tbuckley/cabot-search huggingface dataset:
Prostanoids as anti-inflammatory therapy: separating the good from the bad
Authors: Alan J Knox
Journal: Thorax (2015)

Prostanoids are important endogenous signalling molecules that are produced locally both physiologically and in inflammatory diseases and have potent effects on a number of inflammatory processes. Endogenous prostaglandin production consists of several stages: conversion of membrane phospholipid to arachidonic acid via phospholipase A2, conversion of arachidonic acid to PGG2 by cyclo-oxygenase (COX), a peroxidase reaction to produce PGH2 and then conversion of PGH2 by specific synthases and isomerases to PGE2, PGI2, PGF2α or PGD2. COX is present in most cells, and it is the synthase/isomerase complement of the cell that determines the balance of prostanoids produced by a given cell type. Inflammatory cells tend to produce PGD2 and PGF2α, whereas airway structural cells such as smooth muscle (airway and vascular), fibroblasts, endothelial and epithelial cells produce an abundance of PGE2 or PGI2.1

In contrast to PGD2 and PGF2α, which are predominantly pro-inflammatory, PGE2 is predominantly anti-inflammatory.2 PGE2 inhibits acetylcholine release from parasympathetic nerve endings, mast cell mediator release and cellular responses in eosinophils, macrophages …
Studying alternative splicing regulatory networks through partial correlation analysis
Authors: Liang Chen, Sika Zheng
Journal: Genome biology (2009)

Alternative pre-mRNA splicing is an important gene regulation mechanism for expanding proteomic diversity in higher eukaryotes. Each splicing regulator can potentially influence a large group of alternative exons. Meanwhile, each alternative exon is controlled by multiple splicing regulators. The rapid accumulation of high-throughput data provides us with a unique opportunity to study the complicated alternative splicing regulatory network. We propose the use of partial correlation analysis to identify association links between exons and their upstream regulators or their downstream target genes (exon-gene links) and links between co-spliced exons (exon-exon links). The partial correlation analysis avoids taking the ratio of two noisy random variables, exon expression level and gene expression level, so that it achieves a higher statistical power. We named this analysis procedure pCastNet (partial Correlation analysis of splicing transcriptome Network). Through studies of known alternative exons, conservation patterns, relative positions, functional annotations, and RT-PCR experiments, we concluded that pCastNet can effectively identify exon-gene or exon-exon links. We further found that gene pairs with exon-gene or exon-exon links tend to have similar functions or are present in the same pathways. More interestingly, gene pairs with exon-gene or exon-exon links tend to share cis-elements in promoter regions and microRNA binding elements in 3' untranslated regions, which suggests the coupling of co-alternative-splicing, co-transcription-factor-binding, and co-microRNA-binding. Alternative splicing regulatory networks reconstructed by pCastNet can help us better understand the coordinate and combinatorial nature of alternative splicing regulation. The proposed tool can be readily applied to other high-throughput data such as transcriptome sequencing data.
Association between 24-Hour Urinary Cadmium and Pulmonary Function among Community-Exposed Men: The VA Normative Aging Study
Authors: Brad J. Lampe, Sung Kyun Park, Thomas Robins, Bhramar Mukherjee, Augusto A. Litonjua, Chitra Amarasiriwardena, Marc Weisskopf, David Sparrow, Howard Hu
Journal: Environmental Health Perspectives (2008)

BackgroundHigh levels of cadmium exposure are known to cause emphysema in occupationally exposed workers, but little has been reported to date on the association between chronic environmental cadmium exposure and pulmonary function.ObjectiveIn this study we examined the association between pulmonary function and cadmium body burden in a subcohort of the Normative Aging Study, a community-based study of aging.MethodsWe examined 96 men who had cadmium measured in single 24-hr urinary specimens collected in 1994–1995 and who had one to three tests of pulmonary function between 1994 and 2002 (a total of 222 observations). We used mixed-effect models to predict pulmonary function based on individual 24-hr urinary cadmium output, adjusted for age, height, time elapsed from the baseline, and smoking status. We assessed effect modification by smoking status.ResultsAmong all subjects, a single log-unit increase in baseline urinary cadmium was inversely associated with forced expiratory volume in 1 sec (FEV1) percent predicted [β = −7.56%; 95% confidence interval (CI) −13.59% to −1.53%]; forced vital capacity (FVC) percent predicted (β = −2.70%; 95% CI −7.39% to 1.99%), and FEV1/FVC ratio (β = −4.13%; 95% CI −7.61% to −0.66%). In models including an interaction between urinary cadmium and smoking status, there was a graded, statistically significant reduction in FEV1/FVC ratio across smoking status in association with urinary cadmium.ConclusionsThis study suggests that chronic cadmium exposure is associated with reduced pulmonary function, and cigarette smoking modifies this association. These results should be interpreted with caution because the sample size is small, and further studies are needed to confirm our findings.
ACCF/AHA/AMA–PCPI 2011 Performance Measures for Adults With Coronary Artery Disease and Hypertension
Authors: Joseph Drozda, Joseph V. Messer, John Spertus, Bruce Abramowitz, Karen Alexander, Craig T. Beam, Robert O. Bonow, Jill S. Burkiewicz, Michael Crouch, David C. Goff, Richard Hellman, Thomas James, Marjorie L. King, Edison A. Machado, Eduardo Ortiz, Michael O'Toole, Stephen D. Persell, Jesse M. Pines, Frank J. Rybicki, Lawrence B. Sadwin, Joanna D. Sikkema, Peter K. Smith, Patrick J. Torcson, John B. Wong
Journal: Circulation (2011)
Histogenesis of Clear Cell Adenocarcinoma in the Urinary Tract: Evidence of Urothelial Origin
Authors: Ming-Tse Sung, Shaobo Zhang, Gregory T. MacLennan, Antonio Lopez-Beltran, Rodolfo Montironi, Mingsheng Wang, Puay-Hoon Tan, Liang Cheng
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Clear cell adenocarcinoma in the urinary tract is a rare entity with an appearance resembling its counterpart in the female genital tract. Although several theories have been proposed about its origin, its exact histogenesis has remained uncertain. Experimental Design: We integrated molecular genetic evaluation by fluorescence in situ hybridization and X-chromosome inactivation with conventional morphologic and immunohistochemical analyses in 12 patients with clear cell adenocarcinomas in the urinary tract. Results: Concurrent urothelial carcinoma or urothelial carcinoma in situ was present in six cases (50%) and foci of cystitis glandularis were observed in four cases (33%). Neither intestinal metaplasia nor Müllerian component was identified in any case. Cytoplasmic expression of α-methylacyl-CoA racemase was demonstrable in 10 of 12 tumors (83%). Moderate to diffuse immunostaining for cytokeratin 7 was identified in all 12 tumors (100%), whereas only 3 of 12 (25%) tumors showed positive immunostaining for cytokeratin 20. Focal uroplakin III staining was seen in 6 of 12 tumors (50%). In five cases (42%), focal to moderate CD10 immunoreactivity was observed. Immunostains for OCT4 and CDX2 were completely negative in all tumors. In UroVysion fluorescence in situ hybridization assays, all tumors displayed chromosomal alterations similar to those commonly found in urothelial carcinoma. Identical patterns of nonrandom X-chromosome inactivation in concurrent clear cell adenocarcinoma and urothelial neoplasia were identified in two informative female cases. Conclusions: Our findings support an urothelial origin for most clear cell adenocarcinomas of the urinary tract, despite their morphologic resemblance to certain Müllerian-derived tumors of the female genital tract.
International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders
Authors: A Dispenzieri, R Kyle, G Merlini, J S Miguel, H Ludwig, R Hajek, A Palumbo, S Jagannath, J Blade, S Lonial, M Dimopoulos, R Comenzo, H Einsele, B Barlogie, K Anderson, M Gertz, J L Harousseau, M Attal, P Tosi, P Sonneveld, M Boccadoro, G Morgan, P Richardson, O Sezer, M V Mateos, M Cavo, D Joshua, I Turesson, W Chen, K Shimizu, R Powles, S V Rajkumar, B G M Durie
Journal: Leukemia (2008)
Statins use is associated with a reduced incidence of colorectal adenomatous polyps: a case-control study
Authors: I. Beales, T. Broughton, J. Sington
Journal: Gut (2011)

<h3>Introduction</h3> Colorectal cancer (CRC) remains a major clinical problem: advances in screening and therapies have improved the prognosis, but effective and safe chemopreventative strategies would likely be beneficial. HMG-CoA reductase inhibitors (statins) have been shown to have anti-CRC effects in vitro, inhibiting growth and inducing apoptosis, but studies examining the effects of statins on CRC incidence have produced inconsistent results, possibly because of varying experimental methodologies and duration of statin exposure. Because of the time taken to develop CRC, studies with only short-term statin exposure may have yielded negative results. Adenomatous polyps (APs) are the precursors of CRC, and we hypothesized that statins may affect the incidence of APs, and this effect may be manifest in a shorter time span. <h3>Methods</h3> We performed a case-control study with research ethics and R&amp;D approvals. Patients attending for diagnostic colonoscopy and not undergoing polyp surveillance underwent detailed interviews with trained interviewers to determine drug and risk factor exposure, referral letters and clinical notes were used to corroborate the data. Results were calculated as odds ratios, with logistical regression to adjust for demographic and other risk and preventative factors. <h3>Results</h3> 116 AP and 132 control subjects were interviewed. In the unadjusted analysis, statin use was associated with a reduced AP incidence (OR 0.17 (95% CI 0.09 to 0.32)). Use of aspirin, NSAIDs and metformin were also associated with reduced AP incidence in the unadjusted analysis. However, the effect of statins remained highly significant after adjustment: and was associated with a reduction in the presence of APs (adjusted OR 0.10 (0.04–0.26) (<i>P</i> &lt; 0.01). The majority of statin use was simvastatin but the effects were consistent for all statins. Higher doses of statins and longer duration of statin use were associated with a significantly greater reduction in the incidence of APs. Similar reductions were seen with high- and low risk APs. Interestingly the protective effect of aspirin and other drugs disappeared when adjusted for statin exposure. <h3>Conclusion</h3> Statin use is associated with a reduced incidence of colorectal adenomatous polyps. Further studies examining the potential chemopreventative actions should be undertaken. Subsequent studies examining putative chemopreventative actions should adjust for statin exposure.
Mechanism of Regulation and Suppression of Melanoma Invasiveness by Novel Retinoic Acid Receptor-γ Target Gene Carbohydrate Sulfotransferase 10
Authors: Xiansi Zhao, Carole Graves, Sarah J. Ames, David E. Fisher, Remco A. Spanjaard
Journal: Cancer Research (2009)

Retinoic acid (RA) induces growth arrest and differentiation of S91 murine melanoma cells and serves as a valuable model for this disease. RA acts through activation of RA receptors (RAR), which are members of the nuclear receptor superfamily of ligand-inducible transcription factors. Interestingly, differentiation is mediated by RARgamma, but not by RARalpha or RARbeta, suggesting that RARgamma possesses unique and uncharacterized molecular properties. To address this question, DNA microarrays in combination with RAR isoform-specific agonists were employed to identify novel RARgamma target genes that may play a role in this process. Here, we identified and validated carbohydrate sulfotransferase 10 (CHST10) as a novel RARgamma target gene in S91 cells. The RARgamma-inducible CHST10 promoter was obtained, and two atypical, independently functioning RA response elements were identified in a 425 bp region. Surprisingly, this fragment is bound by RARgamma, but not by RARalpha or RARbeta, thus providing a mechanism for the observed RARgamma-specific regulation. CHST10 is a sulfotransferase that forms HNK-1 glycan on neural cell adhesion proteins and glycolipids, and HNK-1 is thought to modulate cell adhesion and possibly metastasis. We show that CHST10 is also regulated by RARgamma in a significant subset of human melanoma cells, and three-dimensional cell culture migration assays suggest that CHST10 functions as a suppressor of invasiveness, but not proliferation, in these cells. Induction of CHST10 by RARgamma-activating retinoids may present a novel therapeutic strategy to inhibit invasiveness in a subset of melanoma patients.
Gemcitabine, Epirubicin, and Paclitaxel Versus Fluorouracil, Epirubicin, and Cyclophosphamide As First-Line Chemotherapy in Metastatic Breast Cancer: A Central European Cooperative Oncology Group International, Multicenter, Prospective, Randomized Phase III Trial
Authors: Christoph Zielinski, Semir Beslija, Zrinka Mrsic-Krmpotic, Marzena Welnicka-Jaskiewicz, Christoph Wiltschke, Zsuzsanna Kahan, Mislav Grgic, Valentina Tzekova, Moshe Inbar, Jozika Cervek, Ivan Chernozemsky, Janos Szanto, Stanislav Spanik, Maria Wagnerova, Nicolae Ghilezan, Janusz Pawlega, Damir Vrbanec, Dmitry Khamtsov, Victoria Soldatenkova, Thomas Brodowicz
Journal: Journal of Clinical Oncology (2005)

The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC).Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles.Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm.No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.
The European Medicines Agency: An Overview of Its Mission, Responsibilities, and Recent Initiatives in Cancer Drug Regulation
Authors: Francesco Pignatti, Iordanis Gravanis, Ralf Herold, Spiros Vamvakas, Bertil Jonsson, Michel Marty
Journal: Clinical Cancer Research (2011)

The European Medicines Agency (EMA) is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union (EU). Since 2005, the agency has become responsible for the approval of all new oncology drugs in the EU. In this article we describe the mission, role, and responsibilities of the EMA, and provide a brief summary of recent initiatives related to cancer drug regulation. The EMA recently published its Road Map to 2015. Over the next 5 years, the agency aims to continue to stimulate drug development in areas of unmet medical needs. Concerning drug safety, one of the priorities over the next few years will be to establish a more proactive approach in ensuring patient safety. This is the result of new EU legislation coming into force in 2012 that will strengthen the way the safety of medicines for human use is monitored in the EU. In terms of its general operation, the agency is committed to increased openness and transparency, and to build on its interactions with stakeholders, including members of academia, health care professionals, patients, and health technology assessment bodies. The agency recently created an oncology working party to expand the current guideline for the development and evaluation of cancer drugs. The guideline focuses on both exploratory and confirmatory studies for different types of agents. The current revision will address a number of topics, including the use of biomarkers as an integrated part of drug development and the use of progression-free survival as a primary endpoint in registration trials.
[18F]Fluoromethyl-[1,2-2H4]-Choline: A Novel Radiotracer for Imaging Choline Metabolism in Tumors by Positron Emission Tomography
Authors: Julius Leyton, Graham Smith, Yongjun Zhao, Meg Perumal, Quang-De Nguyen, Edward Robins, Erik Årstad, Eric O. Aboagye
Journal: Cancer Research (2009)

Current radiotracers for positron emission tomography imaging of choline metabolism have poor systemic metabolic stability in vivo. We describe a novel radiotracer, [(18)F]fluoromethyl-[1,2-(2)H(4)]-choline (D4-FCH), that employs deuterium isotope effect to improve metabolic stability. D4-FCH proved more resistant to oxidation than its nondeuterated analogue, [(18)F]fluoromethylcholine, in plasma, kidneys, liver, and tumor, while retaining phosphorylation potential. Tumor radiotracer levels, a determinant of sensitivity in imaging studies, were improved by deuterium substitution; tumor uptake values expressed as percent injected dose per voxel at 60 min were 7.43 +/- 0.47 and 5.50 +/- 0.49 for D4-FCH and [(18)F]fluoromethylcholine, respectively (P = 0.04). D4-FCH was also found to be a useful response biomarker. Treatment with the mitogenic extracellular kinase inhibitor PD0325901 resulted in a reduction in tumor radiotracer uptake that occurred in parallel with reductions in choline kinase A expression. In conclusion, D4-FCH is a very promising metabolically stable radiotracer for imaging choline metabolism in tumors.
Analysis of 1-Year Clinical Outcomes in the SIRIUS Trial
Authors: David R. Holmes, Martin B. Leon, Jeffrey W. Moses, Jeffrey J. Popma, Donald Cutlip, Peter J. Fitzgerald, Charles Brown, Tim Fischell, Shing Chiu Wong, Mark Midei, David Snead, Richard E. Kuntz
Journal: Circulation (2004)

Background— This study evaluated a large group of patients enrolled in a double-blind randomized trial of the sirolimus-eluting stent to document whether the initial clinical improvement seen in previous smaller series is maintained out to 12 months and to study the potential treatment effect in patient subsets known to be at increased risk of restenosis. Methods and Results— A total of 1058 patients with de novo native coronary stenosis undergoing clinically indicated percutaneous coronary intervention were randomly assigned to sirolimus-eluting stent (533) or control bare stent (525). Procedural success and in-hospital outcomes were excellent and did not differ between the 2 groups. At 9 months, clinical restenosis, defined as target-lesion revascularization, was 4.1% in the sirolimus limb versus 16.6% in the control limb ( P &lt;0.001). At 12 months, the absolute difference in target-lesion revascularization continued to increase and was 4.9% versus 20% ( P &lt;0.001). There were no differences in death or myocardial infarction rates. In high-risk patient subsets, defined by vessel size, lesion length, and presence of diabetes mellitus, there was a 70% to 80% reduction in clinical restenosis at 1 year. Conclusions— Placement of the sirolimus-eluting stent results in continued clinical improvement at 1 year after initial implantation, with significant reduction in clinical restenosis as defined by target-lesion revascularization. Between 9 and 12 months, the absolute reduction of clinical restenosis continues to increase. Even in high-risk subsets of patients, there is a 70% to 80% relative reduction in clinical restenosis at 12 months with this drug-eluting stent.
Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson’s disease
Authors: Yupin Chen, Dong-qi Zhang, Zhong Liao, Bin Wang, Suzhen Gong, Chuang Wang, Ming-zi Zhang, Guo-hua Wang, Huaibin Cai, Francesca-Fang Liao, Jiang-ping Xu
Journal: Molecular Neurodegeneration (2015)

Compelling evidence suggests that inhibition of the complex I of the electron transport chain and elevated oxidative stress are the earliest events during the pathogenesis of Parkinson's disease (PD). Therefore, anti-oxidants, especially those from natural sources, hold good promise in treating PD as demonstrated mostly by the studies in rodent models. Herein, we determined if polydatin (piceid), a natural polyphenol, could exert anti-oxidative activity and attenuate dopaminergic neurodegeneration in three commonly used rodent models of PD. Male Sprague Dawley rats given rotenone subcutaneously for 5 weeks developed all the essential features of PD, including a strong increase in catalepsy score and a decrease in motor coordination activity, starting at 4 weeks. Selective increase in oxidative damage was found in the striatal region as compared to the hippocampus and cortex, accompanied by massive degeneration of dopaminergic neurons in the substantia nigra (SNc). Co-administration of piceid orally was able to attenuate rotenone-induced motor defects in a dose dependent manner, with 80 mg/kg dosage showing even better effect than L-levodopa (L-dopa). Piceid treatment significantly prevented the rotenone-induced changes in the levels of glutathione, thioredoxin, ATP, malondialdehyde (MDA) and the manganese superoxide dismutases (SOD) in striatum. Furthermore, piceid treatment rescued rotenone-induced dopaminergic neurodegeneration in the SNc region. Similar protective effect of piceid was also observed in two additional models of PD, MPTP in mice and 6-OHDA in rats, showing corrected motor functions, SOD and MDA activities as well as p-Akt and activated caspase-3 levels. In three rodent models of PD, piceid preserves and corrects several major anti-oxidant pathways/parameters selectively in the affected SNc region. This implies its potent anti-oxidant activity as one major underscoring mechanism for protecting the vulnerable SNc neurodegeneration in these models. Taken together, these findings strongly suggest a therapeutic potential of piceid in treating PD.
Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer
Authors: S.X. Bian, D.A. Kuban, L.B. Levy, J. Oh, K.O. Castle, T.J. Pugh, S. Choi, S.E. McGuire, Q.N. Nguyen, S.J. Frank, P.L. Nguyen, A.K. Lee, K.E. Hoffman
Journal: Annals of Oncology (2012)