tbuckley/cabot-search huggingface dataset:
Abstract 480: Regulation of crosstalk between AR and Wnt/Beta-catenin pathways by miR-644a in prostate cancer
Authors: Alexis R. Plaga, Girish C. Shukla
Journal: Cancer Research (2018)

Abstract Prostate Cancer (PCa) is the most commonly diagnosed cancer in males with 161,360 people diagnosed in the United States and is predicted to cause 26,730 deaths in 2017. The current treatment of androgen deprivation therapy (ADT) initially depletes circulating androgens; however, intratumoral androgens rescue androgen receptor (AR) signaling and promotes the development of castration-resistant prostate cancer (CRPC). The dysregulation of the Wnt/B-catenin signaling pathway has been implicated in the development of many cancers including PCa. The disruption of this signaling leads to the stabilization of B-catenin which upregulates many genes involved in tumorigenesis. Additionally, B-catenin acts as AR cofactor. Our previous studies show that AR is a direct target of miR-644a. We hypothesized that targeting the expression of both the B-catenin pathway and AR by conventional drugs and/or tumor suppressor miR-644a would have synergistic therapeutic benefits. In this study, we are investigating miR-644a mediated posttranscriptional downregulation of GSK3-B and B-catenin in the wnt/B-catenin signaling pathway. The effect of miR-644a in combination with inhibitors (B-catenin or GSK3-B) was also assessed using viability assays and a significant downregulation was observed. We will further study the posttranscriptional effects of tumor suppressor miR-644a on the wnt/B-catenin pathway as well as assess if miR-644a can inhibit the cross-talk of these pathways. Citation Format: Alexis R. Plaga, Girish C. Shukla. Regulation of crosstalk between AR and Wnt/Beta-catenin pathways by miR-644a in prostate cancer [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 480.
Abstract 4662: Comparing 2D and 3D culture models for in vitro therapeutic screening of paclitaxel loaded micelles co-administered with iRGD peptide
Authors: Nayela N. Chowdhury, Nandita G. Das, Sudip K. Das
Journal: Cancer Research (2018)

Abstract Clinical efficacy of paclitaxel, a potent chemotherapeutic agent, is limited by its nonspecificity that leads to toxic side effects. Polymeric micellar formulations of paclitaxel were designed with the long term goals of decreasing toxicity by tumor targeting, increasing circulation time, and enhancing permeability and retention in solid tumors. Biodegradable amphiphilic block copolymers that self assemble into micelles were used to entrap hydrophobic paclitaxel in the core. Traditional 2D cell culture models are standard for cytotoxicity assays. However, they lack the diffusion gradient and cell to cell interactions present in solid tumors which 3D multicellular tumor spheroids are capable of providing. We evaluated the in vitro cytotoxicity of polymeric micelles entrapping paclitaxel in 3D multicellular tumor spheroids of triple negative breast cancer cells and compared it with the standard 2D model. We added the cell penetrating iRGD peptide with the expectation that the iRGD peptide will increase the cellular uptake of the paclitaxel micelles. Particle uptake is enhanced due to the interaction of the iRGD peptide with the highly expressed integrin receptor on the cell surface, followed by neuropilin receptor binding which mediates an active transport system for deep tumor permeation. Paclitaxel loaded micelles were prepared and the drug content was analyzed. The cytotoxicity of the micellar paclitaxel nanocarrier system was studied in both the 2D and 3D cell culture models. Micellar paclitaxel induced cytotoxicity was significantly higher than free paclitaxel for the same concentrations of paclitaxel. Furthermore, a synergistic growth inhibitory response was observed upon coadministration of iRGD compared to treatment with the paclitaxel loaded nanocarriers on their own. Significantly higher concentration of the drug was needed in the 3D cultures to achieve comparable levels of cytotoxicity to the 2D cell culture models. This suggested that multicellular tumor spheroids exhibit higher resistance to anticancer drugs, supporting the fact that 3D culture is the better model to study in vitro cytotoxicity and likely to produce biorelevant data. Citation Format: Nayela N. Chowdhury, Nandita G. Das, Sudip K. Das. Comparing 2D and 3D culture models for in vitro therapeutic screening of paclitaxel loaded micelles co-administered with iRGD peptide [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 4662.
Calmodulin Is Essential for Cardiac IKS Channel Gating and Assembly
Authors: LioraShamgar, LijuanMa, NicoleSchmitt, YoniHaitin, AsherPeretz, ReuvenWiener, JoelHirsch, OlafPongs, BernardAttali
Journal: Circulation Research (2006)

The slow IKS K+ channel plays a major role in repolarizing the cardiac action potential and consists of the assembly of KCNQ1 and KCNE1 subunits. Mutations in either KCNQ1 or KCNE1 genes produce the long-QT syndrome, a life-threatening ventricular arrhythmia. Here, we show that long-QT mutations located in the KCNQ1 C terminus impair calmodulin (CaM) binding, which affects both channel gating and assembly. The mutations produce a voltage-dependent macroscopic inactivation and dramatically alter channel assembly. KCNE1 forms a ternary complex with wild-type KCNQ1 and Ca2+-CaM that prevents inactivation, facilitates channel assembly, and mediates a Ca2+-sensitive increase of IKS-current, with a considerable Ca2+-dependent left-shift of the voltage-dependence of activation. Coexpression of KCNQ1 or IKS channels with a Ca2+-insensitive CaM mutant markedly suppresses the currents and produces a right shift in the voltage-dependence of channel activation. KCNE1 association to KCNQ1 long-QT mutants significantly...
Preferential Differentiation of P19 Mouse Embryonal Carcinoma Cells Into Smooth Muscle Cells
Authors: ToruSuzuki, Hyo-SooKim, MasahikoKurabayashi, HiroshiHamada, HidetaFujii, MasanoriAikawa, MasafumiWatanabe, NoboruWatanabe, YasunariSakomura, YoshioYazaki, RyozoNagai
Journal: Circulation Research (1996)

Abstract Investigation of the molecular mechanisms that control smooth muscle cell (SMC) development and differentiation is a prerequisite in understanding the regulatory mechanisms of physiological and pathological SMC-associated vascular processes. The pluripotent murine embryonal carcinoma P19 cell, whose developmental potential resembles that of early embryonic cells, can develop into cell types derived from the neuroectoderm, mesoderm, and endoderm. In the present study, we have shown a unique strategy to enhance SMC differentiation in P19 cells. Under chemical induction of high concentrations of retinoic acid (1 μmol/L), P19 cells showed optimum differentiation into SMCs. Because the P19 cells thus induced also showed differentiation into neuronal cells, a strategy to block neuronal lineage differentiation was developed using a stable transformant antisense RNA construct against Brn-2, a neuronal lineage–specific POU-domain transcription factor; thus, by specifically inhibiting neuronal differentiat...
Dietary Measures to Prevent Sudden Unexpected Death in Epilepsy
Authors: Fulvio A. Scorza, Carla A. Scorza, Josef Finsterer
Journal: JAMA Neurology (2018)

To the Editor We read the article by Devinsky et al1 in which they demonstrate the importance of addressing preventive measures for sudden and unexpected death in epilepsy (SUDEP).1 Our interest in the topic has led us to formulate several questions and areas for discussion.
Calcineurin Inhibitor Attenuates the Development and Induces the Regression of Cardiac Hypertrophy in Rats With Salt-Sensitive Hypertension
Authors: MasakiShimoyama, DoubunHayashi, YunzengZou, EikiTakimoto, MihoMizukami, KoshiroMonzen, SumiyoKudoh, YukioHiroi, YoshioYazaki, RyozoNagai, IsseiKomuro
Journal: Circulation (2000)

Background—It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet. Methods and Results—In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced r...
Abstract 18175: Predicting Low-grade Rejection After Heart Transplantation In Children Using Whole Genome Sequencing
Authors: William Y Shi, Annie Xin, Gordon K Smyth, Yifang Hu, Slavica Praporski, Anne Shipp, Robert G Weintraub, Igor E Konstantinov
Journal: Circulation (2016)

Introduction: Endomyocardial biopsy (EMB) remains the gold standard for detecting rejection after heart transplantation. EMB is costly, invasive and, particularly, burdensome in children. We aimed to predict low-grade rejection by whole genome sequencing (WGS) in blood sample. Hypothesis: WGS can predict low-grade rejection in children after heart transplantation. Methods: A total of 106 blood samples with corresponding EMB from 18 children who underwent heart transplantation from 2011 to 2014 were analysed. There were 18 baseline preoperative samples and 88 samples taken at the time of each EMB. Grade of rejection corresponding to each blood sample was determined (no rejection, n=34, 1R, n=45, and 2R, n=9). An input of 200 ng of total RNA per sample was prepared and indexed separately for Illumina sequencing using the TruSeq RNA Library Prep Kit v2 (Illumina, San Diego, CA). Next generation WGS was performed. Differential expression (DE) analysis was performed using the limma package. A k-nearest neighbo...
Association of a G994→T Missense Mutation in the Plasma Platelet-Activating Factor Acetylhydrolase Gene With Genetic Susceptibility to Nonfamilial Dilated Cardiomyopathy in Japanese
Authors: SahokoIchihara, YoshijiYamada, MitsuhiroYokota
Journal: Circulation (1998)

Background—Although several genes or genetic loci that are responsible for or confer susceptibility to familial dilated cardiomyopathy (DCM) have been identified, genetic defects that underlie nonfamilial DCM remain to be characterized. Mice lacking manganese superoxide dismutase exhibit DCM, suggesting that impairment of the defense mechanisms against oxidative stress is an important susceptibility factor for DCM. Plasma platelet-activating factor (PAF) acetylhydrolase also acts as a key defense against oxidative stress by hydrolyzing PAF and oxidized phospholipids. Thus, abnormalities in the activity of this enzyme may result in predisposition to myocardial damage. Methods and Results—The possible association of a G994 (M allele)→T (m allele) missense mutation in the plasma PAF acetylhydrolase gene with genetic susceptibility to nonfamilial DCM has now been investigated in 122 Japanese individuals with this condition and 226 healthy control subjects. PAF acetylhydrolase activity in plasma was significan...
History of autoimmune conditions and lymphoma prognosis
Authors: Geffen Kleinstern, Matthew J. Maurer, Mark Liebow, Thomas M. Habermann, Jean L. Koff, Cristine Allmer, Thomas E. Witzig, Grzegorz S. Nowakowski, Ivana N. Micallef, Patrick B. Johnston, David J. Inwards, Carrie A. Thompson, Andrew L. Feldman, Brian K. Link, Christopher Flowers, Susan L. Slager, James R. Cerhan
Journal: Blood Cancer Journal (2018)

Abstract Autoimmune conditions are strong risk factors for developing lymphoma, but their role in lymphoma prognosis is less clear. In a prospective cohort study, we evaluated self-reported history of eight autoimmune conditions with outcomes in 736 diffuse large B-cell, 703 follicular, 302 marginal zone (MZL), 193 mantle cell (MCL), 297 Hodgkin lymphoma (HL), and 186 T-cell lymphomas. We calculated event-free survival (EFS) and overall survival (OS), and estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sex, prognostic score, and treatment. History of any of the eight autoimmune conditions ranged from 7.4% in HL to 18.2% in MZL, and was not associated with EFS or OS for any lymphoma subtype. However, there was a positive association of autoimmune conditions primarily mediated by B-cell responses with inferior EFS in MCL (HR = 2.23, CI: 1.15–4.34) and HL (HR = 2.63, CI: 1.04–6.63), which was largely driven by rheumatoid arthritis. Autoimmune conditions primarily mediated by T-cell responses were not found to be associated with EFS or OS in any lymphoma subtype, although there were few events for this exposure. Our results indicate that distinguishing autoimmune conditions primarily mediated by B-cell/T-cell responses may yield insight regarding the impact of this comorbid disease, affecting ~10% of lymphoma patients, on survival.
Abstract 4624: The sTRA glycan is complementary to CA19-9 as a serologic biomarker of pancreatic cancer
Authors: Ying Liu, Daniel Barnett, Ben Staal, Ying Huang, Katie Partyka, Herbert Zeh, Aatur Singhi, Richard R. Drake, Randall E. Brand, Brian B. Haab
Journal: Cancer Research (2018)

Abstract The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic cancer, but not enough to be reliable for detection, diagnosis, or monitoring of the disease. We hypothesized that a glycan called sTRA complements CA19-9, and that the two biomarkers in combination provide added information over either biomarker individually. As an individual marker, the sTRA assay performed equivalently with CA19-9 for distinguishing cancers from benign pancreatic diseases, but in combination, CA19-9 and sTRA showed exclusive elevations in significantly different groups of patients. Using high-specificity cutoffs giving one false-positive detection in each marker, sTRA was elevated in 34/46 (74%) patients with low CA19-9 in stage III/IV cancers and 28/70 (40%) with low CA19-9 in stage I/II cancers. A three-marker panel consisting of CA19-9 and two versions of the sTRA assay gave 81% sensitivity and 88% specificity (84% accuracy) in a training set of 72 stage I-IV cancers and 75 benign disease controls, compared to 57% sensitivity and 92% specificity (75% accuracy) for CA19-9 alone. The application of the fixed three-marker classifier to a test set of 25 cancers and 25 benign controls gave 80% sensitivity and 84% specificity, compared to 56% sensitivity and 96% specificity for CA19-9 alone. In an analysis of patient-matched tumor tissue and plasma samples, we found that the tumors secreting both sTRA and CA19-9 into the blood tended to be conventional PDAC with well-to-moderate differentiation and heavy marker staining in the ductal lumens, but the tumors secreting only sTRA showed sTRA staining in glands with extremely large and unpolarized nuclei and vacuolated or foamy cytoplasm. Those without plasma elevations in either marker did not have glandular features of typical adenocarcinoma. Surprisingly, about half of the patients without plasma elevations of CA19-9 nevertheless showed strong tumor staining. Such tumors expressed CA19-9 mostly in poorly differentiated patches of cells with compact nuclei and cytoplasm. Thus, sTRA and CA19-9 are complementary serologic biomarkers that together could increase the diagnostic accuracy for PDAC and potentially identify distinct subgroups of tumors. Citation Format: Ying Liu, Daniel Barnett, Ben Staal, Ying Huang, Katie Partyka, Herbert Zeh, Aatur Singhi, Richard R. Drake, Randall E. Brand, Brian B. Haab. The sTRA glycan is complementary to CA19-9 as a serologic biomarker of pancreatic cancer [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 4624.
Abstract 2922: The utility of BET inhibition in the sensitization and re-sensitization of pancreatic cancer cells to paclitaxel
Authors: Feda H. Hamdan, Ana P. Kutschat, Madhobi Sen, Xin Wang, Steven A. Johnsen
Journal: Cancer Research (2018)

Abstract While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. As late diagnosis and resistance to conventional therapies are major contributors to high mortality rates, novel treatment options are needed to improve the prognosis of pancreatic cancer patients. Recent findings showed that inhibition of the Bromodomain and Extraterminal Domain (BET) family of epigenetic reader proteins is effective, both alone and in combination with conventional chemotherapy, in decreasing pancreatic tumor growth in patient-derived xenografts. Thus, we aim to evaluate the potential role of and mechanisms of action of BET inhibitors (BETi) as an adjuvant therapy option in pancreatic ductal adenocarcinoma. We established L3.6 pancreatic cells that are resistant to paclitaxel by maintaining them in incrementally higher concentrations for 3 months. Paclitaxel-resistant cells showed a half maximal inhibitory concentration (IC50) 100-fold higher than that of parental cells. Intriguingly, we report that low, non-cytostatic concentrations of the BETi, JQ1, not only sensitized cells to paclitaxel, but also induced significant re-sensitization of chemoresistant cells. In order to elucidate the mechanism by which BETi induces chemo-sensitization, we investigated the differential gene expression profiles of resistant and sensitive cells. Thereby, we uncovered that BETi reverses the regulation of transcriptionally-activated genes in resistant cells. Interestingly, these genes showed a major tendency to gain BRD4 at putative enhancer regions. We anticipate that enhancer RNAs (eRNAs) transcribed at these particular enhancers may provide us with novel biomarkers which can be used to predict chemotherapeutic resistance and the possibility of re-sensitization by BETi. In conclusion, we provide evidence that BETi can potentially be used as adjuvant agents in pancreatic cancer. However, approaches may likely be largely independent of their anti-proliferative effects that require higher concentrations and possibly lead to intolerable adverse effects, but rather to their transcriptional regulatory functions that attenuate the activated programs in chemoresistant cancers. Citation Format: Feda H. Hamdan, Ana P. Kutschat, Madhobi Sen, Xin Wang, Steven A. Johnsen. The utility of BET inhibition in the sensitization and re-sensitization of pancreatic cancer cells to paclitaxel [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 2922.
Infections, Inflammation, and the Risk of Coronary Heart Disease
Authors: MerjaRoivainen, MaaritViik-Kajander, TimoPalosuo, PetriToivanen, MaijaLeinonen, PekkaSaikku, LeenaTenkanen, VesaManninen, TapaniHovi, MattiMänttäri
Journal: Circulation (2000)

Background—The role of infections and inflammation in the pathophysiology of coronary heart disease is emerging. We studied the independent and joint effects of these 2 components on coronary risk. Methods and Results—We measured baseline levels of C-reactive protein (CRP) and antibodies to adenovirus, enterovirus, cytomegalovirus, and herpes simplex virus as well as to Chlamydia pneumoniae (Cpn) and Helicobacter pylori in 241 subjects who suffered either myocardial infarction or coronary death during the 8.5-year trial in the Helsinki Heart Study, a coronary primary prevention trial. The 241 controls in this nested case-control study were subjects who completed the study without coronary events. Antibody levels to herpes simplex type I (HSV-1) and to Cpn were higher in cases than in controls, whereas the distributions of antibodies to other infectious agents were similar. Mean CRP was higher in cases (4.4 versus 2.0 mg/L; P<0.001), and high CRP increased the risks associated with smoking and with high an...
Abstract LB-393: LINC01137 functions as a ceRNA promoting SMAD3 signaling and ESCC metastasis
Authors: Mingming Shao, Jiahui Chu, Qionghua Cui, Linna Peng, Yingying Luo, Jiang Chang, Wen Tan, Chen Wu, Dongxin Lin
Journal: Cancer Research (2018)

Abstract BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the leading cause of cancer-related death in China and some other parts of the world. Studies have shown that certain long non-coding RNAs (lncRNAs) are involved in cancer development and progression. In this study, we sought to identify lncRNAs that are associated with metastasis of ESCC and to explore their functions and therapeutic implications. METHODS: We performed RNA sequencing and analyzed the association of lncRNAs with ESCC survial time. The significantly associated lncRNAs that were overexpressed in ESCC were selected for further study. Knockdown or overexpression of interest lncRNAs were performed to investigate their effects on ESCC cell invasion and metastasis in vitro and in vivo in mice xengraft models. Biochemical assays such as RNAi, RNA immunoprecipitation, RNA pulldown and chromatin immunoprecipitation assays were used to examine the interactions among lncRNAs, mRNAs and microRNAs and between proteins and DNA. Patient survival time differentiated by RNA expression levels was estimated by Kaplan-Meier plotting and hazard ratios for death were calculated by Cox models. RESULTS: RNA sequencing identified 9 overexpressed lncRNAs were associated with ESCC survival. Among these lncRNAs, LINC01137 had the strongest effects on invasion and metastasis of ESCC cell lines in vitro and in vivo in mice. We found that ESCCwith high expression of LINC01137 had significantly more lymph node metastases compared with ESCC with low expression of LINC01137. Functional analyses demonstrated that LINC01137 may compete with HOXA1 mRNA for miR-608 binding. Higher expression level of LINC01137 in cells may prevent miR-608 from inhibiting HOXA1 translation. We found that HOXA1 is a transcription activator of SMAD2/3 and knockdown of LINC01137 substantilly reduced the SMAD3 signaling. Treatment of ESCC cells overexpressing LINC01137 with Halofuginone, a plant derivative that can inhibit SMAD3 phosphorylation, significantly reduced the abilities of migration and invasion. CONCLUSION: These results suggest that LINC01137 might function as a ceRNA competing with miR-608 for suppressing HOXA1 expression, which promotes SMAD3 signaling to enhance metastasis of ESCC cells. Citation Format: Mingming Shao, Jiahui Chu, Qionghua Cui, Linna Peng, Yingying Luo, Jiang Chang, Wen Tan, Chen Wu, Dongxin Lin. LINC01137 functions as a ceRNA promoting SMAD3 signaling and ESCC 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-393.