tbuckley/cabot-search huggingface dataset:
Apoptosis: Directly Targeted at Last
Authors: Anthony Letai
Journal: Journal of Clinical Oncology (2022)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy. February 18, 2022 ARTICLE CITATION DOI: 10.1200/JCO.22.00304 Journal of Clinical Oncology - published online before print March 23, 2022 PMID: 35319999 Apoptosis: Directly Targeted at Last Anthony Letai , MD, PhD1xAnthony LetaiSearch for articles by this author Show More 1Dana Farber Cancer Institute, Boston, MA https://doi.org/10.1200/JCO.22.00304 First Page Full Text PDF Figures and Tables © 2022 by American Society of Clinical OncologySUPPORTSupported by National Cancer Institute (NCI R35CA242427).AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTApoptosis: Directly Targeted at LastThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Anthony LetaiStock and Other Ownership Interests: Zentalis, Flash Therapeutics, DialecticConsulting or Advisory Role: Zentalis, Flash Therapeutics, Anji Onco, Dialectic TherapeuticsResearch Funding: Novartis Institutes for BioMedical Research (Inst), AbbVie (Inst)Patents, Royalties, Other Intellectual Property: I am an inventor on several patents involving BH3 profiling technology. These are owned by my employer, Dana-Farber Cancer Institute (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/174250No other potential conflicts of interest were reported. Companion Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy
Nandrolone-Induced Tumor Progression in Hormone-Sensitive Prostate Cancer
Authors: Shikha Goyal, Renu Madan, Narendra Kumar, Rajender Kumar
Journal: Clinical Nuclear Medicine (2022)

Abstract Hormone-sensitive prostate cancer responds favorably to testosterone suppression induced by GnRH analogs or antagonists. This effect may theoretically be countered by anabolic steroids. We describe a patient of a recurrent hormone-sensitive prostate cancer who was on salvage androgen deprivation therapy with degarelix and developed rapid progression after over-the-counter nandrolone injections.
<i>MEOX2</i>homeobox gene promotes growth of malignant gliomas
Authors: Anna Schönrock, Elisa Heinzelmann, Bianca Steffl, Engin Demirdizen, Ashwin Narayanan, Damir Krunic, Marion Bähr, Jong-Whi Park, Claudia Schmidt, Koray Özduman, M Necmettin Pamir, Wolfgang Wick, Felix Bestvater, Dieter Weichenhan, Christoph Plass, Julian Taranda, Moritz Mall, Şevin Turcan
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10, and aberrantly activated receptor tyrosine kinase signaling pathways. Previously, we identified Mesenchyme Homeobox 2 (MEOX2), a gene located on chromosome 7, as an upregulated transcription factor in GBM. Overexpressed transcription factors can be involved in driving GBM. Here, we aimed to address the role of MEOX2 in GBM. Methods Patient-derived GBM tumorspheres were used to constitutively knockdown or overexpress MEOX2 and subjected to in vitro assays including western blot to assess ERK phosphorylation. Cerebral organoid models were used to investigate the role of MEOX2 in growth initiation. Intracranial mouse implantation models were used to assess the tumorigenic potential of MEOX2. RNA-sequencing, ACT-seq, and CUT&amp;Tag were used to identify MEOX2 target genes. Results MEOX2 enhanced ERK signaling through a feed-forward mechanism. We identified Ser155 as a putative ERK-dependent phosphorylation site upstream of the homeobox-domain of MEOX2. S155A substitution had a major effect on MEOX2 protein levels and altered its subnuclear localization. MEOX2 overexpression cooperated with p53 and PTEN loss in cerebral organoid models of human malignant gliomas to induce cell proliferation. Using high-throughput genomics, we identified putative transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor. Conclusions We identified MEOX2 as an oncogenic transcription regulator in GBM. MEOX2 increases proliferation in cerebral organoid models of GBM and feeds into ERK signaling that represents a core signaling pathway in GBM.
Abstract 11605: Analysis of 10-yr MACE Risk of LDL-C ≥160-189 Mg/dL Compared to &lt;160 Mg/dL in Young Adults (ages 20-39) in an Integrated Healthcare System
Authors: Viet T Le, Jeffrey L Anderson, Peter Calderone, Ana C Perez, Stacey Knight, Heidi T May, Benjamin D Horne, Joseph B Muhlestein, Kirk U Knowlton
Journal: Circulation (2021)

Introduction: Adults &lt;40-yrs (20-39) may have elevated cardiovascular risk based on higher LDL-C (e.g., ≥160 mg/dL). We sought to compare the risk of MACE (all-cause death, MI, ischemic stroke, heart failure hospitalization, and peripheral vascular disease [PVD]) in adults &lt;40-yrs and LDL-C ≥160 to 189 compared with LDL-C &lt;160 mg/dL. Hypothesis: Adults &lt;40-yrs with LDL-C ≥160-189 mg/dL are minimally addressed in the current cholesterol management guidelines but may have a higher risk of MACE compared to other healthy controls. Methods: Patients (pts) from 20- 39 yrs of age with at least three lipid labs and outpatient primary care encounters at Intermountain Healthcare, a large integrated healthcare system, prior to January 2010 and an LDL-C measurement between January and December of 2020 (n=14,570) were included and followed for MACE until June 2021. Pts with LDL-C &gt;190 or &lt;160 on statin in 2010 but previously ≥160 were excluded. Pts were identified using MDClone (ADAMS self-service analytics platform). Outcome of interest was MACE during 10-yr follow-up, LDL-C was stratified as ≥160-189 vs &lt;160 mg/dL. Baseline characteristics were compared by either a chi-squared or t-test, as appropriate. Multivariate logistic regression was used to identify the role of LDL-C as a predictor of outcome. A p-value of &lt;0.05 was considered statistically significant. Results: Baseline characteristics are presented in the Table. MACE for LDL-C ≥160-189 mg/dL was not statistically significant compared to LDL-C &lt;160 (OR 1.28, 95% CI 0.94 - 1.74, p&lt;0.115). Conclusions: The risk of 10-yr MACE in adults &lt;40 yrs of age with LDL-C ≥160-189 mg/dL did not confer a statistically significant elevated risk. Our findings are consistent with current guidelines that statin therapy is not mandated in these individuals.
How Can We Fully Realize SNAP’s Health Benefits?
Authors: Craig Gundersen, Hilary Seligman
Journal: New England Journal of Medicine (2022)

Interview with Dr. Hilary Seligman on reforming the Supplemental Nutrition Assistance Program to reduce food insecurity in the United States. (11:03)Download The inability to afford enough food is associated with numerous short-term and downstream health consequences. Recent increases in Supplemental Nutrition Assistance Program benefits are important, but barriers to food security remain for many households.
Total Lesion Glycolysis on 18F-FDG PET/CT Is a Better Prognostic Factor Than Tumor Dose on 90Y PET/CT in Patients With Hepatocellular Carcinoma Treated With 90Y Transarterial Radioembolization
Authors: Sang Hyun Hwang, Hye-Suk Hong, Dongwoo Kim, Gyoung Min Kim, Hye Won Lee, Misu Lee, Do Young Kim, Mi-Ae Park, Mijin Yun
Journal: Clinical Nuclear Medicine (2022)

Purpose This study aimed to evaluate the prognostic value of metabolic parameters on 18 F-FDG PET/CT and tumor dose (TD) on posttreatment 90 Y PET/CT in patients with hepatocellular carcinoma (HCC) who underwent 90 Y transarterial radioembolization (TARE). Patients and Methods Forty-seven HCC patients treated with 90 Y TARE were retrospectively enrolled between January 2013 and October 2018. 18 F-FDG PET/CT was performed before treatment. Maximum tumor SUV–to–mean normal liver SUV ratio (TLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured for each patient. Voxel dosimetry was performed on 90 Y PET/CT images to measure TD. The prognostic significance of metabolic parameters on 18 F-FDG PET/CT, TD on 90 Y PET/CT, and clinical factors for overall survival (OS) was evaluated. In addition, TD on 90 Y PET/CT was analyzed in relation to the administered dose of 90 Y-labeled microspheres and metabolic parameters on 18 F-FDG PET/CT. Results The median patient age was 57 years, and 37 patients (78.7%) were men. During the follow-up period, 25 patients (53.2%) died. In univariable analysis, Barcelona Clinic Liver Cancer stage C, Child-Pugh score, TD on 90 Y PET/CT, TLR, MTV, and TLG were significant prognostic factors affecting OS ( P &lt; 0.05). In multivariable analysis, Barcelona Clinic Liver Cancer stage C and high TLG on 18 F-FDG PET/CT were independent prognostic factors for OS ( P &lt; 0.05). The 1-year OS rates were 72.9% in patients with low TLG and 33.3% in patients with high TLG ( P &lt; 0.05). We also found that TD on 90 Y PET/CT was not correlated with the administered dose of 90 Y-labeled microspheres, but negatively correlated with TLG on pretreatment 18 F-FDG PET/CT ( P &lt; 0.05). Conclusions TLG, a parameter incorporating both the degree of 18 F-FDG uptake and amount of metabolically active tumor volume on pretreatment 18 F-FDG PET/CT, is a better prognostic factor than TD on 90 Y PET/CT for predicting OS in HCC patients treated with 90 Y TARE.
RAS at 40: Update from the RAS Initiative
Authors: Dwight V. Nissley, Frank McCormick
Journal: Cancer Discovery (2022)

The RAS Initiative was launched in 2013 to address unmet clinical needs of patients with KRAS-driven cancers. The Initiative is based at Frederick National Laboratory for Cancer Research in Frederick, MD, and involves multiple collaborations with the RAS research community in academia and industry with the shared goal of developing RAS therapies.
Systems of Care for ST-Segment–Elevation Myocardial Infarction: A Policy Statement From the American Heart Association
Authors: Alice K. Jacobs, Murtuza J. Ali, Patricia J. Best, Mark C. Bieniarz, Vincent J. Bufalino, William J. French, Timothy D. Henry, Lori Hollowell, Edward C. Jauch, Michael C. Kurz, Michael Levy, Puja Patel, Travis Spier, R. Harper Stone, Katie L. Tataris, Randal J. Thomas, Jessica K. Zègre-Hemsey
Journal: Circulation (2021)

The introduction of Mission: Lifeline significantly increased timely access to percutaneous coronary intervention for patients with ST-segment–elevation myocardial infarction (STEMI). In the years since, morbidity and mortality rates have declined, and research has led to significant developments that have broadened our concept of the STEMI system of care. However, significant barriers and opportunities remain. From community education to 9-1-1 activation and emergency medical services triage and from emergency department and interfacility transfer protocols to postacute care, each critical juncture presents unique challenges for the optimal care of patients with STEMI. This policy statement sets forth recommendations for how the ideal STEMI system of care should be designed and implemented to ensure that patients with STEMI receive the best evidence-based care at each stage in their illness.
Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription
Authors: John Pang, Nam Nguyen, Jens Luebeck, Laurel Ball, Andrey Finegersh, Shuling Ren, Takuya Nakagawa, Mitchell Flagg, Sayed Sadat, Paul S. Mischel, Guorong Xu, Kathleen Fisch, Theresa Guo, Gabrielle Cahill, Bharat Panuganti, Vineet Bafna, Joseph Califano
Journal: Clinical Cancer Research (2021)

Human papillomavirus (HPV) plays a major role in oncogenesis and circular extrachromosomal DNA (ecDNA) is found in many cancers. However, the relationship between HPV and circular ecDNA in human cancer is not understood.
Cover Image, Volume 42, Issue 4
Authors: Xiao‐Dong Zhu, Ming‐Zhu Huang, Yu‐Sheng Wang, Wan‐Jing Feng, Zhi‐Yu Chen, Yi‐Fu He, Xiao‐Wei Zhang, Xin Liu, Chen‐Chen Wang, Wen Zhang, Jie‐Er Ying, Jun Wu, Lei Yang, Yan‐Ru Qin, Jian‐Feng Luo, Xiao‐Ying Zhao, Wen‐Hua Li, Zhe Zhang, Li‐Xin Qiu, Qi‐Rong Geng, Jian‐Ling Zou, Jie‐Yun Zhang, Hong Zheng, Xue‐Feng Song, Shu‐Sheng Wu, Cheng‐Yan Zhang, Zhe Gong, Qin‐Qin Liu, Xiao‐Feng Wang, Qi Xu, Qi Wang, Jian‐Mei Ji, Jian Zhao, Wei‐Jian Guo
Journal: Cancer Communications (2022)

The cover image is based on the Original Article XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX) by Wei-Jian Guo et al., https://doi.org/10.1002/cac2.12278.
Lung Microenvironments and Disease Progression in Fibrotic Hypersensitivity Pneumonitis
Authors: Laurens J. De Sadeleer, John E. McDonough, Jonas C. Schupp, Xiting Yan, Arno Vanstapel, Anke Van Herck, Stephanie Everaerts, Vincent Geudens, Annelore Sacreas, Tinne Goos, Celine Aelbrecht, Tim S. Nawrot, Dries S. Martens, Dominique Schols, Sandra Claes, Johny A. Verschakelen, Eric K. Verbeken, Maximilian Ackermann, Anabelle Decottignies, Manon Mahieu, Tillie-Louise Hackett, James C. Hogg, Bart M. Vanaudenaerde, Stijn E. Verleden, Naftali Kaminski, Wim A. Wuyts
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an interstitial lung disease caused by sensitization to an inhaled allergen. Objectives: To identify the molecular determinants associated with progression of fibrosis. Methods: Nine fHP explant lungs and six unused donor lungs (as controls) were systematically sampled (4 samples/lung). According to microcomputed tomography measures, fHP cores were clustered into mild, moderate, and severe fibrosis groups. Gene expression profiles were assessed using weighted gene co-expression network analysis, xCell, gene ontology, and structure enrichment analysis. Gene expression of the prevailing molecular traits was also compared with idiopathic pulmonary fibrosis (IPF). The explant lung findings were evaluated in separate clinical fHP cohorts using tissue, BAL samples, and computed tomography scans. Measurements and Main Results: We found six molecular traits that associated with differential lung involvement. In fHP, extracellular matrix and antigen presentation/sensitization transcriptomic signatures characterized lung zones with only mild structural and histological changes, whereas signatures involved in honeycombing and B cells dominated the transcriptome in the most severely affected lung zones. With increasing disease severity, endothelial function was progressively lost, and progressive disruption in normal cellular homeostatic processes emerged. All six were also found in IPF, with largely similar associations with disease microenvironments. The molecular traits correlated with in vivo disease behavior in a separate clinical fHP cohort. Conclusions: We identified six molecular traits that characterize the morphological progression of fHP and associate with in vivo clinical behavior. Comparing IPF with fHP, the transcriptome landscape was determined considerably by local disease extent rather than by diagnosis alone.
Capecitabine Versus Active Monitoring in Stable or Responding Metastatic Colorectal Cancer After 16 Weeks of First-Line Therapy: Results of the Randomized FOCUS4-N Trial
Authors: Richard A. Adams, David J. Fisher, Janet Graham, Jenny F. Seligmann, Matthew Seymour, Richard Kaplan, Emma Yates, Mahesh Parmar, Susan D. Richman, Philip Quirke, Rachel Butler, Ewan Brown, Fiona Collinson, Stephen Falk, Harpreet Wasan, Kai-Keen Shiu, Gary Middleton, Leslie Samuel, Richard H. Wilson, Louise C. Brown, Timothy S. Maughan
Journal: Journal of Clinical Oncology (2021)

PURPOSE Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy. METHODS FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability. RESULTS Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P &lt; .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups. CONCLUSION Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.
Time for united action on depression: a Lancet–World Psychiatric Association Commission
Authors: Helen Herrman, Vikram Patel, Christian Kieling, Michael Berk, Claudia Buchweitz, Pim Cuijpers, Toshiaki A Furukawa, Ronald C Kessler, Brandon A Kohrt, Mario Maj, Patrick McGorry, Charles F Reynolds, Myrna M Weissman, Dixon Chibanda, Christopher Dowrick, Louise M Howard, Christina W Hoven, Martin Knapp, Helen S Mayberg, Brenda W J H Penninx, Shuiyuan Xiao, Madhukar Trivedi, Rudolf Uher, Lakshmi Vijayakumar, Miranda Wolpert
Journal: The Lancet (2022)
Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAFV600E-Mutant Human Glioma
Authors: Karisa C. Schreck, Andrew Morin, Guisheng Zhao, Amy N. Allen, Patrick Flannery, Michael Glantz, Adam L. Green, Chris Jones, Kenneth L. Jones, Lindsay B. Kilburn, Kellie J. Nazemi, David Samuel, Bridget Sanford, David A. Solomon, Jiawan Wang, Christine A. Pratilas, Theodore Nicolaides, Jean M. Mulcahy Levy
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Selective RAF-targeted therapy is effective in some patients with BRAFV600E-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms. Experimental Design: Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples (N = 15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing (RNA-seq). Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAFV600E-mutant glioma cell lines. Results: Analysis of 15 tissue sample pairs identified 13 alterations conferring putative resistance were identified among nine paired samples (including mutations involving ERRFI1, BAP1, ANKHD1, and MAP2K1). We performed functional validation of mechanisms of resistance, including loss of NF1, PTEN, or CBL, in BRAFV600E-mutant glioma lines, and demonstrate they are capable of conferring resistance in vitro. Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN−/−) restored sensitivity to BRAFi. We identified and validated CRAF upregulation as a mechanism of resistance in one resistant sample. RNA-seq analysis identified two emergent expression patterns in resistant samples, consistent with expression patterns of known glioma subtypes. Conclusions: Resistance mechanisms to BRAFi in glioma are varied and may predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.
Disentangling Signatures of Selection Before and After European Colonization in Latin Americans
Authors: Javier Mendoza-Revilla, J. Camilo Chacón-Duque, Macarena Fuentes-Guajardo, Louise Ormond, Ke Wang, Malena Hurtado, Valeria Villegas, Vanessa Granja, Victor Acuña-Alonzo, Claudia Jaramillo, William Arias, Rodrigo Barquera, Jorge Gómez-Valdés, Hugo Villamil-Ramírez, Caio C. Silva de Cerqueira, Keyla M. Badillo Rivera, Maria A. Nieves-Colón, Christopher R. Gignoux, Genevieve L. Wojcik, Andrés Moreno-Estrada, Tábita Hünemeier, Virginia Ramallo, Lavinia Schuler-Faccini, Rolando Gonzalez-José, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Carla Gallo, Giovanni Poletti, Gabriel Bedoya, Francisco Rothhammer, David Balding, Matteo Fumagalli, Kaustubh Adhikari, Andrés Ruiz-Linares, Garrett Hellenthal
Journal: Molecular Biology and Evolution (2022)

Abstract Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.