tbuckley/cabot-search huggingface dataset:
Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma
Authors: Brandon S Willis, Kevin Mongeon, Hannah Dry, India L Neveras, Nadezda Bryan, Meghana Pandya, Justine Roderick-Richardson, Wendan Xu, Li Yang, Alan Rosen, Corinne Reimer, Liliana Tuskova, Pavel Klener, Jerome T Mettetal, Georg Lenz, Simon T Barry
Journal: Leukemia (2024)

Abstract The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.
Factors Associated With Recurrent Pediatric Firearm Injury
Authors: Zoe M. Miller, Benjamin P. Cooper, Daphne Lew, Rachel M. Ancona, Vicki Moran, Christopher Behr, Marguerite W. Spruce, Lindsay M. Kranker, Michael A. Mancini, Matt Vogel, Doug J.E. Schuerer, Lindsay Clukies, Megan L. Ranney, Randi E. Foraker, Kristen L. Mueller
Journal: Annals of Internal Medicine (2024)

Firearm injuries are the leading cause of death among children aged 0 to 17 years in the United States.
Expanding Opportunities by Adding Accessibility to Diversity, Equity, and Inclusion
Authors: Walter K. Clair, Anne E. Sumner, Eldrin F. Lewis, Eldrin F. Lewis, Johannes Boltze, Walter K. Clair, Shoa L. Clarke, Lisa de las Fuentes, H.E. Hinson, Bina Joe, Kiarri N. Kershaw, Mahasin Mujahid, Henry E. Okafor, Louise Pilote, Nilay S. Shah, Carl G. Streed, Anne E. Sumner, Kyung Woo Park
Journal: Circulation (2024)
Multiomic analysis identifies a high-risk subgroup that predicts poor prognosis in t(8;21) acute myeloid leukemia
Authors: Yu Liu, Wenbing Liu, Anli Lai, Yihan Mei, Ying Wang, Hui Wei, Qing Rao, Runxia Gu, Yingchang Mi, Min Wang, Jianxiang Wang, Shaowei Qiu
Journal: Blood Cancer Journal (2024)
Deep behavioural representation learning reveals risk profiles for malignant ventricular arrhythmias
Authors: Maarten Z H Kolk, Diana My Frodi, Joss Langford, Tariq O Andersen, Peter Karl Jacobsen, Niels Risum, Hanno L Tan, Jesper Hastrup Svendsen, Reinoud E Knops, Søren Zöga Diederichsen, Fleur V Y Tjong
Journal: npj Digital Medicine (2024)

We aimed to identify and characterise behavioural profiles in patients at high risk of SCD, by using deep representation learning of day-to-day behavioural recordings. We present a pipeline that employed unsupervised clustering on low-dimensional representations of behavioural time-series data learned by a convolutional residual variational neural network (ResNet-VAE). Data from the prospective, observational SafeHeart study conducted at two large tertiary university centers in the Netherlands and Denmark were used. Patients received an implantable cardioverter-defibrillator (ICD) between May 2021 and September 2022 and wore wearable devices using accelerometer technology during 180 consecutive days. A total of 272 patients (mean age of 63.1 ± 10.2 years, 81% male) were eligible with a total sampling of 37,478 days of behavioural data (138 ± 47 days per patient). Deep representation learning identified five distinct behavioural profiles: Cluster A (n = 46) had very low physical activity levels and a disturbed sleep pattern. Cluster B (n = 70) had high activity levels, mainly at light-to-moderate intensity. Cluster C (n = 63) exhibited a high-intensity activity profile. Cluster D (n = 51) showed above-average sleep efficiency. Cluster E (n = 42) had frequent waking episodes and poor sleep. Annual risks of malignant ventricular arrhythmias ranged from 30.4% in Cluster A to 9.8% and 9.5% for Clusters D-E, respectively. Compared to low-risk profiles (D-E), Cluster A demonstrated a three-to-four fold increased risk of malignant ventricular arrhythmias adjusted for clinical covariates (adjusted HR 3.63, 95% CI 1.54-8.53, p < 0.001). These behavioural profiles may guide more personalised approaches to ventricular arrhythmia and SCD prevention.
Prolonged Boarding and Racial Discrimination and Dissatisfaction Among Emergency Department Patients
Authors: Rose McKeon Olson, Andrea Fleurant, Sophie Grace Beauparlant, DaMarcus Eugene Baymon, Regan Marsh, Jeffrey Schnipper, Marie Plaisime, Bram Wispelwey
Journal: JAMA Network Open (2024)

Emergency department (ED) boarding times have increased rapidly, but their health equity outcomes are unknown.
Predictive and dynamic signature for anti-angiogenics in combination with PD-1 inhibitor in soft-tissue sarcoma: correlative studies linked to the IMMUNOSARC trial
Authors: David S. Moura, Jesus M. Lopez-Marti, Iva Benesova, Carlos de Andrea, Davide Di Lernia, Serena Lacerenza, Jose L. Mondaza-Hernandez, Marta Martin-Ruiz, Marta Ramirez-Calvo, Giovanni Grignani, Javier Martinez-Trufero, Andres Redondo, Claudia Valverde, Silvia Stacchiotti, Antonio Lopez-Pousa, José A. López-Guerrero, Antonio Gutierrez, Victor Encinas-Tobajas, Nadia Hindi, Dario Sangiolo, Jose A. Lopez-Martin, Zuzana Ozaniak. Strizova, Javier Martin-Broto
Journal: Clinical Cancer Research (2024)

Purpose: The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial. Experimental Design: Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients. Results: The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5–not reached (NR)] versus 17 months (95% confidence interval, 12.0–NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples. Conclusions: Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy.
Neuroanatomical changes observed over the course of a human pregnancy
Authors: Laura Pritschet, Caitlin M Taylor, Daniela Cossio, Joshua Faskowitz, Tyler Santander, Daniel A Handwerker, Hannah Grotzinger, Evan Layher, Elizabeth R Chrastil, Emily G Jacobs
Journal: Nature Neuroscience (2024)

Abstract Pregnancy is a period of profound hormonal and physiological changes experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation are not well studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through 2 years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, standing in contrast to increases in white matter microstructural integrity, ventricle volume and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as a comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to further explore and understand the maternal brain.
Social-Environmental Injustice and Cancer Screening Prevalence
Authors: Kilan C. Ashad-Bishop, Daniel Wiese, Jordan A. Baeker Bispo, Margaret Katana Ogongo, Farhad Islami, Priti Bandi
Journal: JAMA Network Open (2024)

This cross-sectional study characterizes the prevalence of cancer screening across geographic clusters of social risk factors, environmental burden, and compounded social-environmental injustice in densely-populated urban areas of the US.
Therapy-related AML: long-term outcome in a large cohort of AML-patients with intensive and non-intensive therapy
Authors: Sophia Gross, Jana Ihlow, Leonie Busack, Kacper Adamiak, Jens Schrezenmeier, Julia Jesse, Michaela Schwarz, Anne Flörcken, Lam Giang Vuong, Kathrin Rieger, Jan Krönke, Philipp le Coutre, Vivien Boldt, Ann-Christin von Brünneck, David Horst, Thomas Burmeister, Igor-Wolfgang Blau, Ulrich Keller, Lars Bullinger, Jörg Westermann
Journal: Blood Cancer Journal (2024)

Therapy-related acute myeloid leukemia (t-AML) often exhibits adverse (genetic) features. There is ongoing discussion on the impact of t-AML on long-term outcome in AML. Therefore, we retrospectively analyzed clinical and biological characteristics of 1133 AML patients (225 t-AML patients and 908 de novo AML patients) with a median follow-up of 81.8 months. T-AML patients showed more adverse genetic alterations, higher age and more comorbidities as compared to de novo AML. Median OS in intensively treated t-AML patients was 13.7 months as compared to 39.4 months in de novo AML (p < 0.001). With non-intensive therapy, OS did not differ significantly (p = 0.394). With intensive therapy, significant differences in favor of de novo AML were observed in the ELN intermediate I/II (p = 0.009) and adverse (p = 0.016) risk groups but not within favorable risk groups (APL p = 0.927, ELN favorable p = 0.714). However, t-AML was no independent risk factor for OS (p = 0.103), RR (p = 0.982) and NRM (p = 0.320) in the multivariate analysis. A limitation of our study is an ELN 2010 risk stratification due to a lack of more comprehensive molecular data according to ELN 2022. We conclude that therapeutic algorithms in t-AML, in particular with regard to allo-HSCT, should be guided by ELN genetic risk rather than classification as t-AML alone. Our data support the WHO and ICC 2022 classifications, which include t-AML as diagnostic qualifier rather than a separate subcategory.
Sleep Disturbance and Subsequent Suicidal Behaviors in Preadolescence
Authors: Joshua L. Gowin, Joel Stoddard, Ted K. Doykos, Mary D. Sammel, Rebecca A. Bernert
Journal: JAMA Network Open (2024)

Importance Suicide is a leading cause of death among adolescents, who demonstrate high rates of sleep disturbance. Poor sleep appears to confer risk for suicide, but longitudinal investigation of suicidal behaviors remains rare, particularly in the transition from childhood to early adolescence. Objective To evaluate sleep disturbances in preadolescent children (aged 9 and 10 years) in association with longitudinal risk for suicidal ideation and suicide attempts at the 2-year follow-up. Design, Setting, and Participants This cohort study used data from the Adolescent Brain Cognitive Development Study between June 2016 and January 2021. This dataset included children aged 9 or 10 years at baseline and their parents or caregivers who were recruited at 21 sites across the US. Data were analyzed July 2023 to June 2024. Exposures The Sleep Disturbance Scale for Children, a 26-item parent-reported inventory, was administered at baseline, generating a total score and 6 subscales. Central covariates included the Child Behavior Checklist Anxiety and Depression subscale and demographic variables. Main Outcomes and Measures The computerized Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-COMP) assessed parent- and youth-reported suicidal behaviors and outcomes (none; passive, active nonspecific, and active specific suicidal ideation; and suicide attempt) at the 2-year follow-up. Sleep disturbance was further grouped by symptom severity (minimal, moderate, elevated, high, and severe). Results Of the 10 136 youths who reported no baseline suicidal ideation or behavior, 8807 youths (mean [SD] age, 9.9 [0.6] years; 4507 males [51.2%]; 197 Asian individuals [2.2%], 1273 Black individuals [14.5%], and 5775 White individuals [65.6%]) completed the K-SADS-COMP assessment at the 2-year follow-up and were included in the analysis. At the follow-up, 8044 participants (91.3%) had no suicidal behavior, 317 (3.6%) had passive suicidal ideation, 258 (2.9%) had active nonspecific suicidal ideation, 130 (1.5%) had active specific suicidal ideation, and 58 (0.7%) had a first-time suicide attempt. Baseline sleep disturbance was associated with increased incidence risk for suicidal behavior at age 12 years (odds ratio, 2.68; 95% CI, 1.44-4.98; P = .002), adjusting for covariates. Individual subscales or items demonstrating associations with risk included disorders of excessive somnolence and frequency of nightmares. Conclusions and Relevance Results of this longitudinal cohort study revealed that disturbed sleep at age 10 years was associated with risk for suicidal thoughts and behaviors in the next 2 years. The findings highlight the potential importance of sleep as a visible risk factor and intervention target in the prevention of youth suicide.
High mechanical conditioning by tumor extracellular matrix stiffness is a predictive biomarker for anti-fibrotic therapy in HER2-negative breast cancer
Authors: Miguel Quintela-Fandino, Begoña Bermejo, Esther Zamora, Fernando Moreno, Jose Ángel. Garcia-Saenz, Sonia Pernas, Noelia Martinez Jañez, Desirée Jiménez, Encarna Adrover, Raquel Andrés, Silvana Mourón, Maria Jose. Bueno, Luis Manso, Gemma Viñas, Emilio Alba, Antonio Llombart-Cussac, Javier Cortes, Cristina Tebar, Denise J. Roe, Adam Grant, Adam Watson, Ramon Colomer, Ghassan Mouneimne
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Tumor progression has been linked to stiffening of the extracellular matrix caused by fibrosis. Cancer cells can be mechanically conditioned by stiff extracellular matrix, exhibiting a 1,004-gene signature [mechanical conditioning (MeCo) score]. Nintedanib has demonstrated antifibrotic activity in idiopathic pulmonary fibrosis. This study explores nintedanib’s antifibrotic effect on breast cancer outcomes. Experimental Design: We present long-term follow-up and analysis of a neoadjuvant randomized phase II trial in early HER2-negative breast cancer. Patients (N = 130) underwent a baseline biopsy and received 12 paclitaxel courses alone (control arm) or in combination with nintedanib (experimental arm). The tumor MeCo score was determined by RNA sequencing. The primary aim was to assess nintedanib’s impact on event-free survival based on MeCo scores. Results: Follow-up data were retrieved from 111 patients; 75 baseline and 24 post-run-in phase samples were sequenced. After median follow-up of 9.67 years, median event-free survival was not statistically different between arms (P = 0.37). However, in the control arm, high- versus low-MeCo patients had a statistically higher relapse risk: HR = 0.21; P = 0.0075. This risk was corrected by nintedanib in the experimental arm: HR = 0.37; P = 0.16. Nintedanib demonstrated pharmacodynamic engagement, reducing the MeCo score by 25% during the run-in phase (P &amp;lt; 0.01). Patients with low MeCo after run-in had the best long-term prognosis (HR = 0.087; P = 0.03). Conclusions: High MeCo is predictive of poor outcomes in HER2-negative early breast cancer, although this risk can be mitigated by nintedanib, which is able to specifically reduce MeCo.
Challenges and recommendations for the translation of biomarkers of aging
Authors: Chiara M S Herzog, Ludger J E Goeminne, Jesse R Poganik, Nir Barzilai, Daniel W Belsky, Joe Betts-LaCroix, Brian H Chen, Michelle Chen, Alan A Cohen, Steven R Cummings, Peter O Fedichev, Luigi Ferrucci, Alexander Fleming, Kristen Fortney, David Furman, Vera Gorbunova, Albert Higgins-Chen, Lee Hood, Steve Horvath, Jamie N Justice, Douglas P Kiel, George A Kuchel, Jessica Lasky-Su, Nathan K LeBrasseur, Andrea B Maier, Birgit Schilling, Vittorio Sebastiano, P Eline Slagboom, Michael P Snyder, Eric Verdin, Martin Widschwendter, Alex Zhavoronkov, Mahdi Moqri, Vadim N Gladyshev
Journal: Nature Aging (2024)
Tonic and burst-like locus coeruleus stimulation distinctly shift network activity across the cortical hierarchy
Authors: Christina Grimm, Sian N Duss, Mattia Privitera, Brandon R Munn, Nikolaos Karalis, Stefan Frässle, Maria Wilhelm, Tommaso Patriarchi, Daniel Razansky, Nicole Wenderoth, James M Shine, Johannes Bohacek, Valerio Zerbi
Journal: Nature Neuroscience (2024)

Abstract Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain’s topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC–NA system achieves a nuanced regulation of global circuit operations.
A role for germline variants in multiple myeloma?
Authors: Brian A. Walker
Journal: Blood Cancer Discovery (2024)

In Blood Cancer Discovery, Thibaud and colleagues report the incidence of pathogenic germline variants (PGV) in patients with multiple myeloma and that these PGVs are associated with DNA repair pathway genes, including BRCA1 and BRCA2. They find an association of patients with PGVs and previous family or personal history of cancer, and that these patients are diagnosed slightly earlier than those without PGVs. Patients with PGVs had a longer progression-free survival than those without PGVs when they received high-dose melphalan and autologous stem cell transplant, providing a therapeutic rationale for diagnostic germline testing in myeloma. See related article by Thibaud et al., p. 428.
Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial
Authors: Iris Nederlof, Olga I Isaeva, Manon de Graaf, Robbert C A M Gielen, Noor A M Bakker, Adrianne L Rolfes, Hannah Garner, Bram Boeckx, Joleen J H Traets, Ingrid A M Mandjes, Michiel de Maaker, Thomas van Brussel, Maksim Chelushkin, Elisa Champanhet, Marta Lopez-Yurda, Koen van de Vijver, José G van den Berg, Ingrid Hofland, Natasja Klioueva, Ritse M Mann, Claudette E Loo, Frederieke H van Duijnhoven, Victoria Skinner, Sylvia Luykx, Emile Kerver, Ekaterina Kalashnikova, Marloes G J van Dongen, Gabe S Sonke, Sabine C Linn, Christian U Blank, Karin E de Visser, Roberto Salgado, Lodewyk F A Wessels, Caroline A Drukker, Ton N Schumacher, Hugo M Horlings, Diether Lambrechts, Marleen Kok
Journal: Nature Medicine (2024)

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8
Dynamics of tumor evolution after Gammaknife radiosurgery for sporadic vestibular schwannoma: defining volumetric patterns characterizing individual trajectory
Authors: Anne Balossier, Madalina Olteanu, Christine Delsanti, Lucas Troude, Jean-Marc Thomassin, Pierre-Hugues Roche, Marie Chavent, Jean Régis
Journal: Neuro-Oncology (2024)

Abstract Background The definition of tumor control and treatment failure after Gamma Knife radiosurgery (GKRS) for vestibular schwannoma (VS) is still debated. The lack of knowledge on the dynamics of tumor evolution can lead to misinterpretation and subsequent inappropriate second treatment. The aim of this study was to evaluate the post-GKRS dynamics of the evolution of tumor volume and characterize volumetric patterns. Methods We included patients with sporadic VS treated by GKRS with an MRI follow-up of a minimum of 3 years. A clustering was performed in 2 steps: Definition of the patterns of evolution based on a subset of patients with the most comprehensive follow-up, and then the assignment of the remaining patients on a best-fit basis. The minimum length of follow-up was assessed by measuring the consistency of the clusters over time (adjusted rand index and normalized mutual information). An analysis of the discriminant variables was finally performed. Results A total of 1607 patients were included (median follow-up: 67 months). Five patterns were defined with 1 pattern gathering almost all cases of treatment failure. The clustering at 5 years afforded the highest consistency with long-term follow-up. Discriminant variables for clusters were as follows: sex, initial symptoms, delay of diagnosis, Koos grading, fundus invasion, and number of isocenters. Conclusions The definition of these robust distinct patterns is likely to help the physicians tremendously to distinguish tumor control from potential failure. We advocate for no retreatment decision before 5 years post-GKRS. Further investigations are required to decide if the dynamics of evolution can be predicted at GKRS on an individual basis.
Splam: a deep-learning-based splice site predictor that improves spliced alignments
Authors: Kuan-Hao Chao, Alan Mao, Steven L Salzberg, Mihaela Pertea
Journal: Genome biology (2024)

The process of splicing messenger RNA to remove introns plays a central role in creating genes and gene variants. We describe Splam, a novel method for predicting splice junctions in DNA using deep residual convolutional neural networks. Unlike previous models, Splam looks at a 400-base-pair window flanking each splice site, reflecting the biological splicing process that relies primarily on signals within this window. Splam also trains on donor and acceptor pairs together, mirroring how the splicing machinery recognizes both ends of each intron. Compared to SpliceAI, Splam is consistently more accurate, achieving 96% accuracy in predicting human splice junctions.