Histone deacetylase inhibitor induces DNA damage,which normal but not transformed cells can repair

Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (γH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, γH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is associated with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concentrations that cause little or no normal cell death.     

Reciprocal influences between the signalling pathways regulating proliferation and steroidogenesis in adrenal glomerulosa cells

The main regulators of aldosterone secretion in adrenal gland zona glomerulosa (ZG) cells are the hormones angiotensin II (Ang II) and adrenocorticotrophin (ACTH) and small increases in the extracellular potassium (K(+)) concentration. The action of these agonists is mediated by different signalling systems - ACTH is mediated by cAMP and activation of protein kinase A while Ang II and K(+) activate two protein kinases, Ca(2+)-calmodulin-dependent protein kinase (CamK) and diacylglycerol-dependent protein kinase (PKC). Ang II, besides being one of the main agonists for the secretion of aldosterone, also stimulates proliferation of ZG cells, a process mediated by mitogen-activated protein kinases (MAPKs). Recent studies aimed at elucidating the molecular mechanisms underlying cell proliferation have shown that calcineurin is the principal regulator of MAPKs activity. The purpose of this review is to discuss experimental evidence of possible reciprocal influences between the signalling pathways regulating proliferation and steroidogenesis in ZG cells.     

Cancellous bone changes in the radius of patients with rheumatoid arthritis: a cross-sectional quantitative macroradiographic study

OBJECTIVE: Fractal signature analysis (FSA), a computerized method of textural analysis, permits the separate measurement of changes in vertical and horizontal trabeculae based on the fractal dimension over a range of trabecular widths (fractal signature). We determined whether the FSA of high-definition macroradiographs (x5 magnification) quantified radiographic changes at sites of osteopenia and erosion formation in the rheumatoid arthritis (RA) hand. METHODS: Sixty-seven RA patients had macroradiographs of the left wrist and hand. The distal radius was scored and grouped from very mild (RA1) to moderate (RA4) disease. Macroradiographs were digitized and FSA of horizontal and vertical trabecular organization was performed in the radius at sites of periarticular osteopenia, erosion formation and at a mid-metaphyseal site. The RA groups were compared with 11 healthy non-arthritic subjects using ANOVA and Dunnett's tests. RESULTS: Compared to the non-arthritic hands, FSA at the distal radius in groups RA1 to RA4 measured significantly lower (P<0.05) fractal signatures. The fractal signatures were lowest in RA4 involving small, medium to large sized vertical trabeculae at the periarticular osteopenic (0.18 to 0.84 mm, P<0.01) and mid-metaphyseal sites (0.12 to 0.60 and 0.84 to 1.02 mm, P 相似文献   

Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation.

Alpha-Melanocyte-stimulating hormone (MSH) is a potent anti-inflammatory agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation. We showed previously that alpha-MSH inhibits nitric oxide (NO) production in cultured macro-phages. To determine how alpha-MSH acts in vivo, we induced acute hepatic inflammation by administering endotoxin (LPS) to mice pretreated with Corynebacterium parvum, alpha-MSH prevented liver inflammation even when given 30 min after LPS administration. To determine the mechanisms of action of alpha-MSH, we tested its influence on NO, infiltrating inflammatory cells, cytokines, and chemokines. Alpha-MSH inhibited systemic NO production, hepatic neutrophil infiltration, and increased hepatic mRNA abundance for TNF alpha, and the neutrophil and monocyte chemokines (KC/IL-8 and MCP-1). We conclude that alpha-MSH prevents LPS-induced hepatic inflammation by inhibiting production of chemoattractant chemokines which then modulate infiltration of inflammatory cells. Thus, alpha-MSH has an effect very early in the inflammatory cascade.     

Phytoplankton species richness scales consistently from laboratory microcosms to the world's oceans

Species-area relationships have been observed for virtually all major groups of macroorganisms that have been studied to date but have not been explored for microscopic phytoplankton algae, which are the dominant producers in many freshwater and marine ecosystems. Our analyses of data from 142 different natural ponds, lakes, and oceans and 239 experimental ecosystems reveal a strong species-area relationship with an exponent that is invariant across ecosystems that span >15 orders of magnitude in spatial extent. A striking result is that the species-area relationship derived from small-scale experimental studies correctly scales up to natural aquatic ecosystems. These results significantly broaden our knowledge of the effects of island size on biodiversity and also confirm the relevance of experimentally derived data to the analysis and understanding of larger-scale ecological patterns. In addition, they confirm that patterns in microbial diversity are strongly consistent with those that have been repeatedly reported in the literature for macroorganisms.     

Follow-up of patients with unexplained syncope and inducible ventricular tachyarrhythmias: analysis of the AVID registry and an AVID substudy. Antiarrhythmics Versus Implantable Defibrillators

INTRODUCTION: A prospective registry and substudy were conducted in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study to clarify the prognosis and recurrent event rate, risk factors, and impact of implantable cardioverter defibrillator (ICD) therapy in patients with unexplained syncope, structural heart disease, and inducible ventricular tachyarrhythmias. METHODS AND RESULTS: Included in the AVID registry were patients from all participating sites who had "out of hospital syncope with structural heart disease and EP-inducible VT/VF with symptoms." In addition, 13 collaborating sites provided more in-depth clinical and electrophysiologic data as part of a formal prospective substudy. Patients in the substudy were followed by local investigators for recurrent arrhythmic events and mortality. Registry patients were tracked for fatal outcomes by the National Death Index. A total of 429 patients with syncope were entered in the AVID registry, of whom 80 participated in the substudy. Of the substudy patients, 21 patients (26%) had inducible polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF), 11 patients (14%) had sustained monomorphic VT <200 beats/min, and 48 patients (60%) had sustained monomorphic VT > or = 200 beats/min. The ICD was used as sole therapy in 75% of the syncope substudy patients (and with antiarrhythmic drug in an additional 9%) and in 59% of the syncope registry patients. Survival rates at 1 and 3 years were 93% and 74% for the substudy patients and 90% and 74% for the registry patients, respectively. Survival of the syncope substudy patients (predominantly treated by ICD) was similar to the VT patients treated by ICD and superior to the VT patients treated by an antiarrhythmic drug (P = 0.05) in the randomized main trial. Mortality events in the substudy were marginally predicted by ejection fraction (P = 0.06) but not by electrophysiologic study-induced arrhythmia. The significant predictor of increased mortality in the registry was age (P = 0.003) and of reduced mortality was treatment with ICD (P = 0.006). CONCLUSION: The results of these analyses support the role of the ICD as primary antiarrhythmic therapy in patients with unexplained syncope, structural heart disease, and inducible VT/VF at electrophysiologic study.     

Health-related quality of life before,during and after combination therapy with interferon and ribavirin in unselected Swedish patients with chronic hepatitis C

Objective. To study the relationship between health-related quality of life (HRQOL) and mode of acquisition, treatment discontinuations, drop in haemoglobin levels and treatment outcome in patients with chronic hepatitis C (CHC). Material and methods. Consecutive unselected Swedish patients with CHC completed the SF-36 questionnaire before, during and after treatment with interferon and ribavirin. Results. At baseline, HRQOL was reduced in all SF-36 subscales in our patients (n=147) as compared with the general Swedish population. Former intravenous drug users (IVDUs) scored significantly lower in social function (p=0.03) and mental health (p=0.03) than patients who had acquired their infection from blood transfusions (PTH). A decline of >40 points in HRQOL from baseline to week 12 was noticed in the role limitations-physical (RP) score for the IVDU and PTH groups (p<0.0001 and 0.001, respectively). Patients with a ≥20% fall in haemoglobin levels at treatment week 12 had a significantly poorer RP (p=0.006) and role limitations-emotional score (p<0.02) than patients with a <10% fall. Early treatment dropouts had significantly lower HRQOL scores at baseline than adherent patients. At follow-up, sustained viral responders had significantly higher scores than non-responders. Conclusions. Swedish outpatients with CHC have a marked reduction in their HRQOL as compared to the general population. Therapy reduces HRQOL most substantially in those with a marked reduction in haemoglobin. Early dropouts from therapy have significantly lower HRQOL scores at baseline than adherent patients, and sustained viral responders improve their HRQOL significantly more than non-responders.     

Integrating Self Blood Pressure Monitoring Into the Routine Management of Uncontrolled Hypertension: Translating Evidence to Practice

Improving hypertension control is a public health priority and could reduce health disparities. Self blood pressure monitoring (SBPM) is effective but not widely integrated into clinical care. A pragmatic study distributing blood pressure (BP) monitors was conducted to assess its effectiveness in the management of uncontrolled hypertension under conditions consistent with clinic resources. Patients, predominantly black and Hispanic adults from clinics in low‐income, medically underserved communities with uncontrolled BP were enrolled. Follow‐up assessments were conducted 9 months after enrollment. Approximately half (53%) of the patients had controlled hypertension at follow‐up. Systolic and diastolic BP decreased by 18.7 mm Hg and 8.5 mm Hg, respectively, at follow‐up. Although attenuated, decreases persisted after adjustment for regression to the mean. Clinicians were supportive of the program, although collecting follow‐up data from enrolled patients was a common challenge. The integration of SBPM into routine management of uncontrolled hypertension demonstrated substantial improvements in control. Systems to identify and track patients who are self‐monitoring may increase impact. J Clin Hypertens (Greenwich). 2013;00:00–00. ©2013 Wiley Periodicals, Inc.     

Oestrogen and colorectal cancer: mechanisms and controversies

Aim

The role of oestrogen metabolism and action in colorectal cancer (CRC) is controversial. An extensive review of the current literature, encompassing epidemiological evidence, systemic and peripheral oestrogen concentrations, 17β-hydroxysteroid dehydrogenase (17β-HSD) and aromatase in CRC, steroid sulphatase (STS)/oestrone sulphotransferase (EST) and in vitro and in vivo genomic effects was therefore undertaken.

Methods

A literature search (key words: colorectal cancer, oestrogen, oestrogen receptor, 17β-HSD, STS, organic anion transporter) was performed using Embase, Medline, and Pubmed and papers were evaluated on scientific relevance on an individual basis.

Results

Epidemiological data highlights that premenopausal women, or postmenopausal women taking hormone replacement therapy, are significantly less likely than males to develop CRC. This implies that oestrogen signalling is most likely involved in CRC physiology and aetiology. Little is known about oestrogen metabolism in the colon. However, the expression of 17β-HSD, STS, and EST, enzymes involved in oestrogen metabolism, have shown prognostic significance. Evidence also suggests that protective effects are modulated through oestrogen receptor beta, although which metabolite of oestrogen, oestradiol (E₂) or oestrone (E₁), is more active remains undefined. To complicate matters, the changes in the peripheral ratios of these enzymes, oestrogens and receptors most likely influences CRC progression.

Conclusion

Epidemiological evidence, now supported by in vitro and in vivo studies, strongly associates oestrogen action and metabolism with CRC. Initially protective against CRC, once developed, results suggests that oestrogens increase proliferation. Consequently, hormone-ablation therapy, already successful against breast and prostate cancer, may be effective against CRC.