP exhibited similarly good performance [R 2 0.911 (0.873-0.948)], which decreased only modestly if the echocardiography-derived peak RV pressure was used instead of the invasively measured peak RV pressure [R 2 0.802 (0.694-0.909)]. The proposed method enables the reconstruction of the RV pressure curve using only the peak value as input. Thus, it may serve as a fundamental component for developing new echocardiographic tools targeting the afterload-adjusted assessment of RV function.