tbuckley/cabot-search huggingface dataset:
A Population-Based, Case-Control Study of Polymorphisms in Carcinogen-Metabolizing Genes, Smoking, and Pancreatic Adenocarcinoma Risk
Authors: E. J. Duell, E. A. Holly, P. M. Bracci, M. Liu, J. K. Wiencke, K. T. Kelsey
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Cigarette smoking is associated with a twofold increased risk of pancreatic cancer. We conducted a population-based case–control study in six San Francisco Bay area counties from 1994 to 2001 to investigate associations between polymorphisms in genes for two carcinogen-metabolizing enzymes (cytochrome P450 1A1 [CYP1A1] and glutathione S-transferase [GST]), smoking, and adenocarcinoma of the exocrine pancreas. Methods: We used polymerase chain reaction–based methods to analyze blood samples obtained from 309 case subjects and 964 control subjects to determine their genotypes for three CYP1A1 polymorphisms (m1, m2, and m4) and for homozygous deletions of two GST genes, GSTM1 and GSTT1. Control subjects were frequency matched to case subjects by age and sex. All statistical tests were two-sided. Results: None of the genetic polymorphisms themselves affected the risk of pancreatic cancer among Caucasian study participants. However, we observed an interaction between GSTT1-null genotype and cigarette smoking among Caucasians that was more prominent among women than among men. Relative to never smokers with the GSTT1-present genotype, the age-adjusted odds ratios (ORs) of pancreatic cancer for heavy smokers with the GSTT1-null genotype were 5.0 (95% confidence interval [CI] = 1.8 to 14.5) for women and 3.2 (95% CI = 1.3 to 8.1) for men; for heavy smokers with the GSTT1-present genotype they were 2.0 (95% CI = 1.0 to 4.0) for women and 2.1 (95% CI = 1.1 to 3.9) for men. ORs for pancreatic cancer among heavy smokers with both GSTT1-null and GSTM1-null genotypes were similar in magnitude to those among heavy smokers with the GSTT1-null genotype alone. There was no evidence of an interaction between CYP1A1 polymorphisms and smoking. Conclusions: The combination of heavy smoking and a deletion polymorphism in GSTT1 is associated with an increased risk of pancreatic cancer among Caucasians, with the associations possibly stronger in women than in men. J Natl Cancer Inst 2002;94:297–306]
Muscular damage and intravascular haemolysis during an 18 hour subterranean exploration in a cave of 700 m depth
Authors: E Stenner, E Gianoli, B Biasioli, C Piccinini, G Delbello, A Bussani
Journal: British Journal of Sports Medicine (2006)

To verify presence and severity of muscular and/or intravascular damage during a subterranean exploration of long duration.We measured serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) as markers of muscular damage. We also measured haptoglobin as a marker of intravascular haemolysis, and platelets and leucocytes as markers of inflammation.We found in all the participants an increase in CK, LDH, and platelets and leucocytes (mainly due to neutrophilia and monocytosis), and a decrease in the level of haptoglobin and circulating lymphocytes.The observed data suggest that continuous effort during long alpine subterranean explorations, environmental conditions, sleep deprivation, multiple impacts on rocks, and compression caused by bindings of the caving harness cause muscle damage, intravascular haemolysis, inflammation response, and immunological changes.
Effect of dietary phospholipids and their constituents on bile composition in rats and hamsters
Authors: Yochanan Peled, Tuvia Gilat
Journal: Hepatology (1994)

The formation of cholesterol gallstones is a result of an interaction between bile lipid concentration, composition and other factors. The solubilization of cholesterol in bile is affected by the nature of the fatty acids and head groups of biliary phospholipids. In this study we tried to modulate the composition of biliary lipids in the rat and hamster by means of dietary supplementation of whole phospholipids or their constituents (at 3% to 5% of food weight). A striking effect of ethanolamine feeding in rats and hamsters was demonstrated: Biliary cholesterol concentration and cholesterol saturation index were significantly lower (p < 0.03). In rats, bile acid concentration was increased, contributing to decreased bile lithogenicity. Ethanolamine also increased biliary phospholipid output. Other test substances had less marked effects. The addition of lecithin to rat diet significantly increased phospholipid concentration (p < 0.05) compared with controls. Cholesterol and bile acid concentrations were reduced in palmitic acid-fed hamsters (NS). Choline supplementation insignificantly increased the cholesterol saturation index in hamsters. Despite the clear effect of ethanolamine on biliary lipid composition, no change could be demonstrated in the proportion of phosphatidylethanolamine in bile. It is postulated that ethanolamine was methylated in the liver to choline. Our data demonstrate that biliary lipid composition can be modulated by dietary phospholipids or their components.
Genetics of Atopy and Asthma: The Rationale behind Promoter-based Candidate Gene Studies (IL-4 and IL-10)
Authors: LANNY J. ROSENWASSER, LARRY BORISH
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Section:ChooseTop of pageAbstract <<GENERAL APPROACHESMOLECULAR MECHANISMSCONCLUSIONSReferencesCITING ARTICLES
Activation of PPARδ prevents endothelial dysfunction induced by overexpression of amyloid-β precursor protein
Authors: Livius V. d'Uscio, Pritam Das, Anantha V.R. Santhanam, Tongrong He, Steven G. Younkin, Zvonimir S. Katusic
Journal: Cardiovascular Research (2012)

Existing evidence suggests that amyloid-β precursor protein (APP) causes endothelial dysfunction and contributes to pathogenesis of atherosclerosis. In the present study, experiments were designed to: (1) determine the mechanisms underlying endothelial dysfunction and (2) define the effects of peroxisome proliferator-activated receptor delta (PPARδ) ligand on endothelial function in transgenic Tg2576 mice overexpressing mutated human APP.Confocal microscopy and western blot analyses of wild-type mice aortas provided evidence that APP protein is mainly present in endothelial cells. Overexpression of APP significantly impaired endothelium-dependent relaxations to acetylcholine and phosphorylation of endothelial nitric oxide synthase at Ser(1177) in aortas. HPLC analysis revealed that tetrahydrobiopterin (BH(4)) levels were reduced in Tg2576 mice aortas. This was caused by increased oxidation of BH(4) and reduced expression and activity of GTP-cyclohydrolase I. Furthermore, gp91phox protein expression and superoxide anion production were increased in aortas of Tg2576 mice. This augmented superoxide formation was completely prevented by the NADPH oxidase inhibitor VAS2870. Expression of copper-/zinc-superoxide dismutase (Cu/ZnSOD) and extracellular SOD was downregulated. Treatment with PPARδ ligand GW501516 (2 mg/kg/day) for 14 days significantly increased BH(4) bioavailability and improved endothelium-dependent relaxations in Tg2576 mice aortas. GW501516 also normalized protein expression of gp91(phox) and SODs, thereby reducing production of superoxide anion in the aortas.Our results suggest that in APP transgenic mice loss of nitric oxide and increased oxidative stress are the major causes of endothelial dysfunction. The vascular protective effects of GW501516 in Tg2576 mice appear to be critically dependent on prevention of superoxide anion production.
Epidemiology of Alzheimer's disease and other forms of dementia in China, 1990–2010: a systematic review and analysis
Authors: Kit Yee Chan, Wei Wang, Jing Jing Wu, Li Liu, Evropi Theodoratou, Josip Car, Lefkos Middleton, Tom C Russ, Ian J Deary, Harry Campbell, Wei Wang, Igor Rudan
Journal: The Lancet (2013)
<i>AdCD40L</i> Immunogene Therapy for Bladder Carcinoma—The First Phase I/IIa Trial
Authors: Per-Uno Malmström, Angelica S.I. Loskog, Camilla A. Lindqvist, Sara M. Mangsbo, Moa Fransson, Alkwin Wanders, Truls Gårdmark, Thomas H. Tötterman
Journal: Clinical Cancer Research (2010)

Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for high-risk, non-muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease.Patients with invasive bladder cancer scheduled for cystectomy or patients with T(a) tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored.All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-gamma increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells.To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies.
Early ischaemic preconditioning requires Akt- and PKA-mediated activation of eNOS via serine1176 phosphorylation
Authors: Changjun Yang, M.A. Hassan Talukder, Saradhadevi Varadharaj, Murugesan Velayutham, Jay L. Zweier
Journal: Cardiovascular Research (2012)

AimsThe role of endothelial nitric oxide synthase (eNOS)/NO signalling is well documented in late ischaemic preconditioning (IPC); however, the role of eNOS and its activation in early IPC remains controversial. This study investigates the role of eNOS in early IPC and the signalling pathways and molecular interactions that regulate eNOS activation during early IPC.
Molecular Interactions between Dying Tumor Cells and the Innate Immune System Determine the Efficacy of Conventional Anticancer Therapies
Authors: Lionel Apetoh, Antoine Tesniere, François Ghiringhelli, Guido Kroemer, Laurence Zitvogel
Journal: Cancer Research (2008)

Abstract The efficacy of anticancer treatments is mostly assessed by their ability to directly inhibit the proliferation of tumor cells. Recently, we showed that tumor cell death triggered by chemotherapy or radiotherapy initiates an immunoadjuvant pathway that contributes to the success of cytotoxic treatments. The interaction of high mobility group box 1 protein (HMGB1) released from dying tumor cells with Toll-like receptor 4 (TLR4) on dendritic cells was required for the crosspresentation of tumor antigens and the promotion of tumor specific cytotoxic T-cell responses. Breast cancer patients harboring the loss-of-function Asp299Gly polymorphism of TLR4 relapsed earlier after receiving anthracycline-based chemotherapy. These data suggests that HMGB1- and TLR4-dependent immune responses elicited by conventional cancer treatment may increase the probability to achieve a durable therapeutic success. [Cancer Res 2008;68(11):4026–30]
Trials in rheumatoid arthritis: choosing the right outcome measures--comment on the article by Felson et al
Authors: D Porter
Journal: Annals of the Rheumatic Diseases (2007)

Felson et al make a good case for choosing continuous, rather than dichotomous, variables as the primary outcome measures in randomised controlled trials in rheumatoid arthritis;1 however, outcome measures also need to be meaningful to the clinical community. In TICORA we chose two “co-primary” end-points: first, we employed the mean change in disease activity score (DAS) because this was the most sensitive outcome measure available at the time;2 we also used the achievement of a “good” response according to EULAR criteria because we believed that differences in response rates would be more readily understood. Interestingly, our understanding of the clinical relevance of the outcome measures has been borne out: …
Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group Study.
Authors: G Falkson, R S Gelman, D C Tormey, C I Falkson, J M Wolter, F J Cummings
Journal: Journal of Clinical Oncology (1987)

One hundred thirty-one premenopausal women with metastatic breast cancer who had received no prior systemic treatment for metastases were entered on study. Patients without prior chemotherapy with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) or surgical oophorectomy followed directly by CAF (O + CAF). ER-negative patients without prior chemotherapy were directly assigned to treatment with CAF. Among randomized patients 83% have responded, and 37% have achieved a complete remission. Among ER-negative patients the complete response rate was 38%, and the complete plus partial response rate was 70%. Characteristics significantly associated with a longer time to treatment failure were age 45 or over, one or two organ sites, and performance status O. The median survival time of ER-positive patients treated with CAF is 29 months, and with O + CAF it has not yet been reached, whereas for ER-unknown patients the equivalent survival times are 41 months and 43 months respectively. For ER-negative patients treated with CAF the median survival time is 17 months. Characteristics associated with significantly longer survival among randomized patients were age 35 or over (P = .009) and only one or two organ sites involved (P = .02). Neither treatment (P = .33) nor ER status (P = .70) was significant.
Effects of Tryptophan Depletion on Serum Levels of Brain-Derived Neurotrophic Factor in Unmedicated Patients With Remitted Depression and Healthy Subjects
Authors: Alexander Neumeister, Peixiong Yuan, Theresa A. Young, Omer Bonne, David A. Luckenbaugh, Dennis S. Charney, Husseini Manji
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Data suggest the involvement of serotonergic and neurotrophic systems in major depressive disorder. To investigate their potential interaction, the authors studied changes in serum levels of brain-derived neurotrophic factor (BDNF) during tryptophan depletion and sham depletion in unmedicated patients with remitted major depressive disorder and in a group of healthy comparison subjects. METHOD: Twenty-seven patients with remitted major depressive disorder and 20 healthy subjects underwent tryptophan depletion and sham depletion in a randomized, placebo-controlled, double-blind crossover study. Serum BDNF concentrations and plasma tryptophan concentrations as well as behavioral assessments were obtained. RESULTS: During tryptophan depletion, BDNF levels increased in healthy volunteers. By contrast, patients with remitted major depressive disorder were unable to mount this presumed compensatory response, and BDNF levels remained low in these patients. CONCLUSIONS: The results further substantiate the potential role of BDNF in major depressive disorder.
Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression
Authors: David Anz, Moritz Rapp, Stephan Eiber, Viktor H. Koelzer, Raffael Thaler, Sascha Haubner, Max Knott, Sarah Nagel, Michaela Golic, Gabriela M. Wiedemann, Franz Bauernfeind, Cornelia Wurzenberger, Veit Hornung, Christoph Scholz, Doris Mayr, Simon Rothenfusser, Stefan Endres, Carole Bourquin
Journal: Cancer Research (2015)

Abstract The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I–like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy. Cancer Res; 75(21); 4483–93. ©2015 AACR.
Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas
Authors: Sizhi Paul Gao, Kevin G. Mark, Kenneth Leslie, William Pao, Noriko Motoi, William L. Gerald, William D. Travis, William Bornmann, Darren Veach, Bayard Clarkson, Jacqueline F. Bromberg
Journal: Journal of Clinical Investigation (2007)

Persistently activated or tyrosine-phosphorylated STAT3 (pSTAT3) is found in 50% of lung adenocarcinomas. pSTAT3 is found in primary adenocarcinomas and cell lines harboring somatic-activating mutations in the tyrosine kinase domain of EGFR. Treatment of cell lines with either an EGFR inhibitor or an src kinase inhibitor had no effect on pSTAT3 levels, whereas a pan-JAK inhibitor (P6) blocked activation of STAT3 and inhibited tumorigenesis. Cell lines expressing these persistently activated mutant EGFRs also produced high IL-6 levels, and blockade of the IL-6/gp130/JAK pathway led to a decrease in pSTAT3 levels. In addition, reduction of IL-6 levels by RNA interference led to a decrease in tumorigenesis. Introduction of persistently activated EGFR into immortalized breast epithelial cells led to tumorigenesis, IL-6 expression, and STAT3 activation, all of which could be inhibited with P6 or gp130 blockade. Furthermore, inhibition of EGFR activity in multiple cell lines partially blocked transcription of IL-6 and concurrently decreased production and release of IL-6. Finally, immunohistochemical analysis revealed a positive correlation between pSTAT3 and IL-6 positivity in primary lung adenocarcinomas. Therefore, mutant EGFR could activate the gp130/JAK/STAT3 pathway by means of IL-6 upregulation in primary human lung adenocarcinomas, making this pathway a potential target for cancer treatment.
IGKC and Prognosis in Breast Cancer–Letter
Authors: Marcus Schmidt, Patrick Micke, Jan G. Hengstler
Journal: Clinical Cancer Research (2012)

We thank Whiteside and Ferrone for their insightful CCR Translations article (1) in response to our article (2). They accurately describe how our knowledge of the role of the immune system in tumor prognosis has evolved since the 1980s. Their explanation of the beneficial role of tumor-infiltrating plasma cells via antibody-dependent cellular cytotoxicity, similar to the tumor antigen–specific therapeutic antibodies rituximab, cetuximab, or trastuzumab (Fig. 1 in ref. 1), is quite elegant. Nevertheless, to avoid any misunderstanding of our work, 2 specific aspects should be addressed. The first is that the B-cell plasma cell metagene, but not the T-cell metagene, had a significant prognostic impact on metastasis-free survival (third paragraph in ref. 1). In fact, the B-cell plasma cell metagene (or IGKC as a single marker) was associated with metastasis-free interval (MFI) in univariate and multivariate analyses. However, the T-cell metagene is also associated with MFI in the univariate analysis in 3 independent clinical cohorts of fast proliferating carcinomas (Table 2 in ref. 3). Only when adjusted to the B-cell/plasma cell metagene does the T-cell metagene lose its significance. This is explained by the high degree of correlation between the B-cell/plasma and T-cell metagenes, which in turn corresponds to the observation that a tumor with many infiltrating plasma cells also contains a high number of T cells. However, there is also a subgroup of patients with low B-cell/plasma cell and high T cell metagene expression. Therefore, we should avoid the misunderstanding that T-cell infiltration is not relevant in breast cancer.The second comment refers to the Janus-faced nature of the humoral immune system. Clearly, plasma cell infiltration (indicated by the single biomarker IGKC) is associated with better prognosis in breast, lung, and colon cancer. However, a minority of the 60-gene B-cell/plasma cell metagene is associated not with better but with worse prognosis. Do these genes indicate that plasma cells can turn "evil" and also initiate protumor effects, possibly by secreting cytokines that stimulate tumor growth (4)? Although the discovery of tumor-infiltrating plasma cell dates back to the 1980s (5), the quest for a deeper understanding of the Janus-faced humoral immune system has just begun.See the Response, p. 305No potential conflicts of interest were disclosed.
The Diversity of Class II Transposable Elements in Mammalian Genomes Has Arisen from Ancestral Phylogenetic Splits during Ancient Waves of Proliferation through the Genome
Authors: E. H. B. Hellen, J. F. Y. Brookfield
Journal: Molecular Biology and Evolution (2012)

DNA transposons make up 3% of the human genome, approximately the same percentage as genes. However, because of their inactivity, they are often ignored in favor of the more abundant, active, retroelements. Despite this relative ignominy, there are a number of interesting questions to be asked of these transposon families. One particular question relates to the timing of proliferation and inactivation of elements in a family. Does an ongoing process of turnover occur, or is the process more akin to a life cycle for the family, with elements proliferating rapidly before deactivation at a later date? We answer this question by tracing back to the most recent common ancestor (MRCA) of each modern transposon family, using two different methods. The first method identifies the MRCA of the species in which a family of transposon fossils can still be found, which we assume will have existed soon after the true origin date of the transposon family. The second method uses molecular dating techniques to predict the age of the MRCA element from which all elements found in a modern genome are descended. Independent data from five pairs of species are used in the molecular dating analysis: human–chimpanzee, human–orangutan, dog–panda, dog–cat, and cow–pig. Orthologous pairs of elements from host species pairs are included, and the divergence dates of these species are used to constrain the analysis. We discover that, in general, the times to element common ancestry for a given family are the same for the different species pairs, suggesting that there has been no order-specific process of turnover. Furthermore, for most families, the ages of the common ancestor of the host species and of that of the elements are similar, suggesting a life cycle model for the proliferation of transposons. Where these two ages differ, in families found only in Primates and Rodentia, for example, we find that the host species date is later than that of the common ancestor of the elements, implying that there may be large deletions of elements from host species, examples of which were found in their ancestors.