tbuckley/cabot-search huggingface dataset:
Abstract B65: Promotion of colorectal cancer invasion and metastasis through activation of Notch–Dab1–Abl–RhoGEF protein trio
Authors: Masahiro Sonoshita, Yoshiro Itatani, Fumihiko Kakizaki, Yoshiharu Sakai, M. Mark Taketo.
Journal: Cancer Research (2016)

Abstract We have recently identified a metastasis suppressor gene for colorectal cancer: AES/Aes that encodes an endogenous inhibitor of Notch signaling (1). When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here, we show that one of the genes induced by NOTCH signaling in colorectal cancer is DAB1/Dab1. Genetic depletion of DAB1 suppresses cancer invasion and metastasis in the NOTCH signaling-activated mice. DAB1 is phosphorylated by ABL tyrosine kinase, which activates ABL reciprocally. Consistently, inhibition of ABL suppresses cancer invasion in mice. Furthermore, we show that one of the targets of ABL is the RAC/RHOGEF protein TRIO, and that phosphorylation at its Tyr residue 2681 (pY2681) causes RHO activation in colorectal cancer cells. Its unphosphorylatable mutation TRIO Y2681F reduces Rho-GEF activity and inhibits invasion of colorectal cancer cells. Importantly, Trio (pY2681) correlates with significantly poorer prognosis of patients with colorectal cancer after surgery (2). These results indicate that Trio(pY2681) is one of the downstream effectors of Notch signaling activation in colorectal cancer, and can be a prognostic marker, helping to determine the therapeutic modality of patients with colorectal cancer. More recent results will be discussed. (1) Cancer Cell; 19: 125–137, 2011. (2) Cancer Discov; 5:198–211, 2015. Citation Format: Masahiro Sonoshita, Yoshiro Itatani, Fumihiko Kakizaki, Yoshiharu Sakai, M. Mark Taketo. Promotion of colorectal cancer invasion and metastasis through activation of Notch–Dab1–Abl–RhoGEF protein trio. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B65.
Mitochondrial uncoupler triclosan induces vasorelaxation of rat arteries
Authors: Xiyue Zhang, Xinzi Zhang, Yanqiu Zhang, Mingyu Liu, Jing Jin, Jie Yan, Xin Shen, Nan Hu, Deli Dong
Journal: Acta Pharmaceutica Sinica B (2017)

Our previous studies found that mitochondrial uncouplers induced vasodilation. Triclosan, the broad spectrum antibacterial agent, is the active ingredient in soaps and toothpastes. It was reported that triclosan induced mitochondrial uncoupling, so we aim to investigate the effects of triclosan on vascular function of rat mesenteric arteries and aorta. The isometric tension of rat mesenteric artery and thoracic aorta was recorded by multi-wire myograph system. The cytosolic [Ca2+]i, mitochondrial reactive oxygen species (mitoROS), and mitochondrial membrane potential of smooth muscle cells (A10 cells) were measured using laser scanning confocal microscopy. Triclosan treatment relaxed phenylephrine (PE)- and high K+ (KPSS)-induced constriction, and pre-treatment with triclosan inhibited PE- and KPSS-induced constriction of rat mesenteric arteries. In rat thoracic aorta, triclosan also relaxed PE- and KPSS-induced constriction. Triclosan induces vasorelaxation without involving KATP channel activation in smooth muscle cells of arteries. Triclosan treatment increased cytosolic [Ca2+]i, mitochondrial ROS production and depolarized mitochondrial membrane potential in A10 cells. In conclusion, triclosan induces mitochondrial uncoupling in vascular smooth muscle cells and relaxes the constricted rat mesenteric arteries and aorta of rats. The present results suggest that triclosan would indicate vasodilation effect if absorbed excessively in vivo.
Hepcidin Upregulation By Inflammation Is Not Causally Related to Liver Activation of Smad1/5/8 Signaling By Activin B
Authors: Celine Besson-Fournier, Aurelie Gineste, Chloe Latour, Ophelie Gourbeyre, Delphine Meynard, Patricia Aguilar-Martinez, Eric Oswald, Patricia Martin, Helene Coppin, Marie-Paule Roth
Journal: Blood (2016)
Fecal Immunochemical Tests in Patients at Increased Risk for Colorectal Cancer—Is It Prime Time Yet?
Authors: Grigorios I. Leontiadis
Journal: JAMA Internal Medicine (2017)

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Abstract P255: Gut Microbiota Diversity and Specific Microbial Genera Associate with Cardiovascular Disease Risk: Findings From the Bogalusa Heart Study
Authors: Tanika Kelly, Nadim J Ajami, Lydia A Bazzano, Jinying Zhao, Joseph Petrosino, Jiang He
Journal: Circulation (2016)

Recent advances in sequencing technology have made it feasible to characterize human gut microbial communities (or microbiota) and examine their associations with disease outcomes, including cardiovascular disease (CVD) related traits. However, there is a paucity of research examining how the human gut microbiome may influence overall CVD risk in population based studies. The objective of the current study was to identify composite measures of microbiota diversity and specific microbial genera that associate with CVD risk among participants of the Bogalusa Heart Study (BHS). The current BHS cohort includes 1,257 participants who have been screened at least two times in childhood and two times in adulthood for CVD risk factors. For the microbiome study, we selected the 55 participants at highest CVD risk and 57 participants at lowest CVD risk using a z-score based data reduction technique, leveraging longitudinal mean measures of systolic BP, low-density lipoprotein cholesterol, and fasting plasma glucose levels. Next generation 16S rRNA sequencing of the V4 hypervariable region was conducted using genomic bacterial DNA extracted from stool samples of the 112 participants. The Wilcoxon rank sum test was used to examine differences in measures of alpha diversity, including observed operational taxonomic units (OTUs) and the Chao1 index, along with specific microbial taxa between CVD risk groups. Permutation multivariate analysis of variance (PERMANOVA) was used to test compositional differences based on unweighted Unifrac distance as a measure of beta diversity. We observed significantly less alpha diversity in those at high versus those at low CVD risk (P=0.04 and 0.02 for observed OTU and Chao1 index measures, respectively). The PERMANOVA test indicated marginal significance of compositional differences between the two groups (P=0.07). In addition, 10 microbial genera significantly differed between high and low CVD risk participants, including Faecalibacterium (P=0.0014), Subdoligranulum (P=0.01), Turicibacter (P=0.01), Rothia (P=0.01), Lachnospira (P=0.01), Haemophilus (P=0.03), Dialister (P=0.03), Bifidobacterium (P=0.03), Oscillibacter (P=0.04), and Megamonas (P=0.05). In summary, we provide empirical evidence of lower microbial enrichment among BHS participants at high versus those at low CVD risk, along with promising findings of differences in specific microbial genera between CVD risk groups.
"Survival with first-line bosentan in patients with primary pulmonary hypertension". V. V. McLaughlin, O. Sitbon, D. B. Badesch, R. J. Barst, C. Black, N. Galie, M. Rainisio, G. Simonneau, and L. J. Rubin. Eur Respir J 2005; 25: 244-249.
Journal: European Respiratory Journal (2005)
Abstract 90: Akt Mediated Mitochondrial Dysfunction Involves Mitochondrial Endothelial Nitric Oxide Synthase Translocation
Authors: Ruslan Rafikov, Olga Rafikova, Xutong Sun, Saurabh Aggarwal, Stephen M Black
Journal: Circulation Research (2015)

Pulmonary arterial hypertension (PH) is a fatal disease characterized by uncontrolled pulmonary vascular cell proliferation. Mitochondrial dysfunction (MD) of pulmonary endothelial cells (EC) was shown to be one of the primary events implicated into proliferative, apoptosis resistant cell phenotype. However, the particular molecular mechanisms responsible for MD remain unclear. The development of PH in patients is associated with severe nitrosative stress, leading to post-translational protein modifications. Thus, we have recently found that Akt is susceptible to nitration of tyrosine Y350 residue. We hypothesize that nitration of Akt induces activation of Akt signaling and contributes to the development of MD. Nitrosative stress in EC was initiated by eNOS uncoupler ADMA or peroxynitrite donor SIN-1 and resulted in significant Akt nitration and activation (1.5±0.1 fold control; p=0.007; N=3-4), as well as activation of anti-apoptotic (BAD phosphorylation), and proliferative (mTOR phosphorylation) signaling cascades. Increased Akt signaling induced phosphorylation of eNOS at serine S615 (1.47±0.08 fold control, p=0.005, N=3) and S1177 (0.22±0.04 vs. 0.47±0.07, p=0.029, N=3). Phosphorylation of eNOS resulted in its translocation to mitochondria (3± 0.3 fold control; p=0.003; N=3) which, in turn, significantly decreased basal mitochondrial respiration (oxygen consumption rate, pmol/min: untransfected cells 1022±96 vs. mitochondrial targeted phospho-mimetic eNOS mutants S615D 102±9 and S1177D 117±7, p&lt;0.001, N=4-6), perhaps due to previously reported inhibitory effect of NO on mitochondrial respiratory chain. Finally, we have created an anti-oxidant conjugated “shielding” peptide that, by shielding the Akt nitration site, is capable to prevent Akt activation. Indeed, pre-treatment with shielding peptide (100μg/ml, 30min) completely abolished SIN-1 induced nitration of Akt in EC. We conclude that Akt nitration may contribute to proliferative/apoptosis resistant EC phenotype through pathological activation of Akt signaling and Akt mediated mitochondrial eNOS translocation. Besides, our novel shielding peptide based therapeutic strategy opens new avenues in MD prevention.
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study.
Authors: Mathias J. Rummel, Georg Maschmeyer, Arnold Ganser, Andrea Heider, Ulrich von Gruenhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald Ballo, Martina Stauch, Wolfgang Blau, Alexander Burchardt, Juergen Barth, Frank Kauff, Wolfram Brugger
Journal: Journal of Clinical Oncology (2017)

7501 Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or mantle cell lymphoma and was first published in The Lancet in 2013. The final analysis demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group compared to the CHOP-R group, with a median PFS of 69.5 vs. 31.2 months, respectively. In the current analysis, we present updated results for overall survival (OS), time-to-next-treatment (TTNT), and secondary malignancies (sNPL) with a median follow-up of 113 months for patients with indolent lymphomas (excluding MCL). Methods: 447 pts with indolent lymphomas were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: Patient characteristics were well balanced between arms; median age was 64 years. The difference in OS between the two treatment arms was not statistically significant, with 60 deaths in the B-R group vs 68 deaths with CHOP-R (HR 0.82, 95% CI 0.58 – 1.15, p = 0.249). The estimated 10-year survival rates were 71% for B-R and 66% for CHOP-R. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.52, 95% CI 0.38 – 0.69, p &lt; 0.001). Median TTNT was not yet reached in the B-R group (95% CI 124.9 – n.y.r) vs. 56 months in the CHOP-R group (95% CI 39.1 – 82.0). Patients treated initially with B-R needed fewer second-line treatments due to disease progression compared to CHOP-R treated pts: 73 pts (34%) in the B-R group received salvage treatment compared with 106 pts (52%) in the CHOP-R group. For B-R pts, CHOP-R was used as second-line therapy 26 times (36%), whereas B-R was used for pts initially treated with CHOP-R 49 times (46%). 36 pts with sNPL were observed in the B-R group compared with 39 in the CHOP-R group, with 7 hematological malignancies in both groups to date. Conclusions: In pts with previously untreated indolent lymphomas, B-R demonstrates a PFS and TTNT benefit over CHOP-R. Clinical trial information: NCT00991211.
Cholesterol and coronary heart disease mortality in elderly patients
Authors: H. M. Krumholz
Journal: JAMA (1996)

<h3>To the Editor.</h3> —In the Editorial by Drs Denke and Winker,<sup>1</sup>there is the unfortunate implication that our article<sup>2</sup>from the New Haven, Conn, site of the Established Populations for Epidemiologic Studies of the Elderly (EPESE) was published prematurely and should not have preceded a multicenter analysis. The comments reveal a misunderstanding of the nature of the EPESE collaboration and the special features of this observational study. Unlike many multicenter trials, the EPESE sites are a confederation of studies with distinct sampling designs and features. Although the EPESE was a collaboration contract program, individual sites had the option to publish results separately, where unique data were available. For this reason, single-site publications from EPESE far outnumber the pooled analyses. There are unique features of the New Haven site that led us to pursue our analysis separately. New Haven is the only site in which diagnoses of hospitalized acute
The Diverse Roles of Arrestin Scaffolds in G Protein–Coupled Receptor Signaling
Authors: Yuri K. Peterson, Louis M. Luttrell
Journal: Pharmacological Reviews (2017)

The visual/β-arrestins, a small family of proteins originally described for their role in the desensitization and intracellular trafficking of G protein-coupled receptors (GPCRs), have emerged as key regulators of multiple signaling pathways. Evolutionarily related to a larger group of regulatory scaffolds that share a common arrestin fold, the visual/β-arrestins acquired the capacity to detect and bind activated GPCRs on the plasma membrane, which enables them to control GPCR desensitization, internalization, and intracellular trafficking. By acting as scaffolds that bind key pathway intermediates, visual/β-arrestins both influence the tonic level of pathway activity in cells and, in some cases, serve as ligand-regulated scaffolds for GPCR-mediated signaling. Growing evidence supports the physiologic and pathophysiologic roles of arrestins and underscores their potential as therapeutic targets. Circumventing arrestin-dependent GPCR desensitization may alleviate the problem of tachyphylaxis to drugs that target GPCRs, and find application in the management of chronic pain, asthma, and psychiatric illness. As signaling scaffolds, arrestins are also central regulators of pathways controlling cell growth, migration, and survival, suggesting that manipulating their scaffolding functions may be beneficial in inflammatory diseases, fibrosis, and cancer. In this review we examine the structure-function relationships that enable arrestins to perform their diverse roles, addressing arrestin structure at the molecular level, the relationship between arrestin conformation and function, and sites of interaction between arrestins, GPCRs, and nonreceptor-binding partners. We conclude with a discussion of arrestins as therapeutic targets and the settings in which manipulating arrestin function might be of clinical benefit.
Financial Incentives for Linkage to Care and Viral Suppression Among HIV-Positive Patients
Authors: Wafaa M. El-Sadr, Deborah Donnell, Geetha Beauchamp, H. Irene Hall, Lucia V. Torian, Barry Zingman, Garret Lum, Michael Kharfen, Richard Elion, Jason Leider, Fred M. Gordin, Vanessa Elharrar, David Burns, Allison Zerbe, Theresa Gamble, Bernard Branson
Journal: JAMA Internal Medicine (2017)

Achieving linkage to care and viral suppression in human immunodeficiency virus (HIV)-positive patients improves their well-being and prevents new infections. Current gaps in the HIV care continuum substantially limit such benefits.To evaluate the effectiveness of financial incentives on linkage to care and viral suppression in HIV-positive patients.A large community-based clinical trial that randomized 37 HIV test and 39 HIV care sites in the Bronx, New York, and Washington, DC, to financial incentives or standard of care.Participants at financial incentive test sites who had positive test results for HIV received coupons redeemable for $125 cash-equivalent gift cards upon linkage to care. HIV-positive patients receiving antiretroviral therapy at financial incentive care sites received $70 gift cards quarterly, if virally suppressed.Linkage to care: proportion of HIV-positive persons at the test site who linked to care within 3 months, as indicated by CD4+ and/or viral load test results done at a care site. Viral suppression: proportion of established patients at HIV care sites with suppressed viral load (<400 copies/mL), assessed at each calendar quarter. Outcomes assessed through laboratory test results reported to the National HIV Surveillance System.A total of 1061 coupons were dispensed for linkage to care at 18 financial incentive test sites and 39 359 gift cards were dispensed to 9641 HIV-positive patients eligible for gift cards at 17 financial incentive care sites. Financial incentives did not increase linkage to care (adjusted odds ratio, 1.10; 95% CI, 0.73-1.67; P = .65). However, financial incentives significantly increased viral suppression. The overall proportion of patients with viral suppression was 3.8% higher (95% CI, 0.7%-6.8%; P = .01) at financial incentive sites compared with standard of care sites. Among patients not previously consistently virally suppressed, the proportion virally suppressed was 4.9% higher (95% CI, 1.4%-8.5%; P = .007) at financial incentive sites. In addition, continuity in care was 8.7% higher (95% CI, 4.2%-13.2%; P < .001) at financial incentive sites.Financial incentives, as used in this study (HPTN 065), significantly increased viral suppression and regular clinic attendance among HIV-positive patients in care. No effect was noted on linkage to care. Financial incentives offer promise for improving adherence to treatment and viral suppression among HIV-positive patients.clinicaltrials.gov Identifier: NCT01152918.
Abstract 342: Lack of Lipid Phosphate Phosphatase 3 Promotes Cardiac Dysfunction and Early Mortality in Mice
Authors: Manikandan Panchatcharam, Mini Chandra, Benjamin Maxey, Alicia Day, Diana Escalante-Alcalde, Sumitra Miriyala
Journal: Circulation Research (2015)

Lysophosphatidic acid (LPA) is a naturally occurring glycerophospholipid and has been reported to increase heart rate and left ventricular pressure in the heart in vivo . The primary route of circulating LPA production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin (ATX). Lipid phosphate phosphatase-3 (LPP3) is a plasma membrane enzyme that regulates the availability of LPA by dephosphorylation. We made the novel discovery that tissue-specific deficiency of Ppap2b (gene that encodes LPP3) leads to embryonic lethality (endothelial LPP3), exaggerates vascular inflammation, increases heart rate, enhances endothelial permeability, and promotes the development of the neointima after vascular injury. Based on our earlier reports, we have generated mice that specifically lack LPP3 in cardiomyocytes. These mice showed early mortality ~8 months due to cardiac dysfunction. Whereas lack of LPP1 or LPP2 (global knockouts) didn’t had any obvious phenotypic effect. Lack of LPP3 accounts for less than 10 percent activity in cardiomyocytes purified from the Myh6-Ppap2b Δ , which augments our previous finding that the other two LPP isoforms have a lesser role in the cardiovascular system. Blood pressure was similar in Ppap2b fl/fl (96 ± 9 mmHg; n = 19) and Myh6-Ppap2b Δ mice (92 ± 7 mmHg; n = 19), although heart rates were significantly higher in Myh6-Ppap2b Δ 3-month old mice (642 ± 21 bpm, compared to Ppap2b fl/fl with 600± 17 bpm; P&lt;0.001). Knockdown of LPP3 enhanced cardiomyocyte hypertrophy induced by LPA based on analysis of sarcomere organization, cell surface area, levels of fetal genes ANP and BNP, and ANF release from nuclei, which are hallmarks of cardiomyocyte hypertrophy, indicating that LPP3 negatively regulates cardiac dysfunction caused by LPA. We observed an increase in ATX levels accompanied by a decrease in LPP3 expression following infarction in the myocardium of Ppap2b fl/fl mice. Infarction induced expression of IL-6 and KC, were 3 ± 0.5-fold and 2 ± 0.6-fold higher, respectively, in Myh6-Ppap2b Δ mice. Analysis of plasma by cytokine antibody array confirmed the elevation in IL-6 and KC, whereas G-CSF and sICAM-1 appeared lower than in Ppap2b fl/fl .
Single-task and dual-task tandem gait test performance after concussion
Authors: David R Howell, Louis R Osternig, Li-Shan Chou
Journal: British Journal of Sports Medicine (2017)

Objective To examine tandem gait test (TGT) performance during single-task and dual-task conditions. Design Prospective, longitudinal observational study Setting Motion analysis laboratory Participants Ten post-concussion (30% F, 19.0 [95% CI=15.6–22.4] years) and 7 control (57% F, 20.0 [16.7 -23.3] years) participants completed the TGT in single-task and dual-task conditions within 72 hours of sustaining a concussion and again at 1 week, 2 weeks, 1 month, and 2 months post-injury. Exclusion criteria included a current lower extremity injury, diagnosed learning disability, or documented prior concussion within the past year. Independent variables TGT trials were performed without (single-task) and while concurrently performing a cognitive test (dual-task). Outcome measures Participants completed 3 trials in each condition while whole body motion capture was performed. Outcome variables included the average completion time for the 3 trials, mean center-of-mass gait velocity, and cadence. Main results Concussion participants took significantly longer to complete the dual-task TGT than controls (16.4 [13.4 -19.4] vs. 10.1 [6.4 -13.7] seconds) at the 72 hour, 1 week, and 2 week time points (p=.03); single-task TGT times were significantly lower 72 hours post-injury only (p=.04). Cadence was significantly lower for concussion participants across the two month testing period during dual-task TGT (89.5 [68.6 -110.4] vs. 127.0 [97.4 -156.6] steps/minute; p=.04). Mean gait velocity was lower for concussion participants at 72 hours post-injury in both conditions. Conclusions Dual-task TGT deficits lasted longer for concussion participants than single-task TGT deficits. Including a secondary task during dynamic assessments of gait after concussion may increase the sensitivity to movement deficits that are undetectable using single-tasks. Competing interests The authors have no conflicts of interest to report.