tbuckley/cabot-search huggingface dataset:
Pioglitazone Enhances Cytokine-Induced Apoptosis in Vascular Smooth Muscle Cells and Reduces Intimal Hyperplasia
Authors: YoshiakiAizawa, Jun-ichiKawabe, NaoyukiHasebe, NaohumiTakehara, KenjiroKikuchi
Journal: Circulation (2001)

Background Cytokines induce apoptosis in vascular disease lesions through enhancement of inducible nitric oxide (NO) synthase (iNOS) activation. The thiazolidinediones, novel insulin-sensitizing agents, have been demonstrated to modulate cytokine-induced NO production. We have investigated the role of pioglitazone in the apoptosis of vascular smooth muscle cells (VSMCs) in vitro and developed intimal hyperplasia in vivo. Methods and Results Pioglitazone (0.1 to 10 μmol/L) significantly enhanced cytokine-induced expression of iNOS and NO production in a dose-dependent manner in rat VSMCs, but 15-deoxy-Δ12,14-prostaglandin J2 (up to 10 μmol/L), a native peroxisome proliferator-activated receptor-γ ligand, showed no effect. Pioglitazone also significantly enhanced reduction of cell viability, as evidenced by the increase in the number of TUNEL-positive cells. All of these effects of pioglitazone were blocked by treatment with N-monomethyl-l-arginine, an NO synthesis inhibitor. In an in vivo study with a ball...
Role of Lymphocytes in Myocardial Injury, Healing, and Remodeling After Myocardial Infarction
Authors: UlrichHofmann, StefanFrantz
Journal: Circulation Research (2015)

A large body of evidence produced during decades of research indicates that myocardial injury activates innate immunity. On the one hand, innate immunity both aggravates ischemic injury and impedes remodeling after myocardial infarction (MI). On the other hand, innate immunity activation contributes to myocardial healing, as exemplified by monocytes’ central role in the formation of a stable scar and protection against intraventricular thrombi after acute infarction. Although innate leukocytes can recognize a wide array of self-antigens via pattern recognition receptors, adaptive immunity activation requires highly specific cooperation between antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. We have only recently begun to examine lymphocyte activation’s relationship to adaptive immunity and significance in the context of ischemic myocardial injury. There is some experimental evidence that CD4+ T-cells contribute to ischemia–reperfusion injury. Several studies have shown tha...
Is Low Disease Activity Sufficient as a Target in Systemic Lupus Erythematosus? Comment on the Article by Petri et al
Authors: Manuel F. Ugarte‐Gil, Daniel Wojdyla, Guillermo J. Pons‐Estel, Bernardo A. Pons‐Estel, Graciela S. Alarcón
Journal: Arthritis & Rheumatology (2018)
Emerging function and potential diagnostic value of circular RNAs in cancer
Authors: Xianglun Cui, Jianxun Wang, Zongjun Guo, Mengyang Li, Mingyu Li, Si Liu, Haoran Liu, Wenjing Li, Xunhua Yin, Jiaping Tao, Wenhua Xu
Journal: Molecular Cancer (2018)

As a novel class of endogenous RNAs, circRNAs, have a covalently closed continuous loop, with neither a 5'to 3'polarity, nor a polyadenylated tail. Numerous circRNAs have been characterized by abundance, stabilization, conservation, and exhibit tissue/developmental stage-specific expression. Furthermore, circRNAs play vital roles in tumorigenesis and metastasis, such as functioning as a ceRNA or miRNA sponge, interacting with protein and encoding protein. Increasing evidence has revealed that it potentially serves as a required novel biomarker for cancer diagnosis. This review summarized the latest research on circRNAs, including its classification and biogenesis, mechanism and functions, as well as circRNAs in different cancers, as a potential biomarker.
Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer
Authors: Jiangjiang Li, Ya He, Zheqiong Tan, Jingchen Lu, Liling Li, Xin Song, Feng Shi, Longlong Xie, Shuo You, Xiangjian Luo, Namei Li, Yueshuo Li, Xiaolan Liu, Min Tang, Xinxian Weng, Wei Yi, Jia Fan, Jian Zhou, Gao Qiang, ShuangJian Qiu, Weizhong Wu, Ann M. Bode, Ya Cao
Journal: Theranostics (2018)

Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers.However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown.Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer.Methods: Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples.IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients.The biological functions of IDH2 were evaluated by using cell-based assays and in vivo xenograft mouse models.Results: Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers.Targeting IDH2 with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth.Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation.Conclusion: IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG.Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.
High-Energy Phosphate Metabolism and Creatine Kinase in Failing Hearts
Authors: YunYe, GuangrongGong, KoichiOchiai, JingboLiu, JianyiZhang
Journal: Circulation (2001)

Background—This study aimed to create a pig model of heart failure secondary to severe aortic stenosis and to examine the relationship between the alterations in myocardial high-energy phosphate (HEP) metabolism and protein expression of creatine kinase (CK) isoforms. Methods and Results—Sixteen pigs with left ventricular hypertrophy (LVH) secondary to ascending aortic banding and 10 normal pigs (N) were studied. Myocardial protein levels of CK isoforms (Western blot), HEP levels, and CK kinetics (31P MR spectroscopy) were measured under basal conditions. Nine of the 16 animals with LVH developed congestive heart failure (CHF), as evidenced by ascites (100 to 2000 mL). LV weight/body weight ratio (g/kg) was 2.18±0.15 in N hearts, 3.04±0.14 in hearts with LVH (P<0.01), and 4.23±0.36 in hearts with CHF (P<0.01 versus LVH). Right ventricle weight/body weight ratio and LV end-diastolic pressure were significantly higher in hearts with CHF (each P<0.01 versus N or LVH). Myocardial phosphocreatine/ATP ratios an...
Adaptive Evolution of Animal Proteins over Development: Support for the Darwin Selection Opportunity Hypothesis of Evo-Devo
Authors: Jialin Liu, Marc Robinson-Rechavi
Journal: Molecular Biology and Evolution (2018)

A driving hypothesis of evolutionary developmental biology is that animal morphological diversity is shaped both by adaptation and by developmental constraints. Here, we have tested Darwin's "selection opportunity" hypothesis, according to which high evolutionary divergence in late development is due to strong positive selection. We contrasted it to a "developmental constraint" hypothesis, according to which late development is under relaxed negative selection. Indeed, the highest divergence between species, both at the morphological and molecular levels, is observed late in embryogenesis and postembryonically. To distinguish between adaptation and relaxation hypotheses, we investigated the evidence of positive selection on protein-coding genes in relation to their expression over development, in fly Drosophila melanogaster, zebrafish Danio rerio, and mouse Mus musculus. First, we found that genes specifically expressed in late development have stronger signals of positive selection. Second, over the full transcriptome, genes with evidence for positive selection trend to be expressed in late development. Finally, genes involved in pathways with cumulative evidence of positive selection have higher expression in late development. Overall, there is a consistent signal that positive selection mainly affects genes and pathways expressed in late embryonic development and in adult. Our results imply that the evolution of embryogenesis is mostly conservative, with most adaptive evolution affecting some stages of postembryonic gene expression, and thus postembryonic phenotypes. This is consistent with the diversity of environmental challenges to which juveniles and adults are exposed.
Abstract 745: Development of a novel ron receptor targeted antibody-drug conjugates using cysteine bridging technology for potential treatment of pancreatic cancer
Authors: Sreedhar Reddy Suthe, Hang-Ping Yao, Paul C. Trippier, Ming-Hai Wang
Journal: Cancer Research (2018)

Abstract Therapeutics targeting known oncoproteins have been applied for pancreatic cancer treatment but clinical outcomes are not promising. Hence, there is an urgent need to identify novel targets and develop effective drugs to improve pancreatic cancer therapeutic index. Antibody-drug conjugates (ADC) represent a promising class of drugs for targeted cancer therapy. Here we developed a novel ADC targeting RON receptor tyrosine kinase for potential pancreatic cancer treatment. To this end, we have synthesized a bis-alkylating linker (BL), attached to a lysosomal protease-cleavable dipeptide with payload Monomethyl auristatin E (MMAE). The BL-MMAE was then conjugated to Zt/g4 (anti-RON mAb) through cysteine bridging technology to produce Zt/g4-BL-MMAE with a homogeneous conjugation profile and an antibody to drug ratio of 1:4. Zt/g4-BL-MMAE showed significant improvement in drug conjugation homogeneity and serum stability over conventional ADCs prepared through maleimide based linkers. In pancreatic cancer cell lines overexpressing RON, Zt/g4-BL-MMAE specifically targeted RON-expressing tumor cells and was effective in rapid induction of cell surface RON endocytosis. Functional analysis revealed that Zt/g4-BL-MMAE caused cell cycle arrest at G2/M phase, reduction of cell viability and subsequently resulted in massive cell death. The calculated IC50 is in the range of 1 to 2 µg/ml. We conclude that Zt/g4-BL-MMAE is a novel anti-RON ADC with excellent conjugation profile, serum stability, and selective cytotoxicity for pancreatic cancer cells. This work provides a pharmaceutical opportunity for evaluating potentials of RON-targeted ADCs in pancreatic cancer treatment in the future. Citation Format: Sreedhar Reddy Suthe, Hang-Ping Yao, Paul C. Trippier, Ming-Hai Wang. Development of a novel ron receptor targeted antibody-drug conjugates using cysteine bridging technology for potential treatment 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 745.
Abstract LB-390: A transfer RNA derived small RNA affects translation in rapidly dividing cells and a target for hepatocellular carcinoma
Authors: Hak Kyun Kim, Gabriele Fuchs, Shengchun Wang, Wei Wei, Yue Zhang, Hyesuk Park, Biswajoy Roy-Chaudhuri, Pan Li, Jianpeng Xu, Kirk Chu, Feijie Zhang, Mei-sze Chua, Samuel So, Cliff Zhang, Peter Sarnow, Mark A. Kay
Journal: Cancer Research (2018)

Abstract There are tens of thousands of different transfer RNA-derived small RNAs (tsRNAs) of 18-40 nucleotides in length in mammalian cells. In recent years there is accumulating evidence suggesting that these RNAs can play different yet important roles in gene regulations. Nevertheless, in most cases, the biological roles of these RNAs have yet to be defined. Using a variety of locked nucleic acid/antisense oligonucleotide (LNA/ASO)-mediated strategies, we found that inhibition of one specific 3'tsRNA, induces apoptosis in rapidly dividing cells. Inhibition of the tsRNA but not the mature tRNA reduced the translation of ribosomal protein S28 (RPS28) and S15 (RPS15) mRNAs and led to a block in pre-18S ribosomal RNA processing, and ultimately a decrease in the number of 40S ribosomal subunits. Using a modified ChIRP method, we found that the tsRNA binds to ribosomal protein S28 mRNA and by genetic complementation analyses established the binding sites contained within the mRNAs. Furthermore, we established that tsRNA binds to duplexed target sites in RPS28 and RPS15 mRNAs and enhances their translation by perhaps helping to unfold their secondary structures. The systemic delivery of a specific anti-tsRNA oligonucleotides into mice (the tsRNA sequence is the same in mouse and humans) did not cause liver injury in normal mice but induced apoptosis and a significant growth retardation of patient-derived orthotopic hepatocellular carcinomas surgically implanted into mouse livers. Our result establishes a newly defined post-transcriptional mechanism of gene regulation and provides a novel target for cancer therapeutics. Citation Format: Hak Kyun Kim, Gabriele Fuchs, Shengchun Wang, Wei Wei, Yue Zhang, Hyesuk Park, Biswajoy Roy-Chaudhuri, Pan Li, Jianpeng Xu, Kirk Chu, Feijie Zhang, Mei-sze Chua, Samuel So, Cliff Zhang, Peter Sarnow, Mark A. Kay. A transfer RNA derived small RNA affects translation in rapidly dividing cells and a target for hepatocellular 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-390.
Abstract 5010: Advantages in using orthotopic syngeneic tumor models to evaluate immune-based approaches for cancer treatment
Authors: Sylvie Maubant, Philippe Slos, Marc Hillairet de Boisferon, Francis Bichat, Jean-Francois Mirjolet
Journal: Cancer Research (2018)

Abstract Immune checkpoint modulators are now accepted as the fourth pillar of cancer care for both solid tumors and hematological malignancies. In addition to CTLA-4, PD-1 or PD-L1 targeting antibodies, novel immune-oncology targets are currently tested in patients but also new strategies such as bispecific T cell engagers or cell therapies including CAR-T cells. Some of them have been already approved. Prediction of preclinical models is still a long-standing debate, even more when considering modulators of the immune system. Despite significant progresses made in humanized mouse model field during the last decade, having a complete and stable immune system comprising both lymphoid and myeloid subpopulation is not yet possible. Syngeneic tumors thus remain the model of choice to interrogate and better understand the mechanisms of action of new compounds targeting immune cell interactions. In order to improve prediction and relevance of these syngeneic models, orthotopic (OT) models were developed in parallel of standard subcutaneous (SC) models. Here, comparison of regular SC versus OT engraftments are provided. Various models, such as EMT-6 (breast), MBT-2 (bladder) as well as RenCa (kidney) will be described in addition to other OT models like Hepa1-6 (liver) or PAN-02 (pancreas) models. In addition to growth characteristics using imaging for OT models, antitumor efficacy of CTLA-4 and PD-1 targeting antibodies will be detailed for both SC and OT models. One of the most interesting model is MBT-2 (bladder) for which response to CTLA-4 targeting antibody is changing depending engraftment site: significant increase in survival was evidenced for the OT model (treated to control ratio (T/C) of 285%) and only moderate efficacy was observed for the SC model (T/C = 66%). For the PD-1 targeting antibody, OT injection seemed to be the preferential site to observe increased efficacy. Attempting to correlate immune profile and response to treatment, differences in immune infiltrate between OT and SC tumors will also be presented. Citation Format: Sylvie Maubant, Philippe Slos, Marc Hillairet de Boisferon, Francis Bichat, Jean-Francois Mirjolet. Advantages in using orthotopic syngeneic tumor models to evaluate immune-based approaches for cancer treatment [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 5010.
Abstract 4001: Gremlin-1 augments the estrogen-related receptor α signaling: Implications for progression of breast cancer in synergistic manner
Authors: Sin-Aye Park, Bae-Jung Choi, Wonki Kim, Young-Joon Surh
Journal: Cancer Research (2018)

Abstract Gremlin-1 (GREM1), one of the bone morphogenic protein (BMP) antagonists, is known to be involved in organogenesis, tissue differentiation, and pathogenesis of several renal disorders including fibrosis, inflammation, and diabetes. Recently, it has also been reported that aberrant epithelial GREM1 expression initiates colonic tumorigenesis. However, the role of GREM1 in breast cancer remain largely elusive. We observed that GREM1 expression was highly increased in human breast cancer cells and tissues obtained from breast cancer patients. Furthermore, its overexpression is associated with poor prognosis of breast cancer patients, especially those with estrogen receptor (ER)-negative tumors. Suppression of GREM1 expression significantly inhibited the proliferation of SKBR3 human breast cancer cells in culture and xenograft mammary tumor growth while its overexpression enhanced their viability and invasiveness. Estrogen-related receptor α (ERRα) is an orphan nuclear hormone receptor and has recently attracted attention as a novel therapeutic target in the management of triple-negative breast cancers. We observed that ERRα binds directly to GREM1 promoter and modulates GREM1 expression. The mRNA level of GREM1 was reduced by an inverse agonist of ERRα, XCT790 and also by siRNA silencing of ERRα. Conversely, the overexpression of ERRα with its co-factor peroxisome proliferator-activated receptor gamma co-activator 1-α increased the mRNA level of GREM1. Surprisingly, the transcriptional activity of ERRα was found to be regulated by GREM1. The promoter activity of ERRα and the mRNA levels of ERRα target genes were highly increased in GREM1-overexpressing breast cancer cells. Treatment of MCF-7 cells with recombinant GREM1 protein also enhanced the ERRα promoter activity and transcription of its target genes. Taken together, our study identifies for the first time that the GREM1 can act as a downstream signaling molecule of the transcription factor ERRα and suggests a positive feedback loop between ERRα and GREM1, highlighting GREM1 as a potential diagnostic and therapeutic target for the treatment of ER-negative breast cancer. Citation Format: Sin-Aye Park, Bae-Jung Choi, Wonki Kim, Young-Joon Surh. Gremlin-1 augments the estrogen-related receptor α signaling: Implications for progression of breast cancer in synergistic manner [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 4001.
Dose Optimization of H56:IC31 Vaccine for Tuberculosis-Endemic Populations. A Double-Blind, Placebo-controlled, Dose-Selection Trial
Authors: Sara Suliman, Angelique Kany Kany Luabeya, Hennie Geldenhuys, Michele Tameris, Soren T. Hoff, Zhongkai Shi, Dereck Tait, Ingrid Kromann, Morten Ruhwald, Kathryn Tucker Rutkowski, Barbara Shepherd, David Hokey, Ann M. Ginsberg, Willem A. Hanekom, Peter Andersen, Thomas J. Scriba, Mark Hatherill, Rachel Elizabeth Oelofse, Lynnett Stone, Anne Marie Swarts, Raida Onrust, Gail Jacobs, Lorraine Coetzee, Gloria Khomba, Bongani Diamond, Alessandro Companie, Ashley Veldsman, Humphrey Mulenga, Yolundi Cloete, Marcia Steyn, Hadn Africa, Lungisa Nkantsu, Erica Smit, Janelle Botes, Nicole Bilek, Simbarashe Mabwe
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Global tuberculosis (TB) control requires effective vaccines in TB-endemic countries, where most adults are infected with Mycobacterium tuberculosis (M.tb).We sought to define optimal dose and schedule of H56:IC31, an experimental TB vaccine comprising Ag85B, ESAT-6, and Rv2660c, for M.tb-infected and M.tb-uninfected adults.We enrolled 98 healthy, HIV-uninfected, bacillus Calmette-Guérin-vaccinated, South African adults. M.tb infection was defined by QuantiFERON-TB (QFT) assay. QFT-negative participants received two vaccinations of different concentrations of H56 in 500 nmol of IC31 to enable dose selection for further vaccine development. Subsequently, QFT-positive and QFT-negative participants were randomized to receive two or three vaccinations to compare potential schedules. Participants were followed for safety and immunogenicity for 292 days.H56:IC31 showed acceptable reactogenicity profiles irrespective of dose, number of vaccinations, or M.tb infection. No vaccine-related severe or serious adverse events were observed. The three H56 concentrations tested induced equivalent frequencies and functional profiles of antigen-specific CD4 T cells. ESAT-6 was only immunogenic in QFT-negative participants who received three vaccinations.Two or three H56:IC31 vaccinations at the lowest dose induced durable antigen-specific CD4 T-cell responses with acceptable safety and tolerability profiles in M.tb-infected and M.tb-uninfected adults. Additional studies should validate applicability of vaccine doses and regimens to both QFT-positive and QFT-negative individuals. Clinical trial registered with www.clinicaltrials.gov (NCT01865487).
Abstract 18475: Is There Any End in Sight to This Debate on the Optimal Duration of Dual Antiplatelet Therapy After Drug-eluting Coronary Stent Implantation?
Authors: Olusegun Sheyin, Xavier Perez, Bredy Pierre-Louis, Damian Kurian
Journal: Circulation (2015)

Introduction: There is no end in sight to the ongoing debate on the optimal duration of dual antiplatelet therapy (DAPT) following drug-eluting coronary stent (DES) implantation. Hypothesis: Short-term DAPT is less effective than long-term DAPT in preventing adverse cardiovascular and cerebrovascular outcomes following DES. Methods: MEDLINE, EMBASE, Scopus and CENTRAL were searched for eligible randomized controlled trials (RCTs) that compared short-term (≤ 6 months) DAPT with long-term (≥ 12 months) DAPT following DES implantation. The primary end point was a composite of all cause death, myocardial infarction, target vessel revascularization, stroke or major bleeding. The secondary outcome were the individual components of the primary outcome, cardiovascular death, stent thrombosis and any bleeding episode. Results: A total of 15,378 patients from 7 RCTs were studied. There was no statistically significant difference between the short-term and long-term DAPT groups with respect to the occurrence of the primary outcome {Risk ratio (RR) 1.017 (0.872-1.186), I2 = 0%}, all cause death {RR 0.896 (0.708-1.134)}, cardiovascular death {RR 0.924 (0.668-1.279)}, myocardial infarction {RR 1.139 (0.887-1.461)}, target vessel revascularization {RR 1.174 (0.916-1.505)}, stent thrombosis {RR 1.264 (0.786-2.032)} and stroke {RR 0.876 (0.685-1.611)}. However there was a statistically significant lower risk of major bleeding in the short-term DAPT group {RR 0.57 (0.36-0.90), p 0.02}. There was no statistically significant difference in the sub-group analysis of patients with diabetes and patients presenting with acute coronary syndrome, {RR 1.029 (0.745-1.421)} and {RR 1.062 (0.785-1.438)}, respectively. Conclusion: There was no difference in efficacy outcomes between short-term and long-term DAPT following DES, even among high-risk patients. Longer duration of DAPT was found to be associated with increased risk of major bleeding. These results are contrary to findings from the recently published DAPT trial. However, even though the DAPT trial reported a significant decrease in the incidence of stent thrombosis and major adverse cardiac and cerebrovascular events in the long-term DAPT group, there was a paradoxical increase in mortality.