tbuckley/cabot-search huggingface dataset:
Role of lysosomes in physiological activities, diseases, and therapy
Authors: Ziqi Zhang, Pengfei Yue, Tianqi Lu, Yang Wang, Yuquan Wei, Xiawei Wei
Journal: Journal of Hematology & Oncology (2021)

Abstract Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.
Gene expression derived from alternative promoters improves prognostic stratification in multiple myeloma
Authors: Luis V. Valcárcel, Ane Amundarain, Marta Kulis, Stella Charalampopoulou, Ari Melnick, Jesús San Miguel, José I. Martín-Subero, Francisco J. Planes, Xabier Agirre, Felipe Prosper
Journal: Leukemia (2021)

Abstract Clinical and genetic risk factors are currently used in multiple myeloma (MM) to stratify patients and to design specific therapies. However, these systems do not capture the heterogeneity of the disease supporting the development of new prognostic factors. In this study, we identified active promoters and alternative active promoters in 6 different B cell subpopulations, including bone-marrow plasma cells, and 32 MM patient samples, using RNA-seq data. We find that expression initiated at both regular and alternative promoters was specific of each B cell subpopulation or MM plasma cells, showing a remarkable level of consistency with chromatin-based promoter definition. Interestingly, using 595 MM patient samples from the CoMMpass dataset, we observed that the expression derived from some alternative promoters was associated with lower progression-free and overall survival in MM patients independently of genetic alterations. Altogether, our results define cancer-specific alternative active promoters as new transcriptomic features that can provide a new avenue for prognostic stratification possibilities in patients with MM.
Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection
Authors: Lina Ma, Sanjaya K. Sahu, Marlene Cano, Vasanthan Kuppuswamy, Jamal Bajwa, Ja’Nia McPhatter, Alexander Pine, Matthew L. Meizlish, George Goshua, C. Hong Chang, Hanming Zhang, Christina Price, Parveen Bahel, Henry Rinder, Tingting Lei, Aaron Day, Daniel Reynolds, Xiaobo Wu, Rebecca Schriefer, Adriana M. Rauseo, Charles W. Goss, Jane A. O’Halloran, Rachel M. Presti, Alfred H. Kim, Andrew E. Gelman, Charles S. Dela Cruz, Alfred I. Lee, Philip A. Mudd, Hyung J. Chun, John P. Atkinson, Hrishikesh S. Kulkarni
Journal: Science Immunology (2021)

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.
Abstract P168: Parity Is Associated With Higher Arterial Stiffness But Not Its 5-year Change In Older Women: The Atherosclerosis Risk In Communities - Neurocognitive Study
Authors: Alison N Bonner, Shantal Jayawickreme, Angela M Malek, Catherine J Vladutiu, Clare Oliver-Williams, Yamnia I Cortes, Hirofumi Tanaka, Michelle L Meyer
Journal: Circulation (2021)

Introduction: Although studies have demonstrated a J-shaped association of parity with cardiovascular disease, the association with vascular disease is not fully understood. We examined the association between parity and carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness. Hypothesis: Women who were never pregnant or had no live births and women with 5+ live births would have higher cfPWV and 5-year cfPWV change compared to women with 1-2 live births. Materials and Methods: We included 1220 women (average age 73.7; 21.9% Black) from the Atherosclerosis Risk in Communities - Neurocognitive Study, a cohort of 15,792 adults enrolled in 1987-1989 from four communities: Forsyth Co., NC; Jackson, MS; Minneapolis, MN; and Washington Co., MD. Technicians measured cfPWV at visit 5 (2011-13) and visit 6 or 7 (2016-19). At visit 2 (1990-92), women self-reported parity (number of prior live births), which we categorized as never pregnant or pregnant but no live births, 1-2 (referent), 3-4, and 5+ live births. We used linear regression models to evaluate associations of parity with visit 5 cfPWV and 5-year cfPWV change, adjusting for years between visits 5 and 6 or 7, age, race-center, education, body mass index, heart rate, mean arterial pressure, hypertension medication, and diabetes. Results: Participants reported having had no (7.7%), 1-2 (38.7%), 3-4 (40.0%), or 5+ (13.6%) prior live births. Women with 5+ live births had a higher visit 5 cfPWV (β=50.6 cm/s, 95% confidence interval (CI): 3.6-97.7 cm/s; Table) as compared to those with 1-2 live births. No statistically significant associations were observed for other parity groups and visit 5 cfPWV or cfPWV change. Conclusions: In later life, women with 5+ live births had higher arterial stiffness than those with 1-2 live births, but the rate of cfPWV change did not differ by parity. Longitudinal arterial stiffness measurements at mid-life are needed to better understand the effect of pregnancy on the trajectory of arterial stiffness among women in later life.
121MO ctDNA and prognosis in resected esophageal adenocarcinoma (EAC)
Authors: E. Ococks, A.M. Frankell, N. Masque Soler, A. Northrop, H. Coles, N. Grehan, A. Redmond, C. Hughes, G. Devonshire, A. Blasko, R. Fitzgerald, E. Smyth
Journal: Annals of Oncology (2020)
Abstract 17417: Pathogenic and Likely Pathogenic Missense Variants in Cardiovascular Disease Genes Cluster Around Functional Domains
Authors: Nicholas S Ten, Megan Grove, Hannah Wand, Hannah Ison, Mitchel Pariani, Matthew T Wheeler, Euan A Ashley, Victoria N Parikh
Journal: Circulation (2020)

The genetic architecture of inherited cardiomyopathies has mechanistic and potentially therapeutic relevance. We have shown that disease-associated variation in two cardiomyopathy-associated genes clusters in functional protein domains. Here, we extend this hypothesis to a comprehensive list of genes associated with cardiovascular disease. Using ClinVar, we identified 12,043 pathogenic or likely pathogenic (P/LP) variants across 190 cardiovascular disease-associated genes. Only P/LP variants with associated adjudication criteria were included. We interrogated these variants for regional clustering by ranking them by their number of P/LP neighbors within successively larger windows. We found that 87% of variants had at least one nearby variant within a 40 bp neighborhood, and 28% had ≥ 10 neighboring variants (Figure A, p&lt;0.0001 vs. normal distribution). Within variant subtypes, 84% of missense variants and 70% of truncating variants neighbored at least 1 other missense or truncating variant, respectively. 21% of missense and 11% of truncating variants had ≥ 10 neighbors (p&lt;0.0001). LDLR and FBN1 had the highest number of missense P/LP variants within a 40 bp neighborhood. We show that these neighborhoods overlap with functional domains of LDLR and FBN1 (Figure B, C). In summary, we demonstrate that a large portion of P/LP variants are regionally clustered in cardiovascular disease-associated genes, regardless of variant type, and align with known functional domains. Future directions will systematically apply these methods across the genome and explore the potential for novel domain identification and targeting these clusters with genome engineering.
Abstract 15185: Outcomes of Radiofrequency Catheter Ablation of Atrial Arrhythmias in Lung Transplant Recipients
Authors: Stephanie M Kochav, Elizabeth Wang, Isaac Goldenthal, Angelo B Biviano, Elaine Wan, Amardeep S Saluja, Jose Dizon, John P Morrow, Geoffrey Rubin, Marc Waase, Frederick Ehlert, Hasan Garan, Hirad Yarmohammadi
Journal: Circulation (2020)

Introduction: Atrial arrhythmias (AA) are common after lung transplant (LT) and may impact overall mortality. The majority of arrhythmias tend to be organized flutter, amenable to ablation; however the data is limited. Hypothesis: The purpose of this study was to investigate the outcomes of radiofrequency catheter ablation of AA in LT recipients. Methods: All LT recipients undergoing electrophysiology study at our institution between 2011-2018 were retrospectively reviewed. A total of 20 atrial ablations were identified in 16 patients. Mean follow-up was 4 ± 2.9 years. Results: Overall, mean age was 55 ± 13 years, 63% were male, 63% were status post bilateral (vs. single) LT, and mean LVEF was 57%. Transplant indications included interstitial lung disease (44%), COPD (19%), and cystic fibrosis (19%). Antiarrhythmics and beta blockers were used in 44% and 75%, respectively. Mean time from transplant to first ablation was 2.7 years. Of 20 ablations, macro-reentrant flutter (75%) and focal atrial tachycardia (15%) were common, particularly in double LT recipients (Figure). The most common ablation sites were pulmonary vein anastomosis/left atrial ridge (60%), mitral annulus (35%) and left atrial roof (30%). Restoration of sinus rhythm occurred in 19 of 20 procedures and only one complication occurred (e.g. small pericardial effusion without tamponade). Arrhythmia recurred in 10 (63%) patients, however, most were managed conservatively. Repeat ablation was needed in 4 patients, of which AAs originated from different locations. Beta blocker use was associated with a lower risk of SVT recurrence (p=0.04). Reduced LVEF and longer time to procedure post-transplant were associated with repeat ablation (p&lt;0.05). Conclusions: The majority of AAs in LT recipients are atrial flutter originating near the pulmonary vein anastomosis sites. Despite a high immediate procedural success rate, recurrence is high and 25% of patients require multiple ablation attempts.
Abstract 17054: Age-Based Variation in Temporal Trends for Takotsubo Syndrome Differ by Sex
Authors: Varun Pattisapu, HUA HAO, Trevor Trung Nguyen, Noel B Merz, Susan Cheng
Journal: Circulation (2020)

Background: Takotsubo syndrome (TTS) has been increasingly recognized in the United States. Since its initial description in 1990, diagnosed cases of TTS have been rising over time and the extent to which this trend differs by sex and across age is unclear. Methods: Using the National Inpatient Sample (NIS) data from 2006 to 2014, we identified hospitalizations with either a primary or secondary diagnosis of TTS. We analyzed these data stratified by sex and by age groups: &lt;=50 years, 50 to 74 years, and &gt;=75 years. For the trend measurements, the sampling effects were accounted for by applying NIS survey weights using the SAS PROC SURVEYMEANS procedure. Results: We identified a total of N=18,051 TTS cases over the study period, most of which were experienced by women (89.1%). The frequency of diagnosed TTS cases progressively increased from 2006 to 2014 in both women and men, across all age groups. However, the frequency of diagnosed TTS cases increased at a markedly more rapid rate in women compared to men (rate of change of 182.7 per million hospitalization per year in women vs 44.9 per million hospitalization per year in men, P&lt;0.0001). The rate of increase in annual case diagnosis was particularly high for women aged 50 years or older compared to younger women or men of any age group ( Figure ). Conclusion: Our results demonstrate that while increasing recognition of TTS may be contributing to a steady rise of case diagnoses per annum in both sexes and across age groups, the rate of case diagnosis increase is particularly rapid in middle-aged and older women. Further research is needed to validate and investigate the potential determinants underlying our findings.
Abstract 029: Menopause Alters The Gut Microbiome In Hispanic/Latina Women Of The Hispanic Community Health Study/Study Of Latinos (HCHS/SOL), With Implications For Metabolic Syndrome
Authors: Brandilyn Peters-samuelson, Juan Lin, Qibin Qi, Carmen R Isasi, Yasmin Mossavar-Rahmani, Carol A Derby, Nanette Santoro, Krista Perreira, Martha L Daviglus, Michelle Kominiarek, Robert Burk, Robert Kaplan
Journal: Circulation (2021)

Introduction: During menopause, women experience an increase in cardiometabolic risk factors, thought to relate to aging and loss of endogenous estrogen. Menopause may also influence the gut microbiome, which plays a role in cardiometabolic risk. However, the menopause-microbiome relationship has not been examined in a large study and implications for disease are unknown. Hypothesis: Menopause alters gut microbiome composition, which may affect post-menopausal disease risk. Methods: Menopause was defined by self report of 12 months of amenorrhea, not due to surgery or other non-natural causes. Shotgun sequencing was used on stool from 2370 participants (301 pre-menopausal women; 1072 post-menopausal women; 997 men). Between pre- and post-menopausal women and age-matched men, we compared microbiome diversity, composition, and taxa. Results: Pre-menopausal women had higher gut microbiome diversity than post-menopausal women and men (all p&lt;0.05, Figure 1a). Post-menopausal women also differed in overall microbiome composition from pre-menopausal women (p=0.005), while older and younger men did not differ from each other (p=0.70) (Figure 1b). We identified differentially abundant taxa between post- and pre-menopausal women, including class Betaproteobacteria and its genus Sutterella (enriched in post-menopause), and genera Shigella and Escherichia (depleted in post-menopause); associations were similar in comparisons of men vs. women, though the taxa did not differ between older and younger men (Figure 1c). In post-menopausal women, higher abundance of Shigella and Escherichia was associated with impaired fasting glucose (≥100 mg/dL or diabetes treatment) (Figure 1d). Conclusions: Menopause is associated with a gut microbiome more similar to that of men, perhaps related to the common condition of a low estrogen state. In HCHS/SOL, menopause was associated with depletion of gut pathogens, which were related to increased diabetes risk. These findings require confirmation in other racial/ethnic groups.
Endoscopic retrieval of a migrated surgical clip in a choledochojejunal anastomosis using the rendezvous technique
Authors: Takashi Ito, Masaaki Shimatani, Masataka Masuda, Koh Nakamaru, Toshiyuki Mitsuyama, Makoto Takaoka, Makoto Naganuma
Journal: Endoscopy (2021)

It is a rare complication for a surgical clip to migrate into a bile duct [1] [2], and removing a migrated surgical clip endoscopically is technically challenging, particularly in patients with surgically altered anatomy. We report here the first successful endoscopic removal of a migrated surgical clip using the rendezvous technique of percutaneous transhepatic biliary drainage (PTBD) and double-balloon endoscope (DBE)-assisted endoscopic retrograde cholangiography (ERC) ([Video 1]).
Abstract 15703: Cardiac Magnetic Resonance Imaging Can Non-invasively Detect Rejection in Pediatric Heart Transplant Recipients
Authors: Jonathan H Soslow, Justin Godown, David Bearl, Kimberly Crum, Kristen George-Durrett, Maryanne Chrisant, Debra A Dodd, Lazaro E Hernandez
Journal: Circulation (2020)

Introduction: Pediatric heart transplant recipients (PHTx) undergo frequent surveillance endomyocardial biopsies (EMB). Non-invasive screening for acute rejection (AR) could decrease morbidity, improve quality of life, and decrease healthcare costs. Hypothesis: We hypothesized that cardiac magnetic resonance (CMR) extracellular volume (ECV), native T1, and T2 mapping can detect AR in PHTx. Methods: PHTx (n=29) were prospectively enrolled at two sites at time of surveillance EMB or EMB for AR. AR was defined as a clinical change or positive EMB requiring intensification of immunosuppression. Subjects with cardiac allograft vasculopathy (n=3) were excluded; ECV was not measured in 2 subjects without rejection (no IV, poor breathholds). CMR without sedation included standard volumetrics, modified Look-Locker inversion recovery before and after contrast, and T2 mapping. A Wilcoxon rank sum was used to assess for a difference between groups. Results: Median age was 17 y/o (range 9-19). There were 9 subjects with and 17 subjects without AR. Base ECV, mid ECV, 4-ch ECV, and average ECV were increased in AR vs non-rejection (Table 1, Fig 1). Native T1 and T2 times were also increased in patients with AR (Table 1). A cut-off of 29% for mid ECV and 1070ms for mid native T1 identifies all patients with rejection with 6 false positive results in non-rejection (Fig 1) and could potentially decrease the need for EMB by 65%. Conclusions: ECV, native T1, and T2 mapping can non-invasively distinguish between PHTx with and without AR and have potential to decrease the required number of surveillance EMBs.
メトホルミンからSGLT2阻害剤およびGLP1受容体アゴニストJACCフォーカスセミナーへの糖尿病薬【JST・京大機械翻訳】
Authors: Wilcox Tanya, De Block Christophe, Z Schwartzbard Arthur, D Newman Jonathan
Journal: Journal of the American College of Cardiology (2020)
Abstract P158: Work-related Exertion And Standing/walking Are Associated With Leisure-time Physical Activity In Latinos
Authors: Rosenda Murillo, Shreya Desai, Tailisha Gonzalez, Sandra Echeverria, Elizabeth Vasquez
Journal: Circulation (2021)

Introduction: Latinos engage in higher levels of occupational physical activity, yet lower levels of leisure-time physical activity (LTPA), than other racial/ethnic groups. Limited research has examined specific work-based activities that contribute to lower LTPA among Latinos. The purpose of our study was to examine associations between frequency of work-related exertion and standing/walking with LTPA among Latinos. Hypothesis: We hypothesized that higher frequency of work-related exertion and standing/walking would be associated with lower levels of LTPA among Latinos. Methods: We used cross-sectional 2015 National Health Interview Survey (NHIS) data on employed Latinos ≥18 years of age (n=3,305). We examined two types of work-based activities: frequency of exertion and frequency of standing/walking. Frequency of exertion was assessed based on reported frequency of engaging in repeated lifting, pulling, pushing, or bending at work. Frequency of standing/walking was assessed based on frequency with which their work involved standing or walking around. Responses to work-based activity items were on a Likert scale (0=never, 1=seldom, 2= sometimes, 3=often, 4=always). LTPA was measured based on minutes of moderate-to-vigorous LTPA aerobic physical activity per week, which were categorized into none (0 min/week), some LTPA (&gt;0 min/week of activity but less than recommendation), and meeting the LTPA guideline (≥150 min of moderate-vigorous activity or ≥75 min of vigorous activity or 150 min of moderate activity/week). Multinomial logistic regression models that accounted for the complex survey design of NHIS were used to estimate the associations between frequency of work-related exertion and standing/walking with LTPA. All models were adjusted for age, sex, education, shift work, and acculturation proxies (nativity, years living in the US). Results: In adjusted models, compared with those who reported never engaging in exertion at work, individuals reporting always exerting themselves at work were significantly less likely to meet the LTPA guideline (Odds Ratio [OR]: 0.68, 95% Confidence Interval [CI]: 0.50-0.94). In addition, compared with those that reported never standing/walking at work, only those who reported that their job seldom involved standing/walking at work were significantly less likely to meet the LTPA guideline (OR: 0.52, 95% CI: 0.30-0.92). Conclusions: In conclusion, these findings suggest that work-related physical activities may contribute to LTPA levels among Latinos, and associations vary based on the type of physical activities performed at work. Future physical activity promotion efforts among Latinos should consider the role of worksite policies to promote wellness.