tbuckley/cabot-search huggingface dataset:
Genome-wide in vivo CRISPR screen identifies TGFβ3 as actionable biomarker of palbociclib resistance in triple negative breast cancer
Authors: Sophie Poulet, Meiou Dai, Ni Wang, Gang Yan, Julien Boudreault, Girija Daliah, Alan Guillevin, Huong Nguyen, Soaad Galal, Suhad Ali, Jean-Jacques Lebrun
Journal: Molecular Cancer (2024)

Abstract Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors of response and resistance to these drugs remain scarce. We conducted an in vivo genome-wide CRISPR screen using palbociclib as a selection pressure in TNBC. Hits were prioritized using microarray data from a large panel of breast cancer cell lines to identify top palbociclib sensitizers. Our study defines TGFβ3 as an actionable determinant of palbociclib sensitivity that potentiates its anti-tumor effects. Mechanistically, we show that chronic palbociclib exposure depletes p21 levels, contributing to acquired resistance, and that TGFβ3 treatment can overcome this. This study defines TGFβ3 as an actionable biomarker that can be used to improve patient stratification for palbociclib treatment and exploits the synergistic interaction between CDK4/6 and TGFβ3 to propose a new combinatorial treatment for TNBC.
Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis
Authors: Vishal Kothari, Tse W.W. Ho, Ainara G. Cabodevilla, Yi He, Farah Kramer, Masami Shimizu-Albergine, Jenny E. Kanter, Janet Snell-Bergeon, Edward A. Fisher, Baohai Shao, Jay W. Heinecke, Jacob O. Wobbrock, Warren L. Lee, Ira J. Goldberg, Tomas Vaisar, Karin E. Bornfeldt
Journal: Circulation Research (2024)

Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D.
Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets
Authors: Oleksandr Frei, Guy Hindley, Alexey A. Shadrin, Dennis van der Meer, Bayram C. Akdeniz, Espen Hagen, Weiqiu Cheng, Kevin S. O’Connell, Shahram Bahrami, Nadine Parker, Olav B. Smeland, Dominic Holland, Christiaan de Leeuw, Danielle Posthuma, Ole A. Andreassen, Anders M. Dale
Journal: Nature Genetics (2024)
Structure-guided discovery of highly efficient cytidine deaminases with sequence-context independence
Authors: Kui Xu, Hu Feng, Haihang Zhang, Chenfei He, Huifang Kang, Tanglong Yuan, Lei Shi, Chikai Zhou, Guoying Hua, Yaqi Cao, Zhenrui Zuo, Erwei Zuo
Journal: Nature Biomedical Engineering (2024)

Abstract The applicability of cytosine base editors is hindered by their dependence on sequence context and by off-target effects. Here, by using AlphaFold2 to predict the three-dimensional structure of 1,483 cytidine deaminases and by experimentally characterizing representative deaminases (selected from each structural cluster after categorizing them via partitional clustering), we report the discovery of a few deaminases with high editing efficiencies, diverse editing windows and increased ratios of on-target to off-target effects. Specifically, several deaminases induced C-to-T conversions with comparable efficiency at AC/TC/CC/GC sites, the deaminases could introduce stop codons in single-copy and multi-copy genes in mammalian cells without double-strand breaks, and some residue conversions at predicted DNA-interacting sites reduced off-target effects. Structure-based generative machine learning could be further leveraged to expand the applicability of base editors in gene therapies.
LORIS robustly predicts patient outcomes with immune checkpoint blockade therapy using common clinical, pathologic and genomic features
Authors: Tian-Gen Chang, Yingying Cao, Hannah J. Sfreddo, Saugato Rahman Dhruba, Se-Hoon Lee, Cristina Valero, Seong-Keun Yoo, Diego Chowell, Luc G. T. Morris, Eytan Ruppin
Journal: Nature Cancer (2024)
Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Hans Gelderblom, Vivek Bhadri, Silvia Stacchiotti, Sebastian Bauer, Andrew J Wagner, Michiel van de Sande, Nicholas M Bernthal, Antonio López Pousa, Albiruni Abdul Razak, Antoine Italiano, Mahbubl Ahmed, Axel Le Cesne, Gabriel Tinoco, Kjetil Boye, Javier Martín-Broto, Emanuela Palmerini, Salvatore Tafuto, Sarah Pratap, Benjamin C Powers, Peter Reichardt, Antonio Casado Herráez, Piotr Rutkowski, Christopher Tait, Fiona Zarins, Brooke Harrow, Maitreyi G Sharma, Rodrigo Ruiz-Soto, Matthew L Sherman, Jean-Yves Blay, William D Tap, Herbert Loong, Antonella Brunello, Andreas Krieg, Mark Algulnik, Richard Riedel, Scott Okuno, Elizabeth Loggers, Thierry Alcindor, Virginia Ferraresi, César Serrano, R. Lor Randall, Breelyn Wilky, Vinod Ravi
Journal: The Lancet (2024)
In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use
Authors: Juan I. López-Carbonero, Irene García-Toledo, Laura Fernández-Hernández, Pablo Bascuñana, María J. Gil-Moreno, Jordi A. Matías-Guiu, Silvia Corrochano
Journal: Translational Neurodegeneration (2024)

TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer's disease, Huntington's disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.
ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-Induced Peripheral Neuropathy in Black Women With Early-Stage Breast Cancer
Authors: Bryan P. Schneider, Fengmin Zhao, Tarah J. Ballinger, Sofia F. Garcia, Fei Shen, Shamsuddin Virani, David Cella, Casey Bales, Guanglong Jiang, Lisa Hayes, Nadia Miller, Jayanthi Srinivasiah, Erica M. Stringer-Reasor, Ami Chitalia, Andrew A. Davis, Della F. Makower, Jason Incorvati, Melissa A. Simon, Edith P. Mitchell, Angela DeMichele, Kathy D. Miller, Joseph A. Sparano, Lynne I. Wagner, Antonio C. Wolff
Journal: Journal of Clinical Oncology (2024)

Black women experience higher rates of taxane-induced peripheral neuropathy (TIPN) compared with White women when receiving adjuvant once weekly paclitaxel for early-stage breast cancer, leading to more dose reductions and higher recurrence rates. EAZ171 aimed to prospectively validate germline predictors of TIPN and compare rates of TIPN and dose reductions in Black women receiving (neo)adjuvant once weekly paclitaxel and once every 3 weeks docetaxel for early-stage breast cancer.
CD8+ CD28− regulatory T cells after induction therapy predict progression-free survival in myeloma patients: results from the GMMG-HD6 multicenter phase III study
Authors: Katharina Kriegsmann, Gigi Nu Hoang Quy Ton, Mohamed H. S. Awwad, Axel Benner, Uta Bertsch, Britta Besemer, Mathias Hänel, Roland Fenk, Markus Munder, Jan Dürig, Igor W. Blau, Stefanie Huhn, Dirk Hose, Anna Jauch, Christoph Mann, Niels Weinhold, Christof Scheid, Roland Schroers, Ivana von Metzler, Aneta Schieferdecker, Jörg Thomalla, Peter Reimer, Rolf Mahlberg, Ullrich Graeven, Stephan Kremers, Uwe M. Martens, Christian Kunz, Manfred Hensel, Andrea Seidel-Glätzer, Katja C. Weisel, Hans J. Salwender, Carsten Müller-Tidow, Marc S. Raab, Hartmut Goldschmidt, Elias K. Mai, Michael Hundemer
Journal: Leukemia (2024)

In the battle against multiple myeloma (MM), T cell strategies have emerged as crucial, exploiting their natural tumor-cell targeting ability to enhance patient outcomes.Recent studies underscore the dual roles of T cells in MM: while specific T cells can effectively target and destroy MM cells, regulatory T cells may block this response, highlighting the complexity of the immune environment in MM [1,2].Elotuzumab, targeting the SLAM family member 7 (SLAMF7) protein, represents a promising advance enhancing natural killer (NK) cell activity against MM cells modulating T cell responses.This antibody not only boosts NK cell-mediated destruction of MM cells but also affects T cells, including a specific regulatory CD8 + subset, further contributing to its immunomodulatory effects [3][4][5].Despite these promising mechanisms, clinical trials including the German-Speaking Myeloma Multicenter Group (GMMG)-HD6 study have yielded mixed results, highlighting the need for further investigation into its role in MM treatment [6][7][8][9][10].This study aims to delve deeper into the impact of elotuzumab on T cell subsets within the MM microenvironment to elucidate its prognostic implications and refine therapeutic strategies.Within the context of the GMMG-HD6 trial, we performed a planned subgroup-analysis on SLAMF7 high expressing T cell subsets.The GMMG-HD6 trial assessed elotuzumab combined with lenalidomide, bortezomib, dexamethasone (RVd) in newly diagnosed MM patients.Participants were allocated into four groups: RVd/R (RVd induction/consolidation plus lenalidomide maintenance), RVd/Elo-R (RVd induction, elotuzumab+RVd consolidation, and elotuzumab+lenalidomide maintenance), Elo-RVd/R (elotuzumab+RVd induction, RVd consolidation, lenalidomide maintenance), and Elo-RVd/Elo-R (elotuzumab+RVd for both induction/consolidation and elotuzumab+lenalidomide maintenance).Following induction, all underwent stem cell mobilization, high-dose melphalan, autologous stem cell transplantation, and two consolidation cycles, with 26 cycles of maintenance over three years (Fig. 1A).564 patients were initially randomized in the trial.Five patients were excluded from the study due to violation of major eligibility criteria.The intention-to-treat (ITT) population of the study consisted of 559 patients.Peripheral blood (PB) samples for immune cell analysis were collected at baseline (T1)
CNS Protective Effect of Selpercatinib in First-Line <i>RET</i> Fusion-Positive Advanced Non–Small Cell Lung Cancer
Authors: Maurice Pérol, Benjamin J. Solomon, Koichi Goto, Keunchil Park, Ernest Nadal, Emilio Bria, Claudio Martin, Jair Bar, Justin N. Williams, Tarun Puri, Jian Li, Minji K. Uh, Boris K. Lin, Caicun Zhou
Journal: Journal of Clinical Oncology (2024)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Although the CNS activity of selpercatinib in patients with RET fusion-positive non–small cell lung cancer (NSCLC) has been previously described, the ability of potent RET inhibition to prevent new CNS metastases from developing has been challenging to measure without randomized data. Serial CNS scans were studied from LIBRETTO-431, a randomized phase III trial of selpercatinib versus platinum/pemetrexed ± pembrolizumab whose primary results have been previously disclosed. Intracranial outcomes were assessed by neuroradiologic blinded independent central review in patients with baseline and ≥1 postbaseline CNS scans. Of the 192 patients within the intention-to-treat pembrolizumab population with baseline CNS scans, 150 patients were without baseline CNS metastases. The cumulative incidence of CNS progression in these patients was reduced with selpercatinib versus chemotherapy + pembrolizumab (cause-specific hazard ratio [HR], 0.17 [95% CI, 0.04 to 0.69]). The HR for intracranial progression-free survival (PFS) was 0.46 (95% CI, 0.18 to 1.18). Among the 42 patients with baseline CNS metastases, similar trends were observed in the cumulative incidence of CNS progression (cause-specific HR, 0.61 [95% CI, 0.19 to 1.92]) and intracranial PFS (HR, 0.74 [95% CI, 0.28 to 1.97]). These data demonstrate that selpercatinib effectively treats existing CNS disease and prevents or delays the formation of new CNS metastases. These results reinforce the importance of identifying RET fusions in first-line patients with NSCLC and treating with selpercatinib.
Why federated learning will do little to overcome the deeply embedded biases in clinical medicine
Authors: Christopher Martin Sauer, Gernot Pucher, Leo Anthony Celi
Journal: Intensive Care Medicine (2024)

We read with great interest the article by van Genderen et al. [1] which provides a contemporary and comprehensive overview of the potential of federating data access and data sharing in intensive care.Importantly, the authors list the perpetuation of biases encoded in clinical care practice as a major potential shortcoming.Furthermore, they state that this could be mitigated by "ensuring an adequate representation of hospitals from various regions worldwide could lead to more diverse and inclusive health datasets."We agree that the use of diverse and inclusive health datasets should be promoted as a necessary first step to build fair machine learning algorithms.However, we do not believe that this will be sufficient to overcome the deeply embedded biases in medicine from a knowledge system that is designed around a majoritized few.Even with high quality data from the intensive care units from across the world, the social patterning of the data generation process can still produce artificial intelligence (AI) that is bound to preserve and even scale existing disparities in care with resulting inequities in patient outcomes.There are numerous examples of data issues that stem from the social patterning of the data capture and data generation process (Fig. 1).These include, but are certainly not limited to, (1) the differential performance of medical devices used to measure physiologic signals
Publisher Correction: Interventions for improving critical care in low- and middle-income countries: a systematic review
Authors: Duncan Wagstaff, Sumaiya Arfin, Alba Korver, Patrick Chappel, Aasiyah Rashan, Rashan Haniffa, Abi Beane
Journal: Intensive Care Medicine (2024)

clinical workflows"."There was a lack of evidence from low-income countries" should have been deleted.
Pneumocystis pneumonia in intensive care: clinical spectrum, prophylaxis patterns, antibiotic treatment delay impact, and role of corticosteroids. A French multicentre prospective cohort study
Authors: Toufik Kamel, Ralf Janssen-Langenstein, Quentin Quelven, Jonathan Chelly, Xavier Valette, Minh-Pierre Le, Jeremy Bourenne, Denis Garot, Pierre Fillatre, Marie Labruyere, Nicholas Heming, Fabien Lambiotte, Jean-Baptiste Lascarrou, Olivier Lesieur, Konstantinos Bachoumas, Alexis Ferre, Eric Maury, Ludivine Chalumeau-Lemoine, David Bougon, Damien Roux, Olivier Guisset, Remi Coudroy, Thierry Boulain, Auchabie Johann, Beuret Pascal, Darreau Cédric, Desmeulles Isabelle, Guervilly Christophe, Hong Tuan Ha Vivien, Jochmans Sébastien, Jozwiak Mathieu, Louis Guillaume, Navellou Jean-Christophe, Neuville Mathilde, Pichon Nicolas, Sagnier Anne, Schnell David
Journal: Intensive Care Medicine (2024)

Severe Pneumocystis jirovecii pneumonia (PJP) requiring intensive care has been the subject of few prospective studies. It is unclear whether delayed curative antibiotic therapy may impact survival in these severe forms of PJP. The impact of corticosteroid therapy combined with antibiotics is also unclear.
Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances
Authors: Thomas Gilliland, Jacqueline S. Dron, Margaret Sunitha Selvaraj, Mark Trinder, Kaavya Paruchuri, Sarah M. Urbut, Sara Haidermota, Rachel Bernardo, Md Mesbah Uddin, Michael C. Honigberg, Gina M. Peloso, Pradeep Natarajan
Journal: Circulation Research (2024)

Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort.
Human leukocyte antigen (HLA) class I expression on Hodgkin–Reed–Sternberg cells is an EBV‐independent major determinant of microenvironment composition in classic Hodgkin lymphoma
Authors: Berit Müller‐Meinhard, Nicole Seifert, Johanna Grund, Sarah Reinke, Fatih Yalcin, Helen Kaul, Sven Borchmann, Bastian von Tresckow, Peter Borchmann, Annette Plütschow, Julia Richter, Andreas Engert, Michael Altenbuchinger, Paul J. Bröckelmann, Wolfram Klapper
Journal: HemaSphere (2024)

Abstract Hodgkin–Reed–Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA‐I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA‐I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA‐II was associated with only minor differential gene expression in the TME. In HLA‐I‐positive HL the HRSC content and expression of CCL17/TARC in HRSCs are low, independent of the presence of Epstein–Barr virus in HRSCs. Additionally, HLA‐I‐positive HL shows a high content of CD8+ cytotoxic T cells. However, an increased expression of the inhibitory immune checkpoint LAG3 on CD8+ T cells in close proximity to HRSCs is observed. Suggesting interference with cytotoxic activity, we observed an absence of clonally expanded T cells in the TME. While HLA‐I‐positive HL is not associated with an unfavorable clinical course in our cohorts, they share features with the recently described H2 subtype of HL. Given the major differences in TME composition, immune checkpoint inhibitors may differ in their mechanism of action in HLA‐I‐positive compared to HLA‐I‐negative HL.
Biological basis and treatment of frailty and sarcopenia
Authors: Ryosuke Sato, Mirela Vatic, Guilherme Wesley Peixoto da Fonseca, Stefan D Anker, Stephan von Haehling
Journal: Cardiovascular Research (2024)

Abstract In an ageing society, the importance of maintaining healthy life expectancy has been emphasized. As a result of age-related decline in functional reserve, frailty is a state of increased vulnerability and susceptibility to adverse health outcomes with a serious impact on healthy life expectancy. The decline in skeletal muscle mass and function, also known as sarcopenia, is key in the development of physical frailty. Both frailty and sarcopenia are highly prevalent in patients not only with advanced age but also in patients with illnesses that exacerbate their progression like heart failure (HF), cancer, or dementia, with the prevalence of frailty and sarcopenia in HF patients reaching up to 50–75% and 19.5–47.3%, respectively, resulting in 1.5–3 times higher 1-year mortality. The biological mechanisms of frailty and sarcopenia are multifactorial, complex, and not yet fully elucidated, ranging from DNA damage, proteostasis impairment, and epigenetic changes to mitochondrial dysfunction, cellular senescence, and environmental factors, many of which are further linked to cardiac disease. Currently, there is no gold standard for the treatment of frailty and sarcopenia, however, growing evidence supports that a combination of exercise training and nutritional supplement improves skeletal muscle function and frailty, with a variety of other therapies being devised based on the underlying pathophysiology. In this review, we address the involvement of frailty and sarcopenia in cardiac disease and describe the latest insights into their biological mechanisms as well as the potential for intervention through exercise, diet, and specific therapies.
Navigating Remote Blood Pressure Monitoring—The Devil Is in the Details
Authors: Antoinette M. Schoenthaler, Safiya Richardson, Devin Mann
Journal: JAMA Network Open (2024)

Shivan J. Mehta, MD, MBA, MSHP; Kevin G. Volpp, MD, PhD; Andrea B. Troxel, ScD; Joseph Teel, MD; Catherine R. Reitz, MPH; Alison Purcell, MSN, CRNP; Humphrey Shen, BA; Kiernan McNelis, BS; Christopher K. Snider, MPH; David A. Asch, MD, MBA
Clinical Outcomes After Admission of Patients With COVID-19 to Skilled Nursing Facilities
Authors: Brian E. McGarry, Ashvin D. Gandhi, Mah Afroze Chughtai, Jiamin Yin, Michael L. Barnett
Journal: JAMA Internal Medicine (2024)

During the COVID-19 pandemic, stabilized COVID-19-positive patients were discharged to skilled nursing facilities (SNFs) to alleviate hospital crowding. These discharges generated controversy due to fears of seeding outbreaks, but there is little empirical evidence to inform policy.
Mosaic <i>EGFR</i> exon 20 in-frame insertion pathogenic variants are associated with papular epidermal naevus with ‘skyline’ basal cell layer (PENS)
Authors: Didier Bessis, Laura Poujade, Mireille Cossée, Guilaine Boursier, Mouna Barat-Houari, Mylene Tharreau, Luc Durand, Simon-Cabello Aguilar, Jérome Solassol, Marjolaine Willems, Julie Vendrell
Journal: British Journal of Dermatology (2024)

Papular epidermal naevus with ‘skyline’ basal cell layer (PENS) is a type of keratinocytic epidermal naevus for which the molecular genetic mechanism has not yet been identified. EGFR ex20ins could represent a new and specific genetic somatic marker of PENS.