tbuckley/cabot-search huggingface dataset:
Abstract 1626: Sensitive detection of MET exon 14 skipping by RT-qPCR and next generation sequencing
Authors: Mukund Patel, Honey Polur, Patrick Hurban
Journal: Cancer Research (2018)

Abstract The MET receptor tyrosine kinase (MET) gene is a proto-oncogene whose abnormal activation can trigger tumor growth, angiogenesis, and metastasis. Numerous mutations have been identified that lead to over-activation of the gene, including well characterized amplification and somatic mutations. Mutations that lead to the skipping of MET exon 14 are likely to be highly predictive of response to MET inhibition. Exon 14 contains a motif that is required for the efficient recruitment of the ubiquitin ligase, CBL, which targets MET for degradation. Loss of exon 14 leads to prolonged stability of the MET protein which causes increased signaling upon stimulation by hepatocyte growth factor. Over 200 distinct mutations have been identified that cause MET exon 14 skipping ranging from single nucleotide mutations to large insertion/deletions. Due to this complexity, detecting MET exon 14 skipping mutations using DNA-based NGS hybridization capture methods is challenging. RNA-based testing can circumvent the complexity of DNA-based changes. We developed a RT-qPCR assay that detects MET exon 14 skipping independent of the causal mutation. Analytical validation using RNA admixtures demonstrated 1% sensitivity of detecting MET exon 14 mutant transcripts. 100 FFPE lung adenocarcinomas were screened with the RT-qPCR assay. Of 100, two samples (2%) were identified as positive for MET exon 14 skipping. The two positive samples along with three negative samples were orthogonally confirmed using the Illumina TruSight Tumor 170 hybridization capture-based targeted panel assay that simultaneously analyzes DNA and RNA. Overall, the number of samples identified positive for MET exon 14 by RT-qPCR test is in line with the frequency observed from other studies in lung adenocarcinomas of about ~3%. The assay can detect as little as 1% transcripts with MET exon 14 skipping suggesting that we have developed an accurate and sensitive RNA-based assay for use in clinical trials. Citation Format: Mukund Patel, Honey Polur, Patrick Hurban. Sensitive detection of MET exon 14 skipping by RT-qPCR and next generation sequencing [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 1626.
Abstract 3150: Serglycin promotes cell migration mediated through the interaction of its GAG moiety with CD44
Authors: Joanne Jeou-Yuan Chen, Jing-You Guo, Chu-Hsuan Chiu, Mei-June Wang
Journal: Cancer Research (2018)

Abstract Tumor microenvironment (TME) plays an important role in cancer progression. We have recently shown that serglycin (SRGN), a chondroitin sulfate proteoglycan (CSPG), is overexpressed in primary non-small cell lung cancers (NSCLCs), by carcinoma as well as stromal cells, and that the secreted SRGN can bind to CD44 and promotes NSCLC aggressiveness (Oncogene 36:2457, 2007). In this study, we further examined the molecular mechanisms underlying SRGN-elicited cell migration. By gain- and loss-of-function studies, we first showed that SRGN promoted cell migration in a CD44-dependent manner. SRGN promoted SRC activation, leading to increased phosphorylation of paxillin (PAX) at Y118 as well as reduced PAX/FAK complex formation, suggesting that SRGN promotes cell migration through facilitating focal adhesion turnover. In support, knockdown of SRC or treatment of cells with PP2, a SRC family inhibitor, abolished SRGN-elicited migratory activity. In addition, we showed that SRGN induced actin cytoskeleton reorganization and promoted lamellipodia and filopodia formation at the leading edge, facilitating a directional movement during wound closure in NSCLC cells. In consistence, increased levels of activated RAC1, which is required for lamellipodia formation, and CDC42, which is required for filopodia formation, were detected. We further examined the role of CS modification in SRGN-mediated function. We generated the SRGN(S/A) mutant in which the eight serine residues involved in GAG modification were converted to alanine, and showed that SRGN(S/A) mutant not only failed to induce the phosphorylation of SRC and paxillin, but also failed to promote cell migration. In consistence, pre-treatment of SRGN-containing conditional medium with Chondroitinase ABC also suppressed SRGN-elicited cell migration. Taken together, our data demonstrated that SRGN interacts with CD44 through its GAG modifications, leading to increased cell migration by promoting FA turnover and cytoskeleton reorganization. Citation Format: Joanne Jeou-Yuan Chen, Jing-You Guo, Chu-Hsuan Chiu, Mei-June Wang. Serglycin promotes cell migration mediated through the interaction of its GAG moiety with CD44 [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 3150.
Roles of the Two Active Sites of Somatic Angiotensin-Converting Enzyme in the Cleavage of Angiotensin I and Bradykinin
Authors: DimitrisGeorgiadis, FabriceBeau, BertrandCzarny, JoëlCotton, AthanasiosYiotakis, VincentDive
Journal: Circulation Research (2003)

Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. The in vivo contribution of each active site to the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK) is still unknown. To gain insights into the functional roles of these two active sites, the in vitro and in vivo effects of compounds able to selectively inhibit only one active site of ACE were determined, using radiolabeled Ang I or BK, as physiological substrates of ACE. In vitro studies indicated that a full inhibition of the Ang I and BK cleavage requires a blockade of the two ACE active sites. In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites. Thus, in vivo, the cleavage of Ang I and BK by ACE appears to obey to different mechanisms. Remarkably, in ...
Abstract 5537: Circulating tumor DNA analysis for ESR1 mutations in patients with hormone receptor-positive metastatic breast cancer
Authors: Sung Hoon Sim, Su Yeon Jeon, Kyoung Hee An, Sun Young Kong, Min Jung Kwon, Keun Seok Lee, In Hae Park
Journal: Cancer Research (2018)

Abstract Background: ESR1 mutations are known as a major mechanism of resistance to antihormonal therapy in breast cancer. ESR1 mutation frequency is high in metastatic disease when the tumor is refractory to aromatase inhibitor, in contrast to nonmetastatic setting. We tried to detect ESR1 mutations (Y537N, Y537S and D538G) in circulating tumor DNA (ctDNA). Method: Patients who had hormone receptor-positive breast cancer were enrolled in this study. Plasma samples were collected and ctDNA was analyzed by ddPCR and digital targeted DNA panel. Primers and probes for ddPCR were designed for Y537N, Y537S and D538G mutations using sequences of wild-type normal human DNA. Results: A total of 40 patients were enrolled. Histologic type was invasive ductal carcinoma (IDC) in 32, invasive lobular carcinoma (ILC) in 4 and others in 4. Thirty-four patients received endocrine treatment and 6 patients had no prior exposure to endocrine treatment. Using ddPCR, overall mutation rate was 52.5% (n=21). D538G was the most frequent mutation (n=16), followed by Y537N (n=9), and Y537S (n=6). Nine patients showed multiple ESR1 mutations. In patients without endocrine exposure (n=6), 2 patients showed ESR1 mutations (Y537N, Y537S). The mutation detection rate was higher in patients with prior use of aromatase inhibitor (AI) than in prior use of tamoxifen (TMX) only (prior AI, 17/29=58.6%; prior TMX, 2/5= 40%). In 9 cases, we conducted both ddPCR and targeted DNA panel assay using ctDNA at the same time. Overall concordance rate between two platforms was 55.6% (5/9). Among discordant cases (n=4), ESR1 mutations were detected by ddPCR in 3 cases, which were not found in DNA panel assay. Conclusions: ESR1 mutations can be robustly identified with ctDNA analysis. Overall mutation detection rate was comparable to other previous reports. However, there is a significant discordance between clinically available NGS panel assay and ddPCR method in detection of ESR1 mutations. Further study will be needed for clinical implementation of ESR1 mutation analysis using ctDNA. Citation Format: Sung Hoon Sim, Su Yeon Jeon, Kyoung Hee An, Sun Young Kong, Min Jung Kwon, Keun Seok Lee, In Hae Park. Circulating tumor DNA analysis for ESR1 mutations in patients with hormone receptor-positive metastatic breast 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 5537.
Abstract 3373: Analysis of the “centrosome-ome” reveals potential causes of centrosome amplification in human cancer
Authors: Ryan A. Denu, Justin C. Jagodinsky, Mark E. Burkard
Journal: Cancer Research (2018)

Abstract The centrosome is the microtubule organizing center of human cells and facilitates a myriad of cellular functions. This includes the organization of the mitotic spindle for faithful chromosome segregation during mitosis, cell polarization and migration, and primary cilia formation. A numerical increase in centrosomes, or centrosome amplification (CA), is common in cancer and correlates with aggressive clinical features and poor patient outcomes. CA is thought to arise by two major mechanisms: (1) centriole overduplication and (2) cell doubling events. To better assess the relative contributions of these two mechanisms, we analyzed 79 melanomas compared to 17 benign nevi and 60 prostate cancers compared to 20 benign prostate samples. We probed these samples for pericentrin (to mark all centrosomes) and CEP170 (to mark centrosomes with mature centrioles). CEP170 is expected on most or all amplified centrosomes with cell doubling, but not with overduplication (1 per cell expected). We find fewer CEP170-positive centrosomes in cancer samples compared to benign samples, indicating that centriole overduplication is the predominant mechanism leading to CA in human cancer. Given this finding, we next sought to identify the predominant molecular mechanisms leading to centriole overduplication. To address this question, we analyzed mutations, copy number alterations, and RNA expression data in the 366 proteins reported to localize to the centrosome using TCGA data. We identified a list of candidate centrosome proteins that are most frequently altered in cancer. Furthermore, given that cells with CA undergo cell cycle arrest unless other compensatory alterations are made, such as loss of p53, we ranked alterations in centrosome genes by the fold enrichment in p53 mutant versus p53 wild-type tumors. We identified the following candidates: CEP19, CEP72, NDRG1, PTK2, SPATC1, and TBCCD1 (gain-of-function mutations) and AKAP9, CEP76, CTNNB1, MCPH1, NEURL4, and NPM1 (loss-of-function mutations or deletion). In cellulo analysis of these candidates reveals that loss of MCPH1 (microcephalin) causes the most robust increase in centriole number. MCPH1 mutations are known to give rise to microcephaly and CA. MCPH1 gene deletions and/or mRNA downregulation (Z score &amp;lt; 2) are seen in 5-15% of human cancers, depending on the anatomic site of the tumor. We conclude that a myriad of different alterations in centrosome genes can give rise to CA in human cancer, and that loss of MCPH1 is a common and penetrant cause of CA in human cancer. Citation Format: Ryan A. Denu, Justin C. Jagodinsky, Mark E. Burkard. Analysis of the “centrosome-ome” reveals potential causes of centrosome amplification in human 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 3373.
Association of a T29→C Polymorphism of the Transforming Growth Factor-β1 Gene With Genetic Susceptibility to Myocardial Infarction in Japanese
Authors: MitsuhiroYokota, SahokoIchihara, Tong-LangLin, NobuoNakashima, YoshijiYamada
Journal: Circulation (2000)

Background—Transforming growth factor-β (TGF-β) is an important regulator of vascular remodeling and is involved in the pathogenesis of atherosclerosis. A T→C transition at nucleotide 29 of the TGF-β1 gene results in a Leu→Pro substitution at amino acid 10 of the signal peptide. We have now examined a possible association of TGF-β1 genotype with myocardial infarction (MI) in a Japanese population. Methods and Results—TGF-β1 genotype was determined in 315 Japanese patients (234 men and 81 women) with MI and 591 control subjects (289 men and 302 women). We found that age, body mass index, and incidence of habitual smoking, hypertension, diabetes mellitus, and hypercholesterolemia did not differ between the 2 groups for either men or women. Multivariable logistic regression analysis, however, demonstrated the frequency of the T allele to be significantly higher in male subjects with MI than in controls (TT + TC versus CC; P<0.0001, odds ratio 3.5, 95% CI 2.0 to 6.3). In contrast, the T allele was not associa...
Treatment Barriers in Portopulmonary Hypertension
Authors: Batool AbuHalimeh, Michael J. Krowka, Adriano R. Tonelli
Journal: Hepatology (2018)

Portopulmonary hypertension (PoPH) is a form of pulmonary arterial hypertension (PAH) that can develop as a complication of portal hypertension. Treatment of PoPH includes PAH-specific therapies, and in certain cases, such therapies are necessary to facilitate a successful liver transplantation. A significant number of barriers may limit the adequate treatment of patients with PoPH and explain the poorer survival of these patients when compared to patients with other types of PAH. Until recently, only one randomized controlled trial has included PoPH patients, and the majority of treatment data have been derived from relatively small observational studies. In the present article, we review some of the barriers in the treatment of patients with PoPH and implications for liver transplantation.
Apoptosis Signal-Regulating Kinase 1/p38 Signaling Pathway Negatively Regulates Physiological Hypertrophy
Authors: MasayukiTaniike, OsamuYamaguchi, IkukoTsujimoto, ShungoHikoso, ToshihiroTakeda, AtsukoNakai, ShigemikiOmiya, IsamuMizote, YukoNakano, YoshiharuHiguchi, YasushiMatsumura, KazuhikoNishida, HidenoriIchijo, MasatsuguHori, KinyaOtsu
Journal: Circulation (2008)

Background— Mechanical stress on the heart can lead to crucially different outcomes. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy, characterized by a normal cardiac structure and normal or enhanced cardiac function. Pathological stimuli such as hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Apoptosis signal-regulating kinase 1 (ASK1) is known to be involved in pathological cardiac remodeling, but it has not been determined whether ASK1 pathways coordinate the signaling cascade leading to physiological type cardiac growth. Methods and Results— To evaluate the role of ASK1 in the physiological form of cardiac growth, mice lacking ASK1 (ASK1−/−) were exercised by swimming for 4 weeks. ASK1−/− mice showed exaggerated growth of the heart accompanied by typical characteristics of physiological hypertrophy. Their swimming-induced activation of Akt, a key molecule in the signaling cascade of physiological hypertrophy, incre...
Abstract 4117: Imaging hypoxia: Development of a PET-optical smart probe
Authors: Jessica L. Klockow, Kenneth S. Hettie, Frederick T. Chin
Journal: Cancer Research (2018)

Abstract Hypoxia is a characteristic trait of many aggressive tumors. Identification of hypoxic tissues is important for establishing patient treatment plans and prognoses. We show progress towards the development of a hypoxia-activated molecular probe that combines near-infrared (NIR) fluorescence and positron emission tomography (PET) imaging. The fluorescence emission enables facile scrutiny of probe function in vitro and positron emission facilitates translation for clinical use. The probe is a small molecule that possesses a nitro-aromatic group which is sensitive to hypoxic environments. The caged smart probe is non-fluorescent due to photo-induced electron transfer from the nitro-aromatic group. Nitroreductase, an enzyme which is upregulated in hypoxic environments, activates the fluorescence by reducing the nitro group, thereby disabling the quenching effect. Wet chemistry techniques were used to develop the probe which was analyzed by UV/Vis and fluorescence spectroscopies. In vitro and in vivo imaging experiments were also performed. The probe demonstrated membrane permeability and lysosomal accumulation in glioblastoma cells. Additional favorable characteristics include NIR emission and low toxicity to cells. The fluorescence was detected in subcutaneous murine cancer models providing evidence of potential clinical translation toward applications like image-guided surgery. In short, the probe was synthesized in good yield from commercially-available materials and showed promising optical characteristics in cells and animal models. Future work involves F-18 radiolabeling of the probe followed by microPET imaging. Citation Format: Jessica L. Klockow, Kenneth S. Hettie, Frederick T. Chin. Imaging hypoxia: Development of a PET-optical smart probe [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 4117.
Abstract 13024: Cardiopulmonary Best Abstract Award: A Disintegrin and Metalloproteinase With Thrombospondin Motifs 8 Downregulates AMP-activated Protein Kinase and Promotes Matrix Metalloproteinases Activation and Pulmonary Hypertension
Authors: Junichi Omura, Kimio Satoh, Nobuhiro Kikuchi, Taijyu Satoh, Ryo Kurosawa, Masamichi Nogi, Shinichiro Sunamura, Tomohiro Ohtsuki, Katsuya Kozu, Kazuhiko Numano, Koichiro Sugimura, Shunsuke Tatebe, Tatsuo Aoki, Kota Suzuki, Nobuhiro Yaoita, Hiroaki Shimokawa
Journal: Circulation (2016)

Background: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries (PA) and excessive proliferation of PA smooth muscle cells (PASMCs). ADAMTS8, a member of the disintegrin and metalloproteinase, is a secreted extracellular enzyme that is specifically expressed in lung tissue. Methods and Results: To explore a novel therapeutic target of PAH, we performed microarray analysis of PASMCs from patients with PAH (PAH-PASMCs) and found a significant up-regulation of ADAMTS8 in PAH-PASMCs compared with controls (>5-fold, P 1.3-fold, P<0.05, n=5 each). Indeed, immunoreactivity of ADAMTS8 was enhanced in the thickened medial layer of PA in PAH patients (n=2-3). Additionally, hypoxia increased protein level of ADAMTS8 in mouse lung homogenates compared with controls (P<0.05, n=6-10 each). Human recombinant ADAMTS8 (hrADAMTS8, 25 ng/mL) suppressed AMP-activated protein k...
Coronary Heart Disease and Iron Status
Authors: JohnDanesh, PaulAppleby
Journal: Circulation (1999)

Background—Studies of iron status and coronary heart disease (CHD) have yielded conflicting results. In a systematic review (“meta-analysis”), we quantitatively assessed epidemiological associations reported in prospective studies. Methods and Results—Studies were identified by computer-assisted searches of the published literature, scanning of relevant reference lists, hand searching of relevant journals, and discussions with relevant authors. The following was abstracted: size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results. Twelve studies were identified, involving a total of 7800 CHD cases, with several reporting on >1 marker of iron status. For serum ferritin, with 570 CHD cases in 5 studies, comparison of individuals with baseline values ≥200 versus <200 μg/L yielded a combined risk ratio of 1.0 (95% CI, 0.8 to 1.3). For transferrin saturation, with 6194 CHD cases in 5 studies, c...
Corticosteroid therapy for sepsis: a clinical practice guideline
Authors: Francois Lamontagne, Bram Rochwerg, Lyubov Lytvyn, Gordon H Guyatt, Morten Hylander Møller, Djillali Annane, Michelle E Kho, Neill K J Adhikari, Flavia Machado, Per O Vandvik, Peter Dodek, Rebecca Leboeuf, Matthias Briel, Madiha Hashmi, Julie Camsooksai, Manu Shankar-Hari, Mahder Kinfe Baraki, Karie Fugate, Shunjie Chua, Christophe Marti, Dian Cohen, Edouard Botton, Thomas Agoritsas, Reed A C Siemieniuk
Journal: BMJ (2018)

Do corticosteroids reduce death or improve recovery in people with sepsis or septic shock?Our panel make a weak recommendation to give corticosteroids to people with all types and severity of sepsis, based on new evidence.Because we are not certain that they are beneficial, it is also reasonable not to prescribe them.Patients' values and preferences may guide this decision-making process.This rapid recommendation was triggered by two trials, with differing conclusions whose results might change practice:• ADRENAL (3658 patients who had septic shock) found no statistically significant difference in 90 day mortality between the hydrocortisone and placebo groups. 1 • APROCCHSS (1241 patients who had septic shock) found that hydrocortisone plus fludrocortisone reduced 90 day mortality. 2he trials are incorporated into a linked systematic review comparing corticosteroids with placebo. 3This BMJ Rapid Recommendation promptly and transparently translates this evidence using GRADE methodology for trustworthy guidelines.Sepsis is a life threatening organ dysfunction from infection.C urrently most guidelines advise against giving corticosteroids in sepsis in the absence of refractory shock, but these guidelines have not taken into account the new evidence.We do not anticipate that new clinical trials will substantively alter the evidence suggesting a small but uncertain mortality reduction.The box below shows publications linked in this Rapid Recommendation package.The main infographic provides an overview of the absolute benefits and harms.The table at the end of the article shows any evidence that has emerged since the publication of this guideline.
Abstract 19367: Tsg101 Regulates the P62-Keap1-Nrf2 Axis in Cardiomyocytes to Protect Against Cardiac Ischemia/Reperfusion Injury
Authors: Shan Deng, Xiaohong Wang, Kobina Essandoh, Yutian Li, Jiangtong Peng, Xingjiang Mu, Kai Huang, Guo-Chang Fan
Journal: Circulation (2017)

Introduction: Recently, the p62-Keap1-Nrf2 axis has been identified as a master signaling cascade in the regulation of cellular oxidative stress. Thus, any positive regulators of the p62-Keap1-Nrf2...