tbuckley/cabot-search huggingface dataset:
Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Authors: Bappaditya Chandra, Nicole L. Michmerhuizen, Hazheen K. Shirnekhi, Swarnendu Tripathi, Brittany J. Pioso, David W. Baggett, Diana M. Mitrea, Ilaria Iacobucci, Michael R. White, Jingjing Chen, Cheon-Gil Park, Huiyun Wu, Stanley Pounds, Anna Medyukhina, Khaled Khairy, Qingsong Gao, Chunxu Qu, Sherif Abdelhamed, Scott D. Gorman, Simranjot Bawa, Carolyn Maslanka, Swati Kinger, Priyanka Dogra, Mylene C. Ferrolino, Danika Di Giacomo, Cristina Mecucci, Jeffery M. Klco, Charles G. Mullighan, Richard W. Kriwacki
Journal: Cancer Discovery (2021)

NUP98 fusion oncoproteins (FO) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid-liquid phase separation (LLPS) in vitro. A predominant class of NUP98 FOs, including NUP98-HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form and how they drive leukemogenesis. Here we studied NHA9 condensates and show that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three additional leukemia-associated NUP98 FOs (NUP98-PRRX1, NUP98-KDM5A, and NUP98-LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs. We show that homotypic and heterotypic mechanisms of LLPS control NUP98-HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structures. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis. This article is highlighted in the In This Issue feature, p. 873.
Shed CNTNAP2 ectodomain is detectable in CSF and regulates Ca2+ homeostasis and network synchrony via PMCA2/ATP2B2
Authors: M. Dolores Martín-de-Saavedra, Marc Dos Santos, Lorenza Culotta, Olga Varea, Benjamin P. Spielman, Euan Parnell, Marc P. Forrest, Ruoqi Gao, Sehyoun Yoon, Emmarose McCoig, Hiba A. Jalloul, Kristoffer Myczek, Natalia Khalatyan, Elizabeth A. Hall, Liam S. Turk, Antonio Sanz-Clemente, Davide Comoletti, Stefan F. Lichtenthaler, Jeffrey S. Burgdorf, Maria V. Barbolina, Jeffrey N. Savas, Peter Penzes
Journal: Neuron (2021)
Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma
Authors: Liangqing Dong, Dayun Lu, Ran Chen, Youpei Lin, Hongwen Zhu, Zhou Zhang, Shangli Cai, Peng Cui, Guohe Song, Dongning Rao, Xinpei Yi, Yingcheng Wu, Nixue Song, Fen Liu, Yunhao Zou, Shu Zhang, Xiaoming Zhang, Xiaoying Wang, Shuangjian Qiu, Jian Zhou, Shisheng Wang, Xu Zhang, Yongyong Shi, Daniel Figeys, Li Ding, Pei Wang, Bing Zhang, Henry Rodriguez, Qiang Gao, Daming Gao, Hu Zhou, Jia Fan
Journal: Cancer Cell (2021)
State Variation in Potentially Burdensome Transitions Among Assisted Living Residents at the End of Life
Authors: Xiao (Joyce) Wang, Joan M. Teno, Pedro L. Gozalo, David Dosa, Kali S. Thomas, Emmanuelle Bélanger
Journal: JAMA Internal Medicine (2021)

specified for most medical devices (n = 32 of 54 [59%]), but when evidence was cited, it consisted of laboratory data (n = 20 [37%]).The EUAs for drugs and vaccines were supported predominantly by randomized clinical trials (n = 7 of 10 [70%]) (Table 2).Most drugs and vaccines (n = 8 [80%]) were not previously approved by the FDA for other indications.Seventeen products (4%) (ie, 2 drugs, 7 medical devices, 8 diagnostics) were revoked by the FDA mainly because of problems with effectiveness or safety (n = 10 [59%]) after a median (IQR) number of 230 (107-429) days.One drug and 1 vaccine were granted FDA approval.Discussion | Most COVID-19-related EUAs were issued for diagnostic products and supported either by comparisons to various previously authorized assays or by analytical, nonclinical data.Because these diagnostic products were not tested against criterion standard and no evaluation showed that the products correctly identified people with vs without COVID-19 infection, the true sensitivity and specificity as well as realworld frequency of false-positive and false-negative results can only be approximated. 3 Authorizations that were supported by such low-quality data are reasonable at the beginning of a pandemic, when diagnostic products are urgently required.In future public health emergencies, the FDA should consider raising the standard of evidence required for EUAs after several diagnostic products are marketed to ensure their accuracy.Most medical devices were granted EUAs without any documented supporting data, and only a small number were supported by clinical data.Lack of evidence might bring to market devices that are potentially more harmful than beneficial.The rapid uptake of potentially beneficial technologies should be balanced against device-related safety problems. 4 The authorization of chloroquine/hydroxychloroquine use for COVID-19 infection was supported by low-quality retrospective data and was swiftly revoked by the FDA. 5 Regulators should resist political pressure to authorize products that are not supported by high-quality clinical data. 6Doing so might prevent confusion and mistrust in the soundness of medical science and bolster the FDA's reputation. 5 This study has limitations.
Rise in Blood Pressure Observed Among US Adults During the COVID-19 Pandemic
Authors: Luke J. Laffin, Harvey W. Kaufman, Zhen Chen, Justin K. Niles, Andre R. Arellano, Lance A. Bare, Stanley L. Hazen
Journal: Circulation (2021)

ypertension affects almost half of US adults, and blood pressure (BP) control is a national public health priority. 1The coronavirus disease 2019 (COVID-19) pandemic has disrupted both daily life and routine medical care, including the treatment of chronic diseases such as hypertension.Given the unknown impact of the pandemic on BP, this study investigated changes in BP during the pandemic among participants in a US employer-sponsored wellness program.This longitudinal study included employees and their spouses/partners, from all 50 states and the District of Columbia, participating in an annual employer-sponsored wellness program operated by Quest Diagnostics.Participants were required to have BP measured by trained personnel in all 3 years analyzed (2018-2020).The annual BP changes for 2019 versus 2018, January to March 2020 versus 2019, and April to December 2020 versus 2019 were estimated for comparisons between prepandemic (January 2019-March 2020) and pandemic (April-December 2020) periods.Most US jurisdictions put in place COVID-19 stay-at-home orders between mid-March and the start of April 2020, thus establishing prepandemic and pandemic time periods.The mixed model for repeated measures was fitted to assess the adjusted effects of time (pandemic versus prepandemic), sex, and age on changes in BP.Data analyses were performed using SAS Studio 3.6 on SAS version 9.4.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting cross-sectional studies 2 and was deemed exempt by the Western Institutional Review Board in accordance with 45 CFR §160 and §164.
Telomerase reverse transcriptase preserves neuron survival and cognition in Alzheimer’s disease models
Authors: Hong Seok Shim, James W. Horner, Chang-Jiun Wu, Jiexi Li, Zheng D. Lan, Shan Jiang, Xueping Xu, Wen-Hao Hsu, Tomasz Zal, Ivonne I. Flores, Pingna Deng, Yuan-Ta Lin, Li-Huei Tsai, Y. Alan Wang, Ronald A. DePinho
Journal: Nature Aging (2021)
Differences in Cardiovascular Risk, Coronary Artery Disease, and Cardiac Events Between Black and White Individuals Enrolled in the PROMISE Trial
Authors: Lili Zhang, Devvora Olalere, Thomas Mayrhofer, Daniel O. Bittner, Hamed Emami, Nina M. Meyersohn, Stefan B. Puchner, Aiden Abidov, Jamaluddin Moloo, Rowena J. Dolor, Daniel B. Mark, Maros Ferencik, Udo Hoffmann, Pamela S. Douglas, Michael T. Lu
Journal: JAMA Cardiology (2021)

Race and ethnicity have been studied as risk factors in cardiovascular disease. How risk factors, epicardial coronary artery disease, and cardiac events differ between Black and White individuals undergoing noninvasive testing for coronary artery disease is not known.To assess differences in cardiovascular risk burden, coronary plaque, and major adverse cardiac events between Black and White individuals assigned to receive coronary computed tomography angiography (CCTA) or functional testing for stable chest pain.A nested observational cohort study within the PROMISE trial was conducted at 193 outpatient sites in North America. A total of 1071 non-Hispanic Black (hereafter Black) and 7693 non-Hispanic White (hereafter White) participants with stable chest pain undergoing noninvasive cardiovascular testing were included. This analysis was conducted from February 13, 2015, to November 2, 2021.The primary end point was the composite of death, myocardial infarction, or hospitalization for unstable angina over a median follow-up of 24.4 months.Among 1071 Black individuals (12.2%) (women, 646 [60.3%]; mean [SD] age, 59 [8] years) and 7693 White individuals (87.8%) (women, 4029 [52.4%]; mean [SD] age, 61.1 [8.4] years), Black participants had a higher cardiovascular risk burden (more hypertension and diabetes), yet there was a similarly low major adverse cardiovascular events rate over a median 2-year follow-up (32 [3.0%] vs 243 [3.2%]; P = .84). Sensitivity analyses restricted to the 79.8% (6993 of 8764) individuals with a normal or mildly abnormal noninvasive testing result and the 54.3% (4559 of 8396) not receiving statin therapy yielded similar findings. In comparison of Black and White individuals in the CCTA group (n = 3323), significant coronary stenosis (hazard ratio [HR], 7.21; 95% CI, 1.94-26.76 vs HR, 4.30; 95% CI, 2.62-7.04) and high-risk plaque (HR, 3.47; 95% CI, 1.00-12.06 vs HR, 2.21; 95% CI, 1.37-3.57) were associated with major adverse cardiovascular events in both Black and White patients. However, with respect to epicardial coronary artery disease burden, Black individuals had a less-prevalent coronary artery calcium score greater than 0 (45.1% vs 63.2%; P < .001), coronary stenosis greater than or equal to 50% (32 [8.7%] vs 430 [14.6%]; P = .001), and high-risk plaque (139 [37.6%] vs 1547 [52.4%]; P < .001).The findings of this study suggest that, despite a greater cardiovascular risk burden in Black persons, rates of coronary artery calcium, stenosis, and high-risk plaque observed via CCTA were lower in Black persons than White persons. This result suggests differences in cardiovascular risk burden and coronary plaque in Black and White individuals with stable chest pain.
Bispecific antibody-activated T cells enhance NK cell-mediated antibody-dependent cellular cytotoxicity
Authors: Zhaoming Wang, Chaobo Yin, Lawrence G. Lum, Andrean Simons, George J. Weiner
Journal: Journal of Hematology & Oncology (2021)

Resistance to anti-cancer monoclonal antibody (mAb) therapy remains a clinical challenge. Previous work in our laboratory has shown that T cell help in the form of interleukin-2 maintains long-term NK cell viability and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Lack of such T cell help may be a potential mechanism for resistance to mAb therapy. Here, we evaluate whether concomitant treatment with anti-CD3 × anti-cancer bispecific antibodies (bsAbs) can overcome this resistance by enhancing T cell help, and thereby maintaining long-term NK cell-mediated ADCC. Normal donor peripheral blood mononuclear cells were depleted of T cells, replenished with defined numbers of autologous T cells (from 0.75 to 50%) and co-cultured with mono-/bispecific antibody-treated target tumor cells for up to 7 days. At low T cell concentrations, bsAb-activated T cells (mainly CD4+ T cells) were more effective than resting T cells at maintaining NK cell viability and ADCC. Brief (4 h to 2 day) bsAb exposure was sufficient to enhance long-term ADCC by NK cells. These findings raise the hypothesis that local T cell activation mediated by systemic treatment with anti-CD3 X anti-cancer bsAb may enhance the anti-tumor efficacy of monospecific mAbs that mediate their primary therapeutic effect via NK-mediated ADCC.
Disparities in Severe Maternal Morbidity and Mortality—A Call for Inclusion of Disability in Obstetric Research and Health Care Professional Education
Authors: Hilary K. Brown
Journal: JAMA Network Open (2021)

Jessica L. Gleason, PhD, MPH; Jagteshwar Grewal, PhD; Zhen Chen, PhD; Alison N. Cernich, PhD; Katherine L. Grantz, MD, MS
Abstract 11324: Immediate Percutaneous Coronary Intervention in Patients with Refractory Out of Hospital Cardiac Arrest
Authors: Daniel Rob, Jana Smalcova, Tomas Kovarnik, David Zemanek, Ales Kral, Ondrej Smid, Petra Kavalkova, Michael Huptych, Arnost Komarek, Jan Belohavek
Journal: Circulation (2021)

Background: An increasing number of cardiac centres are using immediate percutaneous coronary intervention (PCI) and extracorporeal cardiopulmonary resuscitation (ECPR) in patients with refractory out of hospital cardiac arrest (r-OHCA). Published evidence regarding PCI in OHCA has been mainly reporting to patients with early return of spontaneous circulation and the influence of PCI and ECPR on survival in the population of patients with r-OHCA and acute coronary syndrome (ACS) remains unclear. Methods: In this post hoc analysis of the randomized r-OHCA trial, all patients with ACS as a cause of r-OHCA were included. The effect of successful PCI and ECPR on 180-days survival was examined using Kaplan-Meier estimates and multivariable Cox regression. Results: In total, 256 patients were evaluated in Prague OHCA study and 127 (49.6 %) had ACS as the cause of r-OHCA constituting current study population. The mean age was 58 years (46.3-64) and duration of resuscitation was 52.5 minutes (36.5-68). ECPR was used in 51 (40.2 %) of patients. Immediate PCI was performed in 86 (67.7%) patients and TIMI flow 2 or 3 was achieved in 75 (87.2%) patients. The overall 180-days survival of patients with successful PCI was 40 % compared to 7.7 % with no or failed immediate PCI (log-rank p &lt; 0.001). After adjustment for confounders, successful PCI was associated with a lower risk of death (HR 0.47, CI 0.24-0.93, p = 0.031). Likewise, ECPR was associated with a lower risk of death (HR 0.11, CI 0.05-0.24, p&lt; 0.001). Conclusion: In this post hoc analysis of the randomized r-OHCA trial, successful immediate PCI as well as ECPR were associated with improved 180-days survival in patients with r-OHCA due to ACS.
Abstract 12233: Comparing EMS Witnessed Cardiac Arrest in Germany and Norway
Authors: Ingvild B Tjelmeland, Jo Kramer-johansen, Jan-Thorsten Gräsner, Stephan Seewald
Journal: Circulation (2021)

Introduction: Health registries are a unique source of information about current practice and can describe the burden of disease in a population. However, comparing data from different countries/states we are not always sure if we are comparing patients from similar populations. Method: The aim of this study was to gain a better understanding of the information in the German Resuscitation Registry (GRR) and the Norwegian Cardiac Arrest Registry (NorCAR) through a cross-sectional comparative-study of these two population-based public registries. We included all out-of-hospital cardiac arrest patients witnessed by ambulance personnel, between 1 st January 2015 and 31 st December 2019. Proportions were assessed with Chi-square tests. Results: A total of 3,688 cases from Germany and 2,016 cases from Norway were included in the analysis, resulting in an incidence of 8.6 ambulance witnessed cardiac arrests per 100,000 inhabitants in Germany and 7.8 in Norway. A higher proportion of patients had resuscitation terminated on scene in Norway, 43% vs 30% (p&lt;0.01), while the proportion of patients arriving to hospital with spontaneous circulation was higher in Germany, 49% vs 40% (p&lt;0.01). However, 24-hour survival and the overall survival was higher in Norway, with 24-hour survival of 36% vs 31% (p&lt;0.01), and the overall survival of 28% vs 19% (p&lt;0.01). Conclusion: The incidence of cardiac arrests observed by ambulance personnel was higher in Germany, but survival was higher in Norway. We speculate that the major difference between countries is in the post-resuscitation care after admission to hospital.
Key tips for using computer-aided diagnosis in colonoscopy – observations from two different platforms
Authors: Chieh Sian Koo, Dmitrii Dolgunov, Calvin Jianyi Koh
Journal: Endoscopy (2021)

There is an artificial intelligence (AI) revolution in the field of endoscopy. The use of computer-aided detection (CADe) and diagnosis (CADx) to replicate expert-level interpretation of colon polyps makes AI an attractive tool for both novice and experienced endoscopists to have in their armamentarium. Its clinical utility is further supported by two systematic reviews demonstrating a consistent increase in adenoma detection rate compared to conventional colonoscopy [1] [2]. Several large prospective studies have also shown that CADx may also be used in a "diagnose-and-leave" strategy for benign hyperplastic polyps which could save both time and money [3].
Authors’ Reply
Authors: Raymond C. Harris, Ming-Zhi Zhang
Journal: Journal of the American Society of Nephrology (2021)

We appreciate Liu and Zhang's interest in our recent study. We agree that, given previous studies by Lassen et al .[1][1] and Lorenz et al .,[2][2] our findings that selective myeloid deletion of interferon regulatory factor 4 (IRF4) decreased development of tubulointerstitial fibrosis[3][3] after
A Phase II Study to Investigate the Efficacy and Safety of Eltrombopag in Combination with Dexamethasone As First-Line Treatment in Adults Patients with Newly Diagnosed Primary ITP (XPAG-ITP)
Authors: Mascha Binder, Axel Matzdorff, Falk Nimmerjahn, Mathias Rummel, Oliver Meyer, Tamara Tesanovic, Tanja Sauer
Journal: Blood (2021)
Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer
Authors: Ying Jin, Yamei Chen, Huarong Tang, Xiao Hu, Shawna M. Hubert, Qian Li, Dan Su, Haimiao Xu, Yun Fan, Xinmin Yu, Qixun Chen, Jinshi Liu, Wei Hong, Yujin Xu, Huan Deng, Dapeng Zhu, Pansong Li, Yuhua Gong, Xuefeng Xia, Carl M. Gay, Jianjun Zhang, Ming Chen
Journal: Clinical Cancer Research (2021)

Here, we have investigated treatment resistance mechanisms in small cell lung cancer (SCLC) by focusing on comparing the genotype and phenotype in tumor samples of treatment-resistant and treatment-sensitive SCLC.We conducted whole-exome sequencing on paired tumor samples at diagnosis and relapse from 11 patients with limited-stage (LS)-SCLC and targeted sequencing of 1,021 cancer-related genes on cell-free DNA at baseline and paired relapsed samples from 9 additional patients with LS-SCLC. Furthermore, we performed label-free mass spectrometry-based proteomics on tumor samples from 28 chemo-resistant and 23 chemo-sensitive patients with extensive-stage (ES)-SCLC. The main findings were validated in vitro in chemo-sensitive versus chemo-resistant SCLC cell lines and analyses of transcriptomic data of SCLC cell lines from a public database.Genomic analyses demonstrated that at relapse of LS-SCLC, genes in the PI3K/AKT signaling pathway were enriched for acquired somatic mutations or high-frequency acquired copy-number variants. Pathway analysis on differentially upregulated proteins from ES-SCLC cohort revealed enrichment in the HIF-1 signaling pathway. Importantly, 7 of 62 PI3K/AKT pathway genes containing acquired somatic copy-number amplifications were enriched in HIF-1 pathway. Analyses of transcriptomic data of SCLC cell lines from public databases confirmed upregulation of PI3K/AKT and HIF-1 pathways in chemo-resistant SCLC cell lines. Furthermore, chemotherapy-resistant cell lines could be sensitive to PI3K inhibitors in vitro.PI3K/AKT pathway activation may be one potential mechanism underlying therapeutic resistance of SCLC. This finding warrants further investigation and provides a possible approach to reverse resistance to chemo/radiotherapy.
Post-TKA abelacimab reduced VTE at 8 to 12 d compared with enoxaparin
Authors: Andrew S. Dunn
Journal: Annals of Internal Medicine (2021)

ACP Journal ClubDecember 2021Post-TKA abelacimab reduced VTE at 8 to 12 d compared with enoxaparinAndrew S. Dunn, MD, MPHAndrew S. Dunn, MD, MPHIcahn Mount Sinai School of Medicine, New York, New York, USA (A.S.D.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202112210-136 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationVerhamme P, Yi BA, Segers A, et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med. 2021;385:609-17. https://pubmed.ncbi.nlm.nih.gov/34297496Clinical Impact RatingsGIM/FP/GP: References1. Weitz JI, Bauersachs R, Becker B, et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty. JAMA. 2020;323:130-9. [PMID: 31935028] Google Scholar2. Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107:I9-16. [PMID: 12814980] Google Scholar Author, Article, and Disclosure InformationAffiliations: Icahn Mount Sinai School of Medicine, New York, New York, USA (A.S.D.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-7323.This article was published at Annals.org on 7 December 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics December 2021Volume 174, Issue 12Page: JC136 ePublished: 7 December 2021 Issue Published: December 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...