tbuckley/cabot-search huggingface dataset:
Abstract 14058: Transvascular Total Left Ventricular Unloading for Acute Myocardial Infarction Strikingly Reduced Myocardial Oxygen Consumption, Limited the Infarct Size and Prevented Heart Failure in the long term
Authors: Takahiro Arimura, Keita Saku, Takamori Kakino, Takuya Akashi, Yoshinori Murayama, Takeshi Tohyama, Takuya Nishikawa, Takuya Kishi, Tomomi Ide, Kenji Sunagawa
Journal: Circulation (2015)

Backgrounds: Despite the latest progresses of early reperfusion, myocardial infarction (MI) remains a leading cause of chronic heart failure (CHF). Left ventricular (LV) assist device (VAD) mechanically unloads LV, thus myocardial oxygen consumption (MVO2). Theoretical analysis indicates that the partial VAD (p-VAD) where LV remains ejecting decreases preload (EDV) while increases afterload (ESV), thereby marginally decreases MVO2. In contrast, total LVAD (t-VAD) where LV no longer ejects, markedly decreases ESV as well as EDV, thus markedly reduces MVO2. We examined whether t-VAD in ischemia reperfusion (IR) could reduce the infarct size and prevent heart failure in the long term. Methods: First, in normal dogs, we examined the impact of p-VAD and t-VAD on MVO2 by Fick principle (coronary flow and arterial venous O2 difference). Second, we occluded the left anterior descending coronary artery for 3 hours and reperfused. We started transvascular LVAD (Impella®) from 1 hour after ischemia to 1 hour after reperfusion. We compared cardiac function, infarct size and hormones 1 month after ischemia among 3 groups, control group (IR, n=8), p-VAD (n=6), and t-VAD (n=6). Results: t-VAD markedly decreased MVO2 (p&lt;0.05, Figure 1). 1 month after ischemia, t-VAD normalized LV end-systolic elastance (IR: 6.5±3.2, p-VAD: 9.7±1.3, t-VAD: 12.8±5.1 mmHg/ml, p&lt;0.05) and reduced LV end-diastolic pressure (16.5±2.7, 6.4±2.9, 4.4±1.5 mmHg, p&lt;0.05), and NT proBNP (3391±1364, 2084±348, 1632±228 pg/ml, p&lt;0.05) indicating the successful prevention of heart failure. t-VAD markedly reduced the infarct size by more than 80% relative to IR (p&lt;0.05, Figure 2) despite the fact that it started 1 hour after the onset of ischemia. Conclusions: Transvascular total left ventricular unloading for acute myocardial infarction strikingly reduces the MI size and prevents heart failure in the chronic phase. It might serve as a new therapeutic strategy in the management of patients with acute MI.
Pathogenesis of Rickettsial Diseases: Pathogenic and Immune Mechanisms of an Endotheliotropic Infection
Authors: Abha Sahni, Rong Fang, Sanjeev K. Sahni, David H. Walker
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate hosts cause human diseases with a spectrum of severity, primarily by targeting microvascular endothelial cells, resulting in endothelial dysfunction. Endothelial cells and mononuclear phagocytes have important roles in the intracellular killing of rickettsiae upon activation by the effector molecules of innate and adaptive immunity. In overwhelming infection, immunosuppressive effects contribute to the severity of illness. Rickettsia-host cell interactions involve host cell receptors for rickettsial ligands that mediate cell adhesion and, in some instances, trigger induced phagocytosis. Rickettsiae interact with host cell actin to effect both cellular entry and intracellular actin-based mobility. The interaction of rickettsiae with the host cell also involves rickettsial evasion of host defense mechanisms and exploitation of the intracellular environment. Signal transduction events exemplify these effects. An intriguing frontier is the array of rickettsial noncoding RNA molecules and their potential effects on the pathogenesis and transmission of rickettsial diseases.
Abstract 16715: Magnetic Resonance Imaging Based Arterial Signal Enhancement is Associated With Markers of Peripheral Artery Disease
Authors: Jonathan Holbrook, Tatiana Belousova, Christina M Short, Addison A Taylor, Vijay Nambi, Joel D Morrisett, Christie M Ballantyne, Jean Bismuth, Dipan J Shah, Gerd Brunner
Journal: Circulation (2016)

Introduction: Peripheral artery disease (PAD) is associated with impaired lower extremity (LE) function. Contrast-enhanced magnetic resonance imaging (CE-MRI) may quantitatively measure first-pass ...
Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma
Authors: Noémie Braekeveldt, Kristoffer von Stedingk, Susanne Fransson, Angela Martinez-Monleon, David Lindgren, Håkan Axelson, Fredrik Levander, Jakob Willforss, Karin Hansson, Ingrid Øra, Torbjörn Backman, Anna Börjesson, Siv Beckman, Javanshir Esfandyari, Ana P. Berbegall, Rosa Noguera, Jenny Karlsson, Jan Koster, Tommy Martinsson, David Gisselsson, Sven Påhlman, Daniel Bexell
Journal: Cancer Research (2018)

Abstract Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX–Avatar studies into preclinical cancer research. Significance: These findings underpin the complexity of PDX modeling as a means to advance translational applications against neuroblastoma. Cancer Res; 78(20); 5958–69. ©2018 AACR.
Abstract 11: Neighborhood Social Cohesion and Meeting Physical Activity Guidelines: Does the Association Differ by Race/Ethnicity?
Authors: Stella Yi, Chau Trinh-Shevrin, Irene H Yen, Simona C Kwon
Journal: Circulation (2016)

Introduction: Neighborhood social cohesion is associated with physical activity (PA), but prior studies have used local population samples and presented results in aggregate across racial/ethnic groups. Hypothesis: Neighborhood social cohesion is associated with PA in a large, nationally representative dataset and may be modified by race/ethnicity. Methods: Data from the National Health Interview Survey (NHIS) 2013-14 survey waves were combined (n=64,754). NHIS 2013-14 included four questions on neighborhood social cohesion - participants rated agreement/disagreement with the following statements (scale: 1-strongly disagree, 2-disagree, 3-agree, 4-strongly agree): 1) people in this neighborhood help each other out; 2) there are people I can count on in this neighborhood; 3) people in this neighborhood can be trusted; and 4) this is a close-knit neighborhood. A neighborhood cohesion score was constructed by summing the responses to the questions (range: 4 to 16). The primary outcome of meeting aerobic PA guidelines (150 minutes/week of moderate or 75 minutes/week of vigorous PA) was calculated using self-reported moderate or vigorous minutes/week. Multivariable regression models for meeting PA guidelines were run, adjusting for age, race/ethnicity, sex, education, income, nativity (U.S.- or foreign-born), and English proficiency; additional models were run with neighborhood cohesion as a binary variable (above/below median) to assess potential effect modification by race/ethnicity. All data were analyzed using complex survey weighting in STATA 12.1 and SUDAAN 10.0. Results: About half of U.S. adults reported meeting PA guidelines (49.6). Neighborhood social cohesion was fairly high, with a median value of 12 (IQR: 11-15) and was higher in those 65+ years of age, and with higher education, income and length of time living in one’s neighborhood. In adjusted analyses, a one-unit increase in neighborhood social cohesion was associated with an increased odds of meeting PA guidelines (OR:1.04 (1.03, 1.05), p&lt;0.001). Neighborhood social cohesion and PA was associated in whites and Hispanics (OR:1.30 (1.20, 1.42), p&lt;0.001; OR: 1.18 (1.03, 1.34), p&lt;0.001, respectively), and not in blacks or Asian American subgroups (Chinese, Filipino and Asian Indians). Conclusions: Neighborhood social cohesion was associated with meeting PA guidelines in this nationally representative sample of U.S. adults. However this association appears to be driven by whites and Hispanics. While neighborhood characteristics may be an important aspect of public health planning and epidemiologic inquiry, additional studies are needed to further investigate which neighborhood factors affect ability to meet PA guidelines for blacks and Asian Americans.
Deep phenotyping of osteoarthritis: a step forward
Authors: Francis Berenbaum
Journal: Annals of the Rheumatic Diseases (2018)

Is osteoarthritis (OA) only one and the same disease or is it actually a nebula of several diseases for which we still lack markers allowing to differentiate them? This issue is currently the subject of much debate in the medical and scientific community and remains unresolved. It is not a trivial question because deciphering disease phenotypes could be used to select a group of patients for whom a particular treatment will be effective or for whom the prognosis will be better or worse.

According to the Osteoarthritis Research Society International (OARSI), OA is a disorder involving movable joints characterised by cell stress and extracellular matrix degradation initiated by microinjury and macroinjury that activate maladaptive repair responses, including proinflammatory pathways of innate immunity. The disease manifests first as a molecular derangement (abnormal joint tissue metabolism), followed by anatomical and/or physiological derangements (characterised by cartilage degradation, bone remodelling, osteophyte formation, joint inflammation and loss of normal joint function), which can culminate in illness.1 It is clear that this complex definition reveals, on the one hand, a poor understanding of the underlying mechanisms, and on the other hand the potential extent of heterogeneity of the disease. With such a definition, it is easy to imagine the theoretical possibility of many different disease subgroups, depending on clinical, biological, genetics and/or imaging variables.

Some believe that the successive failures of the many therapeutic trials carried out in recent years to delay OA are due to the phenotypic heterogeneity of the patients included in these trials, masking the possible efficacy of the drug X reserved for the only phenotype Y. This reasoning is analogous to what is now consensually accepted in cancer, where drugs used to be poorly effective in clinical trials before patient selection have become remarkably effective in specific phenotypes based on tumour gene signatures. …
Assessment of Clinical Trial Evidence for High-Risk Cardiovascular Devices Approved Under the Food and Drug Administration Priority Review Program
Authors: L. Camille Jones, Sanket S. Dhruva, Rita F. Redberg
Journal: JAMA Internal Medicine (2018)

This study uses publicly available FDA summaries to analyze the quality of evidence in pivotal studies that support cardiovascular premarket device approval under FDA priority review from 2007 to 2017.
Midbody Positioning and Distance Between Daughter Nuclei Enable Unequivocal Identification of Cardiomyocyte Cell Division in Mice
Authors: Michael Hesse, Michael Doengi, Alexandra Becker, Kenichi Kimura, Nadine Voeltz, Valentin Stein, Bernd K. Fleischmann
Journal: Circulation Research (2018)

New strategies in the field of cardiac regeneration are directed at identifying proliferation-inducing substances to induce regrowth of myocardium. Current screening assays utilize neonatal cardiomyocytes and markers for cytokinesis, such as Aurora B-kinase. However, detection of cardiomyocyte division is complicated because of cell cycle variants, in particular, binucleation.To analyze the process of cardiomyocyte binucleation to identify definitive discriminators for cell cycle variants and authentic cardiomyocyte division.Herein, we demonstrate by direct visualization of the contractile ring and midbody in Myh6 (myosin, heavy chain 6)-eGFP (enhanced green fluorescent protein)-anillin transgenic mice that cardiomyocyte binucleation starts by formation of a contractile ring. This is followed by irregular positioning of the midbody and movement of the 2 nuclei into close proximity to each other. In addition, the widespread used marker Aurora B-kinase was found to also label binucleating cardiomyocytes, complicating the interpretation of existing screening assays. Instead, atypical midbody positioning and the distance of daughter nuclei on karyokinesis are bona fide markers for cardiomyocyte binucleation enabling to unequivocally discern such events from cardiomyocyte division in vitro and in vivo.The 2 criteria provide a new method for identifying cardiomyocyte division and should be considered in future studies investigating cardiomyocyte turnover and regeneration after injury, in particular in the postnatal heart to prevent the assignment of false positive proliferation events.
Hepatocellular Carcinoma Detection by Plasma Methylated DNA: Discovery, Phase I Pilot, and Phase II Clinical Validation
Authors: John B. Kisiel, Brian A. Dukek, Reddappa V.S.R. Kanipakam, Hassan M. Ghoz, Tracy C. Yab, Calise K. Berger, William R. Taylor, Patrick H. Foote, Nasra H. Giama, Kristeen Onyirioha, Mohamed A. Abdallah, Kelli N. Burger, Seth W. Slettedahl, Douglas W. Mahoney, Thomas C. Smyrk, Jason T. Lewis, Maria Giakoumopoulos, Hatim T. Allawi, Graham P. Lidgard, Lewis R. Roberts, David A. Ahlquist
Journal: Hepatology (2018)

Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation‐specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele‐specific real‐time target and signal amplification assays on independent plasma‐extracted DNA from 21 HCC cases and 30 controls with cirrhosis. A phase II plasma study was then performed in 95 HCC cases, 51 controls with cirrhosis, and 98 healthy controls using target enrichment long‐probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross‐validated by randomly splitting the data 2:1 for training and testing. Random forest (rForest) regression models performed on the training set predicted disease status in the testing set; median areas under the receiver operating characteristics curve (AUCs; and 95% confidence interval [CI]) were reported after 500 iterations. In phase II, a six‐marker MDM panel (homeobox A1 [ HOXA1 ], empty spiracles homeobox 1 [ EMX1 ], AK055957 , endothelin‐converting enzyme 1 [ ECE1 ], phosphofructokinase [ PFKP ], and C‐type lectin domain containing 11A [ CLEC11A ]) normalized by beta‐1,3‐galactosyltransferase 6 ( B3GALT6 ) level yielded a best‐fit AUC of 0.96 (95% CI, 0.93‐0.99) with HCC sensitivity of 95% (88%‐98%) at specificity of 92% (86%‐96%). The panel detected 3 of 4 (75%) stage 0, 39 of 42 (93%) stage A, 13 of 14 (93%) stage B, 28 of 28 (100%) stage C, and 7 of 7 (100%) stage D HCCs. The AUC value for alpha‐fetoprotein (AFP) was 0.80 (0.74‐0.87) compared to 0.94 (0.9‐0.97) for the cross‐validated MDM panel ( P &lt; 0.0001). Conclusion : MDMs identified in this study proved to accurately detect HCC by plasma testing. Further optimization and clinical testing of this promising approach are indicated.
Abstract 15543: Increased Local Hepcidin Expression With Subsequent Degradation Of Ferroportin-1 is Associated With Iron Accumulation in the Aged Brain
Authors: Tatsuya Sato, Marina Bayeva, Arineh Khechaduri, Hsiang-Chun Chang, Hossein Ardehali
Journal: Circulation (2015)

Background: Age is a major risk factor for a number of neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. Several studies have shown that neurodegenerative disorders are sometimes associated with iron accumulation in the brain. Iron is an essential trace metal, however, excess iron can cause cellular damage due to increased oxidative stress and thus promote aging, yet how and why iron accumulates in the aged brain is unclear. The goal of this study is to delineate the mechanism of iron accumulation in the brain with aging. Results: We assessed the levels of iron in various tissues of aged mice (defined as 22 months old) vs young mice (defined as 4 months old). We found that non-heme iron was preferentially increased in the brain tissue of aged mice, while the levels were unaltered in other tissues. This was associated with increased ferritin (iron storage protein) levels in the brain, consistent with iron accumulation. To study the mechanism, we measured the mRNA levels of various proteins involved in iron homeostasis, and determined that the levels of hepcidin (HAMP) and tranferrin receptor-2 were increased in the brains, but not in the livers, of aged mice. HAMP is generally produced in the liver and functions to reduce intestinal iron uptake through degradation of basolateral iron exporter ferroportin-1 (FPN1), thus reducing systemic iron levels. However, HAMP is also detected in other tissues, such as the brain and the heart, where its function is less clear. To determine whether the increase in HAMP in the brain affects iron homeostasis, we measured the levels of FPN1 in the brain and showed that while its mRNA level was not altered, the protein level of FPN1 was significantly reduced in aged mice. Thus, the increase in HAMP in aged mice was associated with a reduction in FPN1 levels and iron accumulation in the brain, likely through reduced iron export from neurons and glial cells. Conclusions: Our results demonstrate that iron levels are significantly increased in the brain with aging. This increase is due to higher levels of HAMP protein, with subsequent degradation of iron exporter FPN1 and cellular iron accumulation secondary to defective export. Thus, targeting HAMP may lead to novel therapies for age-related neurodegenerative disorders.
Analysis of the Effect of Gentian Violet on Apoptosis and Proliferation in Cutaneous T-Cell Lymphoma in an In Vitro Study
Authors: Jianqiang Wu, Gary S. Wood
Journal: JAMA Dermatology (2018)

Triggering the extrinsic apoptotic pathway is an effective way to kill cutaneous T-cell lymphoma (CTCL) cells in vitro and ex vivo.To compare small molecules that induce extrinsic apoptosis in CTCL to identify and analyze compounds that induce high levels of tumor cell death and block tumor cell growth.From November 5, 2014, to January 30, 2018, this study performed high-throughput small molecule screening of 1710 compounds followed by detailed analysis of the ability of gentian violet (GV) to promote apoptosis and inhibit proliferation of CTCL cells.In vitro and ex vivo analyses using enzyme-linked immunosorbent assays, flow cytometry, and immunoblotting.Apoptosis, cleaved caspases, extrinsic apoptotic death receptors and ligands, cell proliferation, nuclear factor-κB expression, and other factors.This study used high-throughput screening to detect cleaved caspase 8 induced in CTCL cells by 1710 unique compounds. The nonprescription, topical antimicrobial remedy GV induced more total apoptosis than did nitrogen mustard (mechlorethamine). Furthermore, GV induced 4 to 6 times greater apoptosis in CTCL lines than in normal keratinocytes, suggesting a favorable topical toxicity profile. In addition to increasing caspase 8, GV also upregulated death receptors 4 and 5, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, and Fas ligand but not the Fas receptor, TNF receptor, or TNF-α ligand. These results are consistent with induction of extrinsic apoptosis via the Fas and TNF-related apoptosis-inducing ligand pathways. Increased phosphorylation of phospholipase C-γ1, Ca2+ influx, and reactive oxygen species were also detected, indicating that the mechanism of Fas ligand upregulation involves key elements of the activation-induced cell death pathway. In ex vivo studies, 1-μmol/L GV induced up to 90% CTCL apoptosis in Sézary blood cells. In addition, GV reduced expression of antiapoptotic myeloid cell leukemia 1 and proproliferative nuclear factor-κB components and increased inhibitory κB levels. This finding was associated with cell cycle arrest and reduced CTCL tumor cell proliferation. Furthermore, the CTCL killing associated with GV was augmented when used in combination with methotrexate.This study found that GV attacked tumor viability and growth in CTCL. Although purple at neutral pH, GV can be rendered colorless by altering its pH. These preclinical findings may help to broaden knowledge of the antineoplastic features of GV and provide a rationale for clinical studies of its use as a novel, inexpensive, topical therapy for CTCL that is available worldwide.
Abstract 13099: Geriatric Nutritional Risk Index Predict Cardiovascular Events in Patients With Pheripheral Artery Disease
Authors: Masatoshi Minamisawa, Takashi Miura, Hirohiko Motoki, Yasushi Ueki, Tomoaki Mochidome, Yasutaka Oguchi, Hitoshi Nishimura, Soichiro Ebisawa, Jun Koyama, Uichi Ikeda
Journal: Circulation (2016)

Introduction: Geriatric nutritional risk index (GNRI) is a simple nutritional assessment tool for elderly patients. Lower GNRI is associated with a worse prognosis in patients with critical limb ischemia or hemodialysis. However, few data are available regarding the prognostic impact of GNRI value for risk stratification in patients with peripheral artery disease (PAD). Hypothesis: We hypothesized that GNRI values would predict adverse cardiovascular (CV) events in patients with PAD. Methods: We retrospectively enrolled 480 consecutive patients with PAD who were hospitalized for CV diseases between 2005 and 2012. GNRI on admission was calculated as follows: 14.89 * serum albumin (g/dL) + 41.7 * body mass index/22. Patients were divided into two groups stratified by GNRI (median value 103.3). The study endpoint was the composite of major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction, and stroke. Results: Over a 3.7-year median follow-up, adverse events were observed in 164 patients (34.2 %). In Kaplan–Meier analysis, patients with low GNRI (&lt; 103.3, n = 239) showed worse prognoses than those with high GNRI (≥ 103.3, n = 241) (MACE incidence 42.7 % vs. 25.7 %, P &lt; 0.001). In multivariate Cox proportional hazards analysis after the adjustment for age, sex, estimated glomerular filtration rate, B-type natriuretic peptide, and left ventricular ejection fraction, Low GNRI (&lt;103.3) was significantly associated with the incidence of MACE (hazard ratio: 2.14, 95% confidence interval: 1.34–3.41; P &lt; 0.001). Conclusions: In patients with PAD, GNRI is an independent predictor of MACE. Simple assessment of GNRI may be useful for predicting CV events in those patients.