tbuckley/cabot-search huggingface dataset:
Clinical and genomic features of classical and basal transcriptional subtypes in pancreatic cancer
Authors: Harshabad Singh, Joanne Xiu, Kevin S. Kapner, Chen Yuan, Raja R. Narayan, Matthew Oberley, Alex Farrell, Rishi Surana, Brandon M. Huffman, Kimberly Perez, James M. Cleary, Alexander C. Jordan, Andressa Dias Costa, Hannah L. Williams, Srivatsan Raghavan, Benjamin Weinberg, Michael J. Pishvaian, Rachna Shroff, Sanjay Goel, Stephanie K. Dougan, Jonathan A. Nowak, David Spetzler, George Sledge, Brian M. Wolpin, Andrew J. Aguirre
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype. Experimental Design: We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences. Classical and basal subtypes were identified using purity independent subtyping algorithm on RNA sequencing, and two cohorts were analyzed: (i) the biomarker cohort included patients with complete molecular profiling data (n = 7,250) and (ii) the outcome cohort included patients with metastatic disease with available survival outcomes (n = 5,335). A total of 3,842 patients were shared between the two cohorts. Kaplan–Meier curves and Cox proportional hazards regression were used to assess patient survival. Results: In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC) and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy sites. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial-mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcome cohort, the SB subtype was associated with shorter overall survival time, regardless of whether they received FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line chemotherapy. The mutant KRAS allele type was prognostic of outcomes; however, this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors. Conclusions: The SB subtype is a strong independent predictor of worse outcomes, regardless of the up-front chemotherapy regimen used. Clinical trials should further investigate pancreatic cancer transcriptional subtypes as a prognostic and predictive biomarker.
NeuroCARE: A Randomized Controlled Trial of a Psychological Intervention for Caregivers of Patients With Primary Malignant Brain Tumors
Authors: Deborah A. Forst, Alyx F. Podgurski, Sumita M. Strander, Jessica D. Whitman, Shibani Datta, Kedie Pintro, Nora K. Horick, Kelcie D. Willis, Timothy S. Sannes, Joseph A. Greer, Areej El-Jawahri, Jamie M. Jacobs, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2024)

PURPOSE Caregivers of patients with primary malignant brain tumors (PMBT) experience significant psychological distress. We assessed the effect of a psychological intervention (NeuroCARE) on anxiety symptoms among PMBT caregivers. METHODS We conducted a randomized trial of NeuroCARE versus usual care in PMBT caregivers with elevated anxiety (Generalized Anxiety Disorder-7 score ≥5) within 6 months of the patient's diagnosis. NeuroCARE was developed for PMBT caregivers and consists of six telehealth sessions with a behavioral health specialist. Participants completed surveys at baseline, 11-week (postintervention), and 16-week (1-month postintervention) time points. The primary outcome was 11-week anxiety symptoms (Hospital Anxiety and Depression Scale [HADS]-Anxiety Subscale). We also measured depression symptoms (HADS-Depression Subscale), quality of life (QOL; Caregiver QOL survey), caregiver burden (Caregiver Reaction Assessment), self-efficacy (Lewis Cancer Self-Efficacy Scale), coping (Measure of Current Status), and post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist for DSM-5). We conducted analysis of covariance and linear mixed-effects regression analyses to examine intervention effects on study outcomes. RESULTS We enrolled 120 caregivers (60/group) between October 2019 and June 2022; 105 were evaluable for the primary outcome. At 11 weeks, NeuroCARE participants reported significantly lower anxiety symptoms than usual care participants ( M, 8.87 v 10.69; P = .008). NeuroCARE caregivers also reported significantly lower depression symptoms ( M, 6.08 v 7.77; P = .004), and better self-efficacy ( M, 128.81 v 111.17; P &lt; .001) and coping ( M, 32.25 v 25.65; P &lt; .001) at 11 weeks. Study groups did not differ significantly in 11-week QOL, caregiver burden, or PTSD symptoms. In longitudinal analyses, intervention effects on depression symptoms, self-efficacy, and coping were sustained. CONCLUSION A novel, population-specific psychological intervention led to improved anxiety and depression symptoms, self-efficacy, and coping among PMBT caregivers.
Single or Double Induction With 7 + 3 Containing Standard or High-Dose Daunorubicin for Newly Diagnosed AML: The Randomized DaunoDouble Trial by the Study Alliance Leukemia
Authors: Christoph Röllig, Björn Steffen, Christoph Schliemann, Jan-Henrik Mikesch, Nael Alakel, Regina Herbst, Mathias Hänel, Richard Noppeney, Maher Hanoun, Martin Kaufmann, Barbora Weinbergerova, Kerstin Schäfer-Eckart, Tim Sauer, Andreas Neubauer, Andreas Burchert, Claudia D. Baldus, Jolana Mertová, Edgar Jost, Dirk Niemann, Jan Novák, Stefan W. Krause, Sebastian Scholl, Andreas Hochhaus, Gerhard Held, Tomas Szotkowski, Andreas Rank, Christoph Schmid, Lars Fransecky, Sabine Kayser, Markus Schaich, Michael Kramer, Frank Fiebig, Annett Haake, Johannes Schetelig, Jan Moritz Middeke, Friedrich Stölzel, Uwe Platzbecker, Christian Thiede, Carsten Müller-Tidow, Wolfgang E. Berdel, Gerhard Ehninger, Jiri Mayer, Hubert Serve, Martin Bornhäuser
Journal: Journal of Clinical Oncology (2024)

PURPOSE To determine the optimal daunorubicin dose and number of 7 + 3 induction cycles in newly diagnosed AML, this randomized controlled trial compared a once daily dose of 60 mg/m 2 with 90 mg/m 2 daunorubicin in the first 7 + 3 induction and one versus two cycles of 7 + 3 induction. PATIENTS AND METHODS Patients age 18-65 years with newly diagnosed AML were randomly assigned to 60 versus 90 mg/m 2 daunorubicin once daily plus cytarabine. Patients with marrow blasts below 5% on day 15 after first induction were randomly assigned to receive a second induction cycle or no second induction cycle. RESULTS Eight hundred and sixty-four patients with a median age of 52 years were randomly assigned. After a preplanned interim analysis showing no significant difference in response between 60 and 90 mg/m 2 , all consecutive patients received 60 mg/m 2 daunorubicin once daily. The proportion of good early responders was 44% versus 48% ( P = .983) with a composite complete remission (CRc) rate of 90% versus 89% after induction ( P = .691); the 3-year relapse-free survival (RFS) after 60 versus 90 mg/m 2 once daily was 54% versus 50% ( P = .561), and the 3-year overall survival (OS) was 65% versus 58% ( P = .242). Among 389 good responders, CRc rates at the end of induction were 87% after single induction and 85% after double induction. The 3-year RFS was 51% versus 60% (hazard ratio [HR], 1.3; P = .091), and the 3-year OS was 76% versus 75% after single versus double induction (HR, 1.0; P = .937). CONCLUSION The use of 90 mg/m 2 daunorubicin once daily in the context of classical 7 + 3 induction does not significantly improve early response and does not lead to higher remission rates or longer survival than 60 mg/m 2 once daily. In patients with a good early response after first induction, a second induction has only a limited impact on RFS and does not result in an OS benefit.
Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors
Authors: Jennifer A. Chan, Susan Geyer, Tyler Zemla, Michael V. Knopp, Spencer Behr, Sydney Pulsipher, Fang-Shu Ou, Amylou C. Dueck, Jared Acoba, Ardaman Shergill, Edward M. Wolin, Thorvardur R. Halfdanarson, Bhavana Konda, Nikolaos A. Trikalinos, Bernard Tawfik, Nitya Raj, Shagufta Shaheen, Namrata Vijayvergia, Arvind Dasari, Jonathan R. Strosberg, Elise C. Kohn, Matthew H. Kulke, Eileen M. O’Reilly, Jeffrey A. Meyerhardt
Journal: New England Journal of Medicine (2024)

Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear.
AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers
Authors: Brian Belmontes, Katherine K. Slemmons, Chun Su, Siyuan Liu, Antonia N. Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew. Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H. Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R. Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, Francois Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M. Townsley, John R. Butler, Matthew P. Bourbeau, Sean Caenepeel, Paul E. Hughes
Journal: Cancer Discovery (2024)

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.
Intracranial Pressure Elevation and MOGAD
Authors: Nanthaya Tisavipat, Natthapon Rattanathamsakul, Abdul-Rahman Salman, Laura Cacciaguerra, Sean J. Pittock, Eoin P. Flanagan, John J. Chen
Journal: JAMA Neurology (2024)

This cross-sectional study examines the frequency of increased intracranial pressure and its association with myelin oligodendrocyte glycoprotein antibody-associated disease in patients of various ages.
Viral Load–Based Prediction of Hepatocellular Carcinoma Risk in Noncirrhotic Patients With Chronic Hepatitis B
Authors: Gi-Ae Kim, Young-Suk Lim, Seungbong Han, Gwang Hyeon Choi, Won-Mook Choi, Jonggi Choi, Dong Hyun Sinn, Yong-Han Paik, Jeong-Hoon Lee, Yun Bin Lee, Ju-Yeon Cho, Nae-Yun Heo, Man-Fung Yuen, Vincent Wai-Sun Wong, Stephen L. Chan, Hwai-I Yang, Chien-Jen Chen
Journal: Annals of Internal Medicine (2024)

A nonlinear association between serum hepatitis B virus (HBV) DNA levels and hepatocellular carcinoma (HCC) risk has been suggested in patients with chronic hepatitis B (CHB).
Efficacy and Safety of Erenumab for Nonopioid Medication Overuse Headache in Chronic Migraine
Authors: Stewart J. Tepper, David W. Dodick, Michel Lanteri-Minet, David Dolezil, Raquel Gil-Gouveia, Christian Lucas, Karolina Piasecka-Stryczynska, Gyöngyi Szabó, Daniel D. Mikol, Mahan Chehrenama, Denise E. Chou, Yiping Yang, Gabriel Paiva da Silva Lima
Journal: JAMA Neurology (2024)

Patients with chronic migraine and medication overuse headaches (CM-MOH) represent a particularly burdened subpopulation. This trial provides first, to our knowledge, American Academy of Neurology class I evidence for a preventive therapy in CM-MOH.
Enterotoxigenic <i>Escherichia coli</i> heat labile enterotoxin affects neutrophil effector functions via cAMP/PKA/ERK signaling
Authors: Jinglin Ma, Leen Hermans, Matthias Dierick, Hans Van der Weken, Eric Cox, Bert Devriendt
Journal: Gut Microbes (2024)

Enterotoxigenic
The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (<scp>SPIRRIT</scp>‐<scp>HFpEF</scp>): Rationale and design
Authors: Lars H. Lund, Stefan James, Adam D. DeVore, Kevin J. Anstrom, Marat Fudim, Keith D. Aaronson, Ulf Dahlström, Patrice Desvigne‐Nickens, Jerome L. Fleg, Song Yang, Michael Fu, Camilla Hage, Claes Held, Patric Karlström, Magnus Nygren, Eric D. Peterson, Tymon Pol, Shelly Sapp, Johan Sundström, Ollie Östlund, Jonas Oldgren, Bertram Pitt
Journal: European Journal of Heart Failure (2024)

Aims Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT‐HFpEF) is a unique pragmatic registry‐based randomized controlled trial. Methods SPIRRIT‐HFpEF is a multicentre, prospective, randomized, open‐label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N‐terminal pro‐B‐type natriuretic peptide &gt;300 ng/L (in sinus rhythm) or &gt;750 ng/L (in atrial fibrillation), with pre‐specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event‐driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients. Conclusion SPIRRIT‐HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry‐based trials in heart failure and other chronic conditions.
GDF-15 predicts epithelioid hemangioendothelioma aggressiveness and is down-regulated by sirolimus through ATF4/ATF5 suppression
Authors: Silvia Stacchiotti, Silvia Martini, Sandro Pasquali, Anna M. Frezza, Alessia Beretta, Stefano Percio, Mara Lecchi, Monica Tortoreto, Marta Barisella, Paola Collini, Gian Paolo Dagrada, Alessandra Merlini, Paul H. Huang, Andrew Jenks, Robin L. Jones, William D. Tap, Matilde Ingrosso, Carlo Morosi, Silvia Brich, Claudia Giani, Paolo Verderio, Paolo G. Casali, Hugh Leonard, Alessandro Gronchi, Valentina Zuco, Nadia Zaffaroni
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness. Experimental Design: A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness. Results: ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness. Conclusions: This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug’s activity in patients.
Differential Diagnosis of Suspected Multiple Sclerosis in Pediatric and Late-Onset Populations
Authors: Le H. Hua, Andrew J. Solomon, Silvia Tenembaum, Antonio Scalfari, Àlex Rovira, Kevin Rostasy, Scott D. Newsome, Ruth Ann Marrie, Melinda Magyari, Orhun Kantarci, Bernhard Hemmer, Cheryl Hemingway, Mary Pat Harnegie, Jennifer S. Graves, Jeffrey A. Cohen, Riley Bove, Brenda Banwell, John R. Corboy, Emmanuelle Waubant
Journal: JAMA Neurology (2024)

While the typical onset of multiple sclerosis (MS) occurs in early adulthood, 2% to 10% of cases initially present prior to age 18 years, and approximately 5% after age 50 years. Guidance on approaches to differential diagnosis in suspected MS specific to these 2 age groups is needed.
Epidural Analgesia During Labor and Neonatal Hypoxic-Ischemic Encephalopathy
Authors: Marie-Coralie Cornet, Michael W. Kuzniewicz, Aaron W. Scheffler, Stephanie L. Gaw, Peter Yeh, Thomas B. Newman, Yvonne W. Wu
Journal: JAMA Network Open (2024)

Importance Epidural analgesia is used by approximately 70% of birthing persons in the US to alleviate labor pain and is a common cause of elevated temperature in the birthing parent during labor, which, in turn, is associated with adverse neonatal outcomes such as hypoxic-ischemic encephalopathy (HIE). Objective To determine whether epidural analgesia is associated with increased risk of HIE after adjusting for the birthing person’s maximal temperature before epidural placement and for the propensity to get an epidural. Design, Setting, and Participants This retrospective, population-based cohort study was conducted at 15 Kaiser Permanente Northern California hospitals. Participants included singleton neonates born at 35 weeks’ or later gestational age between 2012 and 2019. Elective cesarean deliveries and deliveries within 2 hours of hospital admission were excluded. Data analysis was performed from November 2022 to June 2024. Exposure The primary exposure was epidural analgesia during labor. Main Outcomes and Measures The primary outcome was HIE, defined as the presence of both neonatal acidosis (ie, pH &amp;amp;lt;7 or base deficit ≥10) and encephalopathy. The presence and timing of epidural analgesia and demographic, pregnancy, and labor characteristics were extracted from electronic medical records. A propensity score for receiving epidural analgesia was created including demographic variables and comorbidities predating epidural placement. Logistic regression was used to evaluate the association between epidural analgesia and HIE, adjusting for maximal birthing parent’s temperature before epidural placement and the propensity for receiving an epidural. Results Among 233 056 infants born at 35 weeks’ or later gestational age by vaginal or unplanned cesarean delivery after at least 2 hours of in-hospital labor, 177 603 (76%) were exposed to epidural analgesia and 439 (0.19%) had HIE. On unadjusted analysis, epidural analgesia was associated with an increased risk of maximal temperature greater than 38 °C during labor (risk ratio [RR], 8.58; 95% CI, 8.06-9.14). Each degree increase in maximal temperature during labor was associated with nearly triple the odds of HIE (odds ratio [OR], 2.82; 95% CI, 2.51-3.17). However, there was no significant association between epidural analgesia and the risk of HIE either on crude (RR, 1.21; 95% CI, 0.96-1.53) or adjusted (adjusted OR, 0.93; 95% CI, 0.73-1.17) analyses. Conclusions and Relevance In this cohort study including more than 230 000 parent-infant dyads, epidural analgesia was associated with increased maximal temperature during labor, a known risk factor for HIE. However, epidural analgesia was not associated with increased odds of HIE.
Next-Gen Therapeutics: Pioneering Drug Discovery with iPSCs, Genomics, AI, and Clinical Trials in a Dish
Authors: Zehra Yildirim, Kyle Swanson, Xuekun Wu, James Zou, Joseph Wu
Journal: The Annual Review of Pharmacology and Toxicology (2024)

In the high-stakes arena of drug discovery, the journey from bench to bedside is hindered by a daunting 92% failure rate, primarily due to unpredicted toxicities and inadequate therapeutic efficacy in clinical trials. The FDA Modernization Act 2.0 heralds a transformative approach, advocating for the integration of alternative methods to conventional animal testing, including cell-based assays that employ human induced pluripotent stem cell (iPSC)-derived organoids, and organ-on-a-chip technologies, in conjunction with sophisticated artificial intelligence (AI) methodologies. Our review explores the innovative capacity of iPSC-derived clinical trial in a dish models designed for cardiovascular disease research. We also highlight how integrating iPSC technology with AI can accelerate the identification of viable therapeutic candidates, streamline drug screening, and pave the way toward more personalized medicine. Through this, we provide a comprehensive overview of the current landscape and future implications of iPSC and AI applications being navigated by the research community and pharmaceutical industry.
Atlas of telomeric repeat diversity in Arabidopsis thaliana
Authors: Yueqi Tao, Wenfei Xian, Zhigui Bao, Fernando A Rabanal, Andrea Movilli, Christa Lanz, Gautam Shirsekar, Detlef Weigel
Journal: Genome biology (2024)

Telomeric repeat arrays at the ends of chromosomes are highly dynamic in composition, but their repetitive nature and technological limitations have made it difficult to assess their true variation in genome diversity surveys.