tbuckley/cabot-search huggingface dataset:
Extracellular microvesicles/exosomes: discovery, disbelief, acceptance, and the future?
Authors: Mariusz Z. Ratajczak, Janina Ratajczak
Journal: Leukemia (2020)

Abstract There are concepts in science that need time to overcome initial disbelief before finally arriving at the moment when they are embraced by the research community. One of these concepts is the biological meaning of the small, spheroidal vesicles released from cells, which are described in the literature as microparticles, microvesicles, or exosomes. In the beginning, this research was difficult, as it was hard to distinguish these small vesicles from cell debris or apoptotic bodies. However, they may represent the first language of cell–cell communication, which existed before a more specific intercellular cross-talk between ligands and receptors emerged during evolution. In this review article, we will use the term “extracellular microvesicles” (ExMVs) to refer to these small spheroidal blebs of different sizes surrounded by a lipid layer of membrane. We have accepted an invitation from the Editor-in-Chief to write this review in observance of the 20th anniversary of the 2001 ASH Meeting when our team demonstrated that, by horizontal transfer of several bioactive molecules, including mRNA species and proteins, ExMVs harvested from embryonic stem cells could modify hematopoietic stem/progenitor cells and expand them ex vivo. Interestingly, the result that moved ExMV research forward was published first in 2005 in Leukemia , having been previously rejected by other major scientific journals out of simple disbelief. Therefore, the best judge of a new concept is the passage of time, although the speed of its adoption is aided by perseverance and confidence in one’s own data. In this perspective article, we will provide a brief update on the current status of, hopes for, and likely future of ExMV research as well as therapeutic and diagnostic applications, with a special emphasis on hematopoiesis.
Fecal Microbiota Transplantation for multidrug-resistant organism: Efficacy and Response prediction
Authors: Hye Seong, Sang Kil Lee, Jae Hee Cheon, Dong Eun Yong, Hong Koh, Yun Koo Kang, Woo Young Jeong, Woon Ji Lee, Yujin Sohn, Yunsuk Cho, Jong Hoon Hyun, Yae Jee Baek, Moo Hyun Kim, Jung Ho Kim, Jin Young Ahn, Nam Su Ku, Su Jin Jeong, Joon Sup Yeom, Min Seok Cho, Je Hee Lee, Byung-Yong Kim, Jun Yong Choi
Journal: Journal of Infection (2020)
Revealing the Impact of Structural Variants in Multiple Myeloma
Authors: Even H. Rustad, Venkata D. Yellapantula, Dominik Glodzik, Kylee H. Maclachlan, Benjamin Diamond, Eileen M. Boyle, Cody Ashby, Patrick Blaney, Gunes Gundem, Malin Hultcrantz, Daniel Leongamornlert, Nicos Angelopoulos, Luca Agnelli, Daniel Auclair, Yanming Zhang, Ahmet Dogan, Niccolò Bolli, Elli Papaemmanuil, Kenneth C. Anderson, Philippe Moreau, Hervé Avet-Loiseau, Nikhil C. Munshi, Jonathan J. Keats, Peter J. Campbell, Gareth J. Morgan, Ola Landgren, Francesco Maura
Journal: Blood Cancer Discovery (2020)

The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients by low coverage long-insert whole genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (TNFRSF17), SLAMF and MCL1. Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as CCND1 and MYC. Importantly, in 31% of patients two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis.
Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients
Authors: Kazusa Ishii, Marie Pouzolles, Christopher D. Chien, Rebecca A. Erwin-Cohen, M. Eric Kohler, Haiying Qin, Haiyan Lei, Skyler Kuhn, Amanda K. Ombrello, Alina Dulau-Florea, Michael A. Eckhaus, Haneen Shalabi, Bonnie Yates, Daniel A. Lichtenstein, Valérie S. Zimmermann, Taisuke Kondo, Jack F. Shern, Howard A. Young, Naomi Taylor, Nirali N. Shah, Terry J. Fry
Journal: Journal of Clinical Investigation (2020)

Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both CD8+ and CD4+ CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1β and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights.
Niacin Attenuates Pulmonary Hypertension Through H-PGDS in Macrophages
Authors: Daile Jia, Peiyuan Bai, Naifu Wan, Jiao Liu, Qian Zhu, Yuhu He, Guilin Chen, Jing Wang, Han Chen, Chen Wang, Ankang Lyu, Michael Lazarus, Yunchao Su, Yoshihiro Urade, Ying Yu, Jian Zhang, Yujun Shen
Journal: Circulation Research (2020)

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling, accompanied by varying degrees of perivascular inflammation. Niacin, a commonly used lipid-lowering drug, possesses vasodilating and proresolution effects by promoting the release of prostaglandin D 2 (PGD 2 ). However, whether or not niacin confers protection against PAH pathogenesis is still unknown. Objective: This study aimed to determine whether or not niacin attenuates the development of PAH and, if so, to elucidate the molecular mechanisms underlying its effects. Methods and Results: Vascular endothelial growth factor receptor inhibitor SU5416 and hypoxic exposure were used to induce pulmonary hypertension (PH) in rodents. We found that niacin attenuated the development of this hypoxia/SU5416–induced PH in mice and suppressed progression of monocrotaline-induced and hypoxia/SU5416–induced PH in rats through the reduction of pulmonary artery remodeling. Niacin boosted PGD 2 generation in lung tissue, mainly through H-PGDS (hematopoietic PGD 2 synthases). Deletion of H-PGDS, but not lipocalin-type PGDS, exacerbated the hypoxia/SU5416–induced PH in mice and abolished the protective effects of niacin against PAH. Moreover, H-PGDS was expressed dominantly in infiltrated macrophages in lungs of PH mice and patients with idiopathic PAH. Macrophage-specific deletion of H-PGDS markedly decreased PGD 2 generation in lungs, aggravated hypoxia/SU5416–induced PH in mice, and attenuated the therapeutic effect of niacin on PAH. Conclusions: Niacin treatment ameliorates the progression of PAH through the suppression of vascular remodeling by stimulating H-PGDS–derived PGD 2 release from macrophages.
A Case of Primary Sinonasal Yolk Sac Tumor
Authors: Peipei Wang, Guozhu Hou, Fang Li, Xin Cheng
Journal: Clinical Nuclear Medicine (2020)

Yolk sac tumor (YST) is a rare and highly malignant germ cell tumor that is extremely rare in the nasal region. Herein, we present a case of biopsy-proven nasal YST admixed with transitional cell carcinoma in a 58-year-old woman. Complementary F-FDG PET/CT revealed the only FDG-avid mass in the right nasal cavity. This case indicates that YST could occur in the nasal region primarily, and F-FDG PET/CT is a useful tool to distinguish between primary and metastatic lesions.
Reply to Guglielmo Mantica, Nazareno Suardi, and Carlo Terrone’s Letter to the Editor re: Ming-Chun Chan, Sharon E.K. Yeo, Yew-Lam Chong, Yee-Mun Lee. Stepping Forward: Urologists’ Efforts During the COVID-19 Outbreak in Singapore. Eur Urol 2020;78:e38?9
Authors: Ming-Chun Chan, Sharon E.K. Yeo, Yew-Lam Chong, Yee-Mun Lee
Journal: European Urology (2020)
Vericiguat reduced a composite of CV death or HF hospitalization in patients with HF and reduced LVEF
Authors: Tauben Averbuch, Harriette G.C. Van Spall
Journal: Annals of Internal Medicine (2020)

Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med. 2020;382:1883-93. 32222134.
Sepsis-associated severe interleukin-6 storm in critical coronavirus disease 2019
Authors: Lan Huang, Xuan Zhao, Yu Qi, Hong Li, Guanchao Ye, Yafei Liu, Yi Zhang, Jianjun Gou
Journal: Cellular and Molecular Immunology (2020)

Coronavirus disease 2019 (COVID-19) is a respiratory disease caused by a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1,2Due to its high transmission and the lack of effective vaccines or antiviral drugs, this novel infectious disease has changed the social and economic lives of human beings in unprecedented ways.Most COVID-19 infections are mild or even asymptomatic, but the poor prognosis of severe or critically ill patients is still a major challenge.The host immune response is a key determinant for viral clearance.Accumulating evidence suggests that typical lymphopenia and cytokine release syndrome are two features that predict poor prognosis in COVID-19. 3In particular, the levels of blood interleukin-6 (IL-6) are closely correlated with the severity of COVID-19 and have been considered an independent biomarker for predicting poor prognosis. 4However, the sources and dynamics of increased IL-6 in COVID-19 patients remain largely unknown.Here, we reported that septic shock or sepsis was strongly associated with a dramatic rise in blood IL-6 in critical cases and further demonstrated maximal IL-6 levels over a certain threshold as a powerful biomarker for fatal outcomes in COVID-19 patients.A total of 29 severe or critical patients with confirmed COVID-19 infections were admitted to the First Affiliated Hospital of Zhengzhou University, China.The basic characteristics of these patients are shown in Supplementary Table S1.With the development of COVID-19, the levels of blood cytokines might change dynamically.However, blood samples were collected on admission for the detection of plasma cytokines in most reports. 5n this cohort, the frequency of cytokine detection was determined by the treating physicians (range 1-8).The maximal levels of six inflammatory cytokines in COVID-19 patients are shown in Supplementary Table S2.The medians of the maximal plasma IL-2, IL-4, tumor necrosis factor-α (TNF-α), and interferon-γ levels were in the normal range, while the medians of the maximal plasma IL-6 and IL-10 levels were much higher than normal values.Furthermore, the maximal level of plasma IL-10 in the critical group was significantly higher than that in the severe group (median 32.35 pg/ml (interquartile range (IQR) 9.14-49.03)vs. 7.49 pg/ml (IQR 5.95-9.31);P = 0.003).Notably, the maximal level of plasma IL-6 was more significantly increased in critical cases than in severe cases (median 1072.98 pg/ml (IQR 453.85-9163.64)vs. 49.14 pg/ml (IQR 27.98-101.30);P = 0.001).Interestingly, the levels of IL-6 in four patients in the critical group exceeded the upper
Trump appointees tamper with renowned CDC publication, claiming that scientists are trying to “hurt the president”
Authors: Owen Dyer
Journal: BMJ (2020)

Public relations staff installed by the Trump administration at the US Department of Health and Human Services have been seeking to edit or block the key weekly publication of the Centers for Disease Control and Prevention (CDC), claiming that its covid-19 reporting is aimed at hurting the president’s bid for re-election.

The top spokesman of the US health department, assistant secretary of public affairs Michael Caputo, and a scientific advisor he appointed sent peremptory emails to CDC director Robert Redfield demanding changes to the agency’s Morbidity and Mortality Weekly Report ( MMWR ), for decades a fixture of the US public health landscape.1

The emails were shared with the website Politico by three anonymous CDC whistleblowers.2 Redfield has resisted most changes so far, they said, but the public relations appointees have won …
A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress–induced bone loss
Authors: Fan Yang, Yunhui Liu, Shanping Chen, Zhongquan Dai, Dazhi Yang, Dashuang Gao, Jie Shao, Yuyao Wang, Ting Wang, Zhijian Zhang, Lu Zhang, William W. Lu, Yinghui Li, Liping Wang
Journal: Journal of Clinical Investigation (2020)

Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress–induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress–induced mood disorders, such as anxiety, influence bone metabolism.
Clinical characteristics of 345 patients with coronavirus disease 2019 in Japan: A multicenter retrospective study
Authors: Makoto Ishii, Hideki Terai, Hiroki Kabata, Katsunori Masaki, Shotaro Chubachi, Hiroki Tateno, Morio Nakamura, Kazumi Nishio, Hidefumi Koh, Risa Watanabe, Soichiro Ueda, Takeshi Terashima, Yusuke Suzuki, Kazuma Yagi, Naoki Miyao, Naoto Minematsu, Takashi Inoue, Ichiro Nakachi, Ho Namkoong, Satoshi Okamori, Shinnosuke Ikemura, Hirofumi Kamata, Hiroyuki Yasuda, Ichiro Kawada, Naoki Hasegawa, Koichi Fukunaga
Journal: Journal of Infection (2020)
Association Between Reproductive Life Span and Incident Nonfatal Cardiovascular Disease
Authors: Shiva R. Mishra, Hsin-Fang Chung, Michael Waller, Annette J. Dobson, Darren C. Greenwood, Janet E. Cade, Graham G. Giles, Fiona Bruinsma, Mette Kildevæld Simonsen, Rebecca Hardy, Diana Kuh, Ellen B. Gold, Sybil L. Crawford, Carol A. Derby, Karen A. Matthews, Panayotes Demakakos, Jung Su Lee, Hideki Mizunuma, Kunihiko Hayashi, Lynnette L. Sievert, Daniel E. Brown, Sven Sandin, Elisabete Weiderpass, Gita D. Mishra
Journal: JAMA Cardiology (2020)

Early menarche and early menopause are associated with increased risk of cardiovascular disease (CVD) in midlife, but little is known about the association between reproductive life span and the risk of CVD.
Risk Prediction Models for Post‐Operative Mortality in Patients With Cirrhosis
Authors: Nadim Mahmud, Zachary Fricker, Rebecca A. Hubbard, George N. Ioannou, James D. Lewis, Tamar H. Taddei, Kenneth D. Rothstein, Marina Serper, David S. Goldberg, David E. Kaplan
Journal: Hepatology (2020)

Patients with cirrhosis are at increased risk of postoperative mortality. Currently available tools to predict postoperative risk are suboptimally calibrated and do not account for surgery type. Our objective was to use population-level data to derive and internally validate cirrhosis surgical risk models.
5 classes of antihypertensive drugs were not linked to positive COVID-19 test results or severe COVID-19
Authors: Thomas Fekete
Journal: Annals of Internal Medicine (2020)

Source CitationReynolds HR, Adhikari S, Pulgarin C, et al. Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19. N Engl J Med. 2020;382:2441-8. https://pubmed.ncbi.nlm.nih.gov/32356628/AbstractClinical Impact RatingsGIM/FP/GP: Hospitalists: Infectious Disease: Critical Care: Public Health:
Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms
Authors: Chunfang Xie, Julien Slagboom, Laura-Oana Albulescu, Govert W. Somsen, Freek J. Vonk, Nicholas R. Casewell, Jeroen Kool
Journal: Acta Pharmaceutica Sinica B (2020)

Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we investigated the inhibiting effects of the small molecules varespladib (nonspecific phospholipase A2 inhibitor), marimastat (broad spectrum matrix metalloprotease inhibitor) and dimercaprol (metal ion chelator) against coagulopathic toxins found in Crotalinae (pit vipers) snake venoms. Venoms from Bothrops asper, Bothrops jararaca, Calloselasma rhodostoma and Deinagkistrodon acutus were separated by liquid chromatography, followed by nanofractionation and mass spectrometry identification undertaken in parallel. Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study. Anticoagulant venom toxins were mostly identified as phospholipases A2, while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases. Varespladib was found to effectively inhibit most anticoagulant venom effects, and also showed some inhibition against procoagulant toxins. Contrastingly, marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins. The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates, and highlights their potential as future snakebite treatments.
Challenging the “Scoop and Run” Model for Management of Out-of-Hospital Cardiac Arrest
Authors: Alexander X. Lo
Journal: JAMA (2020)

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Pulmonary Vascular Pruning on Computed Tomography and Risk of Death in the Framingham Heart Study
Authors: Andrew J. Synn, Wenyuan Li, Raúl San José Estépar, George R. Washko, George T. O’Connor, Connie W. Tsao, Murray A. Mittleman, Mary B. Rice
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

"Pulmonary Vascular Pruning on Computed Tomography and Risk of Death in the Framingham Heart Study." American Journal of Respiratory and Critical Care Medicine, 203(2), pp. 251–254
Remote Optimization of Guideline-Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Akshay S. Desai, Taylor Maclean, Alexander J. Blood, Joshua Bosque-Hamilton, Jacqueline Dunning, Christina Fischer, Liliana Fera, Katelyn V. Smith, Kavishwar Wagholikar, David Zelle, Thomas Gaziano, Jorge Plutzky, Benjamin Scirica, Calum A. MacRae
Journal: JAMA Cardiology (2020)

Optimal treatment of heart failure with reduced ejection fraction (HFrEF) is scripted by treatment guidelines, but many eligible patients do not receive guideline-directed medical therapy (GDMT) in clinical practice.To determine whether a remote, algorithm-driven, navigator-administered medication optimization program could enhance implementation of GDMT in HFrEF.In this case-control study, a population-based sample of patients with HFrEF was offered participation in a quality improvement program directed at GDMT optimization. Treating clinicians in a tertiary academic medical center who were caring for patients with heart failure and an ejection fraction of 40% or less (identified through an electronic health record-based search) were approached for permission to adjust medical therapy according to a sequential titration algorithm modeled on the current American College of Cardiology/American Heart Association heart failure guidelines. Navigators contacted participants by telephone to direct medication adjustment and conduct longitudinal surveillance of laboratory tests, blood pressure, and symptoms under supervision of a pharmacist, nurse practitioner, and heart failure cardiologist. Patients and clinicians declining to participate served as a control group.Navigator-led remote optimization of GDMT compared with usual care.Proportion of patients receiving GDMT in the intervention and control groups at 3 months.Of 1028 eligible patients (mean [SD] values: age, 68 [14] years; ejection fraction, 32% [8%]; and systolic blood pressure, 122 [18] mm Hg; 305 women (30.0%); 892 individuals [86.8%] in New York Heart Association class I and II), 197 (19.2%) participated in the medication optimization program, and 831 (80.8%) continued with usual care as directed by their treating clinicians (585 [56.9%] general cardiologists; 443 [43.1%] heart failure specialists). At 3 months, patients participating in the remote intervention experienced significant increases from baseline in use of renin-angiotensin system antagonists (138 [70.1%] to 170 [86.3%]; P < .001) and β-blockers (152 [77.2%] to 181 [91.9%]; P < .001) but not mineralocorticoid receptor antagonists (51 [25.9%] to 60 [30.5%]; P = .14). Doses for each category of GDMT also increased from baseline in the intervention group. Among the usual-care group, there were no changes from baseline in the proportion of patients receiving GDMT or the dose of GDMT in any category.Remote titration of GDMT by navigators using encoded algorithms may represent an efficient, population-level strategy for rapidly closing the gap between guidelines and clinical practice in patients with HFrEF.