tbuckley/cabot-search huggingface dataset:
Letter by Wu et al Regarding Article, “Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis”
Authors: Zhenguo Wu, Wencheng Zhang, Jianmin Yang
Journal: Circulation (2021)

We read with great interest the recent article by Jeon et al, 1 in which they revealed that Ninj1 (nerve injury-induced protein-1) is a matrix metalloproteinase 9 substrate, and the absence of Ninj1 exerts a proinflammatory effect by enhancing mitogen-activated protein kinase signaling and blocking the phosphoinositide 3-kinase/protein kinase B pathway in macrophages.They further showed that soluble Ninj1-mimetic peptides acted as anti-inflammatory mediators of macrophages and attenuated monocyte recruitment and atherosclerosis.Their results showed the important role of the soluble form of an adhesion molecule as a therapeutic target for atherosclerosis.However, there are some aspects that, in our opinion, need further research.A previous study described that Ninj1 reduced leukocyte recruitment into lesion sites and exerted an anti-inflammatory effect, 2 and another study showed Ninj1 mediated the activation of mitogen-activated protein kinase signaling and the inhibition of phosphoinositide 3-kinase/protein kinase B signaling, 3 which were at opposite poles of this article.Therefore, more studies should be performed to explore the reason for the differences.In addition, a previous study showed that Ninj1 was expressed in endothelial cells and mediated endothelial dysfunction. 3 It would be interesting to explore the function of endothelium-derived Ninj1 in atherosclerosis.Ninj1 also showed a high expression in hepatocellular carcinoma 4 and exerted its oncogenic function by repressing p53-dependent growth suppression. 5Thus, the safety of soluble Ninj1-mimetic peptides in treating atherosclerosis also needs further research.
Genetic Variants of SARS-CoV-2: What Do We Know So Far?
Authors: Shazia Jamil, Shirin Shafazand, Susan Pasnick, W. Graham Carlos, Ryan Maves, Charles Dela Cruz
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Genetic Variants of SARS-CoV-2: What Do We Know So Far?." American Journal of Respiratory and Critical Care Medicine, 203(12), pp. P30–P32
The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions
Authors: Samantha Christine Sernoskie, Alison Jee, Jack Paul Uetrecht
Journal: Pharmacological Reviews (2021)

Idiosyncratic drug reactions (IDRs) range from relatively common, mild reactions to rarer, potentially life-threatening adverse effects that pose significant risks to both human health and successful drug discovery. Most frequently, IDRs target the liver, skin, and blood or bone marrow. Clinical data indicate that most IDRs are mediated by an adaptive immune response against drug-modified proteins, formed when chemically reactive species of a drug bind to self-proteins, making them appear foreign to the immune system. Although much emphasis has been placed on characterizing the clinical presentation of IDRs and noting implicated drugs, limited research has focused on the mechanisms preceding the manifestations of these severe responses. Therefore, we propose that to address the knowledge gap between drug administration and onset of a severe IDR, more research is required to understand IDR-initiating mechanisms; namely, the role of the innate immune response. In this review, we outline the immune processes involved from neoantigen formation to the result of the formation of the immunologic synapse and suggest that this framework be applied to IDR research. Using four drugs associated with severe IDRs as examples (amoxicillin, amodiaquine, clozapine, and nevirapine), we also summarize clinical and animal model data that are supportive of an early innate immune response. Finally, we discuss how understanding the early steps in innate immune activation in the development of an adaptive IDR will be fundamental in risk assessment during drug development. <h3>Significance Statement</h3> Although there is some understanding that certain adaptive immune mechanisms are involved in the development of idiosyncratic drug reactions, the early phase of these immune responses remains largely uncharacterized. The presented framework refocuses the investigation of IDR pathogenesis from severe clinical manifestations to the initiating innate immune mechanisms that, in contrast, may be quite mild or clinically silent. A comprehensive understanding of these early influences on IDR onset is crucial for accurate risk prediction, IDR prevention, and therapeutic intervention.
Abstract 15980: Associations of Anemia With Stroke, Bleeding, and Mortality in Atrial Fibrillation: A Systematic Review and Meta-analyses
Authors: Samuel J Tu, Nicole Hanna-Rivero, Adrian D Elliott, Nicholas Clarke, Sonia Huang, Bradley M Pitman, Celine Gallagher, Rajiv Mahajan, Dennis H Lau, Prashanthan Sanders, Christopher X Wong
Journal: Circulation (2020)

Background: Anemia frequently co-exists with atrial fibrillation (AF). We performed a systematic review and meta-analyses to comprehensively assess the effect of anemia on stroke/systemic thromboembolism, bleeding, and mortality in patients with AF. Methods: MEDLINE and Embase were searched until May 2020. Cohort studies and secondary analyses of randomised controlled trials examining the association of anemia with the above outcomes in AF were included and random-effects meta-analyses of reported hazard ratios were undertaken. Results: Twenty-eight studies involving 365,484 patients with mean follow-up of 2.0 years were included. Of the studies that provided the relevant information, 41% of patients were female, mean age was 74.7 years, 76% were on oral anticoagulation, and prevalence of anemia was 16%. Anemia was associated with a 78% increase in all-cause mortality (HR 1.78, 95% CI 1.44-2.20), a 15% increase in stroke/systemic thromboembolism (HR 1.15, 95% CI 1.01-1.31), and a 78% increase in major bleeding (HR 1.78, 95% CI 1.54-2.05). Including studies that reported odds ratios and excluding conference abstracts did not discernibly alter the results. Between-study heterogeneity was substantial in the majority of meta-analyses performed. Additional meta-analyses for cardiovascular/non-cardiovascular mortality and gastrointestinal bleeding as outcomes, and using hemoglobin as a continuous predictor, yielded similar results. Conclusion: Anemia is common in patients with AF and is associated with an increased risk of stroke/systemic thromboembolism, major bleeding, and all-cause mortality. Future studies are required to explore the causes of anemia in AF, and whether further investigation and treatment may be clinically beneficial in affected individuals.
Abstract 15126: Myocardial Tissue Reverse Remodeling After Guideline-directed Medical Therapy in Idiopathic Dilated Cardiomyopathy
Authors: Pengfei Yue, Yuanwei Xu, Yangjie Li, Xiaoyue Zhou, Yucheng Chen
Journal: Circulation (2020)

Background: The prognosis of idiopathic dilated cardiomyopathy (DCM) patients has improved remarkably in the recent decades with guideline-directed medical therapy (GDMT) and some patients undergo left ventricular reverse remodeling (LVRR). Objectives: We aim to study the dynamic changes of myocardial tissue characteristics by cardiovascular magnetic resonance (CMR), and investigate the association between myocardial tissue characteristics and cardiac functional remodeling in DCM patients after treatment. Methods: A total of 133 prospectively and consecutively enrolled DCM patients underwent baseline and follow-up CMR examinations with a median interval of 13.7 months (IQR: 12.2-18.5 months). The CMR protocol included cine, late gadolinium enhancement (LGE), pre- and post-contrast T1, and T2 mapping. LVRR was defined as an absolute increase in LV ejection fraction (EF) of &gt;10% to a final value of ≥ 35% with a relative decrease in LV end-diastolic volume (EDV) of &gt;10%. Results: Forty-two (31.6%) patients experienced LVRR during follow-up. At baseline, new onset heart failure, lower LVEF and the absence of LGE were independent predictors of LVRR. Patients with LVRR showed significant decrease of myocardial native T1, indexed matrix and cell volumes, while patients without LVRR also showed significant albeit smaller decrease of native T1 and indexed matrix and cell volumes. The changes of myocardial tissue characteristics were significantly correlated with the improvement of LVEF and indexed LVEDV. Conclusions: In idiopathic DCM patients, significant improvements in myocardial tissue characteristics were observed and accompanied with the improvement in LVEF and reduction in indexed LVEDV after GDMT.
Abstract 17473: GRK2 in the Mitochondria: Uncovering Novel Mechanisms in Heart Failure
Authors: Kimberly M Ferrero, Gizem Kayki Mutlu, Jessica M Pfleger, Douglas G Tilley, Walter J Koch
Journal: Circulation (2020)

Introduction: During heart failure, levels and activity of G protein-coupled receptor kinase 2 (GRK2) increase. GRK2 is canonically studied in the phosphorylation of GPCRs and β-adrenergic desensitization. Noncanonical activities of GRK2 are being uncovered, however. Our lab has recently discovered that in cardiac myocytes, GRK2 translocates to the mitochondria ( mtGRK2 ) following injury and is associated with negative effects on metabolism and cell survival. Hypothesis: GRK2 plays a role in regulating mitochondrial function following cardiac stress and contributes to HF pathogenesis in a novel manner, by interacting with a novel group of mitochondrial proteins involved in pro-death signaling, bioenergetics and substrate utilization. Methods: Mitochondrial translocation of GRK2 was validated with either protein kinase C inhibitor (chelerythine) administration or hypoxia/reoxygenation stress in primary neonatal rat ventricular myocytes or a cardiac-like cell line. Immunoprecipitation of the GRK2 interactome basally and under stress conditions was conducted endogenously in vitro, in vivo , and with purified recombinant GRK2 peptides. Proteins were separated via SDS-PAGE and potential binding partners were identified by mass spectroscopy (LCMS) and proteomics analysis conducted with Ingenuity Pathway (IPA; Qiagen) software to determine which partners in the GRK2 interactome were potentially involved in mitochondrial dysfunction. Results: Subunits of Complexes I, II, IV and V of the electron transport chain were identified as potential mtGRK2 interacting partners. Several mtGRK2-ETC interactions were increased following oxidative stress-induced translocation of GRK2. Finally, mtGRK2 appears to phosphorylate some of the interactome partners identified in mitochondrial dysfunction. Conclusions: The phosphorylation of subunits of the ATP synthesis machinery by mtGRK2, or other mechanisms of interaction between these proteins, may be regulating some of the phenotypic effects of HF previously observed by our lab, such as increased ROS production and reduced fatty acid metabolism. Further research is essential to elucidate the novel role of GRK2 in regulating mitochondrial bioenergetics and cell death in failing hearts.
P0340 : Clinical patterns of hepatocellular carcinoma (HCC) in non alcoholic fatty liver disease (NAFLD): A multicenter case-control study
Authors: F. Piscaglia, G. Svegliati Baroni, A. Barchetti, A. Pecorelli, S. Marinelli, C. Tiribelli, S. Bellentani, L. Bolondi, M. Zoli, F. Trevisani, D. Malagotti, E. Bugianesi, E. Vanni, L. Mezzabotta, G. Cabibbo, S. Petta, A. Fracanzani, S. Fargion, F. Marra, B. Fani, R. Sacco, F. Morisco, F. Caporaso, M. Guarino
Journal: Journal of Hepatology (2015)
Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: John A Spertus, Jennifer T Fine, Perry Elliott, Carolyn Y Ho, Iacopo Olivotto, Sara Saberi, Wanying Li, Chantal Dolan, Matthew Reaney, Amy J Sehnert, Daniel Jacoby
Journal: The Lancet (2021)
Abstract MP42: Adherence To Healthy Dietary Patterns In Pregnancy And Placental Dna Methylation- An Epigenome Wide Association Study
Authors: Cuilin Zhang, Jing Wu, Marion Ouidir, Stefanie Hinkle, Fasil Ayele
Journal: Circulation (2021)

Background: Accumulating evidence support the intergenerational impacts of diet in pregnancy. The underlying mechanisms, however, remain unclear. Placental epigenetic mechanisms may be involved although data from human epidemiological studies are sparse. We aimed to investigate associations of dietary quality in pregnancy with epigenome-wide placental DNA methylation in a multiracial pregnancy cohort. Methods: DNA methylation was measured using the Illumina Infinium Human Methylation450 Beadchip on placentas obtained at delivery from 301 pregnant women who participated in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort. Dietary information during periconception and early first trimester was collected using food frequency questionnaires, and diet in the second and third trimester was collected using a 24-hour dietary recall during four study visits. Scores for adherence to three healthy dietary patterns, alternate Healthy Eating Index (aHEI), alternate Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH), were calculated. For associations of each dietary pattern score with methylation, we conducted analyses using robust linear regression models after the adjustment for age, pre-pregnancy body mass index, race/ethnicity, physical activity, total energy intakes, and population stratification. Genes annotating the top significant CpG sites (false discovery rate (FDR) adjusted P&lt;0.05) were queried for enrichment of functional pathways using the Ingenuity Pathway Analysis tool. Results: Adherence to aHEI was significantly associated with methylation of 8 CpG sites, with the most significant association manifested in cg16724319- MDH1B (P=1.9x10 -10 ). Adherence to aMED was related to methylation of 14 CpG sites, with the most significant association manifested in cg07835181- CLCN7 (P=1.7x10 -11 ). DASH was significantly related to 33 CpG sites, with the most significant association manifested in cg26292547- REV3L (P=4.4x10 -10 ). Further, genes annotating the significant CpG sites were enriched in pathways related to cardiovascular and nervous system development and function, cancer, organismal injury and abnormalities, and reproductive system diseases. Conclusion: Findings from the epigenome wide study suggest that overall dietary quality in pregnancy is associated with placental DNA methylation changes at different loci potentially related to cardiovascular, neurological, reproductive, and cancer phenotypes.
Abstract P075: Genetic European Ancestry And Incident Diabetes Mellitus In Black Individuals-Insights From The SPRINT Trial
Authors: Vibhu Parcha, Brittain F Heindl, Rajat Kalra, Shreya Rao, Ambarish Pandey, Barbara Gower, Peng Li, Garima Arora, Pankaj Arora
Journal: Circulation (2021)

Background: A metabolic paradox of lower triglyceride (TG) and higher high-density lipoprotein cholesterol (HDL-C) levels but a higher incidence of diabetes has been described in Blacks. We evaluated the association of genetic ancestry-related variants with the risk of incident diabetes in self-identified Black individuals in the Systolic Blood Pressure (BP) Intervention Trial (SPRINT). Methods: The genetic European ancestry proportions were estimated using 106 biallelic genotype markers in non-diabetic Black participants. Participants were stratified into tertiles (T1-T3) of European ancestry proportions. Multivariable-adjusted association of baseline metabolic syndrome indices (fasting plasma glucose [FPG], TG, HDL-C, body mass index [BMI], and BP) with the ancestry proportion was assessed. Multivariable-adjusted Cox regression was used to assess the risk of incident diabetes (FPG ≥126 mg/dL or self-reported diabetes treatment) across tertiles. Results: In 2,466 participants with median European ancestry 19% (13 - 27%), those in T1 were relatively younger, with lower Framingham risk score, and worse renal function (p&lt;0.05 for all). At baseline, higher European ancestry proportion was associated with higher TG and lower HDL-C levels after controlling for clinical and demographic factors (p&lt;0.05 for both). FPG, BMI, and BP were not significantly associated with ancestry proportion. Compared with T1, those in second (HR: 0.64 [95% CI: 0.45-0.90]) and third tertiles (HR: 0.61 [0.44-0.89]) had a lower risk of incident diabetes after controlling for covariates. Specifically, a 5% increment in European ancestry was associated with a 29% lower risk of incident diabetes (HR: 0.71 [0.55-0.93]). No interaction was observed between intensive BP control strategy and European ancestry proportion tertiles on incident diabetes. Conclusions: Genetic factors may account for racial differences in TG and HDL-C levels. The higher risk of incident diabetes in Blacks may similarly be genetically determined.
超音波検査を用いた閉塞性血栓動脈炎(Buerger病)におけるらせん状側枝の分類
Authors: Fujii Yuichi, Takemoto Hiroaki, Nishioka Kenji, Hidaka Takayuki, Soga Junko, Hata Takaki, Idei Naomi, Nakamura Hideshi, Teragawa Hiroki, Yoshizumi Masao, Chayama Kazuaki, Higashi Yukihito
Journal: Circulation (2008)
Drug Overdose Deaths Before and After Shelter-in-Place Orders During the COVID-19 Pandemic in San Francisco
Authors: Ayesha Appa, Luke N. Rodda, Caroline Cawley, Barry Zevin, Phillip O. Coffin, Monica Gandhi, Elizabeth Imbert
Journal: JAMA Network Open (2021)

Mortality From Drug Overdose, Homicide, Unintentional Injuries, Motor Vehicle Crashes, and Suicide During the COVID-19 Pandemic
Direct comparison of risankizumab and fumaric acid esters in systemic therapy–naïve patients with moderate-to-severe plaque psoriasis: a randomized controlled trial
Authors: D. Thaçi, K. Eyerich, A. Pinter, M. Sebastian, K. Unnebrink, S. Rubant, D. A. Williams, P. Weisenseel
Journal: British Journal of Dermatology (2021)

Summary Background Fumaric acid esters (FAEs; Fumaderm®) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi®) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. Objectives To compare risankizumab treatment to FAEs in patients with psoriasis. Methods This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8–24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. Results Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P &amp;lt; 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician’s Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. Conclusions Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.
Inherited Variants in <i>SCARB1</i> Cause Severe Early-Onset Coronary Artery Disease
Authors: Sara N. Koenig, Holly C. Sucharski, Elizabeth M. Jose, Emma K. Dudley, Francesca Madiai, Omer Cavus, Aaron D. Argall, Jordan L. Williams, Nathaniel P. Murphy, Caullin B. R. Keith, Mona El Refaey, Richard J. Gumina, Konstantinos D. Boudoulas, M. Wesley Milks, Gbemiga Sofowora, Sakima A. Smith, Thomas J. Hund, Nathan T. Wright, Elisa A. Bradley, Karolina M. Zareba, Loren E. Wold, Ernest L. Mazzaferri, Peter J. Mohler
Journal: Circulation Research (2021)

Rationale: Coronary artery disease (CAD) is a pervasive and critical health care problem. Elevated high-density lipoprotein-associated cholesterol (HDL-C) is associated with improved atherosclerotic cardiovascular disease outcomes on a population level, but clinical trials aimed at HDL-C elevation have not succeeded in improving atherosclerotic cardiovascular disease event risk. Nevertheless, human variants in the HDL receptor, encoded by SCARB1 , are associated with dyslipidemia, suggesting that HDL metabolism, not HDL-C, is a suitable target for therapy. However, variants in SCARB1 have never been directly attributed to CAD by Mendelian inheritance. Objective: To determine if compound heterozygous variants in SCARB1 cause disease in 2 brothers with severe, early-onset CAD. Methods and Results: Using whole exome sequencing, we have identified rare, compound heterozygous variants in SCARB1 that segregate with severe, premature CAD, following patterns of Mendelian inheritance. Using induced pluripotent stem cell–derived hepatocyte-like cells from the proband, we discovered the maternal variant (c.754_755delinsC) to be the first identified SCARB1 null allele, characterized by the absence of RNA and protein expression. Further, we demonstrate that the variant on the paternal allele (c.956G&gt;T [p.G319V]) results in decreased cholesterol uptake, decreased SR-BI:HDL binding, and increased affinity for SR-BI dimerization. Finally, we generated a p.G319V knock-in mouse model that displays nearly 100% homozygous lethality and elevated plasma cholesterol in heterozygous animals, confirming pathogenicity of this variant. Conclusions: In summary, our data provide the first molecular mechanism to show the Mendelian inheritance of CAD as a result of human SCARB1 variants. The rarity of these variants supports pathogenicity in this family. Furthermore, SR-BI p.G319V, which has previously been reported benign in the context of heterozygosity, was uniquely presented alongside a null allele, demonstrating the disease-contributing capability of loss-of-function SCARB1 variants within the population.
Prevalence of pulmonary embolism in patients with COVID-19 at the time of hospital admission and role for pre-test probability scores and home treatment
Authors: Mitja Jevnikar, Olivier Sanchez, Marc Humbert, Florence Parent
Journal: European Respiratory Journal (2021)

We thank A. Porfidia and co-workers for their interest in our study describing the prevalence of pulmonary embolism (PE) in patients with coronavirus disease 2019 (COVID-19) at the time of hospital admission [1]. We fully agree on the need to consider a PE diagnostic algorithm in COVID-19 at the time of hospital admission, because indiscriminate execution of computed tomography pulmonary angiography (CTPA) cannot be a workable, routine approach in such patients. There is a high prevalence of pulmonary embolism in patients with COVID-19 at the time of hospital admission despite a low level of clinical suspicion <https://bit.ly/3ungLrQ>
Cell-surface SLC nucleoside transporters and purine levels modulate BRD4-dependent chromatin states
Authors: Kai-Chun Li, Enrico Girardi, Felix Kartnig, Sarah Grosche, Tea Pemovska, Johannes W. Bigenzahn, Ulrich Goldmann, Vitaly Sedlyarov, Ariel Bensimon, Sandra Schick, Jung-Ming G. Lin, Bettina Gürtl, Daniela Reil, Kristaps Klavins, Stefan Kubicek, Sara Sdelci, Giulio Superti-Furga
Journal: Nature Metabolism (2021)