The electroreduction of water for sustainable hydrogen production is a critical component of several developing clean-energy technologies, such as water splitting and fuel cells. However, finding a cheap and efficient alternative catalyst to replace currently used platinum-based catalysts is still a prerequisite for the commercialization of these technologies. Here we report a robust and highly active catalyst for hydrogen evolution reaction that is constructed by in situ growth of molybdenum disulfide on the surface of cobalt diselenide. In acidic media, the molybdenum disulfide/cobalt diselenide catalyst exhibits fast hydrogen evolution kinetics with onset potential of −11 mV and Tafel slope of 36 mV per decade, which is the best among the non-noble metal hydrogen evolution catalysts and even approaches to the commercial platinum/carbon catalyst. The high hydrogen evolution activity of molybdenum disulfide/cobalt diselenide hybrid is likely due to the electrocatalytic synergistic effects between hydrogen evolution-active molybdenum disulfide and cobalt diselenide materials and the much increased catalytic sites.
There is substantial research into new catalysts for electroreduction of water. Here, the authors report a robust and active molybdenum disulfide/cobalt diselenide hydrogen evolution catalyst with onset potential of 11 mV and Tafel slope of 36 mV per decade, approaching the activity of platinum.
BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.)
BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype 6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC50, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC50s of >4 μM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC50. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid 495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside analogs). Plasma and liver exposures in vivo in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6- to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥10-fold above the inhibitor EC50s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for the treatment of HCV. Phase 3 studies are ongoing.
The aim of this study was to investigate the contribution of chromosomal anomalies and the frequency of particular types of aberrations in general couples preparing for pregnancy and make recommendations for pregnancy on the basis of the medical literature. A total of 6,198 general couples were included in the present study. The karyotypes were generated from the peripheral blood lymphocyte cultures and the cytogenetic analysis was performed using G-banding. In 12,396 cases, chromosomal anomalies were detected in 59 cases (0.48%, 59/12,396). Among of them, the frequency of translocation was 0.35% (n = 43). Sex chromosomal anomalies accounted for 0.07% (n = 9), including Klinefelter syndrome (KS) (n = 4), Turner syndrome (TS) (n = 4), and XYY syndrome (n = 1). The others, including inversions (n = 6) and deletion (n = 1), accounted for 0.06%. Our study indicates that clinically important chromosomal defects are present at a remarkable frequency in the general couples in eastern China, suggesting pre-pregnancy cytogenetic analysis should be routinely performed among general couples in this area so that informed decision can be made, which will help to improve the quality of the pregnancy.
Compound xueshuantong capsule (CXC) is an oral traditional Chinese herbal formula (CHF) comprised of Panax notoginseng (PN), Radix astragali (RA), Salvia miltiorrhizae (SM), and Radix scrophulariaceae (RS). The present investigation was designed to explore the core bioactive components promoting blood circulation in CXC using high-performance liquid chromatography (HPLC) and animal studies. CXC samples were prepared with different proportions of the 4 herbs according to a four-factor, nine-level uniform design. CXC samples were assessed with HPLC, which identified 21 components. For the animal experiments, rats were soaked in ice water during the time interval between two adrenaline hydrochloride injections to reduce blood circulation. We assessed whole-blood viscosity (WBV), erythrocyte aggregation and red corpuscle electrophoresis indices (EAI and RCEI, respectively), plasma viscosity (PV), maximum platelet aggregation rate (MPAR), activated partial thromboplastin time (APTT), and prothrombin time (PT). Based on the hypothesis that CXC sample effects varied with differences in components, we performed grey relational analysis (GRA), principal component analysis (PCA), ridge regression (RR), and radial basis function (RBF) to evaluate the contribution of each identified component. Our results indicate that panaxytriol, ginsenoside Rb1, angoroside C, protocatechualdehyde, ginsenoside Rd, and calycosin-7-O-β-D-glucoside are the core bioactive components, and that they might play different roles in the alleviation of circulation dysfunction. Panaxytriol and ginsenoside Rb1 had close relevance to red blood cell (RBC) aggregation, angoroside C was related to platelet aggregation, protocatechualdehyde was involved in intrinsic clotting activity, ginsenoside Rd affected RBC deformability and plasma proteins, and calycosin-7-O-β-D-glucoside influenced extrinsic clotting activity. This study indicates that angoroside C, calycosin-7-O-β-D-glucoside, panaxytriol, and protocatechualdehyde may have novel therapeutic uses.
This study investigated the occurrence of 12 veterinary antibiotics (VAs) and the susceptibility of Escherichia coli (E. coli) in a rural water system that was affected by livestock production in northern China. Each of the surveyed sites was determined with at least eight antibiotics with maximum concentration of up to 450 ng L−1. The use of VAs in livestock farming probably was a primary source of antibiotics in the rivers. Increasing total antibiotics were measured from up- to mid- and downstream in the two tributaries. Eighty-eight percent of the 218 E. coli isolates that were derived from the study area exhibited, in total, 48 resistance profiles against the eight examined drugs. Significant correlations were found among the resistance rates of sulfamethoxazole-trimethoprim, chloromycetin and ampicillin as well as between tetracycline and chlortetracycline, suggesting a possible cross-selection for resistance among these drugs. The E. coli resistance frequency also increased from up- to midstream in the three rivers. E. coli isolates from different water systems showed varying drug numbers of resistance. No clear relationship was observed in the antibiotic resistance frequency with corresponding antibiotic concentration, indicating that the antibiotic resistance for E. coli in the aquatic environment might be affected by factors besides antibiotics. High numbers of resistant E. coli were also isolated from the conserved reservoir. These results suggest that rural surface water may become a large pool of VAs and resistant bacteria. This study contributes to current information on VAs and resistant bacteria contamination in aquatic environments particularly in areas under intensive agriculture. Moreover, this study indicates an urgent need to monitor the use of VAs in animal production, and to control the release of animal-originated antibiotics into the environment.
Accumulating preclinical and clinical evidence implicates epithelial-mesenchymal transition (EMT) in acquired resistance to anticancer drugs; however, mechanisms by which the mesenchymal state determines drug resistance remain unknown.
To explore a potential role for altered cellular metabolism in EMT and associated drug resistance, we analyzed the metabolome and transcriptome of three lung cancer cell lines that were rendered drug resistant following experimental induction of EMT. This analysis revealed evidence of metabolic rewiring during EMT that diverts glucose to the TCA cycle. Such rewiring was at least partially mediated by the reduced expression of pyruvate dehydrogenase kinase 4 (PDK4), which serves as a gatekeeper of the TCA cycle by inactivating pyruvate dehydrogenase (PDH). Overexpression of PDK4 partially blocked TGFβ-induced EMT; conversely, PDK4 inhibition via RNAi-mediated knockdown was sufficient to drive EMT and promoted erlotinib resistance in EGFR mutant lung cancer cells. We identified a novel interaction between PDK4 and apoptosis-inducing factor (AIF), an inner mitochondrial protein that appears to play a role in mediating this resistance. In addition, analysis of human tumor samples revealed PDK4-low as a predictor of poor prognosis in lung cancer and that PDK4 expression is dramatically downregulated in most tumor types.
Together, these findings implicate PDK4 as a critical metabolic regulator of EMT and associated drug resistance.
Electronic supplementary material
The online version of this article (doi:10.1186/2049-3002-2-20) contains supplementary material, which is available to authorized users.
Tumor metabolism; EMT; Drug resistance; Pyruvate dehydrogenase kinase
Chromatin is a supramolecular assembly of DNA and histone proteins, organized into nucleosome repeat units. The dynamics of chromatin organization regulates DNA accessibility to eukaryotic transcription and DNA repair complexes. However, the structural and dynamic properties of chromatin at high concentrations characteristic of the cellular environment (> ~200 mg/ml) are largely unexplored at the molecular level. Here, we apply magic angle spinning nuclear magnetic resonance to directly probe the dynamic histone protein regions in 13C,15N-enriched recombinant nucleosome arrays at cellular chromatin concentrations and conditions designed to emulate distinct states of DNA condensation, with focus on the flexible H3 and H4 N-terminal tails which mediate chromatin compaction. 2D 1H-13C and 1H-15N spectra reveal numerous correlations for H3 and H4 backbone and side-chain atoms, enabling identification of specific residues making up the dynamically disordered N-terminal tail domains. Remarkably, we find that both the H3 and H4 N-terminal tails are overall dynamic even in a highly condensed state. This significant conformational flexibility of the histone tails suggests that they remain available for protein binding in compact chromatin states to enable regulation of heterochromatin. Furthermore, our study provides a foundation for quantitative structural and dynamic investigations of chromatin at physiological concentrations.
Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival.
Vanadium dioxide (VO2) with its unique sharp resistivity change at the metal-insulator transition (MIT) has been extensively considered for the near-future terahertz/infrared devices and energy harvesting systems. Controlling the epitaxial quality and microstructures of vanadium dioxide thin films and understanding the metal-insulator transition behaviors are therefore critical to novel device development. The metal-insulator transition behaviors of the epitaxial vanadium dioxide thin films deposited on Al2O3 (0001) substrates were systematically studied by characterizing the temperature dependency of both Raman spectrum and Fourier transform infrared spectroscopy. Our findings on the correlation between the nucleation dynamics of intermediate monoclinic (M2) phase with microstructures will open a new avenue for the design and integration of advanced heterostructures with controllable multifunctionalities for sensing and imaging system applications.
DNA double-strand breaks (DSBs) are highly cytotoxic lesions and pose a major threat to genome stability if not properly repaired. We and others have previously shown that a class of DSB-induced small RNAs (diRNAs) is produced from sequences around DSB sites. DiRNAs are associated with Argonaute (Ago) proteins and play an important role in DSB repair, though the mechanism through which they act remains unclear. Here, we report that the role of diRNAs in DSB repair is restricted to repair by homologous recombination (HR) and that it specifically relies on the effector protein Ago2 in mammalian cells. Interestingly, we show that Ago2 forms a complex with Rad51 and that the interaction is enhanced in cells treated with ionizing radiation. We demonstrate that Rad51 accumulation at DSB sites and HR repair depend on catalytic activity and small RNA-binding capability of Ago2. In contrast, DSB resection as well as RPA and Mre11 loading is unaffected by Ago2 or Dicer depletion, suggesting that Ago2 very likely functions directly in mediating Rad51 accumulation at DSBs. Taken together, our findings suggest that guided by diRNAs, Ago2 can promote Rad51 recruitment and/or retention at DSBs to facilitate repair by HR.
Rad51; Ago2; diRNA; Homologous recombination; DSB
Silage making has become a significant method of forage conservation worldwide. To determine how tomato pomace (TP) may be used effectively as animal feed, it was ensilaged for 90 days and microbiology counts, fermentation characteristics and chemical composition of tomato pomace silage (TPS) were evaluated at the 30th, 60th, and 90th days, respectively. In addition, 103 lactic acid bacteria were isolated from TPS. Based on the phenotypic and chemotaxonomic characteristics, 16S rDNA sequence and carbohydrate fermentation tests, the isolates were identified as 17 species namely: Lactobacillus coryniformis subsp. torquens (0.97%), Lactobacillus pontis (0.97%), Lactobacillus hilgardii (0.97%), Lactobacillus pantheris (0.97%), Lactobacillus amylovorus (1.9%), Lactobacillus panis (1.9%), Lactobacillus vaginalis (1.9%), Lactobacillus rapi (1.9%), Lactobacillus buchneri (2.9%), Lactobacillus parafarraginis (2.9%), Lactobacillus helveticus (3.9%), Lactobacillus camelliae (3.9%), Lactobacillus fermentum (5.8%), Lactobacillus manihotivorans (6.8%), Lactobacillus plantarum (10.7%), Lactobacillus harbinensis (16.5%) and Lactobacillus paracasei subsp. paracasei (35.0%). This study has shown that TP can be well preserved for 90 days by ensilaging and that TPS is not only rich in essential nutrients, but that physiological and biochemical properties of the isolates could provide a platform for future design of lactic acid bacteria (LAB) inoculants aimed at improving the fermentation quality of silage.
Lactic Acid Bacteria; Silage; Tomato Pomace; 16S rRNA Gene
Purpose. To compare the corneal biomechanical properties of keratoconic patients and age-matched controls using corneal visualization Scheimpflug technology (Corvis ST). Methods. Sixty keratoconic eyes from 47 keratoconus patients and 60 normal eyes from 60 controls were enrolled in this prospective study. Tomography and biomechanical parameters of all eyes were obtained with the Pentacam and Corvis ST, respectively. Intraocular pressure was measured using a Goldmann applanation tonometer.
Results. The tomography and biomechanical parameters of the keratoconic corneas were significantly different from those of the normal corneas except for the anterior chamber angle, first applanation length, the highest concavity time, and peak distance. The deformation amplitude was the best predictive parameter (area under the curve: 0.882), with a sensitivity of 81.7%, although there was a significant overlap between keratoconic and normal corneas that ranged from 1.0 to 1.4 mm. In both the keratoconus and control groups, the deformation amplitude was negatively correlated with intraocular pressure, central corneal thickness, and corneal volume at 3 and 5 mm. Conclusions. Corvis ST offers an alternative method for measuring corneal biomechanical properties. The possibility of classifying keratoconus based on deformation amplitude deserves clinical attention.
With the rapid development of e-business, personalized recommendation has become core competence for enterprises to gain profits and improve customer satisfaction. Although collaborative filtering is the most successful approach for building a recommender system, it suffers from “shilling” attacks. In recent years, the research on shilling attacks has been greatly improved. However, the approaches suffer from serious problem in attack model dependency and high computational cost. To solve the problem, an approach for the detection of abnormal item is proposed in this paper. In the paper, two common features of all attack models are analyzed at first. A revised bottom-up discretized approach is then proposed based on time intervals and the features for the detection. The distributions of ratings in different time intervals are compared to detect anomaly based on the calculation of chi square distribution (χ2). We evaluated our approach on four types of items which are defined according to the life cycles of these items. The experimental results show that the proposed approach achieves a high detection rate with low computational cost when the number of attack profiles is more than 15. It improves the efficiency in shilling attacks detection by narrowing down the suspicious users.
Fifty-nine VvWRKY genes were identified. Phylogenetic tree and synteny analysis revealed the specific evolutionary relationship of these genes. Meanwhile, differential expression patterns indicated their possible roles in specific tissues and under different stresses.
WRKY proteins comprise a large family of transcription factors that play important roles in plant defence regulatory networks, including responses to various biotic and abiotic stresses. To date, no large-scale study of WRKY genes has been undertaken in grape (Vitis vinifera L.). In this study, a total of 59 putative grape WRKY genes (VvWRKY) were identified and renamed on the basis of their respective chromosome distribution. A multiple sequence alignment analysis using all predicted grape WRKY genes coding sequences, together with those from Arabidopsis thaliana and tomato (Solanum lycopersicum), indicated that the 59 VvWRKY genes can be classified into three main groups (I–III). An evaluation of the duplication events suggested that several WRKY genes arose before the divergence of the grape and Arabidopsis lineages. Moreover, expression profiles derived from semiquantitative PCR and real-time quantitative PCR analyses showed distinct expression patterns in various tissues and in response to different treatments. Four VvWRKY genes showed a significantly higher expression in roots or leaves, 55 responded to varying degrees to at least one abiotic stress treatment, and the expression of 38 were altered following powdery mildew (Erysiphe necator) infection. Most VvWRKY genes were downregulated in response to abscisic acid or salicylic acid treatments, while the expression of a subset was upregulated by methyl jasmonate or ethylene treatments.
Evolution; expression profile analysis; grape (Vitis vinifera L.); phylogenetic analysis; synteny analysis; WRKY genes.
Mechanical ventilation is an important supportive therapy in the intensive care unit (ICU) to assist the critically ill patients with respiratory failure. But longer ventilation time has been proven to contribute to the lung injury which has been recognized as ventilator-induced lung injury (VILI). Recently studies have suggested that NF-κB signaling pathways may play a critical role in the process of inflammation and autophagy, and autophagy can reduce the damage of VILI partly by activating the NF-κB pathways. Thus, we propose that autophagy may facilitate ventilator-induced lung injury partly through activation of NF-κB pathway, which might be a new potential therapeutic target for ventilator-induced lung injury. Although the exact mechanism of autophagy and its exact role in the VILI need to be further explored, at least it provides us a potential target in the future prevention of VILI.
autophagy; ventilator-induced lung injury; NF-κB pathway
Plant respiratory burst oxidase homolog (rboh) genes appear to play crucial roles in plant development, defense reactions and hormone signaling. In this study, a total of seven rboh genes from grape were identified and characterized. Genomic structure and predicted protein sequence analysis indicated that the sequences of plant rboh genes are highly conserved. Synteny analysis demonstrated that several Vvrboh genes were found in corresponding syntenic blocks of Arabidopsis, suggesting that these genes arose before the divergence of the respective lineages. The expression pattern of Vvrboh genes in different tissues was assessed by qRT-PCR and two were constitutively expressed in all tissues tested. The expression profiles were similarly analyzed following exposure to various stresses and hormone treatments. It was shown that the expression levels of VvrbohA, VvrbohB and VvrbohC1 were significantly increased by salt and drought treatments. VvrbohB, VvrbohC2, and VvrbohD exhibited a dramatic up-regulation after powdery mildew (Uncinula necator (Schw.) Burr.) inoculation, while VvrbohH was down-regulated. Finally, salicylic acid treatment strongly stimulated the expression of VvrbohD and VvrbohH, while abscisic acid treatment induced the expression of VvrbohB and VvrbohH. These results demonstrate that the expression patterns of grape rboh genes exhibit diverse and complex stress-response expression signatures.
reactive oxygen species; synteny analysis; phylogenetic analysis; gene expression
Whether cisplatin plus vinorelbine (VC) or cisplatin plus docetaxel (DC) are equally effective in the treatment of advanced non-small-cell lung cancer (NSCLC) remains controversial. The aim of this study was to compare the VC and DC regimens in the first-line treatment of advanced NSCLC. A search was conducted through PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and the Chinese Biomedical Literature database (CBM). The language of the publication was not considered to be a limitation. The recruited trials were evaluated for eligibility and quality and the data were extracted and analyzed. The endpoints were overall response, survival rate and toxicity. We analyzed 9 randomized controlled trials (RCTs), including a total of 1,886 patients. Patients receiving DC therapy exhibited a significantly higher response rate [relative risk (RR)=0.83, 95% CI: 0.73–0.95 and P=0.007] and 2-year survival rate (RR=0.65, 95% CI: 0.50–0.84 and P=0.001). However, the 1-year survival rate for the two cisplatin-based regimens were comparable (RR=0.90, 95% CI: 0.81–1.01 and P=0.07). Patients receiving the VC regimen more frequently developed grade 3/4 leucopenia, anemia and vomiting, whereas those receiving DC chemotherapy were more prone to grade 3/4 diarrhea. The incidence of grade 3/4 neutropenia, thrombocytopenia and nausea were similar between the two arms. In conclusion, our study indicated that DC is superior to the VC regimen in terms of tumor response rate, 2-year survival rate and safety for the first-line treatment of advanced NSCLC.
non-small-cell lung cancer; vinorelbine; docetaxel; cisplatin; meta-analysis
The phytohormone gibberellic acid (GA3) is widely used in the table grape industry to induce seedlessness in seeded varieties. However, there is a paucity of information concerning the mechanisms by which GAs induce seedlessness in grapes.
In an effort to systematically analyze the cause of this GA3-induced seed abortion, we conducted an in depth characterization of two seeded grape cultivars (‘Kyoho’ and ‘Red Globe’), along with a seedless cultivar (‘Thompson Seedless’), following treatment with GA3. In a similar fashion to the seedless control, which exhibited GA3-induced abortion of the seeds 9 days after full bloom (DAF), both ‘Kyoho’ and ‘Red Globe’ seeded varieties exhibited complete abortion of the seeds 15 DAF when treated with GA3. Morphological analyses indicated that while fertilization appeared to occur normally following GA3 treatment, as well as in the untreated seedless control cultivar, seed growth eventually ceased. In addition, we found that GA3 application had an effect on redox homeostasis, which could potentially cause cell damage and subsequent seed abortion. Furthermore, we carried out an analysis of antioxidant enzyme activities, as well as transcript levels from various genes believed to be involved in seed development, and found several differences between GA3-treated and untreated controls.
Therefore, it seems that the mechanisms driving GA3-induced seedlessness are similar in both seeded and seedless cultivars, and that the observed abortion of seeds may result at least in part from a GA3-induced increase in cell damage caused by reactive oxygen species, a decrease in antioxidant enzymatic activities, and an alteration of the expression of genes related to seed development.
Daclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coverage in vitro. Viral RNA declines have been observed in the clinic for both alpha interferon-ribavirin (IFN-α–RBV) and IFN-RBV-free regimens that include DCV. Follow-up specimens (up to 6 months) from selected subjects treated with DCV in 14-day monotherapy studies were analyzed for genotype and phenotype. Variants were detected by clonal sequencing in specimens from baseline and were readily detected by population sequencing following viral RNA breakthrough and posttreatment. The major amino acid substitutions generating resistance in vivo were at residues M28, Q30, L31, and Y93 for genotype 1a (GT-1a) and L31 and Y93 for GT-1b, similar to the resistance substitutions observed with the in vitro replicon system. The primary difference in the resistance patterns observed in vitro and in vivo was the increased complexity of linked variant combinations observed in clinical specimens. Changes in the percentage of individual variants were observed during follow-up; however, the overall percentage of variants in the total population persisted up to 6 months. Our results suggest that during the 14-day monotherapy, most wild-type virus was eradicated by DCV. After the end of DCV treatment, viral fitness, rather than DCV resistance, probably determines which viral variants emerge as dominant in populations.
To investigate the correlation of endocrine gland-derived vascular endothelial growth factor (EG-VEGF), vascular endothelial growth factor (VEGF) and transforming growth factor beta 1 (TGF-β1) with the corresponding reproductive outcome in patients who received in vitro fertilization-embryo transfer (IVF-ET).
Sixty-seven women undergoing IVF-ET at a university tertiary hospital were recruited for a prospective study. Concentrations of EG-VEGF, VEGF and TGF-β1 were measured by enzyme-linked immunosorbent assay (ELISA) in follicular fluid (FF) collected during oocyte retrieval (OR) and in serum collected 2 days after OR.
In FF, concentrations of both EG-VEGF and VEGF were negatively correlated with peak E2 and the number of MII oocytes retrieved, and positively correlated with each other. In serum, concentrations of all the three growth factors were positively correlated with the rate of good quality embryo, and with one another. Patients in the pregnancy group had lower peak E2 concentrations and higher serum EG-VEGF concentrations than those in the non-pregnancy group, but such tendency was not observed in the case of VEGF and TGF-β1.
Both concentrations of EG-VEGF and VEGF in FF were negatively correlated with ovarian response and oocyte maturation. Concentrations of all the three growth factors in serum were positively correlated with embryo quality, but only serum concentrations of EG-VEGF were associated with the pregnancy outcome.
IVF-ET; EG-VEGF; VEGF; TGF-β1; Pregnancy
Gastric cancer is the second most frequent cause of cancer-related death in the world and also causes much morbidity. The acquired resistance of cancer cells to drug reagents is becoming a major obstacle for successful cancer therapy. Recently, many studies have revealed that macroautophagy (here referred to as autophagy) may be a prosurvival factor and protect the cancer cell from the development of drug-induced death. Thus, we propose that autophagy may play an important role in the resistance of gastric cancer to therapy. Although the exact role of autophagy in tumor cells is still unclear and further studies are needed to prove the role of autophagy in gastric cancer, recent research findings suggest a new direction in investigating the mechanism underlying resistance of gastric cancer to therapy.
autophagy; gastric cancer; chemotherapy
Several directly-acting and host-targeting antivirals that inhibit hepatitis C virus replication have entered clinical trials. Amongst the most advanced of these are RG7128, an inhibitor of the NS5B polymerase; BMS-790052, an inhibitor of NS5A; and alisporivir, an inhibitor of human cyclophilins. These agents have potent antiviral activity in chronic HCV patients, act additively or synergistically with inhibitors of the HCV NS3/4A protease, and improve the rate of virologic response produced by traditional pegylated interferon plus ribavirin therapy. No cross resistance has been observed; moreover, nucleoside NS5B and cyclophilin inhibitors appear to suppress resistance to non-nucleoside NS5B and NS3/4A inhibitors. Several recent reports of virologic responses produced by combinations of agents that inhibit HCV replication in the absence of interferon provide optimism that eradication of HCV will be possible without interferon in the future.