tbuckley/cabot-search huggingface dataset:
Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases
Authors: RobertVisse, HideakiNagase
Journal: Circulation Research (2003)

Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication.
Diabetes: simple patient characteristics should help inform choice of second line drug, study finds
Authors: Jacqui Wise
Journal: BMJ (2018)

GPs should consider a patient’s sex and body mass index when deciding which diabetes drug to prescribe as second line treatment, a large UK study has suggested.1 For example, obese women are more likely to have good blood glucose control with thiazolidinediones than with sulfonylureas, while the reverse is true in non-obese men.

This simple form of personalised medicine, which does not need expensive technology to implement, could reduce the risk of potentially harmful side effects …
Abstract 4278: Somatic MAPK pathway mutations are associated with high mutational burden and good survival in head and neck squamous cell carcinoma (HNSCC)
Authors: Hoi-Lam Ngan, Andrew Y. Fong, Sharon Chan, Shing Chun Yu, Laura R. H. Ip, Jennifer R. Grandis, Vivian Lui
Journal: Cancer Research (2018)

Abstract Somatic mutations of the MAPK pathway occur in ~14% of head and neck squamous cell carcinoma (HNSCC; TCGA Provisional; www.cbioportal.org). Notably, mutations found in MAPK signaling components are apparent hotspot or activating mutations, potentially driving activation of the MAPK pathway. These mutations include HRAS p.G12V/D/A/C/S &amp; p.G13V/R, MAPK1 p.E322K/*, BRAF p.D594N &amp; p.V600E mutations. We found that this MAPK pathway mutated subset of HNSCC tumors have a higher mutational burden than MAPK-wildtype (WT) tumors. The average rate of non-synonymous mutations in MAPK pathway mutated tumors is 265.1±42.84 mutation/tumor vs 143.5±5.83 mutation/tumor in WT tumors in the TCGA cohort (P=0.0005). MAPK pathway mutations are not associated with HPV positivity (P=0.5815). Subsequent analysis shows that this subset of MAPK pathway-mutated tumors is unexpectedly associated with TP53 wildtype status (P=0.005584), as well as CASP8 mutations [29.3%; 27/92 cases vs. a 6.5% rate (27/418 cases) in the MAPK pathway WT group; P=9.91 x10-9]. Based on the current survival data of the TCGA Provisional cohort, it appears that patients whose tumors bearing HRAS, BRAF, MAPK1, MAP2K1, and RPS6KA1 mutations have a long median survival of 7.94 years (95.3 months; P=0.0165) vs. patients without these somatic mutations. Though TP53 WT status is a well-recognized biomarker for good prognosis in HNSCC, it only predicts with a median survival of ~45.8 months in this very same cohort. Thus, our findings suggest that MAPK pathway mutations may serve as potential genomic biomarkers for good prognosis in HNSCC. Recently, both HRAS and MAPK1 hotspot mutations have been shown to serve as potential neo-antigens in cervical cancer. Further investigation is needed to determine if these somatic MAPK pathway mutations are capable of mounting an anti-cancer immunity (via hotspot neo-antigens or neo-antigens due to higher mutational burden per se) in these patients, which may contribute to their improved survival. Acknowledgements: VWYL received funding supports from the Research Grant Council, Hong Kong (General Research Fund: #1711484, #17121616; Theme-based Research: T12-401/13-R) and the Hong Kong Cancer Fund, Hong Kong. Citation Format: Hoi-Lam Ngan, Andrew Y. Fong, Sharon Chan, Shing Chun Yu, Laura R. H. Ip, Jennifer R. Grandis, Vivian Lui. Somatic MAPK pathway mutations are associated with high mutational burden and good survival in head and neck squamous cell carcinoma (HNSCC) [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 4278.
Abstract 3876: Development and <i>in vitro</i> evaluation of cell membrane lipid-extracted nanoliposomes for lung cancer treatment
Authors: Jasmine King, Aarohi Bhatt, Drew Goodrich, Thomas Preteroti, Hanan Alharbi, Robert Campbell
Journal: Cancer Research (2018)

Abstract Background: Every year more deaths are attributed to lung cancer compared to colon, prostate, and breast cancers combined. Lung cancer is typically diagnosed at late stages, and has demonstrated poor treatment outcomes due to acquired drug resistance. Unfortunately, as one method is introduced to overcome drug resistance a new mechanism can arise. In an effort to overcome drug resistance lipid extracts (LE) were derived from target cells, and the ingredients were used to develop nanoliposomes that would selectively target a desired cell population compared to controls. The early studies were designed to demonstrate the use of CLENs (cellular membrane lipid-extracted nanoliposomes) for the targeting of lung cancer. Experimental Procedures: CLENs were initially prepared using various ratios of LE/DOPC/Chol/PEG by thin film evaporation. Particle size and zeta potential values were determined for all preparations of CLENs (with and without drug). CLENs were evaluated for selectivity for target compared to control cells. Cytotoxicity studies were performed on various doxorubicin hydrochloride-loaded CLENs using a cell model of lung cancer (ChagGo-K-1). For cellular uptake studies ChaGo-K-1 cells were seeded at 10,000 cells/mL in a 48-well plate and allowed to incubate for 24 hours prior to cell studies. A fluorescence microplate reader was used to determine fluorescence intensity values for the two studies. Results: ChaGo-K-1 CLENs demonstrated an average particle size of 206+/-2 nm and zeta-potential of -21+/-3 mV, illustrating favorable characteristics for drug delivery and interstitial drug targeting. The cellular uptake studies suggested that ChaGo-K-1 CLENs were selective for ChaGo-K-1 cells in vitro, when compared to all other control varieties of CLENs. Drug-loaded ChaGo-K-1 CLENs displayed significant cytotoxicity against ChaGo-K-1 cells compared to control cells. Fluorescence microscopy revealed association of ChagGo-K-1 CLENs with target cells. Conclusions: Based on promising early finding CLENs may represent a relatively tumor specific drug delivery system that can be used to overcome drug resistance, improve efficacy, and to limit off-target drug effects. Preclinical studies will investigate whether the relative selectivity and cytotoxicity observed against lung cancer cells in vitro translates to favorable tumor uptake and efficacy in vivo. Citation Format: Jasmine King, Aarohi Bhatt, Drew Goodrich, Thomas Preteroti, Hanan Alharbi, Robert Campbell. Development and in vitro evaluation of cell membrane lipid-extracted nanoliposomes for lung 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 3876.
Abstract 12938: Circulating Long Noncoding RNAs Predicts Adverse Cardiovascular Outcomes in Patients With End-Stage Renal Disease
Authors: Yin-Chun Shi, Yen-Ting Chen, Chun-Fu Lai, Chin-Hsien Lin, Jian Gu, Kai-Wen Chuang, Ying-Tung Lee, Kai-Chien Yang
Journal: Circulation (2016)

Introduction: Cardiovascular (CV) disease is the major cause of death in uremic patients. Conventional risk factors fail to predict adverse CV outcomes with uremia. This study aimed to test the hypothesis that circulating long non-coding RNAs (lncRNA) can be a useful biomarker to predict CV events and death in uremic patients. Methods: Cell free, circulating lncRNA profiling was conducted using plasma RNA from end-stage renal disease (ESRD, n=33), chronic kidney disease (CKD, n=8) and healthy (n=19) subjects by RNA sequencing. Participants were followed up for 3 years for major adverse CV events (MACE: acute coronary syndrome, heart failure, stroke and CV death). Results: A total of 512 million sequencing reads were obtained from 60 plasma RNA samples. Among the 1897 lncRNAs detected in human plasma, 486 (363 up,123 down) and 41 (34 up, 7 down) were significantly dysregulated with ESRD and CKD, respectively. Hierarchical clustering analysis revealed that plasma lncRNA expression pattern discriminates ESRD and CKD from control samples. Pathway analysis of the dysregulated lncRNAs in ESRD based on their nearby mRNAs (cis-mRNA) showed significant enrichment of genes involved in unfolded protein response and fatty acyl-CoA biosynthesis, both of which have been implicated in the pathogenesis of uremia. Analysis on an independent microarray dataset obtained from renal biopsy samples of 48 patients with advanced kidney disease and 8 healthy subjects (GSE66494) revealed that ~15% (72 out of 486) of the dysregulated plasma lncRNA with ESRD are similarly dysregulated in diseased kidney tissues, suggesting that circulating lncRNA expression profiles can mirror, at least in part, the changes of lncRNA expression in diseased kidneys. During the follow-up period, 10 ESRD patients experienced MACE; 129 lncRNAs were differentially expressed in ESRD patients with MACE, compared to those without one. Among them, lncRNA FAM66D was a significant predictor of MACE (Hazard ratio 1.2, 95% CI 1.05-1.36, P =0.003) and could discriminate between ESRD patients with and without high risks for MACE (ROC curve AUC 0.92, 95% CI 0.76-1.00). Conclusions: Circulating lncRNAs reflect the disease states of uremia and could serve as a useful biomarker to predict the CV outcomes in uremic patients.
Vasoconstriction to Endogenous Endothelin-1 Is Increased in the Peripheral Circulation of Patients With Essential Hypertension
Authors: StefanoTaddei, AgostinoVirdis, LorenzoGhiadoni, IsabellaSudano, MassimoNotari, AntonioSalvetti
Journal: Circulation (1999)

Background—In humans, endothelin (ET)-1 could be implicated in the pathophysiology of several cardiovascular diseases, including essential hypertension. We therefore evaluated the role of ET-1 in control of vascular tone in essential hypertension. Methods and Results—We used strain-gauge venous plethysmography to test changes in forearm blood flow induced by intrabrachial infusion of TAK-044 (10, 30, and 100 μg · 100 mL−1 · min−1), an ETA/ETB receptor antagonist, or sodium nitroprusside (1 and 2 μg · 100 mL−1 · min−1), a vasodilator that acts on smooth muscle cells, in hypertensive patients and healthy controls (n=10 in each group). The NO pathway was also evaluated by infusion of NG-monomethyl-l-arginine, (L-NMMA; 10, 30, and 100 μg · 100 mL−1 · min−1), an NO synthase inhibitor, and norepinephrine (3, 9, and 30 ng · 100 mL−1 · min−1) as control. Immunoreactive plasma ET-1 was measured by radioimmunoassay. In hypertensive patients, TAK-044 caused a vasodilation that was significantly (P<0.01) increased co...
Abstract 5261: Indices of diet quality and risk of lung cancer incidence and mortality in the Women's Health Initiative Observational Study
Authors: Ajay A. Myneni, Gary A. Giovino, Amy E. Millen, Michael J. LaMonte, Jean Wactawski-Wende, Marian L. Neuhouser, Jiwei Zhao, James M. Shikany, Lina Mu
Journal: Cancer Research (2018)

Abstract Background: Prospective evidence on the association between diet patterns and lung cancer risk is limited, particularly in older women. We investigated whether commonly used diet quality indices - Healthy Eating Index 2010 (HEI), Alternate Healthy Eating Index 2010 (AHEI), alternate Mediterranean Diet (aMED) and Dietary Approaches to Stop Hypertension (DASH) - were associated with lung cancer incidence and mortality in the Women's Health Initiative Observational Study (WHI OS). Methods: Self-reported diet intake (food frequency questionnaires) and relevant covariate information was obtained from 86,090 race-ethnically diverse postmenopausal women aged 50-79 years at baseline (1993-1998). During a median follow-up of approximately 17 years, 1,491 lung cancer cases and 1,393 lung cancer deaths were documented. We used cox proportional hazards regression models to estimate hazards risks and 95% confidence intervals [HR (95% CI)] after controlling for age, race/ethnicity, education, body mass index, smoking, physical activity and energy intake. Results and conclusions: Diet quality indices were not associated with lung cancer incidence overall but all four dietary indices showed a protective association (highest versus lowest quintile) against squamous cell carcinoma cases (12.8% of total lung cancer cases) [HEI: 0.56 (0.33-0.96), AHEI: 0.42 (0.24-0.76), aMED: 0.65 (0.39-1.08), DASH: 0.56 (0.32-0.97)]. Diet quality indices were not associated with lung cancer mortality overall or when stratified by histological type, except for HEI with lung cancer mortality overall [fourth versus lowest quintile: 0.82 (0.69-0.99)]. Smoking status did not modify the association between diet quality indices and lung cancer incidence or mortality. Further studies in other populations may help elucidate the relationship between diet patterns and lung cancer, especially by histological type. Citation Format: Ajay A. Myneni, Gary A. Giovino, Amy E. Millen, Michael J. LaMonte, Jean Wactawski-Wende, Marian L. Neuhouser, Jiwei Zhao, James M. Shikany, Lina Mu. Indices of diet quality and risk of lung cancer incidence and mortality in the Women's Health Initiative Observational Study [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 5261.
Antioxidants Improve Impaired Insulin-Mediated Glucose Uptake and Prevent Migration and Proliferation of Cultured Rabbit Coronary Smooth Muscle Cells Induced by High Glucose
Authors: KenichiYasunari, MasakazuKohno, HiroakiKano, KojiYokokawa, MiekoMinami, JunichiYoshikawa
Journal: Circulation (1999)

Background—To explore the role of intracellular oxidative stress in high glucose–induced atherogenesis, we examined the effect of probucol and/or α-tocopherol on the migration and growth characteristics of cultured rabbit coronary vascular smooth muscle cells (VSMCs). Methods and Results—Chronic high-glucose-medium (22.2 mmol/L) treatment increased platelet-derived growth factor (PDGF)-BB–mediated VSMC migration, [3H]thymidine incorporation, and cell number compared with VSMCs treated with normal-glucose medium (5.6 mmol/L+16.6 mmol/L mannose). Probucol and α-tocopherol significantly suppressed high glucose–induced increase in VSMC migration, cell number, and [3H]thymidine incorporation. Probucol and α-tocopherol suppressed high glucose–induced elevation of the cytosolic ratio of NADH/NAD+, phospholipase D, and membrane-bound protein kinase C activation. Probucol, α-tocopherol, and calphostin C improved the high glucose–induced suppression of insulin-mediated [3H]deoxyglucose uptake. Chronic high-glucose ...
Abstract 3797: Chromosome instability as a prognostic factor&amp; an immunotherapeutic target in acute myeloid leukemia
Authors: Ning Jin, Mark Burkard
Journal: Cancer Research (2018)

Abstract Chromosome instability (CIN) is an increased rate of chromosome mis-segregation due to errors in mitosis. CIN generates genetic and karyotypic diversity and is common in hematological malignancies. Low to moderate levels of CIN are well tolerated, and moderate levels can promote cancer proliferation by generating genetic diversity for tumor evolution. However, very high levels of CIN are lethal and enhancing CIN can be therapeutic. Therefore, CIN status could be prognostic for clinical outcomes as well as a therapeutic target. Despite its promise, little is known about CIN in AML. We first determined if CIN is correlated with clinical outcome in patients with acute myeloid leukemia (AML). We quantified the chromosome mis-segregation frequency (lagging chromosomes and chromatin bridges) in dividing AML cells on bone marrow core biopsies. Our study reveals a wide distribution of CIN in AML core biopsy specimens, ranging from 20% to 67%. High CIN correlates with a better overall survival in patients with AML. Recent data suggest that chromosome mis-segregation promotes senescence and initiates immune clearance. Our hypothesis is that chromosome instability is immunogenic due to DNA damage, proteotoxic/oxidative stress with a high mutagenic potential, which can be recognized by immune system. To test this, we used an inhibitor of Monopolar spindle 1 (Mps1) to enhance CIN and tested if that altered immunogenicity. Mps1 is a key component of the mitotic checkpoint and is also involved with chromosome alignment. Inhibition of Mps1 by AZ3146 results in severe chromosome mis-segregation, micronuclei formation, and apoptosis in AML cell lines. In addition, AZ3146 treatment causes activation of γH2AX due to DNA damage, and calreticulin exposure from endoplasmic reticulum stress. This generates danger signals to activate innate immune system (natural killer cells and dendritic cells) and induces immunogenic cell death (ICD) through priming of cytotoxic T cells. This effect is mainly seen in synchronized mitotic cells, suggesting AZ3146 acts specifically on mitosis. Additionally, we observed the overexpression of programed death ligand-1 (PD-L1) after the treatment of AZ3146 in AML cells. As evidence showed, PD-L1 participates in the immune evasion and protects AML blasts from cytotoxic T cells in mouse models of leukemia. Taken together, our observations in Mps1 inhibitor treatment indicate the immunogenicity of CIN in AML. Additionally, these data support combination treatment of mitotic checkpoint inhibitor with immunotherapy to improve therapeutic efficacy in AML patients. Citation Format: Ning Jin, Mark Burkard. Chromosome instability as a prognostic factor&amp; an immunotherapeutic target in acute myeloid leukemia [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 3797.
Targeted Overexpression of CCAAT/Enhancer-Binding Protein-δ Evokes Enhanced Gene Transcription of Platelet-Derived Growth Factor α-Receptor in Vascular Smooth Muscle Cells
Authors: Zhao-HuiYang, YutakaKitami, YasunoriTakata, TakafumiOkura, KunioHiwada
Journal: Circulation Research (2001)

Abstract— Platelet-derived growth factor (PDGF) is thought to play a significant role in various models of vascular remodeling, particularly in the early process of vascular diseases. Its action is mediated by its specific receptor, the PDGF receptor. The PDGF α-receptor (PDGFαR) plays an important role in the growth and proliferation of vascular smooth muscle cells (VSMCs), and its gene expression is thought to be regulated by several potential transcriptional nuclear factors. However, the detailed mechanisms of tissue-specific transactivation of the PDGFαR gene in VSMCs remain to be clarified. We have previously demonstrated that the rat PDGFαR gene contains an enhancer core sequence for CCAAT/enhancer-binding proteins (C/EBPs) in its promoter region, and we have also suggested that C/EBP-δ is the principal factor involved in the induction of tissue-specific transcriptional activity of the PDGFαR gene in VSMCs. To explore the definitive roles of C/EBP-δ protein on PDGFαR gene transcription in VSMCs, we ...
Long-term Smoking Impairs Platelet-Derived Nitric Oxide Release
Authors: KazuyaIchiki, HisaoIkeda, NobuyaHaramaki, TakafumiUeno, TsutomuImaizumi
Journal: Circulation (1996)

Background Long-term smoking impairs endothelium-dependent vasodilation, which is mediated by nitric oxide (NO). However, it is unknown whether long-term smoking impairs the platelet-derived NO release, which regulates platelet aggregation. Methods and Results Platelet-derived electrical current induced by collagen was measured with an NO-selective electrode in 12 smokers and 11 nonsmokers. Collagen-induced intraplatelet cGMP and platelet aggregation was measured in smokers and nonsmokers. S-nitroso-N-acetyl-dl-penicillamine, a direct NO donor, dose dependently increased in electrical current (r=.99). Collagen induced platelet aggregation and dose dependently increased electrical current (r=.94). Collagen-induced electrical current and cGMP were significantly augmented by l-arginine, a precursor of NO, and attenuated by NG-monomethyl-l-arginine, an inhibitor of NO synthesis. Significant correlation was found between collagen-induced electrical current and cGMP (r=.73). These findings indicate that the cha...
Abstract 12066: Integrating and Revealing the Structure of the Quality of Life Instruments for Stable Coronary Patients
Authors: Zugui Zhang, Paul Kolm, Claudine T Jurkovitz, John A Spertus, William S Weintraub
Journal: Circulation (2011)

Introduction Two multi-domain instruments, SAQ and RAND_36, were used to assess quality of life in the COURAGE, a randomized trial evaluating the outcomes of optimal medical therapy (OMT) with or w...