Asprosin: a novel peptide hormone related to insulin resistance in women with polycystic ovary syndrome

Asprosin associated with insulin resistance is a newly discovered peptide hormone. The peptide promotes hepatic glucose production. Polycystic ovary syndrome (PCOS) is a metabolic disorder. Insulin resistance plays a vital role in the pathogenesis of the disease. The aim of this study was to discover the association between insulin resistance and asprosin in women with PCOS. We recruited 78 subjects with PCOS and 78 age-matched and body mass index (BMI)-matched controls into this cross-sectional study. Circulating asprosin levels were validated using ELISA method. We also determined metabolic and hormonal parameters of the involved subjects. We found that circulating asprosin levels were elevated in women with PCOS with respect to controls. Asprosin levels showed a positive correlation with insulin resistance, BMI, and free androgen index (FAI). Moreover, subjects with the highest tertile of asprosin levels represented increased odds of having PCOS as compared to those subjects with the lowest tertile asprosin levels. Increased asprosin levels resulted to high possibility of having PCOS risk associated with insulin resistance.     

Cavum velum interpositum cysts in normal and anomalous fetuses in second trimester of pregnancy: Comparison of its size and prevalence

ObjectiveCavum veli interpositi (CVI) is a potential space below the splenium of corpus callosum and sometimes presents as a cyst.Materials and methodsIn this prospective cross-sectional study, 360 fetuses with normal second trimester scan and 152 s trimester fetuses with structural abnormalities were included.ResultsThe CVI cysts were more common in fetuses with brain anomaly compared to normal fetuses and fetuses with extra-central nervous system (CNS) anomalies (23% vs 18.3% and 18% respectively; p value < 0.01). The mean size of cysts in normal fetuses, fetuses with extra-CNS anomalies and fetuses with brain abnormalities was 4.6 mm, 5.8 mm and 9.2 mm respectively. There was a significant difference between cysts size in normal fetuses and fetuses with brain anomalies (p value < 0.01) and the cut-point was 7.1 mm.ConclusionThe prevalence of CVI cysts is more in fetuses with brain anomaly. Fetuses with a cyst size >7.1 mm need a more detailed brain examination.     

Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells

We explored the potential of Smac mimetics, which antagonize Inhibitor of Apoptosis (IAP) proteins, for chemosensitization of neuroblastoma (NB). Here, we report that Smac mimetics, e.g. BV6, prime NB cells for chemotherapeutics including the topoisomerase II inhibitor doxorubicin (DOX) and vinca alkaloids such as Vincristine (VCR), Vinblastine (VBL) and Vinorelbine (VNR). Additionally, BV6 acts in concert with DOX or VCR to suppress long-term clonogenic growth. While BV6 causes rapid downregulation of cellular IAP (cIAP)1 protein and nuclear factor-kappaB (NF-κB) activation, DOX/BV6- or VCR/BV6-induced apoptosis occurs independently of NF-κB or TNFα signaling, since overexpression of dominant-negative IκBα superrepressor or the Tumor Necrosis Factor (TNF)α-blocking antibody Enbrel fail to block cell death. Mechanistic studies reveal that Receptor-interacting protein (RIP)1 is required for DOX/BV6-, but not for VCR/BV6-induced apoptosis, since transient or stable knockdown of RIP1 or the pharmacological RIP1 inhibitor necrostatin-1 significantly reduce apoptosis. By comparison, VCR/BV6-mediated apoptosis critically depends on the mitochondrial pathway. VCR/BV6 cotreatment causes phosphorylation of BCL-2 during mitotic arrest, enhanced activation of BAX and BAK and loss of mitochondrial membrane potential (MMP). Additionally, overexpression of BCL-2 profoundly suppresses VCR/BV6-induced apoptosis. Thus, BV6 sensitizes NB cells to chemotherapy-induced apoptosis via distinct initial signaling mechanisms depending on the chemotherapeutic drug. These findings provide novel mechanistic insights into Smac mimetic-mediated chemosensitization of NB.     

The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients

Aim

Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.

Methods

The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan–Meier analysis.

Results

The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HR_PFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HR_OS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.

Conclusions

Discrepancies between preclinical success and clinical failure may be due to the patients'' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.     

Trunk exercise training improves muscle size,strength, and function in older adults: A randomized controlled trial

The aim of this study was to assess the effectiveness of a multimodal exercise program to increase trunk muscle morphology and strength in older individuals, and their associated changes in functional ability. Using a single‐blinded parallel‐group randomized controlled trial design, 64 older adults (≥60 years) were randomly allocated to a 12‐week exercise program comprising walking and balance exercises with or without trunk strengthening/motor control exercises; followed by a 6‐week walking‐only program (detraining; 32 per group). Trunk muscle morphology (ultrasound imaging), strength (isokinetic dynamometer), and functional ability and balance (6‐Minute Walk Test; 30 second Chair Stand Test; Sitting and Rising Test; Berg Balance Scale, Multi‐Directional Reach Test; Timed Up and Go; Four Step Square Test) were the primary outcome measures. Sixty‐four older adults (mean [SD]; age: 69.8 [7.5] years; 59.4% female) were randomized into two exercise groups. Trunk training relative to walking‐balance training increased (mean difference [95% CI]) the size of the rectus abdominis (2.08 [1.29, 2.89] cm²), lumbar multifidus (L4/L5:0.39 [0.16, 0.61] cm; L5/S1:0.31 [0.07, 0.55] cm), and the lateral abdominal musculature (0.63 [0.40, 0.85] cm); and increased trunk flexion (29.8 [4.40, 55.31] N), extension (37.71 [15.17, 60.25] N), and lateral flexion (52.30 [36.57, 68.02] N) strength. Trunk training relative to walking‐balance training improved 30‐second Chair Stand Test (5.90 [3.39, 8.42] repetitions), Sitting and Rising Test (1.23 [0.24, 2.23] points), Forward Reach Test (4.20 [1.89, 6.51] cm), Backward Reach Test (2.42 [0.33, 4.52] cm), and Timed Up and Go Test (?0.76 [?1.40, ?0.13] seconds). Detraining led to some declines but all outcomes remained significantly improved when compared to pre‐training. These findings support the inclusion of trunk strengthening/motor control exercises as part of a multimodal exercise program for older adults.     

Comparison of novel risk factors for cardiovascular disease between hemodialysis patients with and without protein-energy wasting

Purpose

The present study was designed to compare novel risk factors for cardiovascular diseases (CVD) between hemodialysis (HD) patients with or without protein-energy wasting (PEW) for determining novel risk factors for CVD in HD patients with PEW.

Methods

In this cross-sectional study, 291 HD patients were randomly selected from among 2,302 adult HD patients in Tehran hemodialysis centers. The presence of PEW in HD patients was determined by subjective global assessment. In addition, 4 mL blood was obtained before dialysis and analyzed for serum concentrations of novel risk factors for CVD, including C-reactive protein (CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), sE-selectin, malondialdehyde (MDA), nitric oxide (NO), endothelin-1 and lipoprotein (a) [Lp (a)].

Results

Serum CRP and sICAM-1 were significantly higher in HD patients with PEW as compared to those without PEW (P < 0.01), whereas there were no significant differences in serum sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a) between the two groups. Serum CRP and sICAM-1 were significantly higher in HD patients with PEW type IIa and IIb than in those with PEW type I (P < 0.01).

Conclusion

The present study indicates that serum CRP and sICAM-1, as two CVD risk factors, increase in HD patients with PEW as compared to those without PEW and these increases occur in HD patients with PEW type IIa and IIb who have inflammation.