tbuckley/cabot-search huggingface dataset:
Chronic Administration of Ghrelin Improves Left Ventricular Dysfunction and Attenuates Development of Cardiac Cachexia in Rats With Heart Failure
Authors: NoritoshiNagaya, MasaakiUematsu, MasayasuKojima, YoshihikoIkeda, FumikiYoshihara, WataruShimizu, HiroshiHosoda, YukiHirota, HideyukiIshida, HidezoMori, KenjiKangawa
Journal: Circulation (2001)

Background— Ghrelin is a novel growth hormone (GH)–releasing peptide that may also induce vasodilation and stimulate feeding through GH-independent mechanisms. We investigated whether ghrelin improves left ventricular (LV) dysfunction and attenuates cardiac cachexia in rats with chronic heart failure (CHF). Methods and Results— Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, rat ghrelin (100 μg/kg SC BID) or saline was administered for 3 weeks. Echocardiography and cardiac catheterization were performed. Serum GH and insulin-like growth factor-1 were significantly higher in both CHF and sham rats treated with ghrelin than in those given placebo (P<0.05 for both). CHF rats given placebo showed an impaired increase in body weight compared with sham rats given placebo (P<0.05). CHF rats treated with ghrelin, however, showed a significantly greater increase in body weight than those given placebo (+10% versus +3%, P<0.05). They showed significantly higher cardiac o...
Different Effects of Carvedilol, Metoprolol, and Propranolol on Left Ventricular Remodeling After Coronary Stenosis or After Permanent Coronary Occlusion in Rats
Authors: HiroyukiYaoita, AtsushiSakabe, KazuhiraMaehara, YukioMaruyama
Journal: Circulation (2002)

Background— Although carvedilol attenuates left ventricular (LV) remodeling in coronary occlusion-reperfusion, it is not known whether it attenuates ischemic LV remodeling because of coronary stenosis (CS) or permanent coronary occlusion (CO). Methods and Results— We administered a vehicle, carvedilol, propranolol (2, 10, and 30 mg/kg per day, each), metoprolol (6, 30, and 90 mg/kg per day), or bunazosin (0.2 and 1 mg/kg per day), orally for 12 weeks to a total of 608 rats with CS or CO. In these groups and the sham (n=40), we assessed LV function by echocardiography, CS severity, myocardial blood flow and coronary flow reserve, serum ascorbyl free radical, and vitamin C. Both CS and CO increased LV end-diastolic and end-systolic diameters and decreased ejection fraction. The 4 agents failed to attenuate LV remodeling caused by CO. In contrast, the 3 β-blockers attenuated (P<0.01) or tended to attenuate the increase in LV end-diastolic diameters caused by CS. With similar blood pressure and heart rate low...
Abstract 3421: Genomic correlates of patient age in diffuse-type gastric cancer
Authors: Hark K. Kim, Soo Y. Cho
Journal: Cancer Research (2018)

Abstract Background: Gastric cancer is increasing in incidence among young white populations in the US. Gastric cancer in young patients is notable for its enrichment of diffuse histology as well as female predominance and aggressive clinical course, whereas gastric cancer is generally more frequent in males. Thus, clinicopathological characteristics of diffuse-type gastric cancer differ according to patient age, but the molecular mechanisms for early-onset gastric cancer's unique clinicopathological characteristics have not been elucidated. While the incidence of intestinal-type gastric cancer is decreasing worldwide, that of diffuse-type gastric cancer remained constant. Nonetheless, relatively small numbers of diffuse-type gastric cancers have been represented in whole exome sequencing studies such as TCGA project. We therefore investigated germline and somatic mutation profiles of diffuse-type gastric cancers with regards to patient age. Methods: We conducted whole exome and targeted sequencing and SNP6.0 array analyses of resected tumor tissue and blood samples collected from young (45 years old or younger) Korean patients with diffuse-type gastric cancer, and compared the genomic data with those from older Korean patients with diffuse-type gastric cancer. Genomic data of Korean diffuse-type gastric cancers were also compared with TCGA diffuse-type gastric cancers, 70% of which were from Caucasians. Results: Among 84 young Korean patients with DGC, 7 patients (8.3%) harbored germline mutations in TP53, CDH1, ATM, RAD51D, or PALB2. Three tumors with strong mutation signatures for inherited DNA repair defects harbored germline mutations in either RAD51D or PALB2, with loss-of-heterozygosity in the tumors. The most significant somatic mutations in young patients with diffuse gastric cancer were CDH1, TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. Within the Korean population and within populations of other ethnicities, mutations in CDH1 (42.2%) or TGFBR1 (7.3%) were more frequent in younger patients than in older patients (17.4% and 0.9%, respectively). In contrast, the RHOA mutation (9.2%) was less frequent in younger patients than in older patients (19.1%). CDH1 alterations, but not RHOA mutations, were associated with poor prognosis (hazard ratio, 3.4 (95% CI, 1.5-7.7)), which may be associated with the aggressive clinical course of diffuse-type gastric cancers in young patients. Conclusions: Our largest-ever genomic analysis of diffuse-type gastric cancer reveals young age-specific mutation profiles (supported by National Cancer Center Grant 1710809 and Multi-omic Research Program). Citation Format: Hark K. Kim, Soo Y. Cho. Genomic correlates of patient age in diffuse-type gastric 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 3421.
Abstract 18826: Cardiac Myosin Binding Protein C Mutants Interact With and Cause Mislocalization of the Hsp70 Family Chaperones
Authors: Amelia A Glazier, Adam Helms, Jaime M Yob, Dattatreya Mellacheruvu, Vi Tang, Sarah Bartolone, Venkatesha Basrur, Alexey I Nesvizhskii, Sharlene Day
Journal: Circulation (2015)

Introduction: Myosin binding protein C (MYBPC3) is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM) and &gt;90% of MYBPC3 mutations produce truncated proteins. Ubiquitin proteasome dysfunction has been observed in human HCM hearts with MYBPC3 mutations and in experimental models, but the mechanisms responsible are unknown. We hypothesize that interactions between truncated MYBPC3 and molecular chaperones could underlie proteasome dysfunction by exhausting a critical chaperone pool required to sustain normal cellular protein quality control. Methods and Results: FLAG-tagged wild-type and two mutant truncated MYBPC3 proteins of different lengths were expressed in neonatal rat cardiomyocytes via adenovirus. Spontaneous contractions per minute were markedly reduced in myocytes expressing mutant compared to wild-type MYBPC3 (non-transduced 49±8; WT 57±7; W1098* 25±3; I154Lfs*5 4±1; n=6, p&lt;0.05). Mutant MYBPC3 expression also caused proteasome dysfunction as evidenced by increased expression of the GFPμ degron reporter (% non-transduced myocytes: WT 55.3±17.6%; W1098* 324.4±117.5%; I154Lfs*5 307.4±52.8%; n=3, p&lt;0.05). Affinity purification mass spectroscopy identified heat shock protein 70kDa (Hsp70) and heat shock cognate 70kDa (Hsc70) as highly abundant interacting proteins with wild-type and W1098* MYBPC3 but not I154Lfs*5. Interaction confidence scores as determined by SAINT analysis were ~3 fold higher for W1098* than for wild-type MYBPC3 (23.5 vs 8.0 for Hsc70 and 77.7 vs. 12.3 for Hsp70). These interactions were confirmed by Western blot and co-localization experiments. In non-transduced myocytes, and in myocytes expressing wild type MYBPC3, Hsc70 showed distinct M-line and Z-disc banding, while in myocytes expressing either mutant MYBPC3, Hsc70 was relocalized from the sarcomere to cytosolic, nuclear, and perinuclear aggregates, similar to non-transduced myocytes that were subjected to heat shock. Conclusions: These results suggest MYBPC3 is a client of Hsp70 chaperones and that mutant proteins may interfere with regular functions and localization of Hsp70 and Hsc70. Further experiments will determine if these interactions are important for maintaining cellular proteostasis in MYBPC3-mutant HCM.
Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs
Authors: Manoj Kumar Jaiswal
Journal: Medicinal Research Reviews (2018)

Over the past decades, a multitude of experimental drugs have been shown to delay disease progression in preclinical animal models of amyotrophic lateral sclerosis (ALS) but failed to show efficacy in human clinical trials or are still waiting for approval under Phase I-III trials. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug approved by the USA Food and Drug Administration for ALS treatment with modest benefits on survival. Recently, an antioxidant drug, edaravone, developed by Mitsubishi Tanabe Pharma was found to be effective in halting ALS progression during early stages. The newly approved drug edaravone is a force multiplier for ALS treatment. This short report provides an overview of the two drugs that have been approved for ALS treatment and highlights an update on the timeline of drug development, how clinical trials were done, the outcome of these trials, primary endpoint, mechanism of actions, dosing information, administration, side effects, and storage procedures. Moreover, we also discussed the pressing issues and challenges of ALS clinical trials and drug developments as well as future outlook.
Abstract B33: Assessing macrophage polarization in sarcomas with PD-L1 correlates
Authors: Galen Hostetter, Lorenzo Sempere, Scott Jewell, Steve Baylin
Journal: Clinical Cancer Research (2018)

Abstract The role of innate and adaptive immunity in a wide range of human tumors has shown critical roles, though sometimes competing, in numerous immune components in both the tumor and the tumor microenvironment (TME). The PD-1/PD-L1 interaction in both tumor and the TME has become high priority in correlative biomarkers of human disease with increasing number of targeted agents showing high levels of durable response. The in situ analysis of viral defense pathway, interferon response, and PD-L1 status has provided strong preliminary data of correlative staining by immunohistochemistry in colon and lung carcinomas. Generally, such human tumors arise in organs with frequent and high exposure to external/foreign antigens. Here we expand our IHC staining to include human tumors arising from sites with varied immune activity to include uterine wall (leiomyosarcoma), subcutaneous connective tissue to include dermatofibrosarcoma protuberans (DFSP), soft tissue sarcoma, fibrosarcoma, and osteosarcoma. IHC panel includes immune markers of CD4, CD8, CD68 (M1 macrophages), CD163 (M2 macrophages); dsRNA antibodies (J2 and K1); MDA 5, RIG 1, STAT 1, and pSTAT1; PD-L1 and PD-1; and interferon response markers IRF 3, IRF 7, and IFIT 1. Immunostaining is ongoing and supports preliminary sarcoma phenotype of quite varied PD-L1 immunoreactivity with lower prevalence than lung and colon carcinomas. Immune markers of T-cell subset and macrophage M1 and M2 are significantly lower in sarcoma samples and detailed analysis of M1 and M2 macrophages in DFSP, STS, fibrosarcomas, and osteosarcoma. Each tumor type is represented on single TMA with 8-12 samples each from the Van Andel Institute Biorepository Core. In our experience, tissue site density and macrophage subtypes and difference in polarized macrophages (M2) in relation to CD4 and CD8 markers were significant in relation to PD-L1 and require further exploration. Improved characterization of PD-L1 pathway and potential surrogate markers to compile immune competency profiles will include early results from our IHC staining for dsRNA fragments to lend support to endogenous retroviral activation in a wide range of both carcinomas and sarcomas. Citation Format: Galen Hostetter, Lorenzo Sempere, Scott Jewell, Steve Baylin. Assessing macrophage polarization in sarcomas with PD-L1 correlates [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B33.
Abstract 976: FOXA1 promotes a luminal growth program in prostate cancer
Authors: Elizabeth J. Adams, Elizabeth Hoover, Wouter R. Karthaus, Charles L. Sawyers
Journal: Cancer Research (2018)

Abstract FOXA1 is an important pioneering transcription factor for androgen receptor (AR), a key driver of prostate cancer. FOXA1 has emerged as one of the most recurrently mutated genes in primary and metastatic castrate resistant prostate cancer, with alterations frequencies ranging from 4-15% in various cohorts. Given the well-established role of FOXA1 in modulating AR function, we hypothesize that FOXA1 mutations contribute to prostate oncogenesis by altering the chromatin landscape, resulting in changes in the AR cistrome and AR transcriptional output. Here we use prostate organoids to show that acute FOXA1WT overexpression promotes lumen formation and drives luminal differentiation. Consistent with this, CRISPR/Cas9-mediated deletion of FOXA1 slows proliferation and organoids lacking FOXA1 fail to form lumens. Assays to evaluate the functionality of recurrent FOXA1 mutations (measured by cell viability, lumen formation, and lumen size) along with RNA-sequencing suggest there are distinct classes of FOXA1 mutations. The first are the gain-of-function mutations (such as FOXA1FE254-255del), which promote growth and lumen formation to a larger extent than wild-type FOXA1. Interestingly, a FOXA1 luciferase reporter assay we developed in HEK293 cells indicates that the majority of mutants tested behave as gain of function. The only mutant to score as loss of function, FOXA1R219S, is found nearly exclusively in prostate cancer, and is enriched in neuroendocrine prostate cancer cohorts. Expression of FOXA1R219S suppresses lumen formation and promotes both basal and epithelial-mesenchymal transition transcriptional programs. However, this mutant also provides a growth advantage beyond what is conferred by FOXA1WT. Taken together, these data suggest that FOXA1R219S is not simply a loss of function allele and instead may drive disease progression through a different set of signaling pathways than the FOXA1 alleles that promote luminal differentiation. Further study of these classes of mutations and how they relate to patient outcome, along with analysis of the FOXA1mut/AR cistromes, is ongoing to determine the genome-wide implications of FOXA1 alterations and how they promote prostate cancer progression. Citation Format: Elizabeth J. Adams, Elizabeth Hoover, Wouter R. Karthaus, Charles L. Sawyers. FOXA1 promotes a luminal growth program 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 976.
Increased Prevalence of Carotid Atherosclerosis in Hepatitis B Virus Carriers
Authors: NobukazuIshizaka, YukoIshizaka, EikoTakahashi, Ei-ichiToda, HidekiHashimoto, MinoruOhno, RyozoNagai, MinoruYamakado
Journal: Circulation (2002)

Background— Recent experimental and epidemiological findings suggest that some infectious agents play a role in the development and promotion of atherosclerosis. We have investigated the possible association between hepatitis B virus surface antigen (HBsAg) positivity and carotid arteriosclerosis. Methods and Results— In this cross-sectional cohort study, we analyzed data from subjects undergoing general health-screening tests, including both high-resolution B-mode carotid ultrasound and assessment of HBsAg status, between 1994 and 2001 at our institute. Of the 4686 study subjects (3137 men and 1549 women; age 22 to 88 years), 1294 (28%) had carotid artery plaque and 40 (0.9%) were positive for HBsAg, indicating they were hepatitis B virus carriers. No HBsAg-positive subjects were positive either for antibodies against the hepatitis C virus (HCV) or for HCV core proteins. Univariate analysis revealed HBsAg positivity was associated with carotid plaque with an odds ratio of 1.58 (95% CI, 1.14 to 2.19, P<0....
Percutaneous Treatment With Drug-Eluting Stent Implantation Versus Bypass Surgery for Unprotected Left Main Stenosis
Authors: AlaideChieffo, NucciaMorici, FrancescoMaisano, ErminioBonizzoni, JohnCosgrave, MatteoMontorfano, FlavioAiroldi, MauroCarlino, IassenMichev, GloriaMelzi, GiuseppeSangiorgi, OttavioAlfieri, AntonioColombo
Journal: Circulation (2006)

Background— Improvements in results with percutaneous coronary intervention (PCI) with drug-eluting stents (DES) may extend their use in patients with left main coronary artery (LMCA) stenosis. Methods and Results— Two hundred forty-nine patients with LMCA stenosis were treated with PCI and DES implantation (n=107) or coronary artery bypass grafting (CABG) (n=142), in a single center, between March 2002 and July 2004. A propensity analysis was performed to adjust for baseline differences between the two cohorts. At 1 year, there was no statistical difference in the occurrence of death in PCI versus CABG both for the unadjusted (OR=0.291; 95% CI=0.054 to 1.085; P=0.0710) and adjusted analyses (OR=0.331; 95% CI=0.055 to 1.404; P=0.1673). PCI was correlated to a lower occurrence of the composite end points of death and myocardial infarction (unadjusted OR=0.235; 95% CI=0.048 to 0.580; P=0.0002; adjusted OR=0.260; 95% CI=0.078 to 0.597; P=0.0005) and death, myocardial infarction, and cerebrovascular events (u...
Abstract 4986: Association of sirtuins and diet in cancer development: Studying the roles of SIRT2/3
Authors: Mohamed A. Ahmed, Carol O'Callaghan, Athanasios Vassilopulos
Journal: Cancer Research (2018)

Abstract Lifestyle factors, especially diet, affects health and lifespan. Dietary restriction (DR) has been shown as a beneficial regimen to increase longevity and protect from cancer. On the other hand, high fat intake has been found to be associated with greater risk of several cancer types. In this regard, several studies suggest that the beneficial effect of calorie restriction (CR) is mediated by the increased activity of sirtuins, a family of NAD-dependent deacetylases that plays a role in aging and age-related diseases. However, the specific role of individual family members in the inhibitory role of CR in tumorigenesis has not been elucidated. With the exception of SIRT1, there is no evidence for the contribution of other sirtuins in the diet-induced effects on tumorigenesis. In this study, we investigated, for the first time, the role of SIRT2 and SIRT3, which are found predominantly in the cytoplasm and mitochondria respectively, in this context. To do this, Sirt2-/- and Sirt3-/- mice were crossed with p53-/- mice to generate: p53+/-, (Sirt2-/-; p53+/-), (Sirt3-/-; p53+/-), p53-/-, (Sirt2-/-; p53-/-), and (Sirt3-/-; p53-/-) mice. Subsequently, mice with the different genotypes were subjected to 3 dietary regimes; ad libitum control diet, 30% calorie restriction diet (CR), and high-fat diet (HFD). As expected, CR reduced tumor incidence and increased survival of mice wild type for both SIRT2 and SIRT3. In contrast, HFD significantly increased body weight, tumor incidence and decreased overall survival. Interestingly, the protective effect of CR was enhanced in (Sirt3-/-; p53-/-) compared to (Sirt3+/+; p53-/-) mice, as evidenced by delayed tumor incidence (median age 257 days vs 189 days) and increased survival. On the other hand, Sirt2 deletion in both p53+/- and p53-/- backgrounds abolished the protective effect of CR. In addition, loss of Sirt2 decreased tumor incidence age (111 days vs 184 days) and accelerated the death of p53 deficient mice on HFD. Our results highlight a new role of SIRT2 in mediating the diet-induced effect on tumorigenesis. Citation Format: Mohamed A. Ahmed, Carol O'Callaghan, Athanasios Vassilopulos. Association of sirtuins and diet in cancer development: Studying the roles of SIRT2/3 [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 4986.
Single Low-Dose Administration of Human Recombinant Hepatocyte Growth Factor Attenuates Intimal Hyperplasia in a Balloon-Injured Rabbit Iliac Artery Model
Authors: SatoshiYasuda, TeruoNoguchi, MasahiroGohda, TakashiArai, NobumasaTsutsui, TakehisaMatsuda, HiroshiNonogi
Journal: Circulation (2000)

Background—Previous studies have shown that repeated systemic administration of human recombinant hepatocyte growth factor (hrHGF) in mg/kg levels modulates the wound-healing process in various diseases. Recently, HGF has been characterized as one of the most potent endothelial-cell–specific growth factors. We tested our hypothesis that local delivery of hrHGF, even at low μg/kg levels (≥2 orders of magnitude lower than systemically administered doses), might attenuate neointimal hyperplasia in response to vascular injury via accelerated reendothelialization. Methods and Results—The iliac artery was denuded in 16 New Zealand White rabbits (3 kg), followed by administration, via a drug delivery catheter, of either hrHGF (10 μg; n=11) or control vehicle (n=5) over 20 minutes. In pilot studies using this device, the drug permeated into the medial tissues, where it persisted for ≥24 hours. Four weeks after the local delivery of hrHGF, computer-assisted morphometric analysis revealed significant reduction in t...
RNA-Binding Proteins Heterogeneous Nuclear Ribonucleoprotein A1, E1, and K Are Involved in Post-Transcriptional Control of Collagen I and III Synthesis
Authors: Bernd-JoachimThiele, AnkeDoller, ThiloKähne, ReinhardPregla, RolandHetzer, VeraRegitz-Zagrosek
Journal: Circulation Research (2004)

Collagen types I and III, coded by COL1A1/COL1A2 and COL3A1 genes, are the major fibrillar collagens produced by fibroblasts, including cardiac fibroblasts of the adult heart. Characteristic for different cardiomyopathies is a remodeling process associated with an upregulation of collagen synthesis, which leads to fibrosis. We report identification of three mRNA-binding proteins, heterogeneous nuclear ribonucleoprote (hnRNP) A1, E1, and K, as positive effectors of collagen synthesis acting at the post-transcriptional level by interaction with the 3′-untranslated regions (3′-UTRs) of COL1A1, 1A2, and 3A1 mRNAs. In vitro, binding experiments (electromobility shift assay and UV cross-linking) reveal significant differences in binding to CU- and AU-rich binding motifs. Reporter gene cell transfection experiments and RNA stability assays show that hnRNPs A1, E1, and K stimulate collagen expression by stabilizing mRNAs. Collagen synthesis is activated via the angiotensin II type 1 (AT1) receptor. We demonstrate...
Electron Microscopic Studies of Phenotypic Modulation of Smooth Muscle Cells in Coronary Arteries of Patients With Unstable Angina Pectoris and Postangioplasty Restenosis
Authors: Ying-HwaChen, Yuh-LienChen, Shing-JongLin, Chia-YuChou, Guang-YuanMar, Mau-SongChang, Shih-PuWang
Journal: Circulation (1997)

Background Proliferation and matrix protein secretion of coronary smooth muscle cells (SMCs) have been suggested as one of the mechanisms responsible for the development of postangioplasty restenosis and an alternative cause of unstable angina. Phenotypic modulation of SMCs may produce a pool of cells potentially responsive to growth stimulation that can synthesize abundant extracellular matrix. This study tested the hypothesis that phenotypic modulation of SMCs occurred during the evolution of postangioplasty restenosis and unstable angina. Methods and Results The SMCs of coronary atherectomy specimens from 24 patients were identified under electron microscope. Volume fractions of synthetic organelles (VFSOs) and other features related to phenotypic modulation of SMCs were measured. The results showed that the VFSO in SMCs from 5 patients with unstable angina (group 2) resembled those from 9 patients with postangioplasty restenosis (group 3; 0.42±0.13 versus 0.36±0.10; P=NS), and both were significantly ...