tbuckley/cabot-search huggingface dataset:
Renal cell carcinoma: A comprehensive genetic map.
Authors: Bin Tean Teh
Journal: Cancer Research (2006)

5691   Renal cell carcinoma is the 10 th  most common cancer consisting of several pathological subtypes. We have attempted to create a comprehensive gene expression map that will assist in diagnosis, prognosis, and therapeutic selection in RCC. We performed expression profiling for 300 kidney specimens (150 clear cell, 38 papillary, 20 chromophobe, 25 metastatic, 4 collecting duct RCC, 20 oncocytoma, 21 Wilms’ tumors, 10 unclassified, and 12 noncancerous renal samples) with Affymetrix HGU133 Plus 2.0 oligonucleotide arrays (54,675 probe sets). We performed both clara and hierarchical clustering on the data set filtered for variation, selected discriminating gene clusters by principal component analysis, and annotated these clusters with the goCluster Bioconductor packages with a false discovery rate of 0.01. In addition, we also correlate the long-term clinical follow-up data in 150 cases of clear cell and papillary RCC with expression data. Comparative genomic microarray analysis was used to infer cytogenetic profiles for the array profiles. To identify potential developmental pathways activated in the separate subtypes, we identified genes activated in every individual RCC subtypes. All array profiles grouped by histology on principal component analysis. We identified a large number of functionally distinct genetic modules of co-expressed genes in the data set, one such example being a distinct angiogenic 21-transcript cluster activated in clear cell RCC, well-known as a hypervascular cancer characterized by dysregulation of hypoxia-response pathways. We additionally generated a 3-transcript predictor that was able to classify the various epithelial RCC subtypes with high accuracy. We report multiple regional expression biases characteristic of each subtype, corresponding to both established and novel cytogenetic aberrations. Finally, we identified the prognostic sets of genes for both clear cell and papillary RCC. We present a comprehensive expression map of kidney cancer, with ontological annotation of co-expressed genetic modules, as well as corresponding inferred cytogenetic profiles. This has allowed the generation of clinically useful predictors of histology and their prognosis. Additionally, we highlight kinases, developmental genes and pathways that potentially participate in tumor progression in each subtype of epithelial RCC which may also serve as potential therapeutic targets.
Tissue factor (TF) expression in primary invasive breast cancer correlates with tumor size and grade but not with outcome
Authors: Vicky Macias, Julia Geynisman, Snjezana Frkovic-Grazio, Matej Bracko, Barbara Susnik, Yi Lu, Andre A. Kajdacsy-Balla, Paul F. Lindholm
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

3606 

Tissue factor (TF) and coagulation factor VIIa activate the extrinsic coagulation pathway and protease-activated receptors. These events and direct intracellular signaling induce gene expression regulating cell growth, motility, invasion and angiogenesis. Increased TF tissue levels have been observed in high grade cancers of various sites and have been associated with aggressive behavior of some tumors. The role of TF expression as a prognostic factor in primary breast carcinoma is not known. The aim of this study is to determine whether TF expression in breast tumors is associated with tumor characteristics and survival outcomes in stage 1 breast carcinoma. Immunohistochemistry with anti-TF monoclonal antibody 4509 (American Diagnostica) was performed on formalin-fixed paraffin-embedded tissues arranged into a tissue microarray of 243 subjects with primary invasive breast carcinoma (pT1N0) operated in 1983-87 at the Institute of Oncology, Ljubljana, Slovenia with a median follow-up of 19 years. Scoring took into account intensity and percentage of cells staining in each tissue core. Results showed a range of 0.00 - 2.60 (mean, 1.016; median 1.000); less than 1 = 42 tumors (17.3%); equal to 1 = 136 tumors (56.0%) and greater than 1 = 65 tumors (26.7%). TF expression data was grouped into 2 categories: less than 1 and greater than or equal to 1. TF expression was significantly related to tumor size (p = 0.004), histologic type (p = 0.043) and histologic grade (p = 0.033) by Pearson chi-square test. By Kaplan-Meier univariate analysis, TF expression was not associated with distant metastasis free survival (DMFS) (p = 0.48) or cancer specific survival (CSS) (p = 0.36). By multivariate analysis, only lymphovascular invasion, mitotic index and histologic type were associated with DMFS and CSS. Although TF expression is related to tumor characteristics (size, grade and histologic type) it does not seem to have a direct prognostic significance in patients with primary stage 1 breast cancer.
Abstract 1245: The Mortality Rate from Cardiovascular Disease is more than Five Times Higher in Individuals with Diabetes Mellitus who have the Hp 2–2 Genotype as Compared to Individuals with Diabetes Mellitus who do not have the Hp 2–2 Genotype
Authors: Uzi Milman, Shany Blum, Chen Shapira, Andrew Levy
Journal: Circulation (2008)

Objective: To determine if the Haptoglobin (Hp) genotype can predict the risk of death from cardiovascular disease in individuals with Diabetes Mellitus (DM) in a prospective community based longitudinal study. Background: The Hp gene is polymorphic in man with two classes of alleles denoted 1 and 2. Retrospective analysis of 5 longitudinal studies has demonstrated that the Hp genotype is a major determinant of the risk of incident CVD in DM individuals. Specifically, individuals with the Hp 2–2 genotype and DM were found to have a 2–5 fold increased risk of CVD as compared to Hp 1–1 or Hp 2–1 DM individuals. Method: 2241 individuals with DM ≥55 years of age from 47 primary health care clinics were Hp genotyped and followed prospectively for three years for incident myocardial infarction, stroke and death (all cause and cardiovascular). All aspects of the medical care of individuals in the cohort were left to the discretion of the patient’s physician. Results: The cohort consisted of 708 individuals with the Hp 2–2 genotype and 1533 individuals with the Hp 1–1 or 2–1 genotype. At baseline there were no significant differences between individuals with and without the Hp 2–2 genotype in their DM characteristics (HbA1c, duration) or in the prevalence of cardiovascular disease (25% in both groups). During the nearly 3 year period of follow up total mortality was increased in individuals with the Hp 2–2 genotype (2.5% vs 1.8%, HR 0.68, CI 0.35–1.25, p=0.2 by log rank). These differences in overall mortality were the result of a greater than 5 fold increase in CV death in Hp 2–2 individuals (1.1% vs 0.2%, HR 0.15, CI 0.038 – 0.44, p=0.001 by log rank). The incidence of non fatal MI was increased by over 50% in the Hp 2–2 group (3.9% vs. 2.5%, p=0.068). These differences were unaffected by adjustment for DM characteristics and conventional cardiovascular risk factors. Conclusions. DM individuals with the Hp 2–2 genotype are at a dramatically increased risk of death due to cardiovascular disease. Pharmacogenomic treatment strategies targeted to this high risk population may provide considerable public health and economic benefit.
Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer
Authors: Marina Petrovic, Ivan Cekerevac, Gordana Kostic, Violeta Iric Cupic, Goran Davidovic, Zorica Lazic, Vojislav Cupurdija, Ljiljana Novkovic
Journal: European Respiratory Journal (2012)

Introduction: Previous studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large independent studies are lacking.  Methods: Associations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 123 case patients. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10-year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model.  Results: Serum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer (IL-6, odds ratio [OR] = 2.89, 95% confidence interval [CI] = 1.28 to 6.23; IL-8, OR = 2.46, 95% CI = 1.02 to 4.12) and with lung cancer risk (IL-6, OR = 1.93, 95% CI = 0.87 to 2.36; IL-8, OR = 1.62, 95% CI = 1.56 to 2.48), compared with the lowest quartile. Increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 2.03, 95% CI = 1.05 to 2.73). The 10-year standardized absolute risks of lung cancer were highest among current smokers with high IL-8 and CRP levels (absolute risk = 7.46%, 95% CI = 4.52% to 10.25%).  Conclusions: Although increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis.
Lung Cancer Risk Prediction Using Common SNPs Located in GWAS-Identified Susceptibility Regions
Authors: Joel L. Weissfeld, Yan Lin, Hui-Min Lin, Brenda F. Kurland, David O. Wilson, Carl R. Fuhrman, Arjun Pennathur, Marjorie Romkes, Tomoko Nukui, Jian-Min Yuan, Jill M. Siegfried, Brenda Diergaarde
Journal: Journal of Thoracic Oncology (2015)

IntroductionGenome-wide association studies (GWAS) have consistently identified specific lung cancer susceptibility regions. We evaluated the lung cancer–predictive performance of single-nucleotide polymorphisms (SNPs) in these regions.MethodsLung cancer cases (N = 778) and controls (N = 1166) were genotyped for 77 SNPs located in GWAS-identified lung cancer susceptibility regions. Variable selection and model development used stepwise logistic regression and decision-tree analyses. In a subset nested in the Pittsburgh Lung Screening Study, change in area under the receiver operator characteristic curve and net reclassification improvement were used to compare predictions made by risk factor models with and without genetic variables.ResultsVariable selection and model development kept two SNPs in each of three GWAS regions, rs2736100 and rs7727912 in 5p15.33, rs805297 and rs1802127 in 6p21.33, and rs8034191 and rs12440014 in 15q25.1. The ratio of cases to controls was three times higher among subjects with a high-risk genotype in every one as opposed to none of the three GWAS regions (odds ratio, 3.14; 95% confidence interval, 2.02–4.88; adjusted for sex, age, and pack-years). Adding a three-level classified count of GWAS regions with high-risk genotypes to an age and smoking risk factor-only model improved lung cancer prediction by a small amount: area under the receiver operator characteristic curve, 0.725 versus 0.717 (p = 0.056); overall net reclassification improvement was 0.052 across low-, intermediate-, and high- 6-year lung cancer risk categories (<3.0%, 3.0%–4.9%, ≥5.0%).ConclusionSpecifying genotypes for SNPs in three GWAS-identified susceptibility regions improved lung cancer prediction, but probably by an extent too small to affect disease control practice.
Reference limits for haemoglobin and ferritin
Authors: A.-L. M Heath, S. Fairweather-Tait, M. Worwood, I. M Morison, E. L Ferguson, H. Rushton, M. J Norris, R. Dover, A. W Sainsbury, J. J H Gilkes, I. D Ramsay
Journal: BMJ (2001)

Editor—Rushton et al suggest that reference ranges for men should be used to assess iron status in women of childbearing age.1 They do, however, make some incorrect assumptions and do not consider the practical implications of such a change.

Women must have sufficient iron stores to prevent iron deficiency from menstrual blood loss or pregnancy. However, one in 150 people in the United Kingdom are homozygous for the C282Y mutation of the HFE gene, which is associated with haemochromatosis.2 Although the clinical penetrance of this genotype is low, widespread measures to increase the intake of iron in younger women will also increase the intake of men and postmenopausal women. It is therefore important that any changes in lower limits of indices of iron status are firmly supported by clinical and experimental evidence.

Rushton et al are incorrect in assuming that different lower limits for ferritin are used for detecting iron deficiency in young men and women. Although reference ranges (95%) in healthy young adults differ—for example, 35-220 μg/l for men and 9-136 μg/l for women2—the limit for iron deficiency used by clinicians is around 15 μg/l for both men and women, a value originally established by determining the highest value found in patients with iron deficiency anaemia.3

The national dietary and nutritional survey reported a median value for haemoglobin concentration in British women of childbearing age of 132 g/l. Increasing the lower cut-off point to 130 g/l, as used for men, would therefore define half the premenopausal adult female population of the United Kingdom as anaemic. Zhu and Haas found that in women with serum concentrations of ferritin  120 g/l, iron supplementation increased serum concentrations of ferritin but not haemoglobin.4 We also have to ask how the iron intake of all these women would be increased. A recent dietary intervention study showed that highly motivated people with mild iron deficiency can improve iron status through diet but that supplements are a more practical option.5 Supplements do, however, produce unpleasant side effects in a notable proportion of individuals, and any programme entailing the use of supplements is likely to have a detrimental effect on the wellbeing of a notable number of women.

We believe that there is no evidence to support reclassification of haemoglobin and serum concentrations of ferritin in women to normal values for men. Furthermore, we are unable to see how such a move could result in a positive outcome for women's health and welfare with no adverse effects.
Abstract 18508: The Association of eNOS Gene Single Nucleotide Polymorphism rs1799983 with High-Sensitivity C-Reactive Protein and Early Recurrence of Atrial Fibrillation after Radiofrequency Catheter Ablation
Authors: Jaemin Shim, Jae Hyung Park, Hee-Sun Mun, Jin Wi, Jae-Sun Uhm, Jong Youn Kim, Boyoung Joung, Moon-Hyoung Lee, Hui-Nam Pak
Journal: Circulation (2012)

Background: Previous reports have demonstrated the association between single nucleotide polymorphism (SNP) of the eNOS gene and atrial fibrillation (AF). This study evaluated whether eNOS gene variants are associated with high-sensitivity C-reactive protein (hsCRP) and AF recurrence after radiofrequency catheter ablation (RFCA). Methods: A total of 500 consecutive patients (56±11 years, 77% male) with paroxysmal (68%) or persistent (32%) AF who underwent RFCA were included. Plasma hsCRP concentration was measured and SNP of the eNOS gene, rs1799983, was genotyped. A 24- to 48-hour Holter ECG recording was performed at 3, 6, and 12 months after the ablation. Results: When we compared the patients with rs1799983 variant allele (T, n=84) and those without T allele (n=416), rs1799983 variant allele carriers are more likely to have coronary artery disease or stroke (31.0% vs. 17.8%, p=0.004). The early recurrence (ER) of AF (within 3 months) was observed in 31.8%, whereas the clinical recurrence (CR) of AF (after 3 months) occurred in 24.8% of the patients during the median 17 months of follow-up. The patients with ER were more likely to have persistent AF (44.4% vs. 27.1%, p&lt;0.001) and larger left atrium (42.8±6.4 vs. 41.2±6.2 mm, p=0.011) than those without the ER. Although rs1799983 variant was not associated with the CR, carriers of the variant allele had an increased risk of the ER (OR 1.717 for TT+GT vs. GG, 95% CI 1.059-2.785, p=0.028) and experienced recurrence earlier than those without variant allele (11±16 vs. 20±25 days, p=0.016). However, there were no significant differences in hsCRP between variant and non-variant patients (2.32±4.94 vs. 2.06±4.36 mg/L, p=0.618). A multiple logistic regression analysis showed that the rs1799983 variant (OR 1.714, 95% CI 1.045-2.812, p=0.033) and persistent AF (OR 1.905, 95% CI 1.234-2.939, p=0.004) were independent predictors of the ER. Conclusions: The rs1799983 variant of the eNOS gene was associated with early recurrence after RFCA, but not with hsCRP level. A study that further investigates the relationship between genetic variations of eNOS and post-ablation inflammatory process will be warranted.
Abstract 16194: Specific Organized Substrates of Ventricular Fibrillation: Comparison of 320-Slice CT Heart Images in Subjects With Ventricular Fibrillation and Subjects With Sustained or Non-Sustained Ventricular Tachycardia
Authors: Hiroyuki Takaoka, Nobusada Funabashi, Koya Ozawa, Masae Uehara, Yoshio Kobayashi
Journal: Circulation (2011)

Purpose: If specific organized substrates of ventricular fibrillation (VF) are identified, they may provide important information for prevention of sudden cardiac death. 320 slice CT can acquire he...
Abstract P124: CGEN-855A, a Small Peptide Agonist of the Formyl Peptide Receptor-Like 1 Reduces Myocardial Reperfusion Injury
Authors: Rong Jiang, Iris Hecht, Caleb Rutledge, Zhiqing Zhao, Galit Rotman, Yossi Cohen, Jakob Vinten-Johansen
Journal: Circulation (2008)

Background: Neutrophils (PMNs) mediate reperfusion injury in part. Reperfusion (R) accelerates the accumulation of PMNs into ischemic myocardium. Postconditioning (PC) inhibits PMN activation and accumulation in area at risk (AAR) myocardium. Formyl-peptide receptor-like1 (FPRL1) agonists directly inhibit PMN transmigration. Accordingly, this study tests the hypotheses that the FPRL1 agonist CGEN-855A applied at R reduces infarct size by inhibition of PMN infiltration; the infarct reduction by CGEN-855A is comparable to that of the mechanical intervention Postconditioning; and since both CGEN-855A and PC share a common property of PMN inhibition, the combination of CGEN-855A and Postconditioning (PC) will not have an additive effect on infarct size reduction. Methods: In anesthetized open-chest rats, the left coronary artery (LCA) was occluded for 30 min and reperfused for 3 hours. Rats (n=10) were randomly assigned to: Control- equal volume vehicle 5 min before R; PC: three cycles of 10-s R followed by 10-s re-occlusion during the first minute of R; 2 mg/kg CGEN-855A administered 5 min before R; 2 mg/kg CGEN-855A + PC at R. Separate experiments were performed to assess PMN accumulation in AAR tissue by immunohistochemistry in control, CGEN-855A and PC groups. Results: The AAR (% left ventricular mass, AAR/LV) was comparable among groups. Infarct size (necrosis as % AAR, AN/AAR), was significantly less in the PC (41.2 ± 2.7*) and CGEN-855A (43.6 ± 2.9*) groups vs Control (57.0 ± 2.3). There was no additive effect of the combination of CGEN-855A and PC at R (44.6 ± 1.3). Both CGEN-855A (30.1 ± 0.6/HPF) and PC (34.8 ± 1.5/HPF) significantly reduced PMN accumulation in AAR tissue vs control (43.2 ± 0.7/HPF). Conclusions: stimulation of the FPRL1 with agonist CGEN-855A exerts cardioprotection at R by reducing infarct size; CGEN-855A peptide inhibits PMN accumulation; the extent of cardioprotection and PMN inhibition by CGEN-855A is similar to that of PC; there is no additive effect of their combination, consistent with a similar physiological pathway of PMN inhibition. *P&lt;0.05 vs Control
Neuropilin-1, a novel vascular endothelial growth factor receptor, promotes chemoresistance in pancreatic cancer cell lines
Authors: Jane S. Wey, Michael J. Gray, Fan Fan, Anna Belcheva, Ray Somcio, Lee M. Ellis
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4879 

Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF) and increases the affinity of VEGF for its tyrosine kinase receptors VEGFR-1 and –2. NRP-1 expression has recently been demonstrated in various tumor cell lines, including a majority of malignant pancreatic cell lines, but not in non-malignant pancreas tissues. METHODS: To determine the role of NRP-1 in pancreatic cancer cells, we stably transfected the cDNA for NRP-1 into the human pancreatic cell lines, FG and Panc-1, with empty vector transfectants serving as controls. We also utilized siRNA technology to reduce the endogenously high NRP-1 expression in Panc-1 cells. Effects of overexpression of NRP-1 on signaling were assessed by Western blot analysis. MTT assays were carried out to assess the effects of NRP-1 levels on sensitivity to the chemotherapeutic agents gemcitabine and 5-fluorouracil (5-FU). RESULTS: Overexpression of NRP-1 led to an upregulation of constitutive MAPK signaling, suggesting the possibility of induction of survival pathways. Overexpression of NRP-1 in FG, a cell line with low endogenous NRP-1 expression, increased survival by >40% after exposure to gemcitabine. It also protected FG cells against apoptosis secondary to 5-FU, increasing the IC50 by greater than two log-fold. In contrast, knockout of NRP-1 in Panc-1 cells by siRNA markedly increased their sensitivity to gemcitabine, inducing over 50% cell death at clinically relevant doses. The Panc-1 cells with reduced NRP-1 expression due to siRNA treatment showed a trend toward greater chemosensitivity in response to 5-FU, although the results were not statistically significant. CONCLUSION: NRP-1 overexpression in pancreatic cancer cell lines is associated with chemoresistance to various types of chemotherapy, whereas NRP-1 knockout by siRNA is able to enhance sensitivity to chemotherapy. Since we have previously shown that NRP-1 also enhances resistance to detachment-induced apoptosis (anoikis) in FG cells, it may protect cancer cells against multiple stressors. Targeting NRP-1 in pancreatic cancer cells may potentially downregulate survival signaling pathways that increase sensitivity to chemotherapy and apoptosis.
Palliative care in general practice
Authors: D. Brooks
Journal: BMJ (1995)

These are not sufficient arguments for an editorial in the BMJ to recommend one class of ,3 blockade and should be accompanied by the proviso that measurements of blood pressure are only a sur- rogate: it is the prevention of cerebrovascular accidents and myocardial infarctions that matters.As a doctor treating patients with hypertension or ischaemic heart disease most days of the week, I tend to use low doses of the most j3I selective lipophilic agent, bisoprolol, for hypertension and the highest affinity non-selective agent, timolol, for ischaemic heart disease.These drugs have been selected on the basis of theoretical arguments and surrogate measures on which Cleophas and Kalmansohn and I agree.As a clinical pharmacologist unhappy at such evidence, I set up the East Anglian comparison of the two classes of drug in ischaemic heart disease that I mentioned in my editorial and included them in a long term randomised comparison of antihypertensive drugs that started in 1986.