tbuckley/cabot-search huggingface dataset:
Nephropathy in Zucker Diabetic Fat Rat Is Associated with Oxidative and Nitrosative Stress
Authors: Praveen N. Chander, Olga Gealekman, Sergey V. Brodsky, Saban Elitok, Akihiro Tojo, Mark Crabtree, Steven S. Gross, Michael S. Goligorsky
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Zucker diabetic fat (ZDF) rats with the metabolic syndrome and hyperlipidemia develop focal and segmental sclerosis. The role of oxidative and nitrosative stress in the nephropathy in ZDF was studied. Renal histology, function, and immunohistologic and biochemical parameters of oxidative and nitrosative stress were evaluated at 8 and 22 wk of age in ZDF and Zucker lean (ZL) rats and after chronic treatment with ebselen, an antioxidant and peroxinitrite scavenger. At 8 wk, ZDF rats showed hyperglycemia, no proteinuria or nephropathy, but higher levels of dihydrobiopterin and 3-nitrotyrosine (3-NT)–modified proteins compared with age-matched ZL rats. At 22 wk, ZDF rats developed focal and segmental sclerosis, proteinuria, decreased creatinine clearance, and renal tissue levels of glutathione and tetrahydrobiopterin with further elevation in dihydrobiopterin and 3-NT–modified proteins, in contrast to age-matched ZL rats. Renal immunohistologic expression of lipid peroxidation products and 3-NT–modified proteins also increased in 22-wk-old ZDF but not in ZL rats. Chronic ebselen treatment of ZDF rats restored renal tissue levels of glutathione and tetrahydrobiopterin; prevented significant accumulation of dihydrobiopterin, lipid peroxidation products, and 3-NT–modified proteins; and ameliorated focal and segmental sclerosis, proteinuria, and fall in creatinine clearance without affecting mean BP, body weight, and blood glucose, compared with the untreated ZDF rats. Chronic ebselen therapy also ameliorated vasculopathy with lipid deposits and tubulointerstitial scarring, inflammation, and upregulated α-smooth muscle actin expression. These findings suggest that ZDF rats develop a progressive nephropathy with glomerular, vascular, and tubulointerstitial pathology. Oxidative and nitrosative stress predates the nephropathy, which is improved by peroxinitrite scavenger ebselen, and thus considered its cause and not consequence.
Tumor necrosis factor-mediated release of platelet-derived growth factor from cultured endothelial cells.
Authors: K A Hajjar, D P Hajjar, R L Silverstein, R L Nachman
Journal: The Journal of Experimental Medicine (1987)

Platelet-derived growth factor (PDGF) is a 30,000-Mr glycoprotein that is chemotactic and mitogenic for vascular smooth muscle cells (SMC). It is also a potent vasoconstrictor. In the present study, we found that the macrophage-derived polypeptide, tumor necrosis factor (TNF), releases a factor from human umbilical vein endothelial cells (EC) that is mitogenic for SMC. Postculture medium from TNF-stimulated EC induced a 90% increase in mitogenesis is compared with controls. This effect was half-maximal at a TNF dose of 114 pM, reflected a 2.5-fold increase in PDGF-specific mRNA synthesis, and peaked at 15 h of TNF stimulation. Mitogenic activity was completely abrogated by preincubation of postculture medium with antibody to platelet PDGF. Stimulation of EC with IL-1 (60-240 pM) led to the release of similar mitogenic activity. Thus, in addition to its effects on the hemostatic and adhesive properties of EC, TNF also promotes release of PDGF, which may serve to modulate proliferation of vascular SMC during wound healing, inflammation, and atherogenesis.
Prediction of Function Divergence in Protein Families Using the Substitution Rate Variation Parameter Alpha
Authors: Saraswathi Abhiman, Carsten O. Daub, Erik L. L. Sonnhammer
Journal: Molecular Biology and Evolution (2006)

Protein families typically embody a range of related functions and may thus be decomposed into subfamilies with, for example, distinct substrate specificities. Detection of functionally divergent subfamilies is possible by methods for recognizing branches of adaptive evolution in a gene tree. As the number of genome sequences is growing rapidly, it is highly desirable to automatically detect subfamily function divergence.
Whole-Exome Sequencing of Muscle-Invasive Bladder Cancer Identifies Recurrent Mutations of <i>UNC5C</i> and Prognostic Importance of DNA Repair Gene Mutations on Survival
Authors: Kai Lee Yap, Kazuma Kiyotani, Kenji Tamura, Tatjana Antic, Miran Jang, Magdeline Montoya, Alexa Campanile, Poh Yin Yew, Cory Ganshert, Tomoaki Fujioka, Gary D. Steinberg, Peter H. O'Donnell, Yusuke Nakamura
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators. Experimental Design: Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients. Results: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22–0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage. Conclusion: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted. Clin Cancer Res; 20(24); 6605–17. ©2014 AACR.
High doses of vitamin D may reduce exacerbations of chronic obstructive pulmonary disease
Authors: Emily Heiden
Journal: Thorax (2012)

Journal club High doses of vitamin D may reduce exacerbations of chronic obstructive pulmonary diseaseThere has been much research providing inconsistent evidence for a correlation between low levels of vitamin D and chronic conditions, such as coronary artery disease, multiple sclerosis and diabetes.It is known that vitamin D plays an integral role in the cathelicidin antimicrobial peptide, which serves a critical function in mammalian innate immune defence against invasive bacterial infection.As such, it has been hypothesised that low levels of vitamin D may be important in chronic obstructive pulmonary disease (COPD), in which there is an abnormal inflammatory reaction to inhaled particles and a reduced immune response.In this study, the authors recruited 182 patients into a double-blind, randomised, placebocontrolled trial exploring vitamin D supplementation and COPD exacerbations.One hundred and fifty patients completed the study.Patients recruited were either current or former smokers over the age of 50 years, with a diagnosis of moderate to severe COPD.They were randomised to receive 100 000 IU of vitamin D or placebo, and were monitored for a year.The primary outcome was time to first exacerbation.While mean vitamin D levels were significantly higher in the treatment group there was no statistically significant difference for median time to first exacerbation.Secondary outcomes, including exacerbation rate and quality of life were also not significantly different between groups.However, there was a significant reduction in exacerbations in the vitamin D group in those patients with a severe vitamin D deficiency at baseline, suggesting that supplementation may be useful in a subset of patients.< Lehouck A, Mathieu C, Carremans C, et al.High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease.
Effect of phenylhexyl isothiocyanate on aberrant histone H3 methylation in primary human acute leukemia
Authors: Yong Zou, Xudong Ma, Yiqun Huang, Lingling Hong, Jen-wei Chiao
Journal: Journal of Hematology & Oncology (2012)

Abstract Background We have previously studied the histone acetylation in primary human leukemia cells. However, histone H3 methylation in these cells has not been characterized. Methods This study examined the methylation status at histone H3 lysine 4 (H3K4) and histone H3 lysine 9 (H3K9) in primary acute leukemia cells obtained from patients and compared with those in the non-leukemia and healthy cells. We further characterized the effect of phenylhexyl isothiocyanate (PHI), Trichostatin A (TSA), and 5-aza-2’-deoxycytidine (5-Aza) on the cells. Results We found that methylation of histone H3K4 was virtually undetectable, while methylation at H3K9 was significantly higher in primary human leukemia cells. The histone H3K9 hypermethylation and histone H3K4 hypomethylation were observed in both myeloid and lymphoid leukemia cells. PHI was found to be able to normalize the methylation level in the primary leukemia cells. We further showed that PHI was able to enhance the methyltransferase activity of H3K4 and decrease the activity of H3K9 methyltransferase. 5-Aza had similar effect on H3K4, but minimal effect on H3K9, whereas TSA had no effect on H3K4 and H3K9 methyltransferases. Conclusions This study revealed opposite methylation level of H3K4 and H3K9 in primary human leukemia cells and demonstrated for the first time that PHI has different effects on the methyltransferases for H3K4 and H3K9.
Specificity of Problem-Solving Skills Training in Mothers of Children Newly Diagnosed With Cancer: Results of a Multisite Randomized Clinical Trial
Authors: Olle Jane Z. Sahler, Michael J. Dolgin, Sean Phipps, Diane L. Fairclough, Martha A. Askins, Ernest R. Katz, Robert B. Noll, Robert W. Butler
Journal: Journal of Clinical Oncology (2013)

Diagnosis of cancer in a child can be extremely stressful for parents. Bright IDEAS, a problem-solving skills training (PSST) intervention, has been shown to decrease negative affectivity (anxiety, depression, post-traumatic stress symptoms) in mothers of newly diagnosed patients. This study was designed to determine the specificity of PSST by examining its direct and indirect (eg, social support) effects compared with a nondirective support (NDS) intervention.This randomized clinical trial included 309 English- or Spanish-speaking mothers of children diagnosed 2 to 16 weeks before recruitment. Participants completed assessments prerandomization (T1), immediately postintervention (T2), and at 3-month follow-up (T3). Both PSST and NDS consisted of eight weekly 1-hour individual sessions. Outcomes included measures of problem-solving skill and negative affectivity.There were no significant between-group differences at baseline (T1). Except for level of problem-solving skill, which was directly taught in the PSST arm, outcome measures improved equally in both groups immediately postintervention (T2). However, at the 3-month follow-up (T3), mothers in the PSST group continued to show significant improvements in mood, anxiety, and post-traumatic stress; mothers in the NDS group showed no further significant gains.PSST is an effective and specific intervention whose beneficial effects continue to grow after the intervention ends. In contrast, NDS is an effective intervention while it is being administered, but its benefits plateau when active support is removed. Therefore, teaching coping skills at diagnosis has the potential to facilitate family resilience over the entire course of treatment.
TENDINOPATHY: MORE QUESTIONS THAN ANSWERS
Authors: H Langberg
Journal: British Journal of Sports Medicine (2013)

Tendinopathy is a big problem for athletes, ordinary people and clinicians. At present neither the aetiology and pathology, nor the rehabilitations is well understood, and good evidence is lacking within all these areas. During the last 10 years substantial research has been performed. New data indicate that in the chronic state, tendinopathy in humans is characterised by focal changes in the expression of matrix proteins, increased collagen turnover, smaller collagen fibrils and increased microvascular volume. These changes are attenuated with increased loading as during running. Despite this new knowledge, models for investigating the development of tendinopathy are still lacking and the complex nature of tendinopathy is still a great challenge. However, by developing novel human and animal models, hopefully a thorough understanding of human tendinopathy will be possible within the near future. In relation to treatment, new methods such as injection of platelet rich plasma (PRP) and large quantities of isotonic saline (HVI) have been developed based on sound rationales, but with only minor scientific evidence. More research is needed in this area too.
Chemotherapy Use among Medicare Beneficiaries at the End of Life
Authors: Ezekiel J. Emanuel, Yinong Young-Xu, Norman G. Levinsky, Gail Gazelle, Olga Saynina, Arlene S. Ash
Journal: Annals of Internal Medicine (2003)

Background: Although many observers believe that cancer chemotherapy is overused at the end of life, there are no published data on this. Objective: To determine the frequency and duration of chemotherapy use in the last 6 months of life stratified by type of cancer, age, and sex. Design: Retrospective cohort analysis. Setting: Administrative databases from Massachusetts and California. Patients: All Medicare patients who died of cancer in Massachusetts and 5% of Medicare cancer decedents in California in 1996. Measurements: Use of intravenous chemotherapy agents, chemotherapy administration, or medical evaluation for chemotherapy from Medicare billing data for each patient in 30-day periods from the date of death backward. Results: In Massachusetts, 33% of cancer decedents older than 65 years of age received chemotherapy in the last 6 months of life, 23% in the last 3 months, and 9% in the last month. In California, the percentages were 26%, 20%, and 9%, respectively. Chemotherapy use greatly declined with age. Chemotherapy use was similar for patients with breast, colon, and ovarian cancer and those with cancer generally considered unresponsive to chemotherapy, such as pancreatic, hepatocellular, or renal-cell cancer or melanoma. Patients with types of cancer that are unresponsive to chemotherapy had shorter duration of chemotherapy use. Conclusion: Among patients who died of cancer, chemotherapy was used frequently in the last 3 months of life. The cancer's responsiveness to chemotherapy does not seem to influence whether dying patients receive chemotherapy at the end of life.
Endothelin signalling regulates volume-sensitive Cl− current via NADPH oxidase and mitochondrial reactive oxygen species
Authors: Wu Deng, Lia Baki, Clive M. Baumgarten
Journal: Cardiovascular Research (2010)

AimsWe assessed regulation of volume-sensitive Cl− current (ICl,swell) by endothelin-1 (ET-1) and characterized the signalling pathway responsible for its activation in rabbit atrial and ventricular myocytes.
Electrical Coupling and Propagation in Engineered Ventricular Myocardium With Heterogeneous Expression of Connexin43
Authors: Philippe Beauchamp, Thomas Desplantez, Megan L. McCain, Weihui Li, Angeliki Asimaki, Ghislaine Rigoli, Kevin Kit Parker, Jeffrey E. Saffitz, Andre G. Kleber
Journal: Circulation Research (2012)

Spatial heterogeneity in connexin (Cx) expression has been implicated in arrhythmogenesis.This study was performed to quantify the relation between the degree of heterogeneity in Cx43 expression and disturbances in electric propagation.Cell pairs and strands composed of mixtures of Cx43(-/-) (Cx43KO) or GFP-expressing Cx43(+/+) (WT(GFP)) murine ventricular myocytes were patterned using microlithographic techniques. At the interface between pairs of WT(GFP) and Cx43KO cells, dual-voltage clamp showed a marked decrease in electric coupling (approximately 5% of WT) and voltage gating suggested the presence of mixed Cx43/Cx45 channels. Cx43 and Cx45 immunofluorescence signals were not detectable at this interface, probably because of markedly reduced gap junction size. Macroscopic propagation velocity, measured by multisite high-resolution optical mapping of transmembrane potential in strands of cells of mixed Cx43 genotype, decreased with an increasing proportion of Cx43KO cells in the strand. A marked decrease in conduction velocity was observed in strands composed of <50% WT cells. Propagation at the microscopic scale showed a high degree of dissociation between WT(GFP) and Cx43KO cells, but consistent excitation without development of propagation block.Heterogeneous ablation of Cx43 leads to a marked decrease in propagation velocity in tissue strands composed of <50% cells with WT Cx43 expression and marked dissociation of excitation at the cellular level. However, the small residual electric conductance between Cx43 and WT(GFP) myocytes assures excitation of Cx43(-/-) cells. This explains the previously reported undisturbed contractility in tissues with spatially heterogeneous downregulation of Cx43 expression.
AICAR inhibits PPARγ during monocyte differentiation to attenuate inflammatory responses to atherogenic lipids
Authors: Dmitry Namgaladze, Marina Kemmerer, Andreas von Knethen, Bernhard Brüne
Journal: Cardiovascular Research (2013)

Transcriptional regulation through peroxisome proliferator-activated receptor γ (PPARγ) is critical for an altered lipid metabolism during monocyte to macrophage differentiation. Here, we investigated how 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMP-dependent protein kinase (AMPK), affects PPARγ during monocyte differentiation.During the differentiation of THP-1 monocytic cells or primary human monocytes to macrophages, we observed that AICAR inhibited the expression of PPARγ target genes, such as fatty acid-binding protein 4 or CD36. This effect was independent of AICAR conversion to AICAR ribotide and AMPK activation. While AICAR increased PPARγ mRNA expression that paralleled differentiation, it inhibited PPARγ protein synthesis without affecting PPARγ protein stability. Monocytes differentiated to macrophages in the presence of AICAR revealed an attenuated uptake of oxidized low-density lipoprotein (oxLDL) and reduced oxLDL-triggered c-Jun N-terminal kinase (JNK) activation. JNK and endoplasmic reticulum stress responses to the saturated fatty acid palmitate were attenuated as well, an effect mimicked by the knockdown of PPARγ. Although PPARγ has been reported to support alternative macrophage activation, AICAR did not inhibit interleukin-4-induced gene expression in differentiating monocytes.Inhibition of PPARγ-dependent gene expression during monocyte differentiation may contribute to an AICAR-elicited macrophage phenotype characterized by reduced inflammatory responses to modified lipoproteins and saturated fatty acids.
New Directions in Tobacco Control
Authors: R. Rajkumar
Journal: JAMA (2001)

THE WORLD HEALTH ORGANIZATION (WHO) ESTIMATES THAT 4 MILLION people will die of tobacco-related illness in 2001 and that this number will climb to 10 million per year by the 2020s. Despite this overwhelming mortality, a significant gap exists between the scientific consensus on the dangers of tobacco use and the political reality of what governments have been able to achieve in terms of tobacco control. Last year, a US Supreme Court judgment stripped the Food and Drug Administration of its authority to regulate tobacco. The past few months have revealed a more insidious setback: a recent study found that the $206 billion master settlement agreement between 46 states and the tobacco industry, which was designed to fund a nationwide campaign to curb tobacco use, has had little effect on cigarette advertising in magazines and on the exposure of young people to these advertisements. Tobacco control involves both politics and science—and since the scientific evidence supporting tobacco regulation is sound and well documented, this suggests that there has been a breakdown in the political process. The health sector and its allied antitobacco forces have been stymied in their efforts to bring about enactment of effective tobacco control measures. While the consensus opinion of the medical community about tobacco-related mortality reflects the strength of epidemiologic and scientific evidence, this opinion does not prescribe any assured method for effecting political change. Having conclusively established the harm that results from tobacco use, the medical community must now find political direction in its antitobacco initiative if it is to be effective. This issue of MSJAMA explores the future of tobacco control. Asaf Bitton, Caroline Fichtenberg, and Stanton Glantz contend that an aggressive national tobacco control program can reduce US smoking prevalence from 22.7% to 10% in 5 years. Anticipating the criticism that such a program might provoke in a nation with a rich and longstanding libertarian tradition, Brion Fox reviews the barriers to tobacco control legislation and argues that such legislation is both appropriate and legally sustainable. Recognizing the emergence of a global tobacco market that demands global regulation, 2 articles present the nascent WHO-sponsored Framework Convention on Tobacco Control (FCTC), the first-ever international health treaty, currently being negotiated. Matthew Myers and Judith Wilkenfeld discuss how the international nature of tobacco trade necessitates an international treaty. Finally, Douglas Bettcher and Chitra Subramaniam describe the ethical and practical imperatives that have led the World Health Organization to pursue the FCTC. As the societal costs of tobacco use continue to grow, the time has come to evaluate the role of legislation in the reduction of tobaccorelated deaths. Having conclusively established the harm that results from tobacco use, the medical community must now find an equally effective political strategy.