tbuckley/cabot-search huggingface dataset:
Remote‐Controlling Potassium Channels in Living Cells through Photothermal Inactivation of Calmodulin
Authors: Ran Chai, Chengfen Xing, Dong Gao, Hongbo Yuan, Yong Zhan, Shu Wang
Journal: Advanced Healthcare Materials (2018)

Abstract Spatiotemporal regulation of cellular functions provides a powerful strategy for understanding underlying mechanisms of cellular bioprocesses. Here, a strategy is reported to realize the remote control of the activities of potassium channels via photothermal inactivation of calmodulin (CaM) by using reduced graphene oxide decorated with calmodulin binding peptide (rGO‐P) as the transducer with near‐infrared light (NIR) irradiation. Upon NIR light irradiation, the CaM/Ca 2+ bound to rGO‐P is inactivated by the photothermal effect of rGO‐P, resulting in the incapability of binding with Ca 2+ . Hence, the closed Kv10.1 channel is converted to be open in the presence of calcium in living cells. Meanwhile, the SK2 channel is induced to be closed from the open state and the Kir2.1 channel is unaffected by the intracellular inactivation of CaM. This strategy gives a noninvasive and effective approach to remotely control the activities of potassium channels, offering an alternative for the development of optogenetics.
Blood Flow and Oxygen Consumption in Muscles after Section of Ventral Roots
Authors: Olgahudlická
Journal: Circulation Research (1967)

Muscles deprived of somatic motor innervation (sensory and sympathetic motor innervation intact) served as a model for studying the role of vasoconstrictor fibers and skeletal muscle tone in the regulation of skeletal muscle blood flow. Blood flow, vascular resistance and O2 consumption of the gastrocnemius muscle of the cat were measured 5 to 7, 10 to 16, and 27 to 44 days after unilateral section of ventral roots L5 to S5 in cats and compared to similar measurements in the normal gastrocnemius muscle and in that with its sciatic nerve cut. After section of the peripheral nerve, total blood flow increased and then returned to normal; after section of the ventral roots, total blood flow did not change significantly. In both cases, blood flow per 100 g of muscle increased as atrophy developed. After section of the ventral roots, O2 consumption and CO2 production per 100 g of muscle increased earlier than blood flow. Peripheral resistance was calculated before and immediately after acute section of both tib...
Abstract 2720: The CD47-blocking innate immune checkpoint inhibitor, TTI-621, triggers CD47-mediated tumor cell apoptosis
Authors: Julia Bershadsky Izrailit, Natasja Nielsen Viller, Xinli Pang, Penka S. Petrova, Robert A. Uger, Jeff Winston, Emma Linderoth
Journal: Cancer Research (2018)

Abstract CD47 is a cell surface glycoprotein of the immunoglobulin superfamily that is utilized by tumor cells to avoid immune destruction. Overexpression of the CD47 ligand on tumor cells provides a “do-not-eat” signal when bound to its receptor, signal regulatory protein α (SIRPα), on macrophages, resulting in inhibition of phagocytosis and tumor survival. TTI-621 is a soluble SIRPα recombinant fusion protein with an IgG1 Fc tail that triggers macrophage phagocytosis of tumor cells in vitro, and potently inhibits tumor growth in vivo. It is currently being evaluated in two clinical studies in patients with hematologic and solid cancers (NCT02663518 and NCT02890368). TTI-621's pro-phagocytic effect has been shown to be a result of blockade of the CD47-SIRPα pathway as well as activation of Fc gamma receptors (FcγR) on macrophages. However, engagement of CD47 has also been shown to directly induce apoptosis in tumor cells. Therefore, the objective of this study was to further examine the pro-apoptotic potential of TTI-621. The induction of apoptosis in tumor cells by TTI-621 was evaluated using flow cytometry and protein expression assays. Ligating CD47 with immobilized TTI-621 efficiently induced apoptosis in malignant T-ALL and DLBCL cells but had no effect on apoptosis in normal peripheral blood mononuclear cells. Immobilized TTI-621 or anti-CD47 mAb promoted caspase-independent but PLCγ-1-dependent apoptosis. Under conditions of cellular stress, both soluble and immobilized TTI-621 induced apoptosis in T-ALL cells. In contrast to immobilized TTI-621, treatment of stressed tumor cells with soluble TTI-621 triggered caspase-dependent but PLCγ-1-independent apoptosis. In addition, anchoring the IgG1 Fc tail of TTI-621 to FcγR-expressing cells enhanced tumor cell apoptosis in a dose-dependent and CD47-dependent manner. These results suggest that in addition to blocking the anti-phagocytic “do-not-eat” signal on tumor cells and activating FcγR on macrophages, binding of TTI-621 to FcγRs on tumor-infiltrating immune cells may provide a cross-linking scaffold to enhance TTI-621-mediated apoptosis via CD47 on cancer cells. Additionally, under conditions of cellular stress, TTI-621 may induce tumor cell death directly via binding to CD47 on malignant cells, in a cell-autonomous, cytotoxic mechanism. Thus, TTI-621 may employ multiple mechanisms to elicit its anti-tumor effects. Citation Format: Julia Bershadsky Izrailit, Natasja Nielsen Viller, Xinli Pang, Penka S. Petrova, Robert A. Uger, Jeff Winston, Emma Linderoth. The CD47-blocking innate immune checkpoint inhibitor, TTI-621, triggers CD47-mediated tumor cell apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2720.
Abstract 13599: Combined Aerobic and Resistance Exercise Training Decrease Oxidative Stress by Augmenting Antioxidant Potential in Patients with Cardiovascular Disease
Authors: NorikoYoshida, EmikoShiotani, HiroshiNiiyama, HaruhitoHarada, AtsushiKato, YasuhiroNishiyama, HisaoIkeda
Journal: Circulation (2014)

Introduction: Oxidative stress plays important roles in pathophysiology of atherosclerotic disease. However, little is known about the effects of aerobic exercise and resistance exercise on the oxidant offense and antioxidant defense systems in cardiovascular disease (CVD). Hypothesis: We hypothesized that combined aerobic and resistance exercise training decrease oxidative stress in patient with CVD. Methods: Thirty-two patients with CVD refer to in-hospital cardiac rehabilitation were divided to aerobic exercise (AE) group (n=15) and combined aerobic and resistance exercise (AE+RE) group (n=17). AE sessions consisted of 50 minutes of exercise (anaerobic threshold level), 5 days/week during training period (mean 27 days). Resistance exercise (30% of 1-repetition maximum) was performed 3 days/week before AE sessions. Serum reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) were measured using the FRAS4 (Diacron International, Italy) before and after training period. BAP/d-ROMs...
Bone Density in Children With Chronic Liver Disease Correlates With Growth and Cholestasis
Authors: Kathleen M. Loomes, Cathie Spino, Nathan P. Goodrich, Thomas N. Hangartner, Amanda E. Marker, James E. Heubi, Binita M. Kamath, Benjamin L. Shneider, Philip Rosenthal, Paula M. Hertel, Saul J. Karpen, Jean P. Molleston, Karen F. Murray, Kathleen B. Schwarz, Robert H. Squires, Jeffrey Teckman, Yumirle P. Turmelle, Estella M. Alonso, Averell H. Sherker, John C. Magee, Ronald J. Sokol
Journal: Hepatology (2018)

Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.
Methylomic Analysis of Ovarian Cancers Identifies Tumor-Specific Alterations Readily Detectable in Early Precursor Lesions
Authors: Thomas R. Pisanic, Leslie M. Cope, Shiou-Fu Lin, Ting-Tai Yen, Pornpat Athamanolap, Ryoichi Asaka, Kentaro Nakayama, Amanda N. Fader, Tza-Huei Wang, Ie-Ming Shih, Tian-Li Wang
Journal: Clinical Cancer Research (2018)

High-grade serous ovarian carcinoma (HGSOC) typically remains undiagnosed until advanced stages when peritoneal dissemination has already occurred. Here, we sought to identify HGSOC-specific alterations in DNA methylation and assess their potential to provide sensitive and specific detection of HGSOC at its earliest stages.MethylationEPIC genome-wide methylation analysis was performed on a discovery cohort comprising 23 HGSOC, 37 non-HGSOC malignant, and 36 histologically unremarkable gynecologic tissue samples. The resulting data were processed using selective bioinformatic criteria to identify regions of high-confidence HGSOC-specific differential methylation. Quantitative methylation-specific real-time PCR (qMSP) assays were then developed for 8 of the top-performing regions and analytically validated in a cohort of 90 tissue samples. Lastly, qMSP assays were used to assess and compare methylation in 30 laser-capture microdissected (LCM) fallopian tube epithelia samples obtained from cancer-free and serous tubal intraepithelial carcinoma (STIC) positive women.Bioinformatic selection identified 91 regions of robust, HGSOC-specific hypermethylation, 23 of which exhibited an area under the receiver-operator curve (AUC) value ≥ 0.9 in the discovery cohort. Seven of 8 top-performing regions demonstrated AUC values between 0.838 and 0.968 when analytically validated by qMSP in a 90-patient cohort. A panel of the 3 top-performing genes (c17orf64, IRX2, and TUBB6) was able to perfectly discriminate HGSOC (AUC 1.0). Hypermethylation within these loci was found exclusively in LCM fallopian tube epithelia from women with STIC lesions, but not in cancer-free fallopian tubes.A panel of methylation biomarkers can be used to accurately identify HGSOC, even at precursor stages of the disease.
Age- and Gender-Specific Familial Risks for Venous Thromboembolism
Authors: BengtZöller, XinjunLi, JanSundquist, KristinaSundquist
Journal: Circulation (2011)

Background—This nationwide study sought to determine age- and gender-specific familial risks in siblings hospitalized for venous thromboembolism (VTE). Methods and Results—The Swedish Multigeneration Register on 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the years 1987–2007. Standardized incidence ratios were calculated for individuals whose siblings were hospitalized for VTE compared with those whose siblings were not affected. Among a total of 45 362 hospitalized cases with VTE, 2393 affected siblings were identified, with a familial standardized incidence ratio of 2.45 (95% confidence interval [CI], 1.66 to 3.61). Gender-specific differences in incidence rates were observed. The familial risks were significantly increased from the age of 10 to 69 years, with a familial standardized incidence ratio of 4.77 (95% CI, 1.96 to 10.83) at ages 10 to 19 years, which decreased to 2.08 (95% CI, 1.35 to 3.20) at ages 60 to 69 years, although the absolute risk increased with age. ...
Abstract 5307: Inferring parsimonious migration histories for metastatic cancers
Authors: Mohammed El-Kebir, Gryte Satas, Benjamin J. Raphael
Journal: Cancer Research (2018)

Abstract Recent studies have attempted to infer the pattern of cellular migrations between a primary tumor and distant metastases using phylogenetic trees constructed from somatic mutations. Several of these studies have challenged the conventional view of monoclonal seeding of a metastasis, and reported complex patterns of migration between primary tumors and metastases, including polyclonal seeding and reseeding. Most current analyses that attempt to infer migration patterns from somatic mutations rely on two key assumptions, sample homogeneity and mutation-migration concordance, that do not typically hold for cancer sequencing datasets. Consequently, standard phylogenetic analysis of mutations may result in incorrect or misleading patterns of metastasis. We introduce a computational model to evaluate migration patterns in a rigorous manner. We use this model as a basis for Metastatic And Clonal History INtegrative Analysis (MACHINA), an algorithm that jointly infers parsimonious clone trees and migration histories of metastatic cancers from DNA sequencing data. We show that MACHINA accurately recovers clone trees and migration histories on simulated data. We apply MACHINA to sequencing data from metastatic ovarian, breast, prostate and skin cancer samples. In several cases, we find simpler migration histories than previously reported, and these alter conclusions regarding metastasis-to-metastasis spread, the anatomical site of the primary tumor, or the occurrence of polyclonal seeding and reseeding in individual patients. MACHINA enables researchers to rigorously assess the validity of different migration patterns in individual patients with metastatic disease and evaluate the prevalence of different migration patterns across large cohorts of patients and tumor types. Citation Format: Mohammed El-Kebir, Gryte Satas, Benjamin J. Raphael. Inferring parsimonious migration histories for metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5307.
Abstract 4077: A new mouse model of gastric adenocarcinoma: A valuable tool for preclinical studies
Authors: Jacob Till, Prince Addai, Neha Bhagwat, Stephanie Yee, Erica Carpenter, Sam Yoon, Sandra Ryeom
Journal: Cancer Research (2018)

Abstract We recently generated the first model of metastatic mixed-type gastric adenocarcinoma that closely recapitulates the human disease. Our model combines conditional loss of E-cadherin (Cdh1fl/fl) and p53 (Trp53fl/fl) with oncogenic Kras (KrasLSL-G12D/+) activation and yellow fluorescence protein (Rosa26LSL-YFP/LSL-YFP) expression in cells of the gastric parietal cell lineage (Atp4b-Cre). Median survival is 76.5 days (range 64-91 days, SD 7.2) with all mice developing local lymph node metastases and lung metastases, half developing paratracheal lymph node metastases, and 20% developing liver metastases. We previously provided proof of concept for the preclinical utility of our model by demonstrating extended survival upon treatment with a MEK inhibitor (PD0325901). Here we demonstrate the utility of this model to investigate the role of the microbiome in gastric carcinogenesis and to determine the use of circulating tumor cells (CTCs) as biomarkers of metastatic disease. The specific pathogen H. pylori is known to be causal in gastric adenocarcinoma. Further, many studies have implicated the microbiome in colon carcinogenesis. However, no studies have investigated the role of the normal microbiome in gastric carcinogenesis in the absence of H. pylori infection. We treated our model of mixed-type gastric adenocarcinoma with a commonly utilized antibiotic cocktail to deplete the gut microbiota and confirmed depletion of the microbiota by qPCR in stomach and fecal contents at necropsy. Microbiome depletion resulted in a 7.5-day increase in median survival (n=6) over vehicle treated mice (n=5, p=0.04). These data suggest a role for the normal microbiota in gastric cancer progression regardless of H. pylori infection. Given the broadly metastatic phenotype of our model, we examined whether the number of CTCs correlated with metastatic burden. Because our gastric cancer model incorporated a yellow fluorescence protein (YFP) as a marker of tumor cells, we used flow cytometry to measure CTCs in cardiac blood samples from terminal mice. We detected CTCs (defined as DAPI-;CD45-;YFP+) in all terminal mice and correlated CTC counts with lung metastatic burden. Mice with macrometastatic disease in the lung had &amp;gt;90 CTCs per 100 μl blood (n=3) as compared to mice with micrometastatic disease of the lung which showed &amp;lt;15 CTCs per 100 μl blood (n=4, p=0.008). These data suggest that our new mouse model of metastatic gastric adenocarcinoma offers a valuable tool for a variety of preclinical studies. Citation Format: Jacob Till, Prince Addai, Neha Bhagwat, Stephanie Yee, Erica Carpenter, Sam Yoon, Sandra Ryeom. A new mouse model of gastric adenocarcinoma: A valuable tool for preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4077.
Abstract 138: PRMT6 promotes lung tumor growth via the modulation of macrophage M2 polarization
Authors: Sreedevi Avasarala, Pei-Ying Wu, Samia Q. Khan, Michelle Van Scoyk, Yanlin Su, Odile David, Vineet Gupta, Mark T. Bedford, Robert A. Winn, Rama Kamesh Bikkavilli
Journal: Cancer Research (2018)

Abstract Lung cancer kills more people in the United States than any other malignancy. High mortalities are in part due to the diagnosis at an advanced inoperable stage where the 5-year survival is only 4%. Therefore, improving survival will require increased knowledge of genes that drive the complex mechanisms of lung cancer initiation and progression. Emerging data implicate novel roles for protein arginine methylation in lung cancers. In protein arginine methylation, nitrogen/s of arginine can be post-translationally modified via the addition of a methyl group, catalyzed by a class of enzymes, protein arginine methyl transferases (PRMTs). Based on the computational analysis, tissue staining, and immunoblotting we have identified an increased expression of PRMT6 in lung tumors. To test the biologic relevance of PRMT6 in lung tumor development, we employed an inducible lung-targeted PRMT6 gain-of-function (GOF) mouse model. For the first time, we show that lung-targeted overexpression of PRMT6 results in spontaneous lung tumor development. We also observed a robust increase in lung tumors in the PRMT6 GOF mice in response to urethane, a KRas mutagen, and a prototypical model to study lung tumorigenesis. Excitingly, we detected an increase in the number of tumor-associated macrophages (TAMs) in the PRMT6 GOF mice. Further characterization of the TAMs from the PRMT6 GOF mice revealed that they were M2 polarized with immunosuppressive, angiogenesis-enhancing, and tumor-promoting activities. Taken together, these results demonstrate a novel role for PRMT6 in lung tumor development by way of macrophage M2 polarization. Therefore, defining the complete mechanism of PRMT6-mediated macrophage M2 polarization could lead to the development of novel therapeutic strategies to treat lung cancer. Citation Format: Sreedevi Avasarala, Pei-Ying Wu, Samia Q. Khan, Michelle Van Scoyk, Yanlin Su, Odile David, Vineet Gupta, Mark T. Bedford, Robert A. Winn, Rama Kamesh Bikkavilli. PRMT6 promotes lung tumor growth via the modulation of macrophage M2 polarization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 138.
Plasma levels of heart failure biomarkers are primarily a reflection of extracardiac production
Authors: Weijie Du, Arnold Piek, E. Marloes Schouten, Cees W.A. van de Kolk, Christian Mueller, Alexandre Mebazaa, Adriaan A.Voors, Rudolf A. de Boer, Herman H.W. Silljé
Journal: Theranostics (2018)

Plasma heart failure (HF) biomarkers, like natriuretic peptides, are important in diagnosis, prognosis and HF treatment. Several novel HF biomarkers have been identified, including Gal-3, GDF-15 and TIMP-1, but their clinical potential remains vague. Here we investigated plasma biomarker levels in relation to tissue expression and structural and functional cardiac changes. Methods: Cardiac remodeling, cardiac function, and plasma and tissue biomarker levels were investigated in mice after myocardial infarction induced by temporal and permanent LAD ligation (tLAD and pLAD). In addition, a pressure overload model induced by transverse aortic constriction (TAC) and an obese/hypertensive HFpEF-like mouse model were investigated. Results: Plasma levels of ANP and its cardiac expression were strictly associated with cardiac remodeling and function. Gal-3, GDF-15 and TIMP-1 cardiac expressions were also related to cardiac remodeling and function, but not their plasma levels. Only directly after myocardial infarction could elevated plasma levels of Gal-3 and TIMP-1 be detected. Eight weeks after infarction, plasma levels were not elevated despite enhanced cardiac expression and low EF (18.3±3.3%, pLAD). Plasma levels of TIMP-1 and GDF-15 were elevated after TAC, but this also correlated with increased lung expression and congestion. In obese-hypertensive mice, elevated plasma levels of Gal-3, GDF-15 and TIMP1 were associated with increased adipose tissue expression and not with cardiac function. Conclusions: The Gal-3, GDF-15 and TIMP-1 plasma pool levels are hardly influenced by dynamic changes in cardiac expression. These biomarkers are not specific for indices of cardiac remodeling, but predominantly reflect stress in other affected tissues and hence provide health information beyond the heart.
Hemodynamic Responses to Tilt and Beta-Adrenergic Blockade in Young Patients with Borderline Hypertension
Authors: Runesannerstedt, Stevojulius, Jamesconway
Journal: Circulation (1970)

Seventeen young patients with borderline hypertension (one female) and 18 normotensive paid volunteers (two females) were studied at rest and in the tilted position after 10 min of 45° head-up tilt. Cardiac output, heart rate, and intra-arterial pressure were recorded. The measurements at rest and during the tilt were repeated after betaadrenergic blockade with propranolol. By comparison with the normotensives, cardiac output and heart rate in those with borderline hypertension were elevated initially, after 50 min of rest, and during tilt. The change of the cardiac output and heart rate to tilt was of the same magnitude in patients and control subjects. Consequently, regulation of the rate and flow in borderline hypertensives appears to be normal but starts from a higher base line level. After blockade with propranolol, cardiac output in patients with borderline hypertension was still slightly elevated, but the difference from controls was not significant. The heart rate, however, remained significantly ...