tbuckley/cabot-search huggingface dataset:
Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction
Authors: DirkWestermann, MarioKasner, PaulSteendijk, FrankSpillmann, AlexanderRiad, KerstinWeitmann, WolfgangHoffmann, WolfgangPoller, MatthiasPauschinger, Heinz-PeterSchultheiss, CarstenTschöpe
Journal: Circulation (2008)

Background— Increased left ventricular stiffness is a distinct finding in patients who have heart failure with normal ejection fraction (HFNEF). To elucidate how diastolic dysfunction contributes to heart failure symptomatology during exercise, we conducted a study using an invasive pressure-volume loop approach and measured cardiac function at rest and during atrial pacing and handgrip exercise. Methods and Results— Patients with HFNEF (n=70) and patients without heart failure symptoms (n=20) were enrolled. Pressure-volume loops were measured with a conductance catheter during basal conditions, handgrip exercise, and atrial pacing with 120 bpm to analyze diastolic and systolic left ventricular function. During transient preload reduction, the diastolic stiffness constant was measured directly. Diastolic function with increased stiffness was significantly impaired in patients with HFNEF during basal conditions. This was associated with increased end-diastolic pressures during handgrip exercise and with de...
Activation of Mitochondrial KATP Channel Elicits Late Preconditioning Against Myocardial Infarction via Protein Kinase C Signaling Pathway
Authors: EnTakashi, YigangWang, MuhammadAshraf
Journal: Circulation Research (1999)

Abstract—Activation of mitochondrial KATP (mitoKATP) channel induces acute ischemic preconditioning (PC) against ischemic injury. The ability of this channel to elicit late PC remains unknown. The present study tests the hypothesis that stimulation of mitoKATP channel induces late PC via the protein kinase C (PKC) signaling pathway. Rats were subjected to 30 minutes of regional ischemia and 120 minutes of reperfusion (I/R). In other groups, rats were pretreated with diazoxide, a specific opener of the mitoKATP channel (7 mg/kg, IV), 12, 24, 48, and 72 hours before they were subjected to I/R. A maximum reduction in infarct size was observed after 24 hours (33.3±2.2% versus I/R group, 62.1 ±2.4%). Pretreatment with diazoxide did not reduce the infarct size significantly after 12, 48, and 72 hours (50.2±4.3%, 50.5±4.6%, and 58.2±4.9%) compared with the I/R group. The protection was blocked with 5-hydroxydecanoic acid (5-HD, 5 mg/kg IV), a relatively selective mitoKATP channel blocker (56.5±2.7%), and chelery...
Corrigendum to ‘An innovative Mg/Ti hybrid fixation system developed for fracture fixation and healing enhancement at load-bearing skeletal site’ [Biomaterials (2018) 173–183]
Authors: Li Tian, Yifeng Sheng, Le Huang, Dick Ho-Kiu Chow, Wing Ho Chau, Ning Tang, To Ngai, Chi Wu, Jian Lu, Ling Qin
Journal: Biomaterials (2018)
Abstract 3100: Replacing fetal calf serum by human platelet lysate in cancer research and toxicology
Authors: Oliver H. Krämer
Journal: Cancer Research (2018)

Abstract Experiments with cultured mammalian cells represent a common in vitro alternative to animal experiments. Fetal calf serum (FCS) is the most commonly used medium supplement. FCS contains a mixture of largely undefined growth factors and cytokines. Since FCS is received from unborn calves older than three months, it represents a massive burden for the pregnant cows and their fetuses. A needle is inserted into the heart of the fetus to collect blood. Since the animal is not under anesthesia, it may suffer pain and discomfort. Furthermore, the undefined nature of FCS is a source of experimental variation, undesired immune responses, and possible contaminations. Thus, alternative, defined, valid, and reliable medium supplements should be identified. We follow the principles of the 3Rs (Replacement, Reduction, Refinement). We established a method to receive human platelet lysate (hPL) from human blood platelets. We investigated if hPL represents potential true alternative for FCS in cell culture experiments and thereby the cruel slaughtering of unborn fetuses. hPL is received by freeze and thawing cycles and centrifugation steps. We successfully adapted three human leukemia cell lines (K562, NB4 and MV4-11) and HCT116 colon cancer cells to culture medium containing 1-5% hPL. We analyzed cell morphology by microscopy. Cell growth kinetics were examined by counting and cell cycle distributions were investigated by flow cytometry. Protein expression patterns were determined globally by global scale proteomics. We additionally determined possible FCS- or hPL-dependent reactions of cells to the well-established anti-cancer drugs Irinotecan, Hydroxyurea and Imatinib, and to epigenetic modulators of the HDAC inhibitor family (FK228 and the new, highly selective HDAC6 inhibitor Marbostat-100) by flow cytometry and Western blot. In these tests, we particularly focused on the expression of the pan-leukemic marker and transcription factor Wilms tumor 1 (WT1) and on the tumor suppressor p53. All tested cell lines grow with 5% FCS and 5% hPL. Cell morphology, cell cycle distribution, and protein expression patterns were not affected by such different culture conditions in resting and treated cells. We further show that the class I HDACs HDAC1-3, but not HDAC6, regulate WT1 and p53. Our findings demonstrate that hPL is a promising replacement for animal serum. Citation Format: Oliver H. Krämer. Replacing fetal calf serum by human platelet lysate in cancer research and toxicology [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 3100.
Abstract 2080: Role of differentially expressed micro RNAs in non-WNT, non-SHH medulloblastoma
Authors: Raikamal Paul, Rakesh Jalali, Epari Sridhar, Aliasagar Moiyadi, Neelam Shirsat
Journal: Cancer Research (2018)

Abstract Medulloblastoma is a common malignant brain tumor in children. It has four distinct molecular subgroups namely WNT, SHH, Group 3 and Group 4. The molecular subgroups differ in their clinical characteristics including age, incidence of metastasis and survival. Group 3 and Group 4 medulloblastomas have overlapping gene expression profile but are distinct in their clinical behavior. Group 3 medulloblastomas have the worst overall survival rates whereas Group 4 medulloblastomas have intermediate survival. Group 3 and Group 4 tumors are not associated with any known signaling pathway and due to their overlapping expression profiles it is often difficult to accurately identify the subgroup, which is very crucial for the appropriate treatment design. MiR-592, located in the intronic region of GRM8 gene, is over expressed in Group 4 medulloblastoma along with its host gene, thus acting as a good marker for Group 4 tumors. MiR-204, on the other hand is expressed from the 6th intron of TRPM3 gene and expressed in some Group 3 and majority of Group 4 medulloblastomas. In order to delineate the role of miR-592 and miR-204 in medulloblastoma biology, effect of expression of these microRNAs on medulloblastoma cell growth and behavior were investigated. The micro RNAs were expressed in a lentiviral mediated inducible manner in Group 3 medulloblastoma cell lines D283, D425 and D341 and their effects on cell proliferation, anchorage-independent growth and invasion potential were studied. MiR-592 expression had marginal effects on the anchorage independent growth potential and the tumorigenic potential of the Group 3 cell line where as miR-204 expression led to significant decrease in the anchorage independent growth, tumorigenic potential, as well as invasion potential of the medulloblastoma cell lines. Further in order to decipher the molecular mechanisms underlying these micro RNA mediated effects, RNA-sequencing analysis of miR-592 and miR-204 expressing medulloblastoma cells were performed to identify genes that are differentially expressed upon micro RNA expression. The results helped us to identify the molecular pathways that are being affected by the micro RNA expression and how they affect the malignant behavior of medulloblastoma cells. Citation Format: Raikamal Paul, Rakesh Jalali, Epari Sridhar, Aliasagar Moiyadi, Neelam Shirsat. Role of differentially expressed micro RNAs in non-WNT, non-SHH medulloblastoma [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 2080.
Abstract 1621: Radotinib, a medicine for chronic myeloid leukemia, induces cell death of mantle cell lymphoma cells
Authors: Sook-Kyoung Heo, Eui-Kyu Noh, Yoo Kyung Jeong, Jeong Yi Kim, Yunsuk Choi, Jaekyung Cheon, SuJin Koh, Jin Ho Baek, Young Joo Min, Jae-Cheol Jo
Journal: Cancer Research (2018)

Abstract Background: Radotinib is a medicine for the treatment of some types of cancer. It is approved in South Korea for use as a second-line treatment of chronic myeloid leukemia (CML). Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and of platelet-derived growth factor receptor (PDGFR). It has been little known the effects of radotinib on mantle cell lymphoma cells (MCL). Methods: First, we examined cytotoxicity of radotinib on MCL cell line, MAVER-1 and REC-1. Also, cytotoxicity of radotinib on both cell lines which have a different genetic back ground. Annexin V positive cell, caspas-3 and -9 activities, cell cycle distribution and mitochondrial membrane potential (MMP) were observed by analyzed with flow cytometric analysis. And diverse signaling pathways were investigated by Western blotting in MCL cells. Results: Interestingly, radotinib caused cell death of MCL cells. And radotinib induces G1-phase arrest in MAVER-1 and REC-1 cells. And it also inhibited the expression of CDK2, CDK4, and cyclin D1, D3 and E. Therefore, radotinib induces G1-phase arrest via suppression of CDK2, CDK4, and cyclin D1, D3 and E. Generally, the intrinsic apoptotic pathway involves mitochondrial activation and caspase and phosphatidylserine externalization. Radotinib induced Annexin V positive cells, and caspase pathway activation including caspase-3, -7 and -9. And its treatment remarkably decreased MMP in MCL cells at 72 h. As well as we observed that cytochrome c accumulated dose dependently in the cytosol of radotinib-treated MAVER-1 and REC-1 cells. Moreover, radotinib decreased the expression of Bcl-xL and Bcl-2, and increased the expression of Bax in MCL cells. These results indicate that radotinib induces cell death of MCL cells by induction of G1-phase arrest and mitochondrial-dependent apoptosis. Furthermore, the expression of p-AKT, AKT and ERK was significantly reduced by radotinib in MCL cells. Conclusion: Radotinib may play an important role as a candidate or chemosensitizer for treatment agent in MCL. These data indicate that radotinib has a potential for anti-cancer therapy in MCL. Citation Format: Sook-Kyoung Heo, Eui-Kyu Noh, Yoo Kyung Jeong, Jeong Yi Kim, Yunsuk Choi, Jaekyung Cheon, SuJin Koh, Jin Ho Baek, Young Joo Min, Jae-Cheol Jo. Radotinib, a medicine for chronic myeloid leukemia, induces cell death of mantle cell lymphoma cells [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 1621.
<i>BRAF</i> V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer
Authors: Fei Wang, Shihua Zhao, Xiaopei Shen, Guangwu Zhu, Rengyun Liu, David Viola, Rossella Elisei, Efisio Puxeddu, Laura Fugazzola, Carla Colombo, Barbara Jarzab, Agnieszka Czarniecka, Alfred K. Lam, Caterina Mian, Federica Vianello, Linwah Yip, Garcilaso Riesco-Eizaguirre, Pilar Santisteban, Christine J. O’Neill, Mark S. Sywak, Roderick Clifton-Bligh, Bela Bendlova, Vlasta Sýkorová, Yangang Wang, Mingzhao Xing
Journal: Journal of Clinical Oncology (2018)

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.
Abstract 19139: Effect of HDL-C Raising and/or Triglyceride Lowering on Cardiovascular Outcomes and All-Cause Mortality in the AIM-HIGH Trial
Authors: Tejas Patel, Bereket Tesfaldet, Jue Chen, Jerome Fleg, Gyorgy Csako, George Sopko, Lawton Cooper, Eileen Navarro, Charu Gandotra, Ruth Kirby, Helena Sviglin, Keith Burkhart, Sean Coady, Henry Chang, Patrice Desvigne-Nickens, Michelle Fennessy, Lijuan Liu, Eric Leifer, Frank Pucino, Subha Raman, Yves Rosenberg, Ahmed Hasan
Journal: Circulation (2016)

Background: Published reports have questioned the benefit of serum HDL-cholesterol (HDL-C) raising and/or triglycerides (TG) lowering for patients at risk for cardiovascular (CV) events. Methods: AIM-HIGH (NCT00120289) patient-level data were reanalyzed to evaluate the effects of HDL-C raising and TG lowering treatment strategies (background statin ± extended-release niacin therapy) on major adverse CV events (MACE: a composite of MI, stroke, and CV death) and all-cause mortality. Four groups, based on percent change from baseline to 6 months in HDL-C and TG due to antidyslipidemic therapy, were compared (Table 1). Time-to-first event analyses were performed, with a multivariate analysis used to adjust for group, age, gender, history of diabetes, and estimated glomerular filtration rate [eGFR]. Results: Kaplan-Meier curves showed a significant difference for MACE (log-rank p<0.05) among the four groups (Figure 1). Surprisingly, a 49%-increased risk of MACE (unadjusted HR 1.49; 95% CI 1.14 to 1.98, p<0.01)...
Abstract 14610: Thoracic Aortic Aneurysm-causing Mutation, R258C, in Smooth Muscle Alpha-actin Inhibits Functional Effects of Wild-type Alpha-actin in Patient-derived Fibroblasts
Authors: Zhenan Liu, Audrey Chang, Frederick Grinnell, Kathleen Trybus, Dianna Milewicz, Kristine Kamm
Journal: Circulation (2015)

Familial thoracic aortic aneurysms and dissections (TAAD) are most commonly caused by missense mutations in smooth muscle α-actin (SMαA), encoded by ACTA2. Although TAAD is hypothesized to result in part from a compromised ability of aortic smooth muscle cells (SMCs) to sense their mechanical environment, the specifics of how ACTA2 mutations affect cellular mechanotransduction remain to be defined. We established hTERT-immortalized lines of dermal fibroblasts from volunteers (WT) and patients with ACTA2 mutations (MT). SMαA expression was induced with adenovirus encoding MRTF-A, a potent co-activator of SM contractile genes, including ACTA2. We focus here on the ACTA2 R258C mutation, a recurrent mutation associated with early onset of TAAD. Quantification of actin expression by 2D-PAGE and western blotting showed that induced WT fibroblasts expressed ~40% β-, 30% γ- and 30% SM-α-actin, while heterozygous MT cells expressed ~40% β-, 30% γ-, 15% WT-SM-α- and 15% MT-SM-α-actin, with un-induced cells expressing &lt;5% SMαA. Cytoskeletal structure was studied by immunofluorescence and confocal microscopy, and by sedimentation for actin distribution in filamentous (F) and monomeric (G) fractions. Cell motile and contractile properties were investigated by scratch-induced cell migration, trans-well migration, and collagen matrix contraction assays. As described for other models of SMαA induction in fibroblasts, we found that MRTF-A induction of SMαA in WT cells significantly increased formation of stress fibers and focal adhesions, F/G ratio (p&lt;0.01), and matrix contraction (p&lt;0.05), and significantly decreased cell migration in scratch-induced (p&lt;0.01) and trans-well (p&lt;0.0001) migration assays. In contrast, expression of MT SMαA in heterozygous R258C MT fibroblasts abrogated the effects of SMαA on formation of stress fibers and focal adhesions, F/G ratio, matrix contraction and cell migration in comparison to induction of SMαA in WT cells. These results demonstrate that R258C MT SMαA disrupts cytoskeletal functions attributed to SMαA in WT fibroblasts and are consistent with defects in mechanotransduction, which may shed light on cellular defects due to ACTA2 mutations in both aortic SMCs and adventitial fibroblasts.
Intravital microscopy of osteolytic progression and therapy response of cancer lesions in the bone
Authors: Eleonora Dondossola, Stephanie Alexander, Boris M. Holzapfel, Stefano Filippini, Michael W. Starbuck, Robert M. Hoffman, Nora Navone, Elena M. De-Juan-Pardo, Christopher J. Logothetis, Dietmar W. Hutmacher, Peter Friedl
Journal: Science Translational Medicine (2018)

A skin window enables noninvasive, longitudinal monitoring of cancer growth and therapy response in tissue-engineered bone in mice.
Abstract LB-389: miR133a-3p sensitizes breast cancer cells by targeting GSTP1
Authors: Minsun Chang, Xiyuan Liu, Eun Young Park
Journal: Cancer Research (2018)

Abstract Breast cancer is a main threat for women's health and mammary carcinogenesis is attributed to estrogen receptor α (ERα)-mediated signaling pathways. Tamoxifen is one of the most effective ERα-targeting antiestrogen therapies to treat breast cancer. However, tamoxifen resistance remains a major hurdle in the long-term management of breast cancer. Glutathione S-transferase P1-1 (GSTP1) is one of the major non-hepatic GST family and plays important role in detoxification. Our previous study has shown that GSTP1 is a modulator for ERα signaling in tamoxifen-resistant MCF7 breast cancer cells (LCC3) and other studies have proposed that GSTP1 is one of biomarkers for the diagnosis of breast cancer risk and drug resistance. In the present study, a microRNA (miR) 133a-3p is identified as a functional modulator for GSTP1 expression and cell proliferation in LCC3 cells. We have found that level of miR133a-3p was much lower and the GSTP1 expression at both mRNA and protein was higher in LCC3 cells compared to MCF7 cells. Treatment of miR133a-3p mimics decreased the levels of GSTP1 in LCC3 cells. Finally, the miR133a-3p mimics resensitized the LCC3 cells against tamoxifen-induced cell death. Our data demonstrated that GSTP1 is the target of miR133a-3p in MCF7-derived breast cancer cells and miR133a-3p may play a critical role to overcome tamoxifen resistance in breast cancer chemotherapy. Citation Format: Minsun Chang, Xiyuan Liu, Eun Young Park. miR133a-3p sensitizes breast cancer cells by targeting GSTP1 [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 LB-389.
OP0038 Dose tapering and discontinuation of biological therapy in rheumatoid arthritis patients in remission in routine care – 2-year outcomes and identification of predictors
Authors: C.H. Brahe, S. Krabbe, M. Østergaard, L. Ørnbjerg, D. Glinatsi, H. Røgind, H.S. Jensen, A. Hansen, J. Nørregaard, S. Jacobsen, L. Terslev, T.K. Huynh, D.V. Jensen, N. Manilo, K. Asmussen, P.B. Frandsen, M. Boesen, Z. Rastiemadabadi, L.M. Carlsen, J. Møller, N.S. Krogh, M.L. Hetland
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> A cohort of routine care rheumatoid arthritis (RA) patients in sustained remission had biological disease-modifying anti-rheumatic drugs (bDMARDs) tapered according to a treatment guideline. Little is known about predictors of successful tapering and discontinuation of bDMARDs. <h3>Objectives</h3> We studied: 1) the proportion of patients whose bDMARD could be successfully tapered or discontinued; 2) unwanted consequences of tapering/discontinuation; 3) potential baseline predictors of successful tapering and discontinuation. <h3>Methods</h3> One-hundred-and-forty-three patients with sustained disease activity score (DAS28-CRP)≤2.6 and no radiographic progression the previous year were included. bDMARD was reduced to 2/3 of standard dose at baseline, ½ after 16 weeks, and discontinued after 32 weeks. Patients who flared (defined as either DAS28-CRP≥2.6 and DAS28-CRP≥1.2 from baseline, or erosive progression on X-ray and/or MRI) stopped tapering and were escalated to the previous dose level. <h3>Results</h3> One-hundred-and-forty-one patients completed 2 year follow-up. At 2 years, 87 patients (62%) had successfully tapered bDMARDs, with 26 (18%) receiving 2/3 of standard dose, 39 (28%) ½ dose and 22 (16%) having discontinued; 54 patients (38%) were receiving full dose. DAS28-CRP<sub>0–2yrs</sub> was 0.1((−0.2)–0.4) (median(interquartile range)) and mean Total-Sharp-Score<sub>0–2yrs</sub> was 0.01 (1.15) (mean(SD)). Radiographic progression was observed in 9 patients (7%). Successful tapering was independently predicted by: ≤1 previous bDMARD, male gender, low baseline MRI combined inflammation score and low MRI combined damage score. Negative IgM-rheumatoid factor predicted successful discontinuation. The association between potential predictors and the proportion of patients with successful tapering of bDMARDs is shown in figure 1. <h3>Conclusions</h3> By implementing a clinical guideline, 62% of RA patients in sustained remission in routine care were successfully tapered, including 16% successfully discontinued at 2 years. Radiographic progression was rare. IgM-RF was an independent predictor for successful discontinuation of bDMARDs. Maximum one bDMARDs, male gender, and low baseline MRI combined inflammation and MRI combined damage scores were independent predictors for successful tapering. <h3>Disclosure of Interest</h3> None declared