tbuckley/cabot-search huggingface dataset:
Epigenetic Epidemiology of Common Complex Disease: Prospects for Prediction, Prevention, and Treatment
Authors: Caroline L. Relton, George Davey Smith
Journal: PLoS Medicine (2010)

There is considerable anticipation of future improvements in disease prevention and treatment following recent advances in genomics [1]. One aspect of genomics that is receiving considerable interest is epigenetics—the regulatory processes that control the transcription of information encoded in the DNA sequence into RNA before their translation into proteins. Programmed developmental changes and the ability of the genome to register, signal, and perpetuate environmental cues are subsumed under the epigenetic banner [2].

Genes are packaged into chromatin and dynamic chromatin remodeling processes are required for the initial step in gene expression (transcription), achieved by altering the accessibility of gene promoters and regulatory regions [3]. Epigenetic factors are responsible for this regulatory process, the major components of which are DNA methylation, histone modifications, and the action of small non-coding RNAs (Figure 1). Unlike DNA sequence, which is largely fixed throughout the lifecourse, epigenetic patterns not only vary from tissue to tissue but alter with advancing age and are sensitive to environmental exposures [4]–[7]. It is this propensity for change that makes epigenetic processes the focus of such interest, as they lie at the interface of the environment and co-ordinated transcriptional control.



Figure 1

Epigenetic modifications.



In rare developmental disorders, the role of aberrant epigenetic processes is well established [8]. Our focus here, however, is on the potential role of epigenetic processes in the context of common complex disease. Tumor-specific changes in epigenetic patterns are a hallmark of numerous cancers, with analysis of the epigenetic machinery beginning to feature prominently in emerging cancer diagnostics and therapies [9]–[11].

There is an increasing body of evidence to demonstrate that epigenetic patterns are altered by environmental factors known to be associated with disease risk (e.g., diet, smoking, alcohol intake, environmental toxicants, stress) [7],[8]; however, an important question remains to be resolved in defining which epigenetic changes are a secondary outcome of either exposure or disease, and which lie on the causal pathway linking the two. Without proven causality, interventions to prevent or treat common complex diseases based upon epigenetic mechanisms will not be fruitful. Conversely, regardless of causality, defining a robust prospective relationship between epigenetic patterns and phenotypic traits may have application in diagnostics or in identifying high-risk individuals for non-epigenetic-based interventions.
Use of Animals in Medical Education
Authors: William C. Scott
Journal: JAMA (1991)

The use of animals in general medical education is essential. Although several adjuncts to the use of animals are available, none can completely replace the limited use of animals in the medical curriculum. Students should be made aware of an institution's policy on animal use in the curriculum before matriculation, and faculty should make clear to all students the learning objectives of any educational exercise that uses animals. The Council on Scientific Affairs recognizes the necessity for the responsible and humane treatment of animals and urges all medical school faculty members to discuss this moral and ethical imperative with their students. (<i>JAMA</i>. 1991;266:836-837)
Emergence of Hydrogen Sulfide as an Endogenous Gaseous Signaling Molecule in Cardiovascular Disease
Authors: David J. Polhemus, David J. Lefer
Journal: Circulation Research (2014)

Long recognized as a malodorous and highly toxic gas, recent experimental studies have revealed that hydrogen sulfide (H2S) is produced enzymatically in all mammalian species including man and exerts several critical actions to promote cardiovascular homeostasis and health. During the past 15 years, scientists have determined that H2S is produced by 3 endogenous enzymes and exerts powerful effects on endothelial cells, smooth muscle cells, inflammatory cells, mitochondria, endoplasmic reticulum, and nuclear transcription factors. These effects have been reported in multiple organ systems, and the majority of data clearly indicate that H2S produced by the endogenous enzymes exerts cytoprotective actions. Recent preclinical studies investigating cardiovascular diseases have demonstrated that the administration of physiological or pharmacological levels of H2S attenuates myocardial injury, protects blood vessels, limits inflammation, and regulates blood pressure. H2S has emerged as a critical cardiovascular signaling molecule similar to nitric oxide and carbon monoxide with a profound effect on the heart and circulation. Our improved understanding of how H2S elicits protective actions, coupled with the rapid development of novel H2S-releasing agents, has resulted in heightened enthusiasm for the clinical translation of this ephemeral gaseous molecule. This review will examine our current state of knowledge about the actions of H2S within the cardiovascular system with an emphasis on the therapeutic potential and molecular cross talk between H2S, nitric oxide, and carbon monoxide.
Four-Gene Expression Ratio Test for Survival in Patients Undergoing Surgery for Mesothelioma
Authors: G. J. Gordon, L. Dong, B. Y. Yeap, W. G. Richards, J. N. Glickman, H. Edenfield, M. Mani, R. Colquitt, G. Maulik, B. Van Oss, D. J. Sugarbaker, R. Bueno
Journal: JNCI Journal of the National Cancer Institute (2009)

Malignant pleural mesothelioma has few effective treatments, one being cytoreductive surgery. We previously developed a gene ratio test to predict outcome of malignant pleural mesothelioma patients undergoing surgery. In this study, we investigated the predictive value and technical assay performance of this test in patients with malignant pleural mesothelioma. Clinical data were obtained prospectively from 120 consecutive patients with malignant pleural mesothelioma who were scheduled for debulking surgery at one institution. Specimens were obtained at surgery or by pleural biopsy examination. Expression data for four genes were collected from tumor specimens, and three ratios of gene expression (TM4SF1/PKM2, TM4SF1/ARHGDIA, and COBLL1/ARHGDIA) were determined by quantitative reverse transcriptase–polymerase chain reaction. Patients were assigned to good or poor outcome groups by the gene ratio test. Survival was estimated by the Kaplan–Meier method and the log-rank test in univariate analyses. A multivariable Cox proportional hazards model was used to control for prognostic factors. Technical robustness was determined by using up to 30 specimens per patient, two biopsy techniques, and two performance sites. All statistical tests were two-sided. The test predicted overall survival ( P < .001) and cancer-specific survival ( P = .007) in univariate analysis and overall survival in multivariable analysis (hazard ratio for death = 2.09, 95% confidence interval [CI] = 1.27 to 3.45, P = .004). The test was reproducible within patients and repeatable between two determinations for specimens with widely varying tumor cell contents. Repeatability between two determinations was 88.5% (95% CI = 84.0% to 92.2%) or, when technically unacceptable test values were excluded, 91.9% (95% CI = 87.4% to 95.1%). Reproducibility between two determinations was 96.1% (95% CI = 86.5% to 99.5%). Combining the gene ratio test and other prognostic factors allowed prospective discrimination between patients at high risk (median survival = 6.9 months, 95% CI = 2.6 to 8.9 months; 3-year survival = 0%) and low risk (median survival = 31.9 months, 95% CI = 21.9 to 41.7 months; 3-year survival = 42%). The gene ratio test for survival of patients with malignant pleural mesothelioma has robust predictive value and technical assay performance.
Consistent dissection of the protein interaction network by combining global and local metrics
Authors: Chunlin Wang, Chris Ding, Qiaofeng Yang, Stephen R Holbrook
Journal: Genome biology (2007)

Abstract We propose a new network decomposition method to systematically identify protein interaction modules in the protein interaction network. Our method incorporates both a global metric and a local metric for balance and consistency. We have compared the performance of our method with several earlier approaches on both simulated and real datasets using different criteria, and show that our method is more robust to network alterations and more effective at discovering functional protein modules.
Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate.
Authors: K J Pienta, B Redman, M Hussain, G Cummings, P S Esper, C Appel, L E Flaherty
Journal: Journal of Clinical Oncology (1994)

PURPOSE Estramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models. This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy. PATIENTS AND METHODS Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d, were administered orally in divided doses for 21 days. Patients were then taken off therapy for 7 days and the cycle then repeated. Therapy continued until evidence of disease progression. RESULTS Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up. Of 18 patients with measurable soft tissue disease, three demonstrated a complete response (CR) and six a partial response (PR) for longer than 2 months. Of these 18 patients, pretreatment prostate-specific antigen (PSA) levels decreased by at least 75% in five men (28%) and by at least 50% in nine (50%). The median survival duration has not been reached in those patients who demonstrated a response either by soft tissue or PSA criteria. Of 24 patients with disease limited to bone, six (25%) demonstrated improvement and nine (38%) demonstrated stability in their bone scans. Five men (21%) demonstrated a decrease of at least 75% in pretreatment PSA levels and 14 (58%) demonstrated at least a 50% decrease; the median survival duration has not been reached in these patients. Pretreatment performance status is an important predictor of survival. CONCLUSION We conclude that the combination of estramustine and VP-16 is an active oral regimen in hormone-refractory prostate cancer.
Nifedipine in the treatment of Raynaud's phenomenon in patients with systemic sclerosis
Authors: R.H.MEYRICK THOMAS, M. RADEMAKER, S.M. GRIMES, A. MACKAY, I.B. KOVACS, E.D. COOK, S.M. BOWCOCK, J.D.T. KIRBY
Journal: British Journal of Dermatology (1987)

A double-blind, placebo-controlled, cross-over trial of nifedipine 10 mg three times daily for 6 weeks, in 10 patients with Raynaud's phenomenon secondary to systemic sclerosis, is reported. A significant reduction in the duration of attacks of Raynaud's phenomenon was observed. Nifedipine therapy also reduced the number and severity of attacks of Raynaud's phenomenon and the development of new digital ulcers, and increased the digital blood flow, but none of these changes was statistically significant. No alteration in red blood cell deformability or leukocyte chemiluminescence was observed during nifedipine treatment.
The −318 C&gt;G Single-Nucleotide Polymorphism in GNAI2 Gene Promoter Region Impairs Transcriptional Activity through Specific Binding of Sp1 Transcription Factor and Is Associated with High Blood Pressure in Caucasians from Italy
Authors: Claudia Menzaghi, Giulia Paroni, Concetta De Bonis, Teresa Soccio, Antonella Marucci, Simonetta Bacci, Vincenzo Trischitta
Journal: Journal of the American Society of Nephrology (2006)

Inhibiting Galpha subunit 2 protein, which is encoded by the GNAI2 gene, is suggested to be pathogenic for essential hypertension and/or insulin resistance. The aim of this study was to determine whether GNAI2 variations modulate the risk for these abnormalities. Seven single-nucleotide polymorphisms (SNP) at the GNAI2 locus were identified. Because of either low allelic frequency or unlikely biologic relevance (i.e., synonymous or intronic), six SNP were not studied further. The -318C>G SNP (allelic frequency 6%) in the promoter region was studied for association with adiposity, systolic BP (SBP) and diastolic BP, fasting insulin and glucose, and lipids levels in 655 nondiabetic Caucasians from Italy. As compared with individuals who carry the C/C genotype, G carriers (i.e., individuals who carry either the G/G or the C/G genotype) had higher SBP (117.8 +/- 16 versus 113.6 +/- 12.6 mmHg; P = 0.010) and were at increased risk for hypertension (odds ratio 2.2; 95% confidence interval 1.1 to 4.5). Compared with the C, the G allele had 2.5-fold reduced transcriptional activity in transfected HEK293 cells. As predicted by the TRANSFAC database, competition with YY1 or Sp1 transcription factors specifically reduced the binding of HeLa cell nuclear proteins to -318C or -318G allele, respectively, as indicated by shifted electrophoretic mobility. A "supershift" of the nuclear proteins/-318G allele complex was observed after anti-Sp1 was added but not anti-YY1 antibody. The GNAI2 -318 C>G SNP impairs transcriptional activity through specific binding of Sp1 and is associated with high SBP in Caucasians from Italy.
Role of routine computed tomography in paediatric pleural empyema
Authors: A Jaffe, A D Calder, C M Owens, S Stanojevic, S Sonnappa
Journal: Thorax (2008)

The incidence of empyema in children is increasing worldwide. While there are emerging data for the best treatment options, there is little evidence to support the imaging modalities used to guide treatment, particularly with regard to the role of routine CT scanning. The aims of this study were to develop a radiological scoring system for paediatric empyema and to assess the utility of routine CT scanning in this disease.Children with empyema were prospectively enrolled over a 3-year period into a randomised clinical trial of video-assisted thoracoscopic surgery versus percutaneous chest drain insertion and urokinase. All children received a preoperative chest radiograph (CXR), pleural ultrasound scan (USS) and chest CT scan. In the urokinase arm the clinician inserted the drain with USS evidence only and did not have access to the CT scan at the time of insertion to reflect clinical practice. A scoring system was developed for each individual radiological modality and used to compare imaging characteristics of the pleural fluid collection and underlying parenchyma and to assess the utility of USS and CT to predict length of stay after the intervention.Of the 60 subjects recruited, 46 had USS images available for review, 36 had a CT scan which met the inclusion criteria and 31 had all three radiological measurements (CT, USS and CXR) available for analysis. There was substantial interobserver agreement for USS grades (kappa = 0.709) and moderate agreement for total CT scores (kappa = 0.520). There were weak correlations between USS grade and total CT score as well as CT loculation and density scores. Of the 25 CXRs showing simple opacification of the underlying parenchyma only, CT demonstrated simple consolidation (n = 14), necrotising pneumonia (n = 7), cavitary necrosis (n = 3) and pneumatoceles (n = 1). No abnormality was detected on CT scanning which directly altered clinical management. Neither the USS score nor the CT score, nor a combination of the two, were able to predict length of hospital stay.CT scanning detects more parenchymal abnormalities than chest radiography. However, the additional information does not alter management and is unable to predict clinical outcome. This suggests that there is no role for the routine use of CT scanning in children if treated with urokinase and percutaneous chest drain. The omission of routine CT scanning in empyema will reduce the exposure of children to unnecessary radiation and reduce costs.The trial is fully registered with clinicaltrials.gov (ID: NCT00144950).
A new role for complement in experimental membranous nephropathy in rats.
Authors: D J Salant, S Belok, M P Madaio, W G Couser
Journal: Journal of Clinical Investigation (1980)

The only established role for complement in mediating immunologic renal disease involves elaboration of leukochemotactic factors and neutrophil-dependent glomerular injury. In the passive Heymann nephritis (PHN) model of experimental membranous nephropathy, rats injected with sheep antibody to rat proximal tubular brush border antigen (Fx1A) form subepithelial deposits of sheep IgG and rat complement (C3), and develop heavy proteinuria after 5 d without glomerular inflammatory changes. To study the role of complement in mediating proteinuria in PHN, 16 rats were treated daily with cobra venom factor from before antibody injection to maintain C3 levels at < 10% of pretreatment values and compared to 16 untreated controls. Proteinuria at 5 d was abolished in C3-depleted rats (4 +/- 1, controls 70 +/- 15 mg/d, P < 0.001), although renal deposition of 125I-labeled antibody ws the same in both groups (188 +/- 35 vs. 191 +/- 22 microgram IgG/2 kidneys, P > 0.5). Nephritogenic doses of both the noncomplement-fixing F(ab')2 portion and the gamma 2 subclass of anti-Fx1A IgG produced subepithelial deposits of immunoglobulin without C3, but proteinuria did not occur despite glomerular deposition of up to 70 microgram/2 kidneys of gamma 2. However, glomerular deposition of as little as 60 microgram of gamma 1 produced C3 fixation in vivo and heavy proteinuria. No neutrophil exudate could be detected histologically in PHN from the time of antibody injection through development of proteinuria. Proteinuria in five PHN rats depleted of neutrophils to < 200/mm3 with antineutrophil serum was not reduced compared to six controls with normal neutrophil counts (34 +/- 9.6 vs. 25 +/- 10.4 mg/d, P > 0.5). These results demonstrate that proteinuria in the PHN model of membranous nephropathy is complement-dependent and strongly suggest a neutrophil-independent mechanism. Thus a new role for the complement system in mediating immunologic glomerular injury is identified.
Therapeutic Approaches to Preserve Islet Mass in Type 2 Diabetes
Authors: Laurie L. Baggio, Daniel J. Drucker
Journal: Annual Review of Medicine (2006)

Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate beta-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in beta-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet beta-cell that lead to stimulation of beta-cell replication and inhibition of beta-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances beta-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands beta-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve beta-cell mass, although it remains unclear whether TZDs affect beta-cell mass via direct mechanisms. Complementary approaches to regeneration of beta-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in beta-cell mass that is characteristic of the natural history of type 2 diabetes.
Divergent Effects of Castration on Prostate Cancer in TRAMP Mice: Possible Implications for Therapy
Authors: Yao Tang, Linbo Wang, Olga Goloubeva, Mohammad Afnan Khan, Bin Zhang, Arif Hussain
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Divergent responses to androgen deprivation have been found in patients and in animal models of prostate cancer. The molecular basis for these different outcomes is unknown. Our aim was to identify the molecular responses of prostate cancer with divergent outcomes to androgen deprivation in TRAMP mice. Experimental Design: Castrated and noncastrated B6xFVB TRAMP mice were evaluated for survival, tumor development, pathology, and expressions of specific proteins at different time points. Results: TRAMP mice responded differentially to androgen deprivation. In the majority, primary tumors regressed after castration (positive response), whereas in others the tumors grew even more aggressively than in the noncastrated mice (negative response). Mice with regressed tumors had the highest survival rates. Androgen receptor was elevated in all tumors from castrated mice despite significant differences in tumor sizes. In positively responding tumors, expressions of Bcl-2 and Grp78 were greatly increased by 10 weeks after castration, whereas expressions of Bax, Bcl-xl, SV40 T antigen, and c-myc were lower. These tumors also showed a reduction in proliferating cells compared with noncastrates and negatively responding tumors. Most of these changes disappeared 20 weeks after castration, by which time there was an increase in the size of primary tumors as well as in distant metastasis. Conclusions: In TRAMP prostate cancer that responded positively to castration, different expression patterns of proteins involved in cellular apoptosis, stress, and proliferation occur ∼10 weeks after castration. This may be an optimal time for targeting Bcl-2, and perhaps Grp78, to enhance the antitumor effects of androgen deprivation.
Irradiance-Dependent Photobleaching and Pain in δ-Aminolevulinic Acid-Photodynamic Therapy of Superficial Basal Cell Carcinomas
Authors: William J. Cottrell, Anne D. Paquette, Kenneth R. Keymel, Thomas H. Foster, Allan R. Oseroff
Journal: Clinical Cancer Research (2008)

Abstract Purpose: In superficial basal cell carcinomas treated with photodynamic therapy with topical δ-aminolevulinic acid, we examined effects of light irradiance on photodynamic efficiency and pain. The rate of singlet-oxygen production depends on the product of irradiance and photosensitizer and oxygen concentrations. High irradiance and/or photosensitizer levels cause inefficient treatment from oxygen depletion in preclinical models. Experimental Design: Self-sensitized photobleaching of protoporphyrin IX (PpIX) fluorescence was used as a surrogate metric for photodynamic dose. We developed instrumentation measuring fluorescence and reflectance from lesions and margins during treatment at 633 nm with various irradiances. When PpIX was 90% bleached, irradiance was increased to 150 mW/cm2 until 200 J/cm2 were delivered. Pain was monitored. Results: In 33 superficial basal cell carcinomas in 26 patients, photobleaching efficiency decreased with increasing irradiance above 20 mW/cm2, consistent with oxygen depletion. Fluences bleaching PpIX fluorescence 80% (D80) were 5.7 ± 1.6, 4.5 ± 0.3, 7.5 ± 0.8, 7.4 ± 0.3, 12.4 ± 0.3, and 28.7 ± 7.1 J/cm2, respectively, at 10, 20, 40, 50, 60 and 150 mW/cm2. At 20-150 mW/cm2, D80 doses required 2.5-3.5 min; times for the total 200 J/cm2 were 22.2-25.3 min. No significant pain occurred up to 50 mW/cm2; pain was not significant when irradiance then increased. Clinical responses were comparable to continuous 150 mW/cm2 treatment. Conclusions: Photodynamic therapy with topical δ-aminolevulinic acid using ∼40 mW/cm2 at 633 nm is photodynamically efficient with minimum pain. Once PpIX is largely photobleached, higher irradiances allow efficient, rapid delivery of additional light. Optimal fluence at a single low irradiance is yet to be determined.