tbuckley/cabot-search huggingface dataset:
Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes
Authors: Xueqi Cao, Sandra Huber, Ata Jadid Ahari, Franziska R. Traube, Marc Seifert, Christopher C. Oakes, Polina Secheyko, Sergey Vilov, Ines F. Scheller, Nils Wagner, Vicente A. Yépez, Piers Blombery, Torsten Haferlach, Matthias Heinig, Leonhard Wachutka, Stephan Hutter, Julien Gagneur
Journal: Genome Medicine (2024)

Abstract Background Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging. Methods To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes. Results We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities. Conclusions Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.
The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology
Authors: Michael Benatar, Joanne Wuu, Edward D. Huey, Corey T. McMillan, Ronald C. Petersen, Ronald Postuma, Caroline McHutchison, Laynie Dratch, Jalayne J. Arias, Anita Crawley, Henry Houlden, Michael P. McDermott, Xueya Cai, Neil Thakur, Adam Boxer, Howard Rosen, Bradley F. Boeve, Penny Dacks, Stephanie Cosentino, Sharon Abrahams, Neil Shneider, Paul Lingor, Jeremy Shefner, Peter M. Andersen, Ammar Al-Chalabi, Martin R. Turner, Ronald C. Petersen, Peggy Allred, Stanley Appel, David Benatar, James Berry, Meg Bradbury, Lucie Bruijn, Jennifer Buczyner, Nathan Carberry, James Caress, Thomas Champney, Kuldip Dave, Stephanie Fradette, Volkan Granit, Anne-Laure Grignon, Amelie Gubitz, Matthew Harms, Terry Heiman-Patterson, Sharon Hesterlee, Karen Lawrence, Travis Lewis, Oren Levy, Tahseen Mozaffar, Christine Stanislaw, Alexander Thompson, Olga Uspenskaya, Patrick Weydt, Lorne Zinman
Journal: Nature Reviews Neurology (2024)
From Rarity to Reality: Osimertinib's Promising Horizon in Treating Uncommon <i>EGFR</i> Mutations in Non-Small Cell Lung Cancer
Authors: Akito Fukuda, Yusuke Okuma
Journal: Clinical Cancer Research (2024)

In the realm of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) therapy with tyrosine kinase inhibitors (TKI), addressing optimal treatment for uncommon EGFR mutations like G719X in exon 18, S768I in exon 20, and L861Q in exon 21 remains a pivotal yet challenging frontier. Contrary to the well-established efficacy of EGFR-TKIs in common EGFR mutations, these uncommon alterations pose unmet medical needs due to a lack of comprehensive evidence. While afatinib, a second-generation EGFR-TKI, has received FDA approval for patients with these uncommon EGFR mutations, the approval was based on a post-hoc analysis of randomized clinical trials. Recent developments include multiple clinical trials investigating the efficacy of both second- and third-generation EGFR-TKIs in patients with uncommon EGFR mutations. A noteworthy example is a prospective phase II trial of osimertinib including the landmark UNICORN study, which has shown promising results in treating uncommon EGFR mutations. Despite various reports on the efficacy of afatinib and osimertinib in treating uncommon EGFR mutations, the appropriate use of these TKIs remains unclear. This review aims to consolidate the findings from the latest clinical trials focused on uncommon EGFR mutations, outlining variations in the therapeutic efficacy of these TKIs based on the specific genetic mutation. By synthesizing these findings, we aim to guide oncologists toward more informed decisions in employing TKIs for NSCLC with uncommon EGFR mutations other than exon 20 insertion. Additionally, we explore potential treatment strategies tailored to these patient populations to address the challenges posed by these mutations.
Study Participants, Future Patients, and Outcomes That Matter in Cancer Clinical Trials
Authors: Brooke E. Wilson, Elizabeth A. Eisenhauer, Christopher M. Booth
Journal: JAMA (2024)

Renata Iskander, MSc; Hannah Moyer, MSc; Karine Vigneault, BSc; Salaheddin M. Mahmud, MD, PhD; Jonathan Kimmelman, PhD
Errors in Figure 2
Journal: JAMA Network Open (2024)

Alejandra Barreto, MPH; Brielle Formanowski, MS; Michelle-Marie Peña, MD; Elizabeth G. Salazar, MD; Sara C. Handley, MD, MSCE; Heather H. Burris, MD, MPH; Robin Ortiz, MD, MSHP; Scott A. Lorch, MD, MSCE; Diana Montoya-Williams, MD, MSHP
Risk Factors and Mortality Among Women With Interval Breast Cancer vs Screen-Detected Breast Cancer
Authors: Huiyeon Song, Thi Xuan Mai Tran, Soyeoun Kim, Boyoung Park
Journal: JAMA Network Open (2024)

Importance The risk factors for interval breast cancer (IBC) compared with those for screen-detected breast cancer (SBC) and their association with mortality outcomes have not yet been evaluated among Korean women. Objective To evaluate risk factors associated with IBC and survival among Korean women with IBC compared with those with SBC. Design, Setting, and Participants This retrospective cohort study used data from the Korean National Health Insurance Service Database. Women who participated in a national mammographic breast cancer screening program between January 1, 2009, and December 31, 2012, were included. Mortality outcomes were calculated from the date of breast cancer diagnosis to the date of death or December 31, 2020. Data were analyzed from March 1 to June 30, 2023. Exposure Breast cancer diagnosed within 6 to 24 months after a negative screening result (ie, IBC) or within 6 months after a positive screening result (ie, SBC). Main Outcomes and Measures Risk factors and survival rates for IBC and SBC. Results This study included 8702 women with IBC (mean [SD] age, 53.3 [8.6] years) and 9492 women with SBC (mean [SD] age, 54.1 [9.0] years). Compared with SBC, the probability of IBC decreased as mammographic density increased. Lower body mass index, menopausal status, hormone replacement therapy (HRT) use, and lack of family history of breast cancer were associated with a higher likelihood of IBC. When stratified by detection time, younger age at breast cancer diagnosis and family history of breast cancer were associated with an increased likelihood of IBC diagnosed at 6 to 12 months but a decreased likelihood of IBC diagnosed at 12 to 24 months. Overall mortality of IBC was comparable with SBC, but total mortality and cancer-related mortality of IBC diagnosed between 6 and 12 months was higher than that of SBC. Conclusions and Relevance The findings of this cohort study suggest that breast density, obesity, and HRT use were associated with IBC compared with SBC. These findings also suggest that higher supplemental breast ultrasound use among Korean women, especially those with dense breasts, could be attributed to a lower incidence of IBC among women with dense breasts compared with women with SBC, due to greater detection. Finally, overall mortality of IBC was comparable with that of SBC.
Exciting Bacteria to a Hypersensitive State for Enhanced Aminoglycoside Therapy by a Rationally Constructed AIE Luminogen
Authors: Chao Chen, Xing Li, Yilin Wang, Yingshu Sun, Yixuan Bao, Jianyu Zhang, Ruoyao Zhang, Ryan T. K. Kwok, Jacky W. Y. Lam, Duo Mao, Peng Hou, Ben Zhong Tang
Journal: Advanced Healthcare Materials (2024)

Abstract The diminishing effectiveness of existing aminoglycoside antibiotics (AGs) compels scientists to seek new approaches to enhance the sensitivity of current AGs. Despite ongoing efforts, currently available approaches remain restricted. Herein, a novel strategy involving the rational construction of an aggregation‐induced‐emission luminogen (AIEgen) is introduced to significantly enhance Gram‐positive bacteria's susceptibility to AGs. The application of this approach involves the simple addition of AIEgens to bacteria followed by a 5 min light irradiation. Under light exposure, AIEgens efficiently generate reactive oxygen species (ROS), elevating intrabacterial ROS levels to a nonlethal threshold. Post treatment, the bacteria swiftly enter a hypersensitive state, resulting in a 21.9‐fold, 15.5‐fold, or 7.2‐fold increase in susceptibility to three AGs: kanamycin, gentamycin, and neomycin, respectively. Remarkably, this approach is specific to AGs, and the induced hypersensitivity displays unparalleled longevity and heritability. Further in vivo studies confirm a 7.0‐fold enhanced bactericidal ability of AGs against Gram‐positive bacteria through this novel approach. This research not only broadens the potential applications of AIEgens but also introduces a novel avenue to bolster the effectiveness of AGs in combating bacterial infections.
Self-Reported Social Determinants of Health and Area-Level Social Vulnerability
Authors: Emily Brignone, Keith LeJeune, Amanda E. Mihalko, Amy L. Shannon, Lawrence I. Sinoway
Journal: JAMA Network Open (2024)

Many health care systems are investing resources in identifying social determinants of health (SDoH) needs and facilitating interventions among the populations they serve. Because self-reported SDoH information is lacking, area-level measures are often used to estimate needs and direct resources.
&amp;lt;SPAN style="font-size: 11.0pt; font-family: 'Arial',sans-serif;"&amp;gt;Chimeric Antigen Receptor T Cell with an Inducible Caspase 9 Suicide Gene Eradicates Uveal Melanoma Liver Metastases via B7-H3 Targeting&amp;lt;/SPAN&amp;gt;
Authors: Marco Ventin, Giulia Cattaneo, Shahrzad Arya, Jingyu Jia, Maria C. Gelmi, Yi Sun, Luke Maggs, Bruce R. Ksander, Robert M. Verdijk, Genevieve M. Boland, Russell W. Jenkins, Rizwan Haq, Martine J. Jager, Xinhui Wang, Sandra Ryeom, Cristina R. Ferrone
Journal: Clinical Cancer Research (2024)

Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of the primary tumor, about 50% of patients will recur with systemic diseases for which there are no effective treatment strategies. Here we investigated the preclinical efficacy of a chimeric antigen receptor (CAR) T-cell-based immunotherapy targeting B7-H3.
CHD2 Regulates Neuron–Glioma Interactions in Pediatric Glioma
Authors: Xu Zhang, Shoufu Duan, Panagiota E. Apostolou, Xiaoping Wu, Jun Watanabe, Matthew Gallitto, Tara Barron, Kathryn R. Taylor, Pamelyn J. Woo, Xu Hua, Hui Zhou, Hong-Jian Wei, Nicholas McQuillan, Kyung-Don Kang, Gregory K. Friedman, Peter D. Canoll, Kenneth Chang, Cheng-Chia Wu, Rintaro Hashizume, Christopher R. Vakoc, Michelle Monje, Guy M. McKhann, Joseph A. Gogos, Zhiguo Zhang
Journal: Cancer Discovery (2024)

High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes the progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler chromodomain helicase DNA-binding protein 2 (CHD2) regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons. Significance: Neurons drive the proliferation and invasion of glioma cells. Here we show that chromatin remodeler chromodomain helicase DNA-binding protein 2 controls the epigenome and expression of axon-guidance and synaptic genes, thereby promoting neuron-induced proliferation of H3.1K27M diffuse midline glioma and the pathogenesis of this deadly disease.
There is More to Length of Survival than Survival: Endpoints in Oncology Trials
Authors: Walter M. Stadler, Theodore G. Karrison
Journal: Clinical Cancer Research (2024)

Summary Progression-free survival as a primary endpoint for comparative trials does not fully capture the therapeutic risk/benefit ratio. Additionally, summarization of the treatment effect via a hazard ratio is problematic when the proportional hazards assumption is violated. Restricted mean survival time metrics may address these challenges but have other limitations. See related article by Chang et al., p. 3282
Integrated Clinical Genotype-phenotype Characteristics of STAT3-mutated Myeloid Neoplasms
Authors: Matthew T. Ye, Zhuang Zuo, Steliana Calin, Fengxi Ye, Hua He, Wataru Kamata, Yaling Yang, M. James You
Journal: Clinical Cancer Research (2024)

STAT3 is a key transcription factor that mediates cancer progression through phosphorylation or gain-of-function mutations. STAT3 activation in myeloid neoplasms (MN) is primarily mediated through phosphorylation. STAT3 mutation has only rarely been reported in MNs.
Time- vs Step-Based Physical Activity Metrics for Health
Authors: Rikuta Hamaya, Eric J. Shiroma, Christopher C. Moore, Julie E. Buring, Kelly R. Evenson, I-Min Lee
Journal: JAMA Internal Medicine (2024)

Current US physical activity (PA) guidelines prescribe moderate to vigorous PA (MVPA) time of at least 150 minutes per week for health. An analogous step-based recommendation has not been issued due to insufficient evidence.
Survival After Intra-Arrest Transport vs On-Scene Cardiopulmonary Resuscitation in Children
Authors: Masashi Okubo, Sho Komukai, Junichi Izawa, SunHee Chung, Ian R. Drennan, Brian E. Grunau, Joshua R. Lupton, Sriram Ramgopal, Thomas D. Rea, Clifton W. Callaway
Journal: JAMA Network Open (2024)

For pediatric out-of-hospital cardiac arrest (OHCA), emergency medical services (EMS) may elect to transport to the hospital during active cardiopulmonary resuscitation (CPR) (ie, intra-arrest transport) or to continue on-scene CPR for the entirety of the resuscitative effort. The comparative effectiveness of these strategies is unclear.
Maintenance of Certification’s Value to Patients and Physicians
Authors: David T. Stern, Frederic W. Hafferty
Journal: JAMA (2024)

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Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial
Authors: Chet Moritz, Edelle C. Field-Fote, Candace Tefertiller, Ilse van Nes, Randy Trumbower, Sukhvinder Kalsi-Ryan, Mariel Purcell, Thomas W. J. Janssen, Andrei Krassioukov, Leslie R. Morse, Kristin D. Zhao, James Guest, Ralph J. Marino, Lynda M. Murray, Jill M. Wecht, Markus Rieger, Jared Pradarelli, Amanda Turner, Jessica D’Amico, Jordan W. Squair, Gregoire Courtine
Journal: Nature Medicine (2024)

Abstract Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARC EX Therapy to improve arm and hand functions in people with chronic SCI. ARC EX Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARC EX Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARC EX Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARC EX Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472 .
Error in Results and Figure
Journal: JAMA Network Open (2024)

Error in Results and Figure In the Original Investigation titled "Comparison of Tuberculin Skin Testing and Interferon-γ Release Assays in Predicting Tuberculosis Disease," 1 published April 3, 2024, the number of patients with pulmonary tuburculousis was incorrectly given as 5 instead of 35 in the Results section and in the caption of the Figure.This article has been corrected.
Health Technology Assessment in the US—A Word of Caution—Reply
Authors: Olivier J. Wouters, Huseyin Naci, Irene Papanicolas
Journal: JAMA Internal Medicine (2024)

In Reply In their Letter to the Editor, Olivença and colleagues question the benefit of adopting health technology assessment (HTA) in the US, and suggest it could result in fewer drugs being available to patients. They raise 3 main critiques of our study.1
Correction:<i>British Thoracic Society Winter Meeting 2023</i>
Authors: R Meharry, J Rodger, H Tedd, A Armstrong, Klm Hester
Journal: Thorax (2024)

presented at the Meeting S45 -Forced Oscillometry Technique in Children with Preschool Wheeze: Feasibility and Relationship to Clinical Parameters P89 -The burden and impact of NTM-LD and perspectives on care, UK data from a European patient survey (ENPADE) P97 -CPET's utility in understanding unexplained exertional dyspnoea in military personnel.
Beyond Trade-Offs: Autonomy, Effectiveness, Fairness, and Normativity in Risk and Crisis Communication
Authors: Federico Germani, Giovanni Spitale, Nikola Biller-Andorno
Journal: The American Journal of Bioethics (2024)

This paper addresses the critiques based on trade-offs and normativity presented in response to our target article proposing the Public Health Emergency Risk and Crisis Communication (PHERCC) framework. These critiques highlight the ethical dilemmas in crisis communication, particularly the balance between promoting public autonomy through transparent information and the potential stigmatization of specific population groups, as illustrated by the discussion of the mpox outbreak among men who have sex with men. This critique underscores the inherent tension between communication effectiveness and autonomy versus fairness and equity. In response, our paper reiterates the adaptability of the PHERCC framework, emphasizing its capacity to tailor messages to diverse audiences, thereby reducing potential stigmatization and misinformation. Through community engagement and feedback integration, the PHERCC framework aims to optimize the effectiveness of communication strategies while addressing ethical concerns. Furthermore, by involving affected communities in the communication strategy from the onset, the framework seeks to minimize ethical trade-offs and enhance the acceptance and effectiveness of public health messages.