tbuckley/cabot-search huggingface dataset:
Abstract 5903: The molecular mechanism for producing BQ323636.1 in Tamoxifen resistance breast cancer cells
Authors: Ka Chun Mok, Ho Tsoi, Ui-Soon Khoo, Ellen Man
Journal: Cancer Research (2018)

Abstract Breast cancer is one of the prevalent causes of cancer in women. Two thirds of breast cancer patients are ER-positive and can be benefited from tamoxifen treatment. However, 50% of the patients will eventually develop the resistance. Identifying molecular targets associated with tamoxifen resistance would help in designing better therapeutic strategies. Previous study from our group identify a novel factor BQ323636.1 (BQ), a spliced variant of NCOR2, could confer tamoxifen resistance. From our in vivo study, nuclear enrichment of BQ in primary breast tumor was found to be associated with tamoxifen resistance. However, the molecular mechanism governed the nuclear import of BQ and was not clear. From bioinformatics prediction, we identified a functional nuclear localization signal (NLS) on BQ. We therefore performed a protein screening to search for the import receptor which could interact with BQ. KPNA1 was found to interact with BQ. To further validate such an interaction, we fused the NLS to GPF reporter protein (GFP-NLS) and performed a co-immunoprecipitation. The result showed that the GFP-NLS was able to interact with KPNA1. Knockdown of KPNA1 by RNAi could prevent the nuclear import of BQ. This confirmed the functional role of KPNA1 in the nuclear import of BQ. In addition, knockdown of KPNA1 in BQ overexpressing breast cancer cells could reverse the tamoxifen resistance. The results highlighted the functional significance of KPNA1 in the tamoxifen resistance. Subsequently, we investigated the functional role of BQ in the nucleus. We found BQ could deplete the gene repressive function of NCOR2. We found that NCOR2 could interact with HSF4 and should repress the expression of HIF1α. In the presence of BQ, the repressive function of NCOR2 on HIF1α was compromised, leading to up-regulation of HIF1α. To further validate the effect of HIF1α in the tamoxifen resistance, HIF1α inhibitor was employed and found that the treatment of the inhibitor could reduce the resistance in BQ overexpressing breast cancer cells. Therefore, our study uncovered the role of KPNA1 in the development of tamoxifen resistance through which KPNA1 could promote the nuclear import of BQ. Subsequently, BQ could lead to the up-regulation of HIF1α which also play significant role in the development of tamoxifen resistance. Citation Format: Ka Chun Mok, Ho Tsoi, Ui-Soon Khoo, Ellen Man. The molecular mechanism for producing BQ323636.1 in Tamoxifen resistance breast cancer 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 5903.
Aldosterone Administration to Mice Stimulates Macrophage NADPH Oxidase and Increases Atherosclerosis Development
Authors: ShlomoKeidar, MarielleKaplan, ElsaPavlotzky, RaymondColeman, TonyHayek, ShadiHamoud, MichaelAviram
Journal: Circulation (2004)

Background— The renin-angiotensin-aldosterone system is involved in the pathogenesis of atherosclerosis, partially because of its pro-oxidative properties. We questioned the effect and mechanisms of action of administration of aldosterone to apolipoprotein E–deficient (E0) mice on their macrophages and aorta oxidative status and the ability of pharmacological agents to block this effect. Methods and Results— Aldosterone (0.2 to 6 μg · mouse−1 · d−1) was administered to E0 mice alone or in combination with eplerenone (200 mg · kg−1 · d−1), ramipril (5 mg · kg−1 · d−1), or losartan (25 mg · kg−1 · d−1). Mouse aortic atherosclerotic lesion area and macrophage and aortic oxidative status were evaluated. Aldosterone administration enhanced the mouse atherosclerotic lesion area by 32%. Mouse peritoneal macrophages and aortic segments from aldosterone-treated mice exhibited increased superoxide anion formation by up to 155% and 69%, respectively, and this effect was probably mediated by NADPH oxidase activation,...
Abstract 156: Neurocognitive Recovery Improves After Discharge for Therapeutic Hypothermia Patients
Authors: David A Hildebrandt, M Nicholas Burke, Meghan Lardy, William Parham, Christopher Kapsner, Ross F Garberich, Richard F Shronts, Timothy D Henry, Michael R Mooney
Journal: Circulation (2012)

OBJECTIVE: Therapeutic Hypothermia (TH) treatment for resuscitated cardiac arrests has been shown to be effective in reducing anoxic encephalopathy among survivors of out of hospital cardiac arrest...
Abstract LB-246: <i>TIGAR</i> amplification promotes glutamine addition in the progression of esophageal squamous cell carcinoma
Authors: Jiahui Chu, Mingming Shao, Jiang Chang, Qionghua Cui, Linna Peng, Yingying Luo, Wen Tan, Chen Wu, Dongxin Lin
Journal: Cancer Research (2018)

Abstract BACKGROUND: Our previous whole-genome sequencing in esophageal squamous-cell carcinoma (ESCC) has identified 23 focal regions with recurrent gain of copy number that contain 1591 genes. Further integrative analysis of copy number alterations with mRNA expression levels showed 141 copy-number amplified genes that had higher mRNA levels, suggesting an important role of these genes in ESCC. This study was to investigate the functional roles of these genes and their potential as biomarkers and therapeutic targets for ESCC. METHODS: An siRNA library was used to knock down all these 141 genes in ESCC cells and change of the malignant phenotype of these cancer cells was examined by using a high-throughput imaging method and in vitro proliferation and colony formation assays. The acting mechanism of the interest genes on malignant phenotypes of cells was explored using biochemical and molecular biological assays. We also examined the effect of the amplified genes on sensitivity of cancer cells to anticancer agents in vitro and in vivo in mice. RESULTS: We found that, among the 141 examined genes, TIGAR was the top one influencing ESCC cell proliferation in vitro and in vivo in xenografts. We confirmed that TIGAR can inhibit glycolysis and divert the carbon flux into the PPP to produce ribose-5-phosphate (R5P) for nuclear synthesis in cells. Overexpression of TIGAR may activate AMPKα that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain energy balance in cells with a reduced glycolysis ability, which was responsible for energy production under normal conditions. We found that ESCC cells overexpressing TIGAR had an addiction to glutamine metabolism and were sensitive to glutaminase inhibitors. Glutamine restriction or glutaminase inhibitors had a synergistic effect with chemotherapy drugs, such as DDP and 5-Fu, on killing of ESCC cells, suggesting that glutaminase inhibitors may be used as adjuvant agents for treatment of ESCC with TIGAR amplification. CONCLUSION: These results suggest that amplification or overexpression of TIGAR may prevent ESCC cells from killing by anticancer drugs and thus may represent a therapeutic target for ESCC. Citation Format: Jiahui Chu, Mingming Shao, Jiang Chang, Qionghua Cui, Linna Peng, Yingying Luo, Wen Tan, Chen Wu, Dongxin Lin. TIGAR amplification promotes glutamine addition in the progression of esophageal squamous cell carcinoma [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-246.
Abstract 3354: Chemically induced degradation of the transcription factor BCL6
Authors: Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Maureen Caligiuri, Christian Dank, John R. Engen, Peter Ettmayer, Daniel Gerlach, Thomas Gerstberger, Bingsong Han, Roxana E. Iacob, Dirk Kessler, David R. Lancia, Mayer Moriz, Nikolai Mischerikow, Klaus Rumpel, Renate Schnitzer, Tilman Voss, Xiaozhang Zheng, Andreas Zoephel, Norbert Kraut, Darryl McConnell, Mark Pearson, Manfred Koegl
Journal: Cancer Research (2018)

Abstract The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We have used structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also cause rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and antiproliferative effects than compounds that merely inhibited co-repressor interaction. The fact that the magnitude of effects elicited by this class of BCL6 degrading compounds greatly exceeds that of our equipotent non-degrading inhibitors offers exciting opportunities for the development of BCL6-based lymphoma therapeutics. To support further research, the most potent BCL6 degrading inhibitor is made freely available to the research community as an in vitro tool compound. Please see http://www.opnMe.com for further infos. Citation Format: Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Maureen Caligiuri, Christian Dank, John R. Engen, Peter Ettmayer, Daniel Gerlach, Thomas Gerstberger, Bingsong Han, Roxana E. Iacob, Dirk Kessler, David R. Lancia, Mayer Moriz, Nikolai Mischerikow, Klaus Rumpel, Renate Schnitzer, Tilman Voss, Xiaozhang Zheng, Andreas Zoephel, Norbert Kraut, Darryl McConnell, Mark Pearson, Manfred Koegl. Chemically induced degradation of the transcription factor BCL6 [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 3354.
Metabolic and lifestyle risk factors for acute pancreatitis in Chinese adults: A prospective cohort study of 0.5 million people
Authors: Yuanjie Pang, Christiana Kartsonaki, Iain Turnbull, Yu Guo, Ling Yang, Zheng Bian, Yiping Chen, Iona Y. Millwood, Fiona Bragg, Weiwei Gong, Qinai Xu, Quan Kang, Junshi Chen, Liming Li, Michael V. Holmes, Zhengming Chen
Journal: PLoS Medicine (2018)

Background Little prospective evidence exists about risk factors and prognosis of acute pancreatitis in China. We examined the associations of certain metabolic and lifestyle factors with risk of acute pancreatitis in Chinese adults. Methods and findings The prospective China Kadoorie Biobank (CKB) recruited 512,891 adults aged 30 to 79 years from 5 urban and 5 rural areas between 25 June 2004 and 15 July 2008. During 9.2 years of follow-up (to 1 January 2015), 1,079 cases of acute pancreatitis were recorded. Cox regression was used to estimate adjusted hazard ratios (HRs) for acute pancreatitis associated with various metabolic and lifestyle factors among all or male (for smoking and alcohol drinking) participants. Overall, the mean waist circumference (WC) was 82.1 cm (SD 9.8) cm in men and 79.0 cm (SD 9.5) cm in women, 6% had diabetes, and 6% had gallbladder disease at baseline. WC was positively associated with risk of acute pancreatitis, with an adjusted HR of 1.35 (95% CI 1.27–1.43; p < 0.001) per 1-SD-higher WC. Individuals with diabetes or gallbladder disease had HRs of 1.34 (1.07–1.69; p = 0.01) and 2.42 (2.03–2.88; p < 0.001), respectively. Physical activity was inversely associated with risk of acute pancreatitis, with each 4 metabolic equivalent of task (MET) hours per day (MET-h/day) higher physical activity associated with an adjusted HR of 0.95 (0.91–0.99; p = 0.03). Compared with those without any metabolic risk factors (i.e., obesity, diabetes, gallbladder disease, and physical inactivity), the HRs of acute pancreatitis for those with 1, 2, or ≥3 risk factors were 1.61 (1.47–1.76), 2.36 (2.01–2.78), and 3.41 (2.46–4.72), respectively (p < 0.001). Among men, heavy alcohol drinkers (≥420 g/week) had an HR of 1.52 (1.11–2.09; p = 0.04, compared with abstainers), and current regular smokers had an HR of 1.45 (1.28–1.64; p = 0.02, compared with never smokers). Following a diagnosis of acute pancreatitis, there were higher risks of pancreatic cancer (HR = 8.26 [3.42–19.98]; p < 0.001; 13 pancreatic cancer cases) and death (1.53 [1.17–2.01]; p = 0.002; 89 deaths). Other diseases of the pancreas had similar risk factor profiles and prognosis to acute pancreatitis. The main study limitations are ascertainment of pancreatitis using hospital records and residual confounding. Conclusions In this relatively lean Chinese population, several modifiable metabolic and lifestyle factors were associated with higher risks of acute pancreatitis, and individuals with acute pancreatitis had higher risks of pancreatic cancer and death.
Attenuated Cardiac Sympathetic Responsiveness During Dynamic Exercise in Patients With Heart Failure
Authors: BengtRundqvist, GraemeEisenhofer, MikaelElam, PeterFriberg
Journal: Circulation (1997)

Background Cardiac norepinephrine (NE) spillover is increased in patients with chronic heart failure. This elevation is partly due to augmented NE release but also to reduced capacity for cardiac NE removal processes. In patients with mild to moderate heart failure, it is not known whether the described alteration in cardiac sympathetic function also affects cardiac NE spillover during intense sympathetic activation and whether other organs respond in proportion to the heart. Methods and Results Twenty-two patients with heart failure and 15 age-matched healthy subjects were studied. Whole-body and regional (NE) spillovers from the heart and kidneys were assessed at baseline and during supine cycling exercise (10 minutes) with the use of steady-state infusions of tritiated NE (isotope dilution). Cardiac performance was evaluated by means of catheterization of the right side of the heart. Cardiac NE spillover was higher (P<.05) at baseline in the patient group than in healthy subjects, whereas renal and who...
Abstract 2379: PTPRT pseudo-phosphatase domain is a denitrase that contributes to its tumor suppressor function
Authors: Yiqing Zhao, Zhenghe Wang
Journal: Cancer Research (2018)

Abstract Department of Genetics &amp; Genome Sciences and Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA. In addition to phosphorylation, tyrosine residues in proteins can have nitration at the 3-carbon position on the phenol ring (Y-NO2). Protein tyrosine nitration occurs under both physiological and pathologic conditions. However, enzymes that add or remove this protein modification remain to be identified. Protein tyrosine phosphatase receptor T (PTPRT) is one of the twelve receptor protein tyrosine phosphatases (RPTPs) that have two catalytic PTP domains in their intracellular parts. While the membrane proximal PTP domains (D1) are protein tyrosine phosphatases, it has been thought that the C-terminal PTP domains (D2) are pseudo-phosphatase that lack enzymatic activity. Here we report that the pseudo-phosphatase domain (D2) of PTPRT is a denitrase that removes nitro-groups from tyrosine residues in paxillin. PTPRT normally functions as a tumor suppressor and is frequently mutated in a variety of human cancers including colorectal cancer. Interestingly, a fifth of tumor-derived mutations of PTPRT are located in the D2 pseudo-PTP domain. We demonstrate that some of the tumor-derived mutations located in the pseudo-phosphatase domain impair the denitrase activity. Moreover, PTPRT mutant mice that inactivate the denitrase activity are susceptible to carcinogen-induced colon tumor formation. Our study uncovers a novel enzyme that functions as a tumor suppressor. Citation Format: Yiqing Zhao, Zhenghe Wang. PTPRT pseudo-phosphatase domain is a denitrase that contributes to its tumor suppressor function [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 2379.
Abstract 447: A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers
Authors: Mengxiong Wang, Renan Ferreira, Mary Law, Elham Yaaghubi, Coy Heldermon, Ronald Castellano, Brian Law
Journal: Cancer Research (2018)

Abstract EGFR and/or HER2 are frequently overexpressed oncoproteins in HER2+ breast cancer, Triple Negative Breast Cancer (TNBC), and Inflammatory Breast Cancer (IBC). However, EGFR and/or HER2 targeting agents have failed to make major advances in improving survival for these cancer patients, largely because these cancers frequently develop resistance to these drugs. The identification of novel treatment strategies is critically needed. Overexpression of EGFR and/or HER2 presents a severe burden to the secretary pathway, as HER-family proteins EGFR, HER2, HER3 share conserved extracellular cysteine-rich and proline-rich repeats that form numerous disulfide bonds and control cis-trans isomerization in the protein folding processes. We demonstrated that the disulfide bond disrupting Agents (DDAs) selectively killed EGFR+ and/or HER2+ breast cancer cells in vitro and decreased tumor growth of HER2+ cancer in a xenograft mouse model. DDA-dependent anti-cancer actions resulted from downregulation of EGFR/HER2/HER3, induction of AKT dephosphorylation, and activation of Endoplasmic Reticulum (ER) stress. We also investigated a novel proteotoxic combination therapy employing DDAs and Proline Isomerase Inhibitors (PIIs) in treating breast cancers. PIIs potentiated the efficacy of DDAs in downregulating EGFR/HER2/HER3 levels and initiating ER stress, and the combination was highly synergistic in reducing EGFR+ and/or HER2+ breast cancer cell viability. Importantly, the combination of DDAs and PIIs overcame single drug resistance, significantly decreased tumor volumes and increased the survival of xenograft mice. Evidence that the drug combination was effective against metastatic breast cancer cells is also provided. Citation Format: Mengxiong Wang, Renan Ferreira, Mary Law, Elham Yaaghubi, Coy Heldermon, Ronald Castellano, Brian Law. A novel proteotoxic combination therapy for EGFR+ and HER2+ 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 447.
Abstract 14641: Deficiency in the E3 Ubiquitin Ligase Parkin Exacerbates Alcoholic Cardiomyopathy: Role of Mitophagy
Authors: XihuiXu, JunRen
Journal: Circulation (2014)

Background: Long-term heavy alcohol consumption has been shown to promote mitochondrial injury, unfavorable geometric and contractile changes in the heart. Parkin, a cytosolic E3 ubiquitin ligase encoded by PARK2 gene, plays an important role in the regulation of selective mitophagy. This study was designed to examine the role of Parkin in alcohol-induced myocardial injury (aka alcoholic cardiomyopathy) and the underlying mechanism with a focus on mitophagy. Methods: Adult male wild-type C57 and PARKIN2 knockout (Parkin-/-) mice were placed on alcohol (4%) or control diet for 4 weeks. Echocardiographic and cardiomyocyte mechanical properties were assessed. Mitochondrial morphology, function and mitophagy were examined using transmission electronic microscopy, Clark-type oxygen electrode, and Western blot, respectively. Results: Our results revealed that chronic alcohol consumption triggered unfavorable geometric and contractile changes [decreased fractional shortening (FS) and ejection fraction (EF), with...
Abstract 112: Cardiac-specific Constitutive Activation of Nrf2 Induces Reductive Stress and Pathological Cardiac Remodeling
Authors: Gobinath Shanmugam, Madhusudhanan Narasimhan, Jolyn Fernandes, Kevin Whitehead, Silvio H Litovsky, John R Hoidal, Sethu Palaniappan, Thomas W Kensler, Dale E Abel, Dean P Jones, Namakkal-Soorapppan Rajasekaran
Journal: Circulation Research (2017)

Background: Heart failure is a growing cause of human morbidity and mortality. Supplementations of free radical scavenging antioxidants have largely failed to protect the myocardium from oxidative stress diseases. While endogenous transcriptional activation of antioxidants appears to be promising, their chronic effects are unknown. Here, we tested a hypothesis that chronic activation of antioxidant system will result in reductive stress (RS) and lead to pathological cardiac hypertrophy. Methods: Novel transgenic (TG) mice expressing constitutively active Nrf2 in the heart (α-MHC-caNrf2-TG) and their littermates were used to study the effects on structure and function of the myocardium. Myocardial glutathione redox state (GSH/GSSG), transcript levels (qPCR), and protein (immunoblotting) for Nrf2-related antioxidants and structure and function analysis (echocardiography - Vevo2100 Imager) in Non-transgenic (NTg), TG-low and TG-high mice (n=6-12/gp.) were performed at 6-8 months of age. Further, changes in cardiomyocytes and rate of survival in TG mice were analyzed. Results: Kaplan-Meier survival plots demonstrated 10 and 40% mortality in TG-low and TG-high, respectively, compared to NTG by 60 weeks of age. The myocardial glutathione and its redox ratio (GSH/GSSG) were significantly increased (p&lt;0.05) in the TG-low and TG-high compared with NTg mice indicates development of RS. A significant increase in Nrf2-ARE (promoter) binding with increased expression of antioxidant genes and proteins (p&lt;0.05) were noted in TG vs. NTg mice. Increased heart-to-body weight and heart weight to tibia length ratios were prominent in TG-high relative to NTg or TG-low mice. Histological analyses (WGA, H&amp;E staining) showed increased cardiomyocyte size, ventricular wall thickening and decreased chamber volume in TG mice. Echocardiography analyses revealed significant hypertrophic cardiomyopathy with abnormally increased ejection fraction (HCM i EF) due to chronic reductive stress. Conclusion: Thus, basal attenuation of the obligatory oxidative signaling with chronic activation of Nrf2-antioxidants could shift the redox equilibrium to “reductive” side and thereby causing pathological cardiac remodeling.
Abstract LB-386: MicroRNA-164a activates the Wnt pathway to promote breast cancer metastasis
Authors: Melvin Kantono, Wei Sun, Beichu Guo
Journal: Cancer Research (2018)

Abstract Breast cancer is the most common type of malignant tumor among women, and is the second leading cause of cancer-related death in women. The triple negative breast cancer (TNBC) remains is one of the major contributors of breast cancer mortality. TNBCs are a type of aggressive breast cancer that exhibits a high rate of distant metastasis and poor survival compared with other breast cancer subtypes. Although immunotherapy with PD-1 and PD-L1 blockade have achieved durable responses in a number of tumors, including TNBC. However, the overall response rates were low. Thus, elucidating the mechanisms responsible for tumor metastasis and the interaction of tumor cells with their microenvironments is critical for developing effective therapeutic approaches to treat metastatic breast cancer. Our results suggest that miR-146 can induce oncogenic transformation and tumor metastasis in the context of breast cancer. We found that miR-146a is highly expressed in TNBC cells, and is critical for the expansion of tumor-initiating cells in breast cancer growth and metastasis. Our preliminary data further indicate that miR-146a promotes breast tumorigenesis by targeting negative regulators of Wnt pathway, which is frequently altered in various tumors. The goal of this study to develop novel therapeutic approaches that could ultimately lead to effective treatment for breast cancer, particularly TNBC. Citation Format: Melvin Kantono, Wei Sun, Beichu Guo. MicroRNA-164a activates the Wnt pathway to promote breast cancer metastasis [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-386.