Abstract-Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell proliferation and migration, primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). Reactive oxygen species (ROS) derived from NAD(P)H oxidase are critically important in many aspects of vascular cell regulation, and both the small GTPase Rac1 and gp91 phox are critical components of the endothelial NAD(P)H oxidase complex. A role of NAD(P)H oxidase in VEGF-induced angiogenesis, however, has not been defined. In the present study, electron spin resonance spectroscopy is utilized to demonstrate that VEGF stimulates O 2 ·Ϫ production, which is inhibited by the NAD(P)H oxidase inhibitor, diphenylene iodonium, as well as by overexpression of dominant-negative Rac1 (N17Rac1) and transfection of gp91 phox antisense oligonucleotides in human umbilical vein endothelial cells (ECs). Antioxidants, including N-acetylcysteine (NAC), various NAD(P)H oxidase inhibitors, and N17Rac1 significantly attenuate not only VEGF-induced KDR tyrosine phosphorylation but also proliferation and migration of ECs. Importantly, these effects of VEGF are dramatically inhibited in cells transfected with gp91 phox antisense oligonucleotides. By contrast, ROS are not involved in mediating these effects of sphingosine 1-phosphate (S1P) on ECs. Sponge implant assays demonstrate that VEGF-, but not S1P-, induced angiogenesis is significantly reduced in wild-type mice treated with NAC and in gp91 phoxϪ/Ϫ mice, suggesting that ROS derived from gp91 phox -containing NAD(P)H oxidase play an important role in angiogenesis in vivo. These studies indicate that VEGF-induced endothelial cell signaling and angiogenesis is tightly controlled by the reduction/oxidation environment at the level of VEGF receptor and provide novel insights into the NAD(P)H oxidase as a potential therapeutic target for angiogenesis-dependent diseases.

Serum LH level at 12-h post-trigger with GnRHa <15.0 IU/l is associated with a dramatically lower oocyte yield but not with the oocyte maturity and fertilization rate. Serum LH levels post-trigger with GnRH agonist do not affect clinical outcomes.

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BackgroundThis study aimed to investigate the relationship between serum profiles of prolactin and thyroid stimulating hormone (TSH) and sexual dysfunction in patients with schizophrenia treated with conventional antipsychotic medication.Material/MethodsA hospital-based cross-sectional study included 118 patients, age range 18–57 years (55 men, 63 women), with a confirmed diagnosis of schizophrenia. All patients were stable after antipsychotic treatment. Serum levels of hormones, including prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone, testosterone, thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3) and free thyroxine (FT4), were detected in venous blood. The Positive and Negative Syndrome Scale (PANSS) score was used to measure symptom severity of patients with schizophrenia. The Mandarin Chinese version of the Arizona Sexual Experience Scale (ASEX), a 5-item scale, was used to measure sexual function.ResultsThere were 66 patients (55.9%) who had hyperprolactinemia, the prevalence of hyperprolactinemia was markedly higher in the sexual dysfunction group than the non-sexual dysfunction group (91.8% vs. 17.5%) (P<0.001). Mean prolactin levels were significantly increased in patients with sexual dysfunction compared with the patients without sexual dysfunction (P<0.001), with a higher incidence in female patients. Subclinical hypothyroidism and hyperprolactinemia were found to be independently associated with sexual dysfunction, and an increased PANSS negative score was an independent risk factor for the development of sexual dysfunction.ConclusionsThe incidence of sexual dysfunction was significantly increased in patients with schizophrenia. Hyperprolactinemia and subclinical hypothyroidism were associated with sexual dysfunction, especially in female patients.

ObjectiveOur network meta-analysis aimed to determine the assistant efficacy of targeted therapy in combined with chemotherapy for advanced/metastatic triple-negative breast cancer (TNBC).ResultsA total of 15 randomized controlled trials (RCTs), involving 2,410 patients, met our inclusion criteria. Eight targeted agents involving 11 treatment arms were included. The methodological quality of included RCTs was acceptable. The results of direct comparisons showed that progression-free survival (PFS) was significantly longer with bevacizumab+chemotherapy when compared to chemotherapy alone (hazard ratio [HR] = 0.62, 95% credible intervals [CrI]: 0.41–0.87). However, there were no statistically significant differences for all other direct comparison groups. The results of indirect comparison of different targeted agents revealed no significant differences regarding all outcomes of interest. According to ranking probabilities, all outcomes favored bevacizumab+chemotherapy and veliparib+chemotherapy. Bayesian and Frequentist network meta-analysis showed similar results, and the probability of bias of small-study effects was small.Materials and MethodsA comprehensive literature search in PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (via ISI Web of Knowledge), BIOSIS Previews (via ISI Web of Knowledge), and Chemical Abstracts (CA) was conducted to identify RCTs involving targeted agents in the treatment of advanced/metastatic TNBC. Two reviewers independently extracted related data and assessed the risk of bias of included studies. Bayesian network meta-analysis was conducted using R-3.3.2 software.ConclusionsLimited evidence showed that targeted agents combined with chemotherapy for advanced/metastatic TNBC were slightly effective. Further investigation of targeted therapies for TNBC is required to improve patient outcomes. The registration number was CRD42014014299.

The existing studies suggest that S-1 is not more effective than capecitabine in the treatment of gastric cancer patients, but does exhibit less toxicity with regard to hand-foot syndrome.

BACKGROUND Skeletal muscle maladaptation accompanies chronic kidney disease (CKD) and negatively affects physical function. Emphasis in CKD has historically been placed on muscle fiber–intrinsic deficits, such as altered protein metabolism and atrophy. However, targeted treatment of fiber-intrinsic dysfunction has produced limited improvement, whereas alterations within the fiber-extrinsic environment have scarcely been examined. METHODS We investigated alterations to the skeletal muscle interstitial environment with deep cellular phenotyping of biopsies from patients with CKD and age-matched controls and performed transcriptome profiling to define the molecular underpinnings of CKD-associated muscle impairments. We examined changes in muscle maladaptation following initiation of dialysis therapy for kidney failure. RESULTS Patients with CKD exhibited a progressive fibrotic muscle phenotype, which was associated with impaired regenerative capacity and lower vascular density. The severity of these deficits was strongly associated with the degree of kidney dysfunction. Consistent with these profound deficits, CKD was associated with broad alterations to the muscle transcriptome, including altered ECM organization, downregulated angiogenesis, and altered expression of pathways related to stem cell self-renewal. Remarkably, despite the seemingly advanced nature of this fibrotic transformation, dialysis treatment rescued these deficits, restoring a healthier muscle phenotype. Furthermore, after accounting for muscle atrophy, strength and endurance improved after dialysis initiation. CONCLUSION These data identify a dialysis-responsive muscle fibrotic phenotype in CKD and suggest the early dialysis window presents a unique opportunity of improved muscle regenerative capacity during which targeted interventions may achieve maximal impact. TRIAL REGISTRATION NCT01452412 FUNDING NIH, NIH Clinical and Translational Science Awards (CTSA), and Einstein-Mount Sinai Diabetes Research Center

Anisodamine, a Chinese traditional medicine herb, has been used for treatment of adult respiratory distress syndrome effectively, but little is known about its mechanism. We attempted to investigate if anisodamine could protect bovine pulmonary endothelial cell injury induced by exogenous oxygen-free radicals that were generated by xanthine/xanthine oxidase or opsonized zymosan-stimulated polymorphonuclear leukocytes. Results showed that with the addition of xanthine/xanthine oxidase into cultured bovine pulmonary endothelial cells, production of malondialdehyde and release of lactate dehydrogenase in supernatant increased, and synthesis of prostacyclin decreased. Damaged cellular membranes were revealed by scanning electron microscopy. The same was true for the addition of opsonized zymosan-stimulated polymorphonuclear leukocytes. While treatment with anisodamine greatly attenuated all of the above-mentioned parameters, results showed that (1) cultured bovine pulmonary endothelial cells could be damaged by oxygen-free radicals, (2) anisodamine had a protective effect on this injury as effective as that of superoxide dismutase and catalase, and (3) the membrane-stable action might contribute to the mechanism of protective effect against this injury.