tbuckley/cabot-search huggingface dataset:
<i>CDKN2A</i> Common Variants and Their Association with Melanoma Risk: A Population-Based Study
Authors: Tadeusz Dębniak, Rodney J. Scott, Tomasz Huzarski, Tomasz Byrski, Andrzej Rozmiarek, Bogusław Dębniak, Elżbieta Załuga, Romuald Maleszka, Józef Kładny, Bohdan Górski, Cezary Cybulski, Jacek Gronwald, Grzegorz Kurzawski, Jan Lubinski
Journal: Cancer Research (2005)

Abstract The population frequencies of the CDKN2A variants remain undetermined. In Poland there are three common variants of CDKN2A: an alanine to threonine substitution (A148T), Nt500c&amp;gt;g and Nt540c&amp;gt;t, which have been detected in other populations. To establish if they are associated with an increased malignant melanoma (MM) risk we did an association study based on genotyping 471 patients with MM and 1,210 random control subjects from the same Polish population. We found a significantly increased frequency of the A148T variant among patients with MM (7.0%) in comparison with the general population (2.9%). The incidence of the A148T variant remained greater in both unselected and familial melanoma subgroups. A statistically significant positive association was seen for unselected MM (odds ratio, 2.529; P = 0.0003), especially in patients diagnosed under 50 years of age (odds ratio, 3.4; P = 0.0002). The A148T carrier population (heterozygous G/A alleles) was more likely to have a relative with malignancy compared with the noncarrier population (57% versus 36%, respectively; P = 0.03). Further examination of the CDKN2A promoter sequence done in 20 melanoma patients with the A148T change (heterozygous G/A alleles) and 20 patients with MM without this alteration identified it was in linkage disequilibrium with a polymorphism in the promoter region at position P-493. We found no statistically significant overrepresentation of the Nt500c&amp;gt;g and the Nt540c&amp;gt;t polymorphisms in the Polish melanoma population. In conclusion, the A148T variant of the CDKN2A gene seems to be associated with an increased risk of development of MM. Additional studies are required to confirm whether this particular change is associated with increased risk of other nonmelanoma malignancies.
Call for Organized Statewide Networks for Management of Acute Myocardial Infarction–Related Cardiogenic Shock
Authors: Vakhtang Tchantchaleishvili, William Hallinan, H. Todd Massey
Journal: JAMA Surgery (2015)

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Abstract 16977: MicroRNA-mediated Regulation of SUMO1 Expression in Heart
Authors: Jae Gyun Oh, Ahyoung Lee, Dongtak Jeong, Alessia Baccarini, Brian D Brown, Changwon Kho, Roger J Hajjar
Journal: Circulation (2014)

Background: Cardiac sarcoplasmic reticulum calcium ATPase pump (SERCA2a) is a key regulator in cardiac cells and its function and expression are decreased in heart failure (HF). Our group has shown that SERCA2a gene transfer induces beneficial effects in HF models and in patients with severe HF. Recently, our group determined that SERCA2a is SUMOylated by small ubiquitin related modifier type 1 (SUMO1), ultimately impacting cardiac function. The expression of SUMO1 in the myocardium is significantly decreased in failing hearts and its knockdown results in severe HF. However, the mechanisms by which SUMO1 is regulated remain unknown. Methods/Results: To identify potential miRNAs targeting SUMO1, we first generated 19 candidates by sequence based prediction. Among 19 candidates, miR-146a was upregulated concurrently with SUMO1 expression in murine models of HF and in human HF ventricular tissues. Using a luciferase reporter assay, we confirmed that miR-146a targets the SUMO1 3’-untranslated region. Overexpression of miR-146a suppressed the expression of SUMO1 in mRNA and adversely affected the calcium transient in cardiomyocytes. Conversely, transfection of ‘decoy’ genes which has tandem complementary sequences of miR-146a increased both mRNA and protein of SUMO1. Introduction of miR-146a ‘decoy’ increased sumoylation of SERCA2a in cardiomyocytes. Conclusion: These findings provide new insight into the regulation of SUMO1 in cardiomyocytes. It implies modulation of miR-146a is a potential target in HF therapy. Key Words: heart failure, microRNA, SUMO, SERCA2a
Finding asthmatics suitable for omalizumab therapy in a district hospital
Authors: Syed Mohammad Tariq, Parthipan Kanthapillai, Farida Parkar
Journal: European Respiratory Journal (2013)

Background: NICE UK guidance recommends omalizumab injections as add-on therapy for severe asthmatics sensitized to a perennial aero-allergen who despite on high dose maintenance inhaled corticosteroid (>1mg equivalent beclomethasone) plus other therapies (LABA, LTRA), have >2 hospital admissions or 3 emergnecy department visits (one leading to admission) in a year.  Aim: We surveyed our asthmatics to identify such patients.  Methods: Databases for admissions, emergency visits, and chest clinic attendences for asthma through year 2008 were checked for patients fulfilling NICE criteria for omalizumab. These patients were further worked up for IgE level and aero-allergen sensitivity.  Results: Of 22 asthmatics, 2 were admitted for reasons other than asthma, 2 had improved requiring  120ku/L, highest level 1302), and 5 were sensitized to 1 or more perennial allergens. These 5 patients had 164 hospital bed days and 10 short courses of oral corticosteroid between them  Conclusion: A small number of severe allergic asthmatics utilise high levels of resources in secondary care. Finding these patients and treating them with add-on omalizumab injections could improve their asthma control with reduced morbidity. The high cost of omalizumab is more than offset by the reduction in emergency visits and hospital admissions.
A Tie-2 DNA vaccine targeting tumor endothelium
Authors: Judith M. Ramage, Ian Spendlove, Rachael Metheringham, Robert S. Moss, Selman Ali, Peter Hewett, Lindy G. Durrant
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4844 

Tie-2 stabilises pericyte/endothelial interactions during angiogenesis and is over expressed on tumor endothelium. A vaccine that targets endothelium over-expressing Tie-2 may result in vessel damage and stimulate an inflammatory cascade resulting in disease regression. To validate the use of Tie-2 as a target, human Tie-2 was used as a xenogenic vaccine in mice. Preliminary studies suggest that immunisation of balb/c mice by gene gun with DNA from the extracellular region of Tie-2 resulted in cessation of tumor growth. To determine if we could design a syngeneic vaccine that would work in both mice and humans a conserved region of Tie- 2 was cloned. HLA-A*0201 transgenic mice were immunised with this construct to determine if a repertoire of HLA-A*0201 T cells exist that recognise Tie-2. Within the Tie-2 region an HLA-A*0201 epitope was identified that is identical between mice and humans. Anchor modification of this epitope, increased binding to MHC. Immunisation of HLA-A*0201 mice with this enhanced peptide stimulated CTL responses that recognise T2 cells pulsed with either enhanced or wild type peptide. We then generated a human DNA vaccine incorporating the identified region of Tie-2 and used site directed mutagenesis to enhance the CD8 epitope. Using a gene gun HLA-A2 transgenic mice were immunized with the Tie-2 DNA construct. High avidity CTL were obtained from all mice immunized with this construct. Tetramer studies indicated a frequency of up to 1 in 1x103 CD8 cells being specific for this epitope. Moreover these CTL recognise endothelial cells over-expressing Tie-2. This Tie-2 construct is currently being screened for toxicity and efficacy in tumor models. These studies provide a novel approach to cancer vaccination.
Internal validity of trials is more important than generalisability
Authors: J. Mant, M. Dawes, S. Graham-Jones
Journal: BMJ (1996)

EDITOR,—Mike Pringle and Richard Churchill raise important issues relating to the practicalities of performing and interpreting the results of randomised controlled trials in general practice.1 They suggest that observational studies are acceptable when a randomised study is too difficult to perform or when its results will be clinically meaningless, reminding us of the complementary (rather than competing) roles that experimental and observational methods should have in the evaluation of health care interventions.2 We are concerned, …
Calcified Left Ventricular Aneurysm
Authors: Stephan Achenbach, Dieter Ropers, Werner G Daniel
Journal: New England Journal of Medicine (2003)

to the editor: Lee and Atwood (March 6 issue) 1 provide an example of a calcified left ventricular aneurysm visualized by computed tomography (CT).On closer inspection, the pattern of calcifications in the apical region of the left ventricle gives reason to suspect the presence of a partly calcified ventricular thrombus as well.The arrow in their image actually points at a smaller calcified area that is clearly disparate from the thin, crescent-shaped calcification of the aneurysm itself and may be part of an apical thrombus.In addition, there are two smaller and less well-defined regions of higher attenuation close to either end of this structure, again raising the suspicion of small calcifications (which may appear less sharply delineated because of motion artifacts).Such a pattern is typical of a partly calcified thrombus (Fig. 1); thus, this diagnosis must be taken into account, and further imaging may be warranted.The findings might have been clearer if CT technology with higher temporal resolution had been used.
Chemosensitivity based approach of neoadjuvant chemotherapy with doxorubicin plus cyclophosphamide or docetaxel plus cyclophosphamide for operable breast cancer
Authors: Takashi Ishikawa, Daisuke Shimizu, Takeshi Sasaki, Ayako Kito, Akinori Nozawa, Kae Kawachi, Takashi Chishima, Yasushi Ichikawa, Hiroshi Shimada
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3619 

BACKGROUND: Active nonanthracycline-containing regimens are emergingfrom clinical trials of breast cancer. US oncology group demonstrated that docetaxel plus cyclophosphamide (TC) was associated with a superior disease free survival compared with a standard adjuvant treatment of doxorubicin plus cyclophosphamide (AC). There is also growing evidence that gene expressions may be markers for anthracycline or taxane sensitivity.    AIM: In this pilot study, we attempt to demonstrate an improved response by chemosensitivity-based approach with AC or TC over a standard regimen of AC.    METHODS: The study included 19 women with operable breast cancer with lymph node metastasis. In addition to routine histological study including ER/PgR status with core needle biopsy specimens before treatment, gene expressions of HER2, topoisomerase II α (TOPO IIα), Cyp3A4, class III β tublin, p53 and ki67 were examined immunohistochemically. According to sensitivity results, patients received chemotherapy four cycles of either standard-dose AC (60 and 600 mg/m2 q3w, respectively) or TC (75 and 600 mg/m2 q3w, respectively). AC was chosen for cases with higher expressions of HER2/TOPO IIα and/or Cyp3A4/classIII β tublin, while TC for cases with the opposite patterns of expressions. When pathological complete response including near pCR (only focal residual tumor cells) (pCR) was not achieved by an initial treatment, crossover to the alternative treatment was recommended. Primary endpoint was pCR rate of this study. Secondary endpoint was to compare pCR rates between AC and TC. The projected pCR rate of this study was estimated to be more than 9% based on previous studies with AC. RESULTS: At present, analysis was completed for 9 cases for AC, and 10 cases for TC. The pCR rate of this study was 21 %. That of AC and TC was 11% and 33 %, respectively.    CONCLUSIONS: TC demonstratedsuperior efficacy compared with AC, providing significant higher pCR rate. The examination of these gene expressions may not be sufficient to predict chemosensitivity, especially for AC.
Abstract 4426: Tumor suppressive effects of wild-type Hras on oncogenic Kras-driven pancreatic tumorigenesis
Authors: Jamie D. Weyandt, Christopher M. Counter
Journal: Cancer Research (2014)

Abstract The RAS proteins are a group of small GTPases that can become constitutively activated by point mutations that are found in a quarter or more of all cancer patients, particularly in pancreatic cancer, in which over 90% of patients have an activating KRAS mutation. There are three well-characterized RAS protein family members: HRAS, NRAS, and KRAS, the latter of which is alternatively spliced at the C-terminus into two proteins, KRAS4A and KRAS4B. The RAS proteins are all nearly identical at their N-termini and core effector binding domains. However, they have divergent C-terminal membrane-binding regions that impart both different subcellular localization and subtle changes in signaling. While oncogenic RAS is well established to promote cancer, recent work has suggested that wild-type RAS proteins also participate in tumorigenesis. In this regard, we previously found that wild-type HRAS is activated downstream of oncogenic KRAS, which promoted tumor growth of human pancreatic cancer cell lines. To examine the role of wild-type Hras during de novo pancreatic tumor development, we tested whether knockout of the wild-type Hras gene altered tumorigenesis in oncogenic Kras-driven mice models of pancreatic cancer. Specifically, Hras homozygous null mice (Hras-/-) were crossed into a Pdx-Cre;LSL-KRasG12D/+ background in the absence or presence of an additional mutant p53 allele (Trp53R172H/+) to induce early and late pancreatic cancer, respectively. Surprisingly, loss of Hras led to an increase in early pancreatic lesions and reduced survival in the model of late disease. Since HRAS is activated downstream of oncogenic KRAS, and high oncogenic signaling can induce a senescent growth arrest, we tested and found that suppressing senescence by mutating both alleles of Trp53 ameliorated the survival difference between wild-type and null Hras mice. We thus hypothesize that wild-type Hras amplifies oncogenic Kras signaling, leading to the growth arrest of senescence and thereby inhibit early tumorigenesis. However, once senescence is suppressed later in tumorigenesis, wild-type RAS proteins instead promote more malignant phenotypes. Citation Format: Jamie D. Weyandt, Christopher M. Counter. Tumor suppressive effects of wild-type Hras on oncogenic Kras-driven pancreatic tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4426. doi:10.1158/1538-7445.AM2014-4426
Differences in Treatment Patterns and Outcomes Between Hispanics and Non-Hispanic Whites Treated for ST-Segment Elevation Myocardial Infarction
Authors: Luis A. Guzman, Shuang Li, Tracy Y. Wang, Martha L. Daviglus, Jose Exaire, Carlos J. Rodriguez, Vilma I. Torres, Marjorie Funk, Jorge Saucedo, Chris Granger, Ileana L. Piña, Mauricio G. Cohen
Journal: Journal of the American College of Cardiology (2012)
B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina
Authors: Renate Schnabel, Edith Lubos, Hans J. Rupprecht, Christine Espinola-Klein, Christoph Bickel, Karl J. Lackner, François Cambien, Laurence Tiret, Thomas Münzel, Stefan Blankenberg
Journal: Journal of the American College of Cardiology (2006)
Selective potentiation of tirapazamine hypoxic cytotoxicity by benzotriazine-1-oxides: mechanism of potentiation and in vivo activity
Authors: Bronwyn G. Siim, Rita Patel, Rachelle Douglas, Michael P. Hay, Frederik B. Pruijn, Willliam R. Wilson
Journal: Cancer Research (2005)

5880   Tirapazamine (TPZ) is a hypoxia selective bioreductive drug currently in advanced clinical trials in combination with chemoradiation. However, high toxicity restricts the number of doses of TPZ that can be administered, and poor extravascular transport limits diffusion of TPZ to target hypoxic regions of tumors. We have developed a series of benzotriazine(BT)-1-oxides that selectively enhance hypoxic cell killing by TPZ. Screening of 96 BT-1-oxides identified 16 analogues that produced hypoxic TPZ potentiation ratios [TPR = (IC50 TPZ)/(IC50 TPZ + BT-1-oxide)] of >5, and hypoxic cytotoxicity ratios [HCR = aerobic(IC50 TPZ + BT-1-oxide)/hypoxic (IC50 TPZ + BT-1-oxide)] of up to 3000 (TPZ alone HCR = 66 ± 10). No aerobic potentiation was observed. Hypoxic potentiation was confirmed by clonogenic assay of HT29 cell suspensions. The BT-1-oxides SN29112 and SN29254 (300 μM) provided an additional 4 logs of cell killing, relative to TPZ alone (30 μM), and were not cytotoxic in the absence of TPZ. Induction of the phosphorylated histone γH2AX was used to confirm that potentiation of TPZ hypoxic cell killing by the BT-1-oxides results from increased DNA breakage. There are two mechanisms that could contribute: (i) enhanced metabolism of TPZ; (ii) BT-1-oxide oxidation of TPZ-induced DNA radicals. While the BT-1-oxides increased the rate of TPZ metabolism, this was insufficient to account for the increase in hypoxic cell killing. Radiosensitization of hypoxic cells was used as a measure of DNA radical oxidizing efficiency. Radiosensitizing efficiency of the BT-1-oxides varied - SN29254 was as efficient a radiosensitizer as misonidazole (on a molar basis). These results suggest that DNA radical oxidation is the main mechanism of TPZ potentiation by the BT-1-oxides. The maximum tolerated dose (MTD) of SN29112 (0.24 mmol/kg) was decreased to 0.18 mmol/kg when administered with TPZ (0.13 mmol/kg; 42% MTD). Plasma pharmacokinetics at these doses showed that concentrations of BT-1-oxide providing potentiation in cell cultures are achievable in vivo. Interestingly, co-administration of SN29112 with TPZ slowed the plasma clearance of both TPZ and its major metabolite, the BT-1-oxide SR4317, increasing the AUC for both. The net effect of this should be prolonged exposure of tumor cells to TPZ and potentiators (both SN29112 and SR4317). The results of tumor excision assays in progress will be presented.
Abstract 4151: Long-Term Local Inflammatory Response After Coronary Artery Stenting With Drug-Eluting Stent
Authors: Tetsuzo Wakatsuki, Toshiyuki Niki, Kenya Kusunose, Koji Yamaguchi, Kunihiko Koshiba, Shusuke Yagi, Noriko Tomita, Yoshio Taketani, Takashi Iwase, Hirotsugu Yamada, Takeshi Soeki, Masashi Akaike, Masataka Sata
Journal: Circulation (2009)

Background: The long-term effects of drug-eluting stent (DES) on coronary local inflammation are not known. Pentraxin3 (PTX3) is produced in response to primary proinflammatory signals from vascular endothelial cells and macrophages instead of from the liver. Objectives: We evaluated the local release of PTX3 and high sensitivity C-reactive protein (hs-CRP) as a local inflammatory marker in nonrestenotic coronary arteries more than six months following DES and bare metal stent (BMS) implantation. Methods: Fifty-two patients treated six months earlier with a coronary stenting for isolated proximal left anterior descending (LAD) stenosis, with no evidence of restenosis, were studied. Twenty patients had been stented with BMS, and 32 had been with DES. We measured serum PTX3 and hs-CRP levels sampled in coronary sinus (CS) and sinus of Valsalva (V). The translesional PTX3 and hs-CRP gradients (Δ) were defined as CS level minus V level. Results: There were no significant differences in risk factors for athero...
Assessment of Osteoarthritis Candidate Genes in a Meta‐Analysis of Nine Genome‐Wide Association Studies
Authors: Cristina Rodriguez‐Fontenla, Manuel Calaza, Evangelos Evangelou, Ana M. Valdes, Nigel Arden, Francisco J. Blanco, Andrew Carr, Kay Chapman, Panos Deloukas, Michael Doherty, Tõnu Esko, Carlos M. Garcés Aletá, Juan J. Gomez‐Reino Carnota, Hafdis Helgadottir, Albert Hofman, Ingileif Jonsdottir, Hanneke J. M. Kerkhof, Margreet Kloppenburg, Andrew McCaskie, Evangelia E. Ntzani, William E. R. Ollier, Natividad Oreiro, Kalliope Panoutsopoulou, Stuart H. Ralston, Yolande F. Ramos, Jose A. Riancho, Fernando Rivadeneira, P. Eline Slagboom, Unnur Styrkarsdottir, Unnur Thorsteinsdottir, Gudmar Thorleifsson, Aspasia Tsezou, André G. Uitterlinden, Gillian A. Wallis, J. Mark Wilkinson, Guangju Zhai, Yanyan Zhu, David T. Felson, John P. A. Ioannidis, John Loughlin, Andres Metspalu, Ingrid Meulenbelt, Kari Stefansson, Joyce B. van Meurs, Eleftheria Zeggini, Timothy D. Spector, Antonio Gonzalez
Journal: Arthritis & Rheumatology (2013)

To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant.SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
DNA-Dependent Protein Kinase Is a Therapeutic Target in Poor Prognosis B-Cell Chronic Lymphocytic Leukemia
Authors: Elaine Willmore, Sarah L. Elliott, Clark J. Crawford, Geoffrey Summerfield, Tryfonia Mainou-Fowler, Graham Jackson, Paul Evans, Paula Newton, Duncan Gowans, Barbara W. Durkacz
Journal: Blood (2008)