tbuckley/cabot-search huggingface dataset:
Abstract 18696: microRNAs Dysregulated in African Americans With Severe Hypertension: Evidences From the Mh-grid Study
Authors: Amadou Gaye, Sharon Davis, Adam Davis, Shurjo Sen, Gibbons Gary
Journal: Circulation (2016)

Introduction: A growing body of evidence demonstrates that miRNA are key players in epigenetic regulation. Because of their regulatory role miRNAs are involved in nearly all physiological and pathophysiological processes and their dysregulation can hence contribute to disease development. Therefore miRNAs have potential therapeutic relevance and studies of miRNA expression could ultimately lead to the discovery of biomarkers for diagnosis, prognosis and treatment of diseases. Hypothesis: Some miRNAs involved in the regulation of the cardiovascular system might be differentially expressed between subjects with severe hypertension (cases) and those with normal blood pressure (controls) . The extreme phenotype (severe hypertension) could allows us to detect signals not identified previously. Methods: Data are from the MH-GRID project, a study of severe hypertension in African Americans aged 30 to 55 years . We conducted miRNA differential expression analysis, looking at the expression levels of 2818 miRNAs, ...
Abstract 683: SOS1 allosterically linked conformational changes modulate KRas4B activation
Authors: Tsung-Jen Liao, Hyunbum Jang, David Fushman, Ruth Nussinov
Journal: Cancer Research (2018)

Abstract Son of sevenless homology 1 (SOS1) is a robust guanine nucleotide exchange factor (GEF) that exchanges GDP by GTP and activates Ras. SOS1 is a large multidomain protein with molecular weight of ~153 kDa. The C-terminal catalytic region, composed of RAS exchanger motif (REM) and CDC25 domains, is responsible for Ras activation. SOS1 offers two Ras binding sites; one at the allosteric site in REM and the other at the catalytic site in CDC25. Experimental studies provided a Ras-SOS1-Ras ternary complex and suggested that Ras binding to REM allosteric site is essential to activate GDP-bound Ras at the CDC25 catalytic site. However, details of SOS1 conformational changes due to different binding modes of Ras at the allosteric and catalytic sites in Ras activation are not well understood. Here, using molecular dynamics (MD) simulations, we examine Ras activation mechanism for SOS1 systems containing GDP- and GTP-bound, and nucleotide-free KRas4B. Among the three Ras isoforms, including HRas, NRas, and KRas (with two splice variants of KRas4A and KRas4B), KRas4B is highly oncogenic, the most frequently mutated in RAS-driven cancers. We observed that the REM domain inherently and sterically obstructs the Ras binding site of CDC25 domain. Upon binding to the REM allosteric site, KRas4B-GTP relieves the steric occlusion, making the CDC25 catalytic site capable of associating with KRas4B-GDP, leading to the nucleotide exchange. Allosteric effects lead to the dislocation of the helix-hairpin motif at the CDC25 catalytic site. This large movement of the helix-hairpin motif causes the Ras catalytic site to open and liberates GDP. Allosteric signals propagating through the REM-CDC25 tandem domains of SOS1 can explain the communication between two Ras proteins modulating the large conformational changes. Our simulations provide insight into the structural correlation of KRas4B-SOS1 as well as the allosteric effect. The conformational changes of SOS1 correspond to the allosteric signaling between two KRas4B at REM and CDC25 domains, promoting Ras activation. Citation Format: Tsung-Jen Liao, Hyunbum Jang, David Fushman, Ruth Nussinov. SOS1 allosterically linked conformational changes modulate KRas4B activation [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 683.
Oncological outcomes in a Mexican cohort of patients with gallbladder cancer.
Authors: MÃ³nica Isabel Meneses Medina, Ana Karen Valenzuela, Zuleyma Nieto, Vanessa Rosas Camargo, Iván Eliud Casanova Sánchez, Armando Gamboa Dominguez, Alan Gabriel Contreras Saldívar, Fidel David Huitzil Melendez
Journal: Journal of Clinical Oncology (2018)

518 Background: gallbladder cancer is the most common malignancy of the biliary tract. Treatment modalities and outcomes for this disease in Mexican population have been infrequently reported. Methods: we retrospectively reviewed medical records from 61 patients with histologically confirmed gallbladder cancer treated at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán from January 2005 to December 2015.Clinical and pathological information was recorded. Survival was estimated by Kaplan Meir method and compared by Log rank test. Results: we found 68.9% women and 31.1% men, with a median age of 68 years (32-93). Clinical stage was advanced in 65.6% (n=40), regional in 23% (n=14), localized in 4.9% (n=3) and in situ in 6.6% (n=4). For patients with localized disease (n=21), which included in situ, localized and regional disease, a potentially curative surgery was attempted in 100% of patients, achieving a R0 resection in 47.6% (n=10) of cases. The morbidity rate was 33.3% (n=7). There were 5 surgical deaths. For advanced disease (n=40), the initial treatment was: 42.5% (n=17) palliative surgery, 25% (n=10) palliative care and for 30% (n=12) systemic chemotherapy, more frequently gemcitabine plus cisplatin (n=7). At progression seven patients received second-line chemotherapy. Median overall survival (OS) in the global cohort was 5.6 months (IC 95, 2.4-8.77). According to clinical stage survival at 5 years was 100% for in situ and 67% for localized disease. Median survival was 6.3 months (IC 95, 2.3-10-3) for regional disease and 4.2 months (IC 95, 1.1-6.4) for advanced disease. For patients with localized disease not achieving R0 resection (p=0.03) and perineural invasion (p=0.025) were associated with decreased survival. For patients with advanced disease poor performance status (p=0.004) and absence of chemotherapy (p=0.002) were adverse prognostic factors. Conclusions: global poor outcomes may be explained by metastatic disease at presentation. Even for patients with apparent localized disease, a potentially curative resection could be offered to only half of the patients.
Blockade of the Nuclear Factor-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans
Authors: YutakaHasegawa, TokuoSaito, TakehideOgihara, YasushiIshigaki, TetsuyaYamada, JuntaImai, KenjiUno, JunhongGao, KeizoKaneko, TatsuoShimosawa, TomoichiroAsano, ToshiroFujita, YoshitomoOka, HidekiKatagiri
Journal: Circulation (2012)

Background—Nuclear factor-κB (NF-κB) signaling plays critical roles in physiological and pathological processes such as responses to inflammation and oxidative stress. Methods and Results—To examine the role of endothelial NF-κB signaling in vivo, we generated transgenic mice expressing dominant-negative IκB under the Tie2 promoter/enhancer (E-DNIκB mice). These mice exhibited functional inhibition of NF-κB signaling specifically in endothelial cells. Although E-DNIκB mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet- or genetics-induced. Obesity-induced macrophage infiltration into adipose tissue and plasma oxidative stress markers were decreased and blood flow and mitochondrial content in muscle and active-phase locomotor activity were increased in E-DNIκB mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-κB signaling prevented age-relat...
Abstract 4862: Protein arginine methyltransferase 5 as a tumor promoter and therapeutic target in gastrointestinal cancers
Authors: Lakshmi Prabhu, Lan Chen, Ahmad Safa, Murray Korc, Zhong-Yin Zhang, Tao Lu
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) are among the most commonly diagnosed forms of cancer in the United States. Due to their widespread prevalence and high mortality rate, it is vital to develop effective therapeutic drugs to combat these deadly diseases. In both CRC and PDAC, the multifunctional factor nuclear factor kappa B (NF-kB), a central coordinator of immune responses, is activated abnormally, leading to tumorigenesis and cancer progression. Therefore, controlling NF-kB activity is critical in the treatment of these cancers. Previously, we discovered a novel mechanism by which NF-kB is activated through methylation by an epigenetic enzyme known as protein arginine methyltransferase 5 (PRMT5). We showed that overexpression of PRMT5 significantly promoted several characteristics associated with cancer, including increased cell proliferation, migration, and anchorage-independent growth in both CRC and PDAC cells, thus, putting forward PRMT5 as a novel therapeutic target in these cancers. In this study, we successfully adapted AlphaLISA technique into a high-throughput screen platform, and further employed this approach to successfully identify PR5-LL-FDA1 as a potent PRMT5 inhibitor from commercially-available screening libraries. Furthermore, we confirmed that treatment of PDAC and CRC cells with PR5-LL-FDA1 led to decreased NF-kB activation, and reduced cancer associated properties in PDAC and CRC cells. Importantly, we show that PR5-LL-FDA1 is more efficacious than the commercial PRMT5 inhibitor, EPZ015666 in both PDAC and CRC. Our work clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC and hold the promise to establish PR5-LL-FDA1 as a promising basis for new drug development in the future. Citation Format: Lakshmi Prabhu, Lan Chen, Ahmad Safa, Murray Korc, Zhong-Yin Zhang, Tao Lu. Protein arginine methyltransferase 5 as a tumor promoter and therapeutic target in gastrointestinal 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 4862.
Mechanisms of Stretch-Induced Changes in [Ca2+]i in Rat Atrial Myocytes
Authors: PasiTavi, ChunleiHan, MattiWeckström
Journal: Circulation Research (1998)

Abstract—To study the effects of stretch on the function of rat left atrium, we recorded contraction force, calcium transients, and intracellular action potentials (APs) during stretch manipulations. The stretch of the atrium was controlled by intra-atrial pressure. The Frank-Starling behavior of the atrium was manifested as a biphasic increase of the contraction force after increasing the stretch level. The development of the contraction force after step increase of the stretch (intra-atrial pressure from 1 to 3 mm Hg) was accompanied by the increase in the amplitude of the calcium transients (P<0.05, n=4) and decrease in the time constant of the Ca2+ transient decay. The APs of the individual myocytes were also affected by stretch; the duration of the AP was decreased at positive voltages (AP duration at 15% repolarization level, P<0.001; n=13) and increased at negative voltages (AP duration at 90% repolarization level, P<0.01; n=13). To study the mechanisms causing these changes we developed a mathemat...
Abstract 11970: Sirtuin1 is a Key Regulator of Enhanced Therapeutic Potential in Juvenile Skeletal Myoblast Sheet Therapy for Treating Heart Failure
Authors: Hideto Ozawa, Shigeru Miyagawa, Satsuki Fukushima, Akima Harada, Emiko Ito, Atsuhiro Saito, Takayoshi Ueno, Koichi Toda, Toru Kuratani, Yoshiki Sawa
Journal: Circulation (2015)

Introduction: Transplantation of autologous somatic tissue-derived stem cells into the heart has been shown to be therapeutically effective for heart failure in adult, though efficacy of this treatment for pediatric patients are poorly established. It is known that juvenile cell behave differently from adult one, associated with expression of aging-related factors such as sirtuin family. Hypothesis: Sirtuin 1 expression is a key regulator of differential therapeutic potentials between juvenile and adult skeletal cells (SCs) for treating heart failure. Methods and Results: Sirtuin 1 knock down (SIRT1-KD) was induced by RNA interference in primary SCs from Lewis rat. The SIRT1-KD SCs showed a longer doubling time, associated with lower expression of VEGF, HGF, and SDF-1, compared to the primary SCs in vitro. Cell-sheets generated by SIRT1-KD SCs or primary SCs were transplanted over the heart surface of the syngeneic Lewis rat that was subjected to left coronary artery (LCA) ligation 2 weeks prior to the treatment (n=5 each). As a result, recovery of ejection fraction was significantly less prominent in the SIRT1-KD group (31.6%) than the primary group (46.9%), in association with degree of histological ventricular remodeling, such as %fibrosis, myocyte size, or capillary density. Subsequently, autologous SC cell-sheet were cardiac-transplanted in 2-month-old juvenile and 20-30 month-old adult mini-pigs that were subjected to ischemia-reperfusion in the LCA territory (n=5 each). The juvenile porcine SCs displayed significantly shorter doubling time and greater Ki67-positivity, in association with up-regulated SIRT1, HIF-1α, HGF, and SDF-1, in vitro. At 2 months after the transplantation, recovery of EF was more prominent in the juvenile group (23.6% to 49.8%) than the adult group (28.8% to 36.2%). Moreover, regional wall motion (%strain) of the infarct-border area more prominently recovered in the juvenile group (-3.6% to -16.1%) than the adult group (-3.3% to -5.4%). Conclusions: Juvenile SCs exhibited an enhanced therapeutic potential in association with upregulated expression of SIRT1 as compared to the adult SCs, suggesting that autologous cell-sheet transplantation may be therapeutically more effective for pediatric cardiomyopathy.
Abstract 19597: Impact of Hyperglycemia on the Exercise Pressor Reflex in Nondiabetic Patients With Heart Failure
Authors: Karel Rodriguez Milian, Katarzyna Barecka, Ross W May, Tomasz Krauze, Andrzej Wykretowicz, Aneta Nowak, Anna Palasz, Przemyslaw Guzik, Marcos A Sanchez-Gonzalez
Journal: Circulation (2015)

Introduction: The HR and BP responses to exercise (exercise pressor reflex, EPR) predict adverse clinical events in patients with Heart Failure (HF). Although studies have shown that hyperglycemia may induce cardiovascular autonomic dysregulation, the association between glycemic status and EPR in HF patients is poorly understood. Hypothesis: Hyperglycemia would be accompanied by altered EPR after the 6-minute walk test (6MWT) in nondiabetic HF patients. Methods: The HR and BP (SBP and DBP) responses to 6MWT were evaluated in 215 HF ambulatory patients aged 62.4 ± 9.4 (M ± SD) years old before (BASE), immediately after (P0), 1 minute after (P1) and 3 minutes after exercise (P3). Patients were assigned to one of two groups based on their 2-hours post meal (breakfast) glycemia into normoglycemic (&lt;140mg/dl; NG; n = 173) and hyperglycemic (HG; n =42). Results: To compare the HR and BP responses to the 6MWT between the groups a 4 X 2 ([BASE X P0 X P1 X P3] X [NG x HG]) repeated measures analysis of covariance using least significant difference as alpha adjustment that controlled for weight and gender were conducted. Significant (P&lt;0.05) time-by-group interactions occurred for HR, SBP, and DBP such that HR at P0, SBP at BASE, P1 and P3 and DBP at P1 and P3 were higher in the HG group compared to the NG. In addition, we found that SBP response to exercise was blunted where as DBP remained elevated at P1 and P3 in HG group only (see Figure 1). Conclusions: These results demonstrate that post-meal hyperglycemia evokes an abnormal EPR in patients with HF. Such effects might be caused by a hyperglycemia-induced impaired autonomic dysregulation. Future attention should be given at the patient’s glycemic status prior to using an exercise test as it significantly contributes to the EPR.
Abstract 5200: Extracellular vesicles in the ascites from gastric cancer patients play critical roles to promote peritoneal dissemination in the intraperitoneal cancer microenvironment
Authors: Atene Ito, shunsuke kagawa, Shuichi Sakamoto, Kazuya Kuwada, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2018)

Abstract Although gastric cancer often develops peritoneal dissemination, the underlying mechanism of peritoneal metastasis is still unclear. Extracellular vesicles (EVs) are known to play roles in cell-cell communication. Here, we investigated the existence of EVs in peritoneal ascites of gastric cancer patients and explored their roles in the intraperitoneal cancer microenvironment. We found that EVs actually existed in peritoneal ascites of advanced gastric cancer patients. On the other hand, immune-fluorescent assay of the ascites by using antibodies against CD14 (Monocytes) and CD45 (Leukocytes) revealed that many macrophages existed along with the cancer cells in the peritoneal cavity. EVs purified from peritoneal ascites with cancer dissemination made peripheral blood mononuclear cells-derived macrophages M2-like phenotype which was confirmed by their morphology and expression of CD163/206 (M2 marker). Next, we purified EVs from the culture medium of gastric cancer cell lines. Gastric cancer-derived EVs induced the M2- differentiation in macrophages and the differentiated macrophages promoted migration ability of gastric cancer cells. Finally, we observed that gastric cancer-derived EVs induced apoptosis of cultured mesothelial cells in vitro. These results suggested that EVs in the ascites of gastric cancer patients are possibly derived from gastric cancer and play critical roles in the intraperitoneal cancer microenvironment by affecting the macrophages phenotype and inducing apoptosis in the mesothelial cells, which would be in part the underlying mechanism of peritoneal metastasis. Citation Format: Atene Ito, shunsuke kagawa, Shuichi Sakamoto, Kazuya Kuwada, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara. Extracellular vesicles in the ascites from gastric cancer patients play critical roles to promote peritoneal dissemination in the intraperitoneal cancer microenvironment [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 5200.
Abstract IA22: Targeting CARs to the TRAC locus enhances T-cell potency
Authors: Michel Sadelain, Justin Eyquem
Journal: Clinical Cancer Research (2017)

Abstract Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumor rejection. The most successful CARs used to date are those targeting CD19, which offer the prospect of complete remissions in patients with chemorefractory/relapsed B cell malignancies. CARs are typically transduced into patient T cells using γ-retroviral or other randomly-integrating retroviral vectors (RVs), which may result in variegated CAR expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific modifications in human primary cells, including site-specific transgene integration into the CCR5 and AAVS1 loci in T lymphocytes. Using CRISPR/Cas9 to edit human T cells, we have established conditions yielding efficient target gene disruption and CAR insertion in a single step. We have found that directing a CD19 CAR to the human T-cell receptor (TCR) alpha chain (TRAC) locus not only results in efficient and uniform CAR expression in human peripheral blood T cells, but, remarkably, also enhances T-cell potency, vastly outperforming that of conventionally generated CAR T cells. We further show that CAR gene expression under the control of the TCR alpha promoter minimizes tonic signaling and allows effective regulation of CAR expression. These findings provide important insights into CAR immunobiology and highlight the potential of CRISPR/Cas9 genome editing to advance immunotherapies. Citation Format: Michel Sadelain, Justin Eyquem. Targeting CARs to the TRAC locus enhances T-cell potency [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA22.
Abstract 1235: Repeated whole-exome sequencing for cell-free tumor DNA profiling of colon cancer patients: Searching for mechanisms of acquired chemoresistance
Authors: Veronika Vymetalkova, Barbara Pardini, Katerina Jiraskova, Marjketa Urbanova, Miroslav Levy, Veronika Veskrnova, Pavel Vodicka, Alessio Naccarati
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is a worldwide health burden with nearly 1.2 million new cases expected each year globally. When CRC is identified early, there is a five-year survival rate of about 90% but it drops to almost 12% once there are distant metastases. Drug resistance is a limiting factor of the efficacy of chemotherapy in CRC treatment. Significant efforts are currently being employed to discriminate patients who will benefit or not from chemotherapy. In fact, there is no current 'gold standard' to differentiate responders from non-responders. In the present work, we focused on good responders (those who benefit from the chemotherapy, not having side effects like toxicity, no relapses and having a complete response with no residual cancer) and non-/bad responders (patients with acquired chemoresistance and lack any response, or developing toxicity). The main aim was to identify markers/mutations in plasma cell-free DNA that could be associated with good/bad responders and chemoresistance. Paired plasma samples from colon cancer patients collected before and after therapy and the relative cell-free tumor DNA (ctDNA) was profiled by a whole exome sequencing approach in order to identify novel acquired mutations. Plasma ctDNA was isolated by QIAamp Circulating Nucleic Acid Kit. The SureSelectXT HS Reagent Kit was used for library preparation and libraries were sequenced by the HiSeq2500 system. Analysis was performed on nine patients (stage II and III) treated with the same 5-FU based therapy. The first sampling was collected at the time of diagnosis (i.e., active disease), and the second after 6-9 months depending on patient` s conditions (i.e., covering the tumor resection, administration of adjuvant chemotherapy). After follow up, three patients were classified as good responders and six as non/poor responders. The bioinformatics analysis is currently running. The number of total reads exceeded 990x106. Total length of all exons was 221,924,089bp. After trimming, the average read length was 113bp. Alignment to human reference genome (hg38) is &amp;gt; 99.8%. Coverage of exons ranges from 17 to 34. Results of the study will be presented during the meeting. Supported by grant AZV MZ 17-30920A, 15-26535A and GACR 17-16857S. Citation Format: Veronika Vymetalkova, Barbara Pardini, Katerina Jiraskova, Marjketa Urbanova, Miroslav Levy, Veronika Veskrnova, Pavel Vodicka, Alessio Naccarati. Repeated whole-exome sequencing for cell-free tumor DNA profiling of colon cancer patients: Searching for mechanisms of acquired chemoresistance [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 1235.
Hypotensive Effect of Ethacrynic Acid
Authors: Jamesconway, Gastoneleonetti
Journal: Circulation (1965)

Ethacrynic acid has been found to possess a similar antihypertensive action to the thiazide diuretics. The use of the two drugs together results in a greater fall in pressure than that obtained with either drug alone. When thiazide therapy is supplemented by ethacrynic acid and dietary restriction of sodium a substantial additional reduction in blood pressure averaging 48/18 mm. Hg was obtained.