Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitry

The interdependence of p53 and MDM2 is critical for proper cell survival and cell death and, when altered, can lead to tumorigenesis. Mitogen-activated protein kinase (MAPK) signaling pathways function in a wide variety of cellular processes, including cell growth, migration, differentiation, and death. Here we discovered that transforming growth factor β-activated kinase 1 (TAK1)-binding protein 1 (TAB1), an activator of TAK1 and of p38α, associates with and inhibits the E3 ligase activity of MDM2 toward p53 and its homolog, MDMX. Depletion of TAB1 inhibits MDM2 siRNA-mediated p53 accumulation and p21 induction, partially rescuing cell cycle arrest induced by MDM2 ablation. Interestingly, of several agents commonly used as DNA-damaging therapeutics, only cell death caused by cisplatin is mitigated by knockdown of TAB1. Two mechanisms are required for TAB1 to regulate apoptosis in cisplatin-treated cells. First, p38α is activated by TAB1 to phosphorylate p53 N-terminal sites, leading to selective induction of p53 targets such as NOXA. Second, MDMX is stabilized in a TAB1-dependent manner and is required for cell death after cisplatin treatment. Interestingly TAB1 levels are relatively low in cisplatin-resistant clones of ovarian cells and in ovarian patient''s tumors compared with normal ovarian tissue. Together, our results indicate that TAB1 is a potential tumor suppressor that serves as a functional link between p53–MDM2 circuitry and a key MAPK signaling pathway.     

Predictors of the rise in vWF after ST elevation myocardial infarction: implications for treatment strategies and clinical outcome: An ENTIRE-TIMI 23 substudy.

AIMS: Prior studies suggest that acute coronary syndromes (ACSs) are associated with endothelial activation and that this is of prognostic significance. We hypothesized that endothelial activation, as measured by a rise in von Willebrand Factor (DeltavWF), was influenced by the thrombolysis in myocardial infarction flow grade (TFG), the corrected TIMI frame count (CTFC) and the choice of anticoagulant therapy after fibrinolysis in ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: Data were drawn from the enoxaparin and tenecteplase tissue plasminogen activator (TNK-tpa) with or without GPIIb/IIIa inhibitor as the reperfusion strategy in the STEMI trial (ENTIRE-TIMI 23). Three hundred and fourteen patients had serial measurements of vWF (baseline and 48-72 h) and angiographic data available. TFG<3 (P=0.0042) or CTFC>/=40 at 60 min (P=0.0035) were associated with a higher DeltavWF. DeltavWF >/=75th percentile was associated with a higher incidence of death or myocardial infarction (MI) at 30 days, compared with <75th percentile (11.2 vs. 4.1%, P=0.027). Enoxaparin independently reduced the DeltavWF (P=0.019) and also the composite of death or MI (OR 0.33, 95% CI 0.12-0.91, P=0.03) compared with unfractionated heparin. CONCLUSION: In STEMI treated by fibrinolysis, coronary flow at 60 min and choice of adjunctive anticoagulant appear to be independent determinants of DeltavWF. Enoxaparin is independently associated with a reduction in DeltavWF and a reduction in death or MI. The clinical benefits of enoxaparin as an adjunctive treatment in STEMI may be mediated in part by a reduction in vWF release.     

Health care providers’ support of patients’ autonomy,phosphate medication adherence,race and gender in end stage renal disease

This study was designed to assess dialysis subjects’ perceived autonomy support association with phosphate binder medication adherence, race and gender. A multi-site cross-sectional study was conducted among 377 dialysis subjects. The Health Care Climate (HCC) Questionnaire assessed subjects’ perception of their providers’ autonomy support for phosphate binder use, and adherence was assessed by the self-reported Morisky Medication Adherence Scale. Serum phosphorus was obtained from the medical record. Regression models were used to examine independent factors of medication adherence, serum phosphorus, and differences by race and gender. Non-white HCC scores were consistently lower compared with white subjects’ scores. No differences were observed by gender. Reported phosphate binder adherence was associated with HCC score, and also with phosphorus control. No significant association was found between HCC score and serum phosphorus. Autonomy support, especially in non-white end stage renal disease subjects, may be an appropriate target for culturally informed strategies to optimize mineral bone health.     

Size of distal radial and distal ulnar arteries in adults of southern Rajasthan and their implications for percutaneous coronary interventions

Aims and objectives

Transradial interventions are gaining popularity in recent years. However the radial artery being small, there is a limitation in using interventional devices through this route. We have measured radial and ulnar arteries size in adult patients at our tertiary care cardiology center in southern Rajasthan.

Method

Adult patients >30 years, who came for Echocardiography at a tertiary care center were included. Radial and ulnar arteries inner diameters were measured 2–3 cm above the Styloid process in both forearms with the Ultrasonography. Patient information about weight, height, diabetes and hypertension were collected. Body mass index and Body surface area were calculated.

Results

We studied 204 patients, which includes 60.8% males. Mean diameter was 2.325 ± 0.4 mm mm for radial arteries and 2.358 ± 0.39 mm for ulnar arteries (p = 0.24). Hypertensive and male patients had larger mean radial artery diameter than non hypertensive (2.383 mm v/s 2.272 mm, p = 0.006) and female patients (2.37 mm v/s 2.26 mm, p = 0.008) respectively. Diabetic patients (2.305 mm) had nonsignificantly smaller radial arteries diameters than nondiabetics (2.329 mm, p = 0.6). We calculated correlations between radial arteries diameters and Body surface area, Body mass index, height and weight of patients, none of these correlations were statistically significant (r = 0.30, r = 0.28, r = 0.07, r = 0.031 respectively).

Conclusion

Mean radial artery diameter (2.325 ± 0.4 mm) in the study was slightly smaller than ulnar artery (2.358 ± 0.39 mm). Males and hypertensives had a larger mean radial artery diameter than females and non hypertensives. Radial artery inner diameter measurement by Ultrasonography may be more helpful than Allen''s test for ideal selection of cases.     

A diabetes perception study among rural and urban individuals of West Bengal,India: are we ready for the pandemic?

International Journal of Diabetes in Developing Countries - Type 2 diabetes is a pandemic in India, yet studies regarding knowledge, attitude, and practices in diabetes in various Indian...     

A New Antifungal Antibiotic from Bacillus sp. KM5 Isolated from Rice Rhizospheric Soil

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Bacterial strain, Bacillus sp. KM5 was recently isolated and characterized by strong antifungal activities...     

Association between percutaneous coronary intervention and long-term C-reactive protein levels in patients with acute coronary syndromes

C-reactive protein (CRP) is an independent predictor of risk in ACS patients, and it has been previously shown that percutaneous coronary intervention (PCI) is associated with an early rise in CRP. To assess the long-term relationship between PCI and CRP, we compared CRP levels at baseline, 30 days, 4 months and 24 months among patients in the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 trial who were treated with PCI and those who did not receive PCI. At study entry, CRP was significantly higher among patients who had undergone PCI (13.2 vs. 9.5 mg/l, P < 0.001). However, by day 30 CRP was significantly lower among patients who had undergone PCI for management of the index event (1.5 vs. 2.1 mg/l, P < 0.001) and remained lower at 4 months and by end of study (average 2 years after ACS). Using a multivariable model, we observed that PCI was associated with 8.6% lower CRP level at month 4 (P = 0.05) and 14.2% at approximately 2 years (P = 0.0028). These analyses suggest that although PCI may acutely increase inflammation, it may also serve a role in decreasing inflammation associated with atherosclerotic plaques via long-term mechanical stabilization.