Humanized disulfide-stabilized diabody against fibroblast growth factor-2 inhibits PD-L1 expression and epithelial-mesenchymal transition in hepatoma cells through STAT3.

Fibroblast growth factor 2 (FGF2) plays an important role in tumor angiogenesis. Humanized disulfide-stable double-chain antibody against fibroblast growth factor-2 (anti-FGF2 ds-Diabody) is a small molecule antibody with good tissue permeability and low immunogenicity, which has potential in tumor-targeted therapy. This study intended to investigate the effect of anti-FGF2 ds-Diabody on the migration and expression of programmed death-ligand1 (PD-L1) in hepatocellular carcinoma (HCC) cells. The anti-FGF2 ds-Diabody was expressed under methanol induction and purified with Ni2+ -affinity chromatography. Anti-FGF2 ds-Diabody significantly inhibited cell viability and proliferation in SK-Hep1 and HepG2 cells as confirmed by CCK-8 assays and colony formation assays. Western blot assays indicated that the proliferation of SK-Hep1 and HepG2 cells was inhibited by anti-FGF2 ds-Diabody through inhibiting the phosphorylation activation of AKT and MAPK. The results of transwell and western blot assays showed that the migration and invasion of SK-Hep1 and HepG2 cells were suppressed by anti-FGF2 ds-Diabody by affecting the epithelial-mesenchymal transition (EMT) process. Meanwhile, anti-FGF2 ds-Diabody inhibited the expression of PD-L1, and STAT3 participated in this process. Analysis of RT-PCR and Western blot suggested that fibroblast growth factor receptor 4 inhibitor 1 (FGFR4-IN-1) suppressed the expression of PD-L1, while STAT3 overexpression reversed this inhibitory effect. In addition, overexpression of STAT3 promoted migration and invasion and restored the suppressive effect of anti-FGF2 ds-Diabody on EMT. In conclusion, anti-FGF2 ds-Diabody could inhibit the expression of PD-L1 and EMT of hepatoma cells through FGF2/FGFR4/STAT3 axis. These results suggested that anti-FGF2 ds-Diabody has potential clinical application in inhibiting metastasis and immune escape of hepatocellular carcinoma.

Selective Manganese-Catalyzed Oxidation of Hydrosilanes to Silanols under Neutral Reaction Conditions.

The first manganese-catalyzed oxidation of organosilanes to silanols with H2 O2 under neutral reaction conditions has been accomplished. A variety of organosilanes with alkyl, aryl, alknyl, and heterocyclic substituents were tolerated, as well as sterically hindered organosilanes. The oxidation appears to proceed by a concerted process involving a manganese hydroperoxide species. Featuring mild reaction conditions, fast oxidation, and no waste byproducts, the protocol allows a low-cost, eco-benign synthesis of both silanols and silanediols.

Iron-Catalyzed Alkylation of Nitriles with Alcohols.

A general, efficient iron-catalyzed α-alkylation of nitriles with primary alcohols through a hydrogen-borrowing pathway has been developed, allowing a wide variety of alkylated nitriles to be readily accessible. Detailed mechanistic studies suggest that the reaction proceeds via an olefin intermediate with the turnover rate limited by the hydrogenation of the olefin with an iron hydride. Apart from participating in the alkylation, the nitrile is found to play an important role in promoting the formation of and stabilizing the active catalytic species.

Scaling Up Human Immunodeficiency Virus Screening and Antiretroviral Therapy Among Men Who Have Sex With Men to Achieve the 90-90-90 Targets in China.

INTRODUCTION: The Joint United Nations Programme on human immunodeficiency virus (HIV)/acquired immune deficiency syndrome has proposed the 90-90-90 targets by 2020. Human immunodeficiency virus epidemic is spreading rapidly among men who have sex with men (MSM) in China. This study investigates how the scale-up of HIV testing and treatment in achieving the targets and its cost-effectiveness. METHODS: We constructed a compartmental model to forecast the HIV epidemic in Chinese MSM based on various "test-and-treat" scale-up scenarios. We assessed their cost effectiveness based on the cost for each HIV infection, death, and disability-adjusted life years (DALYs) prevented by the scale-up. RESULTS: If the current epidemic continued, HIV prevalence among Chinese MSM would increase from 9.2% in 2016 to 12.6% (9.2-15.6%) in 2020 and 16.2% (11.3-20.0%) in 2025. By 2020, 49.2% of infected MSM would be diagnosed and 40.1% of whom on treatment, falling short of the 90-90-90 targets, so would be even by 2025. To achieve these targets by 2020, additional 850,000 HIV screening tests and 112,500 person-years of antiretroviral treatment (ART) annually are necessary. This spending is US $478 million during 2016 to 2020, which almost tripled the status quo. However, by delaying to 2025, an investment of US $1210 million over 2016 to 2025 corresponding to 52% increase to the status quo, will enable extra 340,000 HIV screening tests and 60,000 person-year on ART annually. In both scenarios, the incremental cost-effectiveness ratio was US $733 to 960 for each DALY prevented, indicating highly cost-effective scenarios. CONCLUSIONS: Achieving the 90-90-90 targets by 2020 requires steep increase in investment, but delaying the targets to 2025 is practical and cost-effective.

A cross-sectional survey on the health status and the health-related quality of life of the elderly after flood disaster in Bazhong city, Sichuan, China.

BACKGROUND: Flood is common in China and causes extensive loss of property and human lives. Elderly is a vulnerable population prone to the detrimental impacts of floods. This survey aims to investigate the health status and the HRQoL of the elderly in Bazhong city after a major flood in 2011. METHODS: A total of 1183 elderly (aged > 60) were surveyed through random sampling from eight villages in Bazhong city. Two-week healthcare-seeking rate and chronic diseases prevalence were recorded anonymously. Health-related quality of life (HRQoL) was measured by the Medical Outcomes Study Short Form-36 (MOS SF-36). Multivariate regression analysis was conducted to determine the associated factors of poor HRQoL. RESULTS: The two-week healthcare-seeking rate among post-flood Bazhong elderly was significantly higher than the references rate among rural elderly in Sichuan province (59.3% versus 55.7%, χ2 = 5.134, p = 0.013), but Bazhong elderly demonstrated a significantly lower prevalence of chronic disease (33.2% versus 44.4%, χ2 = 48.847, p < 0.001). All dimension scores among Bazhong elderly were significantly lower than the references scores in rural Sichuan elderly. The determinants of poor physical health included older age, singlehood, poor sleep patterns, and chronic diseases and so on. CONCLUSIONS: A marked decline in health status among elderly in Bazhong after the 2011 flood. Post-flood management targeting elderly need to be sensitive to their age, gender, married status and status of chronic diseases.

Demethylase FTO inhibits the development of prostate cancer by upregulating EGR2 expression in an m6A manner.

Fat mass and obesity-associated protein (FTO) is a demethylase and plays a vital role in various cancers. However, the regulation mechanism of FTO in prostate cancer (PCa) remains unclear. This study aimed to elucidate the mechanism of FTO in PCa. The function and mechanism of FTO-mediated in PCa were determined by gain-of-function assays and RNA-seq. We found that FTO expression in PCa tissues and two PCa cell lines were significantly lower than that in adjacent tissues and normal cell line. PCa cells after overexpression of FTO showed a significant lower in proliferation, migration, and invasion capabilities. RNA-seq displayed that FTO overexpression altered transcriptome landscape in Du145 and PC-3 cells, particularly upregulating EGR2 expression. FTO overexpression induced differential expression genes, including MYLK2, DNA2, CDK, and CDC (6, 7, 20, 25, and 45), which were mainly enriched in adjustment of cell cycle and growth pathways. Furthermore, FTO overexpression significantly reduced the EGR2 methylation level. Arresting the proliferation, migration, and invasion of Du145 cells induced by FTO overexpression was significantly rescued by EGR2 knockdown. FTO overexpression also significantly inhibited tumor growth and promoted EGR2 protein expression. Taken together, FTO suppresses PCa progression by regulating EGR2 methylation. We uncovered a novel regulatory mechanism of FTO in PCa and provide a new potential therapeutic target for PCa.

Preparation of DSPE-PEG-cRGD Modified Cationic Liposomes for Delivery of OC-2 shRNA and The Antitumor Effects on Breast Cancer.

Cationic liposome delivery of interfering RNA (shRNA) plays an important role in tumor therapy. The cyclic Arg-Gly-Asp (cRGD) modified cationic liposomes (cRGD-CL) were designed for targeted delivery of ONECUT2 (OC-2) shRNA (pshOC-2) to breast cancer cells. The characterization analysis of cationic liposome showed that the prepared cRGD-CL/pshOC-2 lipoplexes had uniform particle size (150 ± 1.02 nm), moderate zeta potential (19.8 ± 0.249 mV) and high encapsulation efficiency (up to 96%). The results of flow cytometer showed that the introduction of cRGD could significantly promote the liposomes targeting tumor cells. In MCF-7 cells, the pshOC-2 could down-regulate expression of OC-2 and result in cell apoptosis, inhibition of the wound healing, migration and cell colony formation, in which the signal pathways of Bcl-xL, Bcl-2 were inhibited and the signal pathways of Bax and Cleaved Caspase-3 were promoted. In MCF-7 xenograft mice, intravenous administration of cRGD-CL/pshOC-2 lipoplexes could effectively reduce the expression of OC-2 in tumors and result in apparently antitumor effects, which suggested that the lipoplexes might be deeply penetrated into tumor through receptor-mediated transcytosis. The results revealed that the cationic liposome (cRGD-CL) was an effective delivery system for OC-2 shRNA, which might be an effective therapeutic candidate for breast cancer.

Barriers and Strategies of Cationic Liposomes for Cancer Gene Therapy.

Cationic liposomes (CLs) have been regarded as the most promising gene delivery vectors for decades with the advantages of excellent biodegradability, biocompatibility, and high nucleic acid encapsulation efficiency. However, the clinical use of CLs in cancer gene therapy is limited because of many uncertain factors in vivo. Extracellular barriers such as opsonization, rapid clearance by the reticuloendothelial system and poor tumor penetration, and intracellular barriers, including endosomal/lysosomal entrapped network and restricted diffusion to the nucleus, make CLs not the ideal vector for transferring extrinsic genes in the body. However, the obstacles in achieving productive therapeutic effects of nucleic acids can be addressed by tailoring the properties of CLs, which are influenced by lipid compositions and surface modification. This review focuses on the physiological barriers of CLs against cancer gene therapy and the effects of lipid compositions on governing transfection efficiency, and it briefly discusses the impacts of particle size, membrane charge density, and surface modification on the fate of CLs in vivo, which may provide guidance for their preclinical studies.

An efficient defect engineering strategy to enhance catalytic performances of Co3O4 nanorods for CO oxidation.

Catalytic oxidation of CO at ambient temperature is an important reaction for many environmental applications. Here, we employed a defect engineering strategy to design an extraordinarily effective Sn-doped Co3O4 nanorods (NRs) catalyst for CO oxidation. Our combined theoretical and experimental data demonstrated that Co2+ in the lattice of Co3O4 were substituted by Sn4+. Based on a variety of characterizations and kinetic studies, this catalyst was found to combine the advantages of the nanorod-like morphology for largely exposing catalytically active Co3+ sites and the promotional effect of Sn dopant for adjusting the textural/redox properties. Additionally, the Sn-substituted Co3O4 NRs can be further activated via heat treatment to achieve low-temperature CO oxidation (T100 ∼ -100 °C) with excellent stability at ambient temperature. This study reveals the importance of Sn-substitution of inactive Co2+ in Co3O4 and provides an ultra-efficient catalyst for CO oxidation, making this robust material one of the most powerful catalysts available up to now.

Methadone maintenance treatment programme reduces criminal activity and improves social well-being of drug users in China: a systematic review and meta-analysis.

OBJECTIVE: Methadone maintenance treatment (MMT) has been implemented in China since 2004 and has expanded into a nationwide programme. This study aims to evaluate changes in social functioning, family relations and drug-related criminal behaviour among MMT clients in China. DESIGN: Systematic review and meta-analysis. METHODS: Both English and Chinese literature databases, including PubMed, Chongqing VIP Chinese Science and Technology Journals Database (CQVIP), China National Knowledge Infrastructure (CNKI) and Wanfang Data, were comprehensively searched over the period 2004-2014 for studied indicators. Study selection, quality assessment and data extraction were conducted according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) Statement. Meta-analyses were conducted using Comprehensive Meta-Analysis Biostat software. RESULTS: Thirty-eight articles were included in this review (1 in English and 37 in Chinese). The self-reported arrest rate decreased from 13.1% (95% CI 9.1% to 18.5%) at baseline to 3.4% (95% CI 1.5% to 7.7%) and 4.3% (95% CI 1.6% to 11.4%) after 6 and 12 months of MMT intervention, respectively. The rate of drug selling decreased from 7.6% (95% CI 3.8% to 14.8%) at baseline to 1.9% (95% CI 0.6% to 6.2%) and 3.0% (95% CI 1.0% to 8.9%) after 6 and 12 months of intervention, respectively. Similarly, the rates of selling sex for drugs and drug-related crime decreased from 5.3% (95% CI 2.4% to 11.1%) and 9.9% (95% CI 6.8% to 14.2%) at baseline to 1.1% (95% CI 0.5% to 2.3%) and 3.4% (95% CI 2.5% to 4.5%) at 6 months, then to 0.8% (95% CI 0.3% to 1.9%) and 3.4% (95% CI 0.8% to 13.1%) at 12 months after treatment initiation, respectively. In contrast, the rate of employment of clients and the proportion of clients having a good relationship with their family increased substantially from 26.4% (95% CI 22.9% to 30.1%) and 37.9% (95% CI 32.0% to 44.2%) to 41.6% (95% CI 36.6% to 48.0%) and 59.6% (95% CI 48.1% to 70.2%) at 6 months, then to 59.8% (95% CI 52.4% to 66.8%) and 75.0% (95% CI 69.0% to 80.2%) at 12 months after treatment initiation, respectively. CONCLUSIONS: MMT has significantly reduced criminal activity, and improved employment rate and social well-being, of clients of the MMT programme. MMT is an effective measure to help drug users to resume societal and familial functions in China.

HIV prevalence in China: integration of surveillance data and a systematic review.

BACKGROUND: Asian HIV epidemics are concentrated among particular behavioural groups, but large variations exist in epidemic types, timing, and geographical spread between countries and within countries, especially in China. We aimed to understand the complexity of HIV epidemics in China by systematically analysing prevalence trends by data source, region, population group, and time period. METHODS: We collected HIV prevalence data from official national sentinel surveillance sites at the provincial level from Jan 1, 1995, to Dec 31, 2010. We also searched PubMed, VIP Chinese Journal Database (VIP), China National Knowledge Infrastructure, and Wanfang Data from Jan 1, 1990, to Dec 31, 2012, for independent studies of HIV prevalence. We integrated both sets of data, and used an intraclass correlation coefficient test to assess the similarity of geographical pattern of HIV disease burden across 31 Chinese provinces in 2010. We investigated prevalence trends (and 95% CIs) to infer corresponding incidence by region, population group, and year. FINDINGS: Of 6850 articles identified by the search strategy, 821 studies (384,583 drug users, 52,356 injecting drug users, 186,288 female sex workers, and 87,834 men who have sex with men) met the inclusion criteria. Official surveillance data and findings from independent studies showed a very similar geographical distribution and magnitude of HIV epidemics across China. We noted that HIV epidemics among injecting drug users are decreasing in all regions outside southwest China and have stabilised at a high level in northwest China. Compared with injecting drug users, HIV prevalence in female sex workers is much lower and has stabilised at low levels in all regions except in the southwest. In 2010, national HIV prevalence was 9·08% (95% CI 8·04-10·52) in injecting drug users and 0·36% (0·12-0·71) in female sex workers, whereas incidence in both populations stabilised at rates of 0·57 (0·43-0·72) and 0·02 (0·01-0·04) per 100 person-years, respectively. By comparison, HIV prevalence in men who have sex with men increased from 1·77% (1·26-2·57) in 2000, to 5·98% (4·43-8·18) in 2010, with a national incidence of 0·98 (0·70-1·25) per 100 person-years in 2010. We recorded strong associations between HIV prevalence among at-risk populations in each province, supporting the existence of overlap in risk behaviours and mixing among these populations. INTERPRETATION: HIV epidemics in China remain concentrated in injecting drug users, female sex workers, and men who have sex with men. HIV prevalence is especially high in southwest China. Sex between men has clearly become the main route of HIV transmission.