Association between cystatin C and inflammation in patients with essential hypertension

Background

Serum cystatin C is not only a marker of renal function but also acts as an independent risk factor for cardiovascular damage, heart failure, and death. It is known that the initiation and progression of these cardiovascular events contributes to renal dysfunction and chronic inflammation. In this study, we investigated the relationship between cystatin C and proinflammatory cytokines.

Methods

Eighty-eight patients with essential hypertension participated in the study, which involved measuring proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C reactive protein (CRP).

Results

Positive correlations were detected between cystatin C and estimated glomerular filtration rate (eGFR) (r = ?0.503, p < 0.001), systolic blood pressure (r = ?0.246, p = 0.034), and pulse pressure (r = ?0.295, p = 0.010). In contrast, serum creatinine correlated only with eGFR (r = ?0.755, p < 0.001) and eGFR correlated only with age (r = ?0.339, p = 0.001) and not with the other clinical parameters, whereas cystatin C also correlated with log natural (ln) IL-6 (r = ?0.247, p = 0.033) and ln TNF-α (r = ?0.405, p < 0.001) but not with CRP (r = ?0.188, p = 0.108). In contrast, plasma creatinine and eGFR did not correlate with any of these proinflammatory cytokines. Stepwise regression analysis showed that ln TNF-α, eGFR and pulse pressure were independent determinants of serum cystatin C concentration.

Conclusion

This study showed that cystatin C is a marker of inflammation as well as renal function.     

Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation

Previously, we have shown that a heteroplasmic mutation in mitochondrial DNA-encoded complex I ND5 subunit gene resulted in an enhanced tumorigenesis through increased resistance to apoptosis. Here we report that the tumorigenic phenotype associated with complex I dysfunction could be reversed by introducing a yeast NADH quinone oxidoreductase (NDI1) gene. The NDI1 mediated electron transfer from NADH to Co-Q, bypassed the defective complex I and restored oxidative phosphorylation in the host cells. Alternatively, suppression of complex I activity by a specific inhibitor, rotenone or induction of oxidative stress by paraquat led to an increase in the phosphorylation of v-AKT murine thymoma viral oncogene (AKT) and enhanced the tumorigenesis. On the other hand, antioxidant treatment can ameliorate the reactive oxygen species-mediated AKT activation and reverse the tumorigenicity of complex I-deficient cells. Our results suggest that complex I defects could promote tumorigenesis through induction of oxidative stress and activation of AKT pathway.     

Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression

Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for ≤ 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P = 2.22 × 10??) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 × 10?2?) and in an independent sample of 2755 persons of European descent (P = 1.64 × 10??). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 × 10??) for the relation between the PEAR1 gene and platelet function phenotype. A dose-response relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the G allele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype.     

A randomized trial comparing seed displacement of coated seeds to regular loose seeds at 30 days postimplant

PurposeTo compare 30-day seed displacement and seed loss of standard loose seeds to specially engineered coated seeds.Methods and MaterialsForty patients with prostate cancer were randomized and treated with either loose seeds or loose “coated” seeds. Implants were preplanned using transrectal ultrasound and performed using preloaded needles containing either standard or coated iodine-125 seeds according to randomization. Pelvic X-rays and CT were performed on Days 0 and 30 and a pelvic magnetic resonance scan on Day 30. Cranial–caudal displacement relative to the center of mass (COM) of the seed cloud of the six most peripheral basal and apical seeds was determined from Day 0 and 30 CT scans using custom software. Day 30 magnetic resonance–CT fusion was performed using a seed-to-seed match for soft tissue contouring on MRI.ResultsThe mean displacement for the six basal seeds was 0.32 cm (standard deviation [SD], 0.25 cm) and 0.33 cm (SD, 0.27 cm) toward the COM for the regular and coated seeds, respectively (p = 0.35). For the apical seeds, mean displacement was 0.31 cm (SD, 0.35 cm) and 0.43 cm (SD, 0.26 cm) (p = 0.003) toward the COM. More regular seeds (n = 8) were lost from the apical region as compared with one coated seed (p = 0.015). There was a trend to reduction in total seeds lost: 1% for regular seeds as compared with 0.3% for coated seeds.ConclusionsCoated seeds were found to have a significant anchoring effect that was effective in reducing the number of apical seeds lost because of venous migration.     

Critical role of NF-κB in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and in spite of intense efforts there are limited therapeutic options for patients with PDAC. PDACs harbor a high frequency of Kras mutations and other driver mutations that lead to altered signaling pathways and contribute to therapeutic resistance. Importantly, constitutive activation of nuclear factor κB (NF-κB) is frequently observed in PDAC. An increasing body of evidence suggests that both classical and non-classical NF-κB pathways play a crucial role in PDAC development and progression. In this review, we update the most recent advances regarding different aspects of NF-κB involvement in PDAC development and progression, emphasizing its potential as a therapeutic target and the need to discover pathway-specific cytosolic NF-κB regulators which could be used to design novel therapeutic strategies for PDAC.