tbuckley/cabot-search huggingface dataset:
Adverse drug interactions
Journal: JAMA (1972)

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Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19
Authors: Younes Zaid, Florian Puhm, Isabelle Allaeys, Abdallah Naya, Mounia Oudghiri, Loubna Khalki, Youness Limami, Nabil Zaid, Khalid Sadki, Rafiqua Ben El Haj, Wissal Mahir, Lamiae Belayachi, Bouchra Belefquih, Amina Benouda, Amine Cheikh, Marc-André Langlois, Yahia Cherrah, Louis Flamand, Fadila Guessous, Eric Boilard
Journal: Circulation Research (2020)

In addition to the overwhelming lung inflammation that prevails in COVID-19, hypercoagulation and thrombosis contribute to the lethality of subjects infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Platelets are chiefly implicated in thrombosis. Moreover, they can interact with viruses and are an important source of inflammatory mediators. While a lower platelet count is associated with severity and mortality, little is known about platelet function during COVID-19.
Immune asynchrony in COVID-19 pathogenesis and potential immunotherapies
Authors: Ting Zhou, Tina Tianjiao Su, Tenny Mudianto, Jun Wang
Journal: The Journal of Experimental Medicine (2020)

The outbreak of coronavirus disease 2019 (COVID-19) is an unprecedented global health crisis. Tissue and peripheral blood analysis indicate profound, aberrant myeloid cell activation, cytokine storm, and lymphopenia, with unknown immunopathological mechanisms. Spatiotemporal control of the quality and quantity of the antiviral immune responses involves synchronized cellular and molecular cascades and cross-talk between innate and adaptive immunity. Dysregulated responses in immunity, such as at the stages of immune sensing, alarming, polarization, and resolution, may contribute to disease pathology. Herein, we approach SARS-CoV-2 through an immunomodulatory lens, discussing possible mechanisms of the asynchronized antiviral immune response and proposing potential therapeutic strategies to correct the dysregulation.
Activity of transgene-produced B-domain–deleted factor VIII in human plasma following AAV5 gene therapy
Authors: Steffen Rosen, Stefan Tiefenbacher, Mary Robinson, Mei Huang, Jaydeep Srimani, Donnie Mackenzie, Terri Christianson, K. John Pasi, Savita Rangarajan, Emily Symington, Adam Giermasz, Glenn F. Pierce, Benjamin Kim, Stephen J. Zoog, Christian Vettermann
Journal: Blood (2020)
Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer
Authors: Christopher Mackintosh, Chen Yuan, Fang-Shu Ou, Sui Zhang, Donna Niedzwiecki, I-Wen Chang, Bert H. O’Neil, Brian C. Mullen, Heinz-Josef Lenz, Charles D. Blanke, Alan P. Venook, Robert J. Mayer, Charles S. Fuchs, Federico Innocenti, Andrew B. Nixon, Richard M. Goldberg, Eileen M. O’Reilly, Jeffrey A. Meyerhardt, Kimmie Ng
Journal: JAMA Oncology (2020)

<h3>Importance</h3> Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown. <h3>Objective</h3> To evaluate the association of coffee consumption with disease progression and death in patients with advanced or metastatic colorectal cancer. <h3>Design, Setting, and Participants</h3> This prospective observational cohort study included 1171 patients with previously untreated locally advanced or metastatic colorectal cancer who were enrolled in Cancer and Leukemia Group B (Alliance)/SWOG 80405, a completed phase 3 clinical trial comparing the addition of cetuximab and/or bevacizumab to standard chemotherapy. Patients reported dietary intake using a semiquantitative food frequency questionnaire at the time of enrollment. Data were collected from October 27, 2005, to January 18, 2018, and analyzed from May 1 to August 31, 2018. <h3>Exposures</h3> Consumption of total, decaffeinated, and caffeinated coffee measured in cups per day. <h3>Main Outcomes and Measures</h3> Overall survival (OS) and progression-free survival (PFS). <h3>Results</h3> Among the 1171 patients included in the analysis (694 men [59%]; median age, 59 [interquartile range, 51-67] years). The median follow-up time among living patients was 5.4 years (10th percentile, 1.3 years; IQR, 3.2-6.3 years). A total of 1092 patients (93%) had died or had disease progression. Increased consumption of coffee was associated with decreased risk of cancer progression (hazard ratio [HR] for 1-cup/d increment, 0.95; 95% CI, 0.91-1.00;<i>P</i> = .04 for trend) and death (HR for 1-cup/d increment, 0.93; 95% CI, 0.89-0.98;<i>P</i> = .004 for trend). Participants who consumed 2 to 3 cups of coffee per day had a multivariable HR for OS of 0.82 (95% CI, 0.67-1.00) and for PFS of 0.82 (95% CI, 0.68-0.99), compared with those who did not drink coffee. Participants who consumed at least 4 cups of coffee per day had a multivariable HR for OS of 0.64 (95% CI, 0.46-0.87) and for PFS of 0.78 (95% CI, 0.59-1.05). Significant associations were noted for both caffeinated and decaffeinated coffee. <h3>Conclusions and Relevance</h3> Coffee consumption may be associated with reduced risk of disease progression and death in patients with advanced or metastatic colorectal cancer. Further research is warranted to elucidate underlying biological mechanisms.
Ventricular Tachycardia Storm in a Patient Treated With Ibrutinib for Waldenstrom Macroglobulinemia
Authors: Anantha Sriharsha Madgula, Meghana Singh, Mansour Almnajam, Christopher C. Pickett, Agnes S. Kim
Journal: JACC CardioOncology (2020)

A 68-year-old Caucasian man with a history of Waldenstrom macroglobulinemia (WM) on treatment with ibrutinib for 2 years presented with syncope. He had no prior cardiovascular history or risk factors. On the day of presentation, he had an episode of dizziness followed by a sudden loss of
A polyclonal allelic expression assay for detecting regulatory effects of transcript variants
Authors: Margot Brandt, Alper Gokden, Marcello Ziosi, Tuuli Lappalainen
Journal: Genome Medicine (2020)

Abstract We present an assay to experimentally test the regulatory effects of genetic variants within transcripts using CRISPR/Cas9 followed by targeted sequencing. We applied the assay to 32 premature stop-gained variants across the genome and in two Mendelian disease genes, 33 putative causal variants of eQTLs, and 62 control variants in HEK293T cells, replicating a subset of variants in HeLa cells. We detected significant effects in the expected direction (in 60% of variants), demonstrating the ability of the assay to capture regulatory effects of eQTL variants and nonsense-mediated decay triggered by premature stop-gained variants. The results suggest a utility for validating transcript-level effects of genetic variants.
A crucial role for Jagunal homolog 1 in humoral immunity and antibody glycosylation in mice and humans
Authors: Astrid Hagelkruys, Gerald Wirnsberger, Johannes Stadlmann, Miriam Wöhner, Marion Horrer, Bojan Vilagos, Gustav Jonsson, Melanie Kogler, Luigi Tortola, Maria Novatchkova, Peter Bönelt, David Hoffmann, Rubina Koglgruber, Ulrike Steffen, Georg Schett, Meinrad Busslinger, Andreas Bergthaler, Christoph Klein, Josef M. Penninger
Journal: The Journal of Experimental Medicine (2020)

Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.
Pancreatic Schwannoma on FDG PET/CT
Authors: Xuezhu Wang, Jingqiao Lv, Chao Fu, Xiaoyan Chang, Li Huo
Journal: Clinical Nuclear Medicine (2020)

A 55-year-old woman underwent FDG PET/CT to evaluate a pancreatic mass. The images showed elevated FDG activity in the uncinated process of the pancreas, suggestive of malignancy. However, pathological examination from the resected lesion demonstrated pancreatic schwannoma.
Precision medicine in nonalcoholic fatty liver disease: New therapeutic insights from genetics and systems biology
Authors: Silvia Sookoian, Carlos J. Pirola
Journal: Clinical and Molecular Hepatology (2020)

Despite more than two decades of extensive research focusing on nonalcoholic fatty liver disease (NAFLD), no approved therapy for steatohepatitis—the severe histological form of the disease—presently exists. More importantly, new drugs and small molecules with diverse molecular targets on the pathways of hepatocyte injury, inflammation, and fibrosis cannot achieve the primary efficacy endpoints. Precision medicine can potentially overcome this issue, as it is founded on extensive knowledge of the druggable genome/proteome. Hence, this review summarizes significant trends and developments in precision medicine with a particular focus on new potential therapeutic discoveries modeled via systems biology approaches. In addition, we computed and simulated the potential utility of the NAFLD polygenic risk score, which could be conceptually very advantageous not only for early disease detection but also for implementing actionable measures. Incomplete knowledge of the druggable NAFLD genome severely impedes the drug discovery process and limits the likelihood of identifying robust and safe drug candidates. Thus, we close this article with some insights into emerging disciplines, such as chemical genetics, that may accelerate accurate identification of the druggable NAFLD genome/proteome.
Belimumab as Add-on Therapy in Lupus Nephritis
Authors: Michael Ward, Maria G. Tektonidou
Journal: New England Journal of Medicine (2020)

Nephritis, the most common serious manifestation of systemic lupus erythematosus (SLE), affects up to 50% of patients with this condition. Proliferative lupus nephritis typically manifests with microscopic hematuria, nonnephrotic proteinuria, renal insufficiency, and hypertension, whereas membranous lupus nephropathy manifests with nephrotic syndrome. Current treatment for proliferative lupus nephritis involves intensive immunosuppression, usually with cyclophosphamide or mycophenolate mofetil and high-dose glucocorticoids in a 3-to-6-month induction period, followed by a maintenance period of less intensive immunosuppression. Most patients have an initial response, but relapses are common, and treatment-resistant disease often occurs. Although long-term outcomes have improved since the 1980s, the development of . . .
The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1
Authors: Ranjan Batra, David A. Nelles, Daniela M. Roth, Florian Krach, Curtis A. Nutter, Takahiro Tadokoro, James D. Thomas, Łukasz J. Sznajder, Steven M. Blue, Haydee L. Gutierrez, Patrick Liu, Stefan Aigner, Oleksandr Platoshyn, Atsushi Miyanohara, Martin Marsala, Maurice S. Swanson, Gene W. Yeo
Journal: Nature Biomedical Engineering (2020)
Association Between Congenital Cytomegalovirus and the Prevalence at Birth of Microcephaly in the United States
Authors: Chelsea J. Messinger, Marc Lipsitch, Brian T. Bateman, Mengdong He, Krista F. Huybrechts, Sarah MacDonald, Helen Mogun, Katrina Mott, Sonia Hernández-Díaz
Journal: JAMA Pediatrics (2020)

<h3>Importance</h3> Congenital cytomegalovirus (cCMV) has received far less clinical and public health attention as a teratogenic infection than the Zika virus epidemic. However, cCMV may be responsible for a large fraction of microcephaly cases in the United States. <h3>Objective</h3> To evaluate the association between cCMV and the prevalence at birth of microcephaly in the United States. <h3>Design, Setting, and Participants</h3> This population-based cohort study included pregnant women and their newborns identified in 2 insurance claims databases from the United States: Medicaid Analytic eXtract (January 1, 2000, to December 31, 2013) and IBM Research MarketScan, a database for employer-sponsored private health insurance (January 1, 2011, to September 30, 2015). All pregnancies that resulted in live births in women with full health benefits were included. Analysis began June 2016 and ended May 2020. <h3>Exposures</h3> Congenital cytomegalovirus infection documented in inpatient or outpatient newborn claims records. <h3>Main Outcomes and Measures</h3> The primary outcome was microcephaly at birth documented in inpatient or outpatient newborn and/or maternal claims records. Cases with chromosomal abnormalities or neural tube defects were excluded. The association between cCMV and microcephaly was estimated in the pooled cohort using prevalence ratios (PRs) and 95% CIs. <h3>Results</h3> In the pooled cohort of 2 338 580 pregnancies (2 075 410 pregnancies [88.7%] were among women younger than 35 years), 336 infants (0.014%) had a cCMV diagnosis. The prevalence of microcephaly among newborns with and without a cCMV diagnosis was 655 and 2.8 per 10 000 live births, respectively (PR, 232; 95% CI, 154-350). After restricting to CMV-tested newborns (572 [0.024%]) to correct for preferential testing of infants with microcephaly, the PR was 15 (95% CI, 5.2-41). However, this PR is biased if other cCMV-related outcomes (eg, hearing loss) trigger testing because cCMV prevalence in tested infants, with ([46%]) or without microcephaly (22 of 559 [3.9%]), would overestimate that in the source population. Therefore, the prevalence of cCMV in overall infants with microcephaly (22 of 669 [3.2%]) was compared with that from an external unbiased sample of US infants screened at birth (449 of 100 332 [0.45%]) to estimate a PR of 7.4 (95% CI, 4.8-11.5) as a conservative lower bound. <h3>Conclusions and Relevance</h3> Congenital cytomegalovirus infection increases the prevalence of microcephaly at birth by at least 7-fold. Prevention of CMV infection during pregnancy might substantially reduce the number of newborns with microcephaly and other cCMV-related outcomes in the United States.
The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions
Authors: Mari Takalo, Rebekka Wittrahm, Benedikt Wefers, Samira Parhizkar, Kimmo Jokivarsi, Teemu Kuulasmaa, Petra Mäkinen, Henna Martiskainen, Wolfgang Wurst, Xianyuan Xiang, Mikael Marttinen, Pekka Poutiainen, Annakaisa Haapasalo, Mikko Hiltunen, Christian Haass
Journal: Molecular Neurodegeneration (2020)

Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer's disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD.To assess the role of the protective variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing.Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice.The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.
10-year follow-up and biomarker discovery for adjuvant endocrine therapy; results of the TEAM trial
Authors: E.J. Blok, M.G.M. Derks, P.J.K. Kuppen, E.M.M.K. Kranenbarg, C.C. Engels, G.J. Liefers, H. Putter, C.M. Seynaeve, J.R. Kroep, J.W.R. Nortier, D.W. Rea, A. Hasenburg, C.J. Markopoulos, R. Paridaens, J.M.S. Bartlett, C.J.H. van de Velde
Journal: Cancer Research (2017)
Doxorubicin-Induced Oxidative Stress and Endothelial Dysfunction in Conduit Arteries Is Prevented by Mitochondrial-Specific Antioxidant Treatment
Authors: Zachary S. Clayton, Vienna E. Brunt, David A. Hutton, Nicholas S. VanDongen, Angelo D’Alessandro, Julie A. Reisz, Brian P. Ziemba, Douglas R. Seals
Journal: JACC CardioOncology (2020)

Doxorubicin (DOXO) chemotherapy increases risk for cardiovascular disease in part by inducing endothelial dysfunction in conduit arteries. However, the mechanisms mediating DOXO-associated endothelial dysfunction in (intact) arteries and treatment strategies are not established. We tested the hypothesis that DOXO impairs endothelial function in conduit arteries via excessive mitochondrial reactive oxygen species (ROS) and that these effects could be prevented by treatment with a mitochondrial-targeted antioxidant (MitoQ). Endothelial function (endothelium-dependent dilation [EDD] to acetylcholine) and vascular mitochondrial ROS were assessed 4 weeks following administration (10 mg/kg intraperitoneal injection) of DOXO. A separate cohort of mice received chronic (4 weeks) oral supplementation with MitoQ (drinking water) for 4 weeks following DOXO. EDD in isolated pressurized carotid arteries was 55% lower 4 weeks following DOXO (peak EDD, DOXO: 42 ± 7% vs. sham: 94 ± 3%; p = 0.006). Vascular mitochondrial ROS was 52% higher and manganese (mitochondrial) superoxide dismutase was 70% lower after DOXO versus sham (p = 0.0008). Endothelial function was rescued by administration of the mitochondrial-targeted antioxidant, MitoQ, to the perfusate. Exposure to plasma from DOXO-treated mice increased mitochondrial ROS in cultured endothelial cells. Analyses of plasma showed differences in oxidative stress-related metabolites and a marked reduction in vascular endothelial growth factor A in DOXO mice, and restoring vascular endothelial growth factor A to sham levels normalized mitochondrial ROS in endothelial cells incubated with plasma from DOXO mice. Oral MitoQ supplementation following DOXO prevented the reduction in EDD (97 ± 1%; p = 0.002 vs. DOXO alone) by ameliorating mitochondrial ROS suppression of EDD. DOXO-induced endothelial dysfunction in conduit arteries is mediated by excessive mitochondrial ROS and ameliorated by mitochondrial-specific antioxidant treatment. Mitochondrial ROS is a viable therapeutic target for mitigating arterial dysfunction with DOXO.
Twice-weekly topical calcipotriene/betamethasone dipropionate foam as proactive management of plaque psoriasis increases time in remission and is well tolerated over 52 weeks (PSO-LONG trial)
Authors: Mark Lebwohl, Leon Kircik, Jean-Philippe Lacour, Monika Liljedahl, Charles Lynde, Marie Holst Mørch, Kim A. Papp, Jean-Luc Perrot, Linda Stein Gold, Amrit Takhar, Diamant Thaçi, Richard B. Warren, Andreas Wollenberg
Journal: Journal of the American Academy of Dermatology (2020)

Topical psoriasis treatment relies on a reactive rather than a long-term proactive approach to disease relapse.Assess long-term efficacy and safety of proactive psoriasis management with twice-weekly calcipotriene 0.005%/betamethasone dipropionate 0.064% (Cal/BD) foam.Phase III trial (NCT02899962) included a 4-week open-label lead-in phase (Cal/BD foam once daily) and a 52-week, randomized, double-blind, maintenance phase. A total of 545 patients achieved treatment success (physician's global assessment "clear"/"almost clear," ≥2-grade improvement from baseline) and were randomized to proactive management (Cal/BD foam; n = 272) or reactive management (vehicle foam; n = 273) twice-weekly, with rescue treatment of Cal/BD foam once daily for 4 weeks upon relapse. Primary endpoint was time to first relapse (physician's global assessment "mild" or higher).A total of 251 randomized patients (46.1%) completed the trial. Median time to first relapse was 56 days (proactive) and 30 days (reactive). Patients in the proactive group had an additional 41 days in remission compared with the reactive group over 1 year (P < .001). Number of relapses per year of exposure was 3.1 (proactive) and 4.8 (reactive). Cal/BD foam was well tolerated.Maintenance phase dropout rate (53.9%) was within the expected range but provides challenges in statistical analysis.Long-term proactive management with Cal/BD foam demonstrated superior efficacy vs reactive management.
SARS-CoV-2 in the kidney: bystander or culprit?
Authors: Anitha Vijayan, Benjamin D. Humphreys
Journal: Nature Reviews Nephrology (2020)

A new study examined post-mortem kidney tissue from 63 patients with COVID-19. The results suggest that SARS-CoV-2 has kidney tropism, including the ability to replicate in kidney cells, and that kidney transduction by SARS-CoV-2 is associated with shorter survival time and increased incidence of acute kidney injury.
Corrigendum to: “Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma” [J Hepatol (2020) 121-129]
Authors: Nalee Kim, Jason Cheng, Inkyung Jung, Ja Der Liang, Yu Lueng Shih, Wen-Yen Huang, Tomoki Kimura, Victor H.F. Lee, Zhao Chong Zeng, Ren Zhenggan, Chul Seung Kay, Seok Jae Heo, Jong Yoon Won, Jinsil Seong
Journal: Journal of Hepatology (2020)
HIV Pre-exposure Prophylaxis Medication Sharing Among HIV-Negative Men Who Have Sex With Men
Authors: Gordon Mansergh, Kenneth Mayer, Sabina Hirshfield, Rob Stephenson, Patrick Sullivan
Journal: JAMA Network Open (2020)

This cross-sectional study used data from the M-Cubed randomized clinical trial to assess the prevalence of pre-exposure prophylaxis (PrEP) medication sharing among HIV-negative men who have sex with men.