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This project implemented the Stroke 1-2-0 stroke awareness programme across China and investigated its impact over a 2-year period. We initiated the Stroke 1-2-0 educational campaign and Stroke 1-2-0 special task forces (STF) across the nation. Massive media coverage, community-based educational sessions with videos and other related materials and induction of Stroke 1-2-0 STF were the major means of promotion. We delivered a survey at the end of 2016 and 2018 to evaluate the impact of our effort. A total of 3066 participants responded to the first survey in 2016, and 15 207 participants responded in 2018 across China. The acceptance rate for Stroke 1-2-0 versus FAST (an English-language stroke awareness tool) was 50.2% versus 19.1% in 2016, and changed significantly to 82.2% versus 8.0% in 2018 (p

Exposure to greenness may lead to a wide range of beneficial health outcomes. However, the effects of greenness on preterm birth (PTB) are inconsistent, and limited studies have focused on the subcategories of PTB. A total of 3,751,672 singleton births from a national birth cohort in mainland China were included in this study. Greenness was estimated using the satellite-based Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index with 500-m and 1,000-m buffers around participants' addresses. The subcategories of PTB (20-36 weeks) included extremely PTB (EPTB, 20-27 weeks), very PTB (VPTB, 28-31 week), and moderate-to-late PTB (MPTB, 32-36 weeks). Gestational age (GA) was included as another birth outcome. We used logistic regression models and multiple linear regression models to analyze these associations throughout the entire pregnancy. We found inverse associations between greenness and PTB and positive associations between greenness and GA. Specifically, an increase of 0.1 NDVI exposure within a 500-m buffer throughout the entire pregnancy was significantly associated with decreases in PTB (odds ratio [OR], 0.930; 95% confidence interval [CI], 0.927-0.932), EPTB (OR, 0.820; 95% CI, 0.801-0.839), VPTB (OR, 0.913; 95% CI, 0.908-0.919), MPTB (OR, 0.934; 95% CI, 0.931-0.936), and an increase in GA (β = 0.050; 95% CI, 0.049-0.051 weeks). These results suggest the potential protective effects of greenness on PTB and its subcategories: MPTB, VPTB, and EPTB in China.

BACKGROUND Heat-shock protein 90 (HSP90), an evolutionary conserved protein, is a key member of the epichaperome complex involved in maintenance of protein homeostasis during non-stress and stress conditions. It is overexpressed in gliomas and supports tumor cell survival and resistance. Hsp90 inhibition can impact several pathways essential for glioma cell survival and overcome tumor heterogeneity. Here, we examined the activity and toxicity profile of MPT0B640, an orally bioavailable Hsp90 inhibitor, against gliomas and its ability to cross the blood-brain barrier (BBB). METHODS Using genetically heterogeneous glioma stem-like cell (GSC) lines, we determined the effects of MPT0B640 on cell proliferation (Cell Titre Glo assay), apoptosis induction and cell cycle changes (flowcytometry; AnnexinV/PI staining), and alterations in protein expressions (western blot and reverse-phase protein array, RPPA assays). Pharmacokinetic and pharmacodynamic (PK/PD) studies were performed in non-tumor bearing mice to assess BBB permeability and antitumor effects of MPT0B640. RESULTS MPT0B640 inhibited proliferation of both adherent (LN229, A172, U251-HF) and patient-derived GSCs (GSC262, GSC811, GSC11, GSC23, GSC20 and GSC272) in a dose- and time-dependent fashion with an IC50 range of 50-1000 nM. MPT0B640-treated cells underwent apoptosis and/or cell cycle arrest with downregulation of pro-survival signal kinases, phospho-Akt, p-ERK1/2 and p-S6. PK/PD studies showed increased HSP70 expression (a marker of Hsp90 inhibition) and detectable levels of drug in brain specimens from non-tumor bearing mice after a single dose of MPT0B640, indicating BBB permeability and target inhibition of the agent. Results of ongoing animal studies assessing drug toxicity and animal survival with MPT0B640 will be presented. CONCLUSIONS MPT0B640 is a potent HSP90 inhibitor that has potent antitumor activity against genetically heterogeneous gliomas in vitro, effectively crosses the intact BBB and demonstrates target inhibition warranting further investigation for treatment of gliomas.

BACKGROUND Pathway-specific targeted agents have failed to improve outcome in patients with high grade gliomas. Tumor recurrence is driven by glioma heterogeneity and emergence of therapy-resistant subpopulations. We have previously reported that metabolic targeting of NAMPT, the rate limiting enzyme in the NAD salvage synthesis pathway, circumvents glioma heterogeneity and induces cytotoxicity by mitochondrial membrane depolarization and generation of reactive oxygen species. Based on these data, we examined the potential for NAMPT inhibition to synergize with ionizing radiation to enhance glioma cytotoxicity in vitro and in vivo. METHODS Using a panel of genetically heterogeneous patient-derived glioma stem-like cells (GSC), we examined the effects of NAD targeting using KPT9274, a potent NAMPT inhibitor, in combination with ionizing radiation on cell proliferation and clonogenicity using Cell Titre Glo assay, colony formation assays and secondary sphere formation. Changes in DNA damage-related proteins were visualized by immunofluorescence assay and confocal microscopy. Effects on gene expression and protein levels were assessed using western blot, reverse phase protein array (RPPA) and RNA Seq. RESULTS NAMPT inhibition reduced cell proliferation rate, self-renewal and clonogenic capacity in vitro. Combining KPT-9274 with ionizing radiation caused synergistic inhibition of secondary sphere and colony formation of GSC. RPPA and RNASeq results showed downregulation of several DNA repair proteins which was further confirmed using immunofluorescence staining indicating a crucial role for these proteins in glioma resistance to therapies. Results of ongoing in vivo studies to assess the PK/PD, drug toxicity and survival benefits of this combination therapy in orthotopic GSC intracranial glioma mouse model will be reported. CONCLUSIONS Our results suggest that metabolic targeting through NAMPT inhibition sensitizes glioma cells to radiotherapy. Ongoing studies delineating the mechanistic basis of these effects and their impact in vivo as a potential rationale for clinical assessment will be reported.

To comprehensively evaluate the association of paternal smoking and preterm birth (PTB).We performed a population-based retrospective cohort study in rural areas of China among 5,298,043 reproductive-aged couples who participated in the National Free Pre-Pregnancy Checkups Project (NFPCP), regarding outcome events that occurred in 2010-2016. Multivariate Cox proportional regression was used to estimate hazard ratio (HR) and 95% confident intervals (95%CI), and restricted cubic spline (RCS) were used to estimate the dose-response relationship.Compared to neither-smoker couples, the fully adjusted HR for PTB was 1.04 (95% CI, 1.03-1.04), 1.08 (0.96-1.22), and 1.11 (1.03-1.19) in the couples where only the female smoked, only the male smoked and both, respectively. HR of PTB for paternal smoking was 1.07 (1.06-1.07), compared with women without paternal smoking. Consistent with paternal smoking, preconception paternal smoking showed 1.07-fold higher risk of PTB (95%CI, 1.06-1.09). The multivariable-adjusted HRs of PTB were 1.05 (1.03-1.06), 1.04 (1.03-1.05), 1.05 (1.04-1.07), 1.07 (1.05-1.10) and 1.13 (1.12-1.14) for participants whose husband smoked 1-4, 5-9, 10-14, 15-19, and ≥ 20 cigarettes/day respectively, compared with participants without paternal smoking. The HRs of PTB also increased with the increment of paternal smoking and preconception paternal smoking categories (PPaternal smoking and preconception paternal smoking was independently positively associated with PTB risk. The importance of tobacco control, should be emphasized during preconception and pregnancy counselling should be towards not only women but also their husband.Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality, as well as other system immaturity problem. But as one of important environmental tobacco smoking sources of maternal secondhand smoking in the family, paternal smoking is worthy for deep exploring of its potential impacts on PTB. Moreover, evidence on the independent role of preconception paternal smoking is still lacking. Thus, we conducted a population-based retrospective cohort study to evaluate the association between paternal smoking and risk of PTB among among 5,298,043 reproductive-aged couples who participated in the National Free Pre-Pregnancy Checkups Project (NFPCP), regarding outcome events that occurred in 2010–2016.We found a significant association between paternal smoking and PTB. Smoking reduction should not only be advised to pregnant women but also to their partners to reduce PTB in their fetal. In addition, supporting patients to continue smoking reduction will be crucial when considering the adverse health outcome of smoking. Intervention of tobacco use before and during pregnancy, are critical for prevention of PTB. Avoiding both maternal and paternal smoking during pregnancy will benefit the developing fetus.

Background Tumor-specific metabolic processes essential for cell survival are promising targets to potentially circumvent intratumoral heterogeneity, a major resistance factor in gliomas. Tumor cells preferentially using nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway for synthesis of NAD, a critical cofactor for diverse biological processes including cellular redox reactions, energy metabolism, and biosynthesis. NAMPT is overexpressed in most malignancies, including gliomas, and can serve as a tumor-specific target. Methods Effects of pharmacological inhibition of NAMPT on cellular oxygen consumption rate, extracellular acidification, mitochondrial respiration, cell proliferation, invasion, and survival were assessed through in vitro and ex vivo studies on genetically heterogeneous glioma cell lines, glioma stem-like cells (GSCs), and mouse and human ex vivo organotypic glioma slice culture models. Results Pharmacological inhibition of the NAD salvage biosynthesis pathway using a highly specific inhibitor, KPT-9274, resulted in the reduction of NAD levels and related downstream metabolites, inhibited proliferation, and induced apoptosis in vitro in cell lines and ex vivo in human glioma tissue. These effects were mediated by mitochondrial dysfunction, DNA damage, and increased oxidative stress leading to apoptosis in GSCs independent of genotype, IDH status, or MGMT promoter methylation status. Conversely, NAMPT inhibition had minimal in vitro effects on normal human astrocytes (NHA) and no apparent in vivo toxicity in non-tumor-bearing mice. Conclusions Pharmacological NAMPT inhibition by KPT9274 potently targeted genetically heterogeneous gliomas by activating mitochondrial dysfunction. Our preclinical results provide a rationale for targeting the NAMPT-dependent alternative NAD biosynthesis pathway as a novel clinical strategy against gliomas.

The work by MacMillan et al. (

We explored variables associated with patient-reported outcomes (PROs) including symptom burden, impact on daily life and work, obstacles during therapy, satisfaction level with therapy, and health-related quality of life in 1500 respondents with myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) in a multicenter, cross-sectional study across China, a representative of the developing countries. In multivariate analyses, urban household registration and higher education level were significantly-associated with no symptoms at diagnosis in respondents with ET or MF. CALR mutation was significantly-associated with lower MPN-10 scores in respondents with MF. Higher MPN-10 scores were significantly-associated with negative impact on daily life and work as well as lower satisfaction level in respondents with ET, PV and MF. Receiving ruxolitinib was significantly-associated with high satisfaction and satisfaction in respondents with MF. In addition, other demographics and clinical variables were also impacting PROs.

Background Potential hazards of fine particulate matter (PM2.5) constituents on preterm birth (PTB) have rarely been explored in China. Objective To quantify the associations of PM2.5 constituents with PTB. Methods This study was based on a nationwide cohort of 3,723,169 live singleton births delivered between January 2010 and December 2015 in China. We applied satellite-based estimates of five PM2.5 constituents (organic carbon; black carbon; sulfate; ammonium; and nitrate). We used Cox proportional hazards regression models adjusted for individual covariates, temperature, humidity, and seasonality to evaluate the associations. Results During the entire pregnancy, each interquartile range (29 μg/m3) increase in PM2.5 concentrations was associated with a 7% increase in PTB risk [hazard ratio (HR): 1.07; 95% confidence interval (CI): 1.07-1.08). We observed the largest effect estimates on carbonaceous components (HR: 1.09; 95% CI: 1.08-1.10 for organic carbon and black carbon). Early pregnancy appeared to be the critical exposure window for most constituents. Women who were older, exposed to second-hand smoke, overweight or obese before pregnancy, conceived during winter, and living in northern China or rural areas were more susceptible. Conclusions Carbonaceous components of PM2.5 were associated with higher PTB risk. Findings on characteristics of vulnerability underlined targeted protections on susceptible subgroups.

Background Global crises inevitably increase levels of anxiety in postpartum populations. Effective and efficient measurement is therefore essential. This study aimed to create a 12-item research short form of the 51-item Postpartum Specific Anxiety Scale [PSAS] and validate it for use in rapid response research at a time of global crises [PSAS-RSF-C]. We also present the same 12-items, in five other languages (Italian, French, Chinese, Spanish, Dutch) to increase global accessibility of a psychometric tool to assess maternal mental health. Methods Twelve items from the PSAS were selected on the basis of a review of their factor loadings. An on-line sample of UK mothers (N = 710) of infants up to 12 weeks old completed the PSAS-RSF-C during COVID-19 ‘lockdown’. Results Principal component analyses on a randomly split sample (n = 344) revealed four factors, identical in nature to the original PSAS, which in combination explained 75% of the total variance. Confirmatory factor analyses (n = 366) demonstrated the four-factor model fit the data well. Reliability of the overall scale and of the underlying factors in both samples proved excellent. Conclusions Findings suggest the PSAS-RSF-C may prove useful as a clinical screening tool and is the first postpartum-specific psychometric scale to be validated during the COVID-19 pandemic. This offers psychometrically sound assessment of postpartum anxiety. By increasing the accessibility of the PSAS, we aim to enable researchers the opportunity to measure maternal anxiety, rapidly, at times of global crisis.

BACKGROUND Heat-shock protein 90 (HSP90) is a molecular chaperone involved in the conformational maturation of many client proteins that regulate cell proliferation, survival, and apoptosis. Due to the limited solubility of natural Hsp90 inhibitors, synthetic inhibitors with a more potent impact are being developed. In this study we examined the biological activity of a potent synthetic small molecule Hsp90 inhibitor, SNX-5422 (PF-04929113)and assessed its ability of to inhibit the growth of glioma and to synergize with temozolomide. We also examined the ability of SNX-5422 to cross the blood brain barrier (BBB) and to achieve target inhibition in vivo. METHODS Using a combination of in vitro techniques, the effect of SNX-5422 on the biological impact and HSP90 client protein signaling were studied in glioma lines and patient-derived glioma stem like cells. Its efficacy as a single agent or in combination with TMZ was also assessed in vitro. To assess SNX-5422 ability to cross blood brain barrier, brain and plasma pharmacokinetics was performed in non-tumor bearing mice. RESULTS SNX-5422 exhibited potent growth inhibition in both glioma cells and GSCs with an IC50 range of 100-500nM, and inhibited pro-survival signal kinases, phospho-Akt, p-ERK1/2 and p-S6 following treatment in GSC262 and GSC811. This was accompanied by accumulation of apoptotic cells following SNX-5422 exposure. Combination studies with TMZ showed a synergestic impact on glioma cell proliferation. Pharmacokinetics studies showed a significant drug penetrance into the intact brain further supported by elevated levels of HSP70 (molecular maker for HSP90 inhibition) by IHC. CONCLUSIONS SNX-5422 is effective in downregulating Hsp90 client proteins required for glioma cell survival. In addition, SNX-5422 inhibits tumor growth by promoting apoptosis through modulation of several key signaling pathways and sensitizes glioma cells to TMZ. Given also that SNX-5422 crosses BBB, it warrants further investigation as a clinical agent for treatment of gliomas.

Aims:: To investigate the role of autophagy in the tight junction of human brain endothelial cells during hypoxia and ischemia. Background:: Endothelial cells play an important role in the initiation, progression and recovery from ischemic stroke. The role of autophagy on human brain endothelial cells (HBECs) subjected to oxygen-glucose deprivation (OGD) is not fully elucidated. Objective:: The objective of this study was to investigate the effect of autophagy on HBECs during OGD. Methods:: HBECs were cultured in a 96-well plate and underwent 4 hours of OGD. For drug treatment, 3-Methyladenine (3-MA) (5mmol/L), an inhibitor of autophagy, was added at the start of OGD. Cell viability and cytotoxicity were tested by cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays. Morphological changes in cells were examined by immunofluorescence microscopy. The protein expression of light chain 3 (LC3) was measured. Autophagosomes and endothelial cell tight junctions were observed using transmission electron microscopy. Results:: The results showed that OGD induced serious damage to HBECs. Cell viability was decreased significantly and LDH release increased significantly (p Conclusions:: Autophagy is a key response to oxygen-glucose deprivation stress and its detrimental effects are closely related to the destruction of tight junctions of human brain endothelial cells. Strategies to inhibit autophagy could help to preserve tight junctions.

Purpose: Proficient DNA repair by homologous recombination (HR) facilitates resistance to chemoradiation in glioma stem cells (GSC). We evaluated whether compromising HR by targeting HSP90, a molecular chaperone required for the function of key HR proteins, using onalespib, a long-acting, brain-penetrant HSP90 inhibitor, would sensitize high-grade gliomas to chemoradiation in vitro and in vivo. Experimental Design: The ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize glioblastoma (GBM) to chemoradiation was evaluated in vitro in GSCs, and in vivo using zebrafish and mouse intracranial glioma xenograft models. The effects of HSP90 inhibition on the transcriptome and cytoplasmic proteins was assessed in GSCs and in ex vivo organotypic human glioma slice cultures. Results: Treatment with onalespib depleted CHK1 and RAD51, two key proteins of the HR pathway, and attenuated HR repair, sensitizing GSCs to the combination of radiation and temozolomide (TMZ). HSP90 inhibition reprogrammed the transcriptome of GSCs and broadly altered expression of cytoplasmic proteins including known and novel client proteins relevant to GSCs. The combination of onalespib with radiation and TMZ extended survival in a zebrafish and a mouse xenograft model of GBM compared with the standard of care (radiation and TMZ) or onalespib with radiation. Conclusions: The results of this study demonstrate that targeting HR by HSP90 inhibition sensitizes GSCs to radiation and chemotherapy and extends survival in zebrafish and mouse intracranial models of GBM. These results provide a preclinical rationale for assessment of HSP90 inhibitors in combination with chemoradiation in patients with GBM.

Background: Most evidences regarding ambient PM2.5 or PM10 (particulate matter of median aerodynamic diameter ≤2.5 μm or ≤10 μm) and preterm birth (PTB) come from western countries which has relatively low PM pollution exposure, and the results are still inconsistent. This study aims to examine whether exposure to high concentrations of PM2.5 or PM10 was associated with PTB (

This research explored the relationship among loneliness, depression and self-concept of rural children in China. Seven hundred and twenty-four children (Mage = 9.15 years) from two rural primary schools were selected as respondents to participate in this study. Piers-Harris Children’s Self-concept Scale, Asher Loneliness Scale and the Center for Epidemiologic Studies Depression Scale for Children were used. Of the rural children surveyed, 14.50% and 10.22%, respectively, experienced strong loneliness and severe depression, and 28.52% had low self-concept. There was a significant positive relationship of moderate level between loneliness and depression, and significant negative relationships between total self-concept and depression, and between total self-concept and loneliness. Moreover, a partial mediation role of self-concept was found in the relationship between loneliness and depression. Children’s loneliness was not only directly related to depression, but also was indirectly mediated by self-concept, which demonstrated a partial mediation role in the relationship between loneliness and depression.

Background Epidemiological evidence of the association of long-term ambient fine particulate matter (aerodynamic diameter ≤2.5 μm; PM2.5) exposure with resting heart rate is limited. We explored the association of long-term (3-year average) ambient PM2.5 exposure with tachycardia and resting heart rate. Methods This cross-sectional study surveyed 10,427,948 reproductive-age (20–49 years) adults across China in 2015. Tachycardia was classified as a resting heart rate of >80 beats per minute (bpm). The annual average ambient PM2.5 concentrations were obtained from a hybrid satellite-based geophysical statistical model. Linear mixed models and mixed effects logistic regressions adjusted for potential confounding were performed to explore the associations of PM2.5 with resting heart rate and PM2.5 with tachycardia, respectively. The effect modifiers by sex, age, body mass index, urbanity, race, region, smoking status, and drinking status were also assessed. Attributable cases and population fraction were estimated according to the PM2.5- tachycardia relationship. Results The mean age was 28 years, and 16.3% of the participants had tachycardia. The odds ratio for tachycardia was 1.018 (95% confidence intervals [CI]: 1.017, 1.020) per 10 μg/m3 increase in the 3-year average PM2.5 exposure. A 10 μg/m3 increase in the 3-year average ambient PM2.5 level was associated with a 0.076 (95% CI: 0.073, 0.079) bpm elevation in the resting heart rate. Of the tachycardia burden, 4.0% (95% CI: 3.8%, 4.3%) could be attributed to ambient PM2.5 exposure in Chinese reproductive-age adults. Conclusions Exposures to ambient PM2.5 were associated with elevated resting heart rate. It might be possible to decrease China's avoidable tachycardia burden in reproductive-age adults through decreasing PM2.5 levels.

Background The relationship between PM2.5 exposure and preterm birth remains unclear. Objectives To explore the effect of exposure to PM2.5 on preterm birth in China. Methods The birth outcomes of 426,246 pregnant women enrolled between January 2014 and December 2014 in NFPCP (National Free Pre-pregnancy Checkups Project) were collected, and their individual PM2.5 exposure values were estimated from the China National Environmental Monitoring Centre. The time of gestational exposure to PM2.5 was divided into four periods (the first trimester, the second trimester, the third trimester and the entire pregnancy). The average concentration and the corresponding quartiles of PM2.5 were calculated in these periods by the daily average PM2.5 data. Cox proportional hazards regression was used and he effects of maternal age, education level, occupation, second-hand smoking, alcohol use, pre-pregnancy BMI, baby's sex, number of previous pregnancies, coastal areas and season of conception were adjusted for. Results A total of 426,246 singleton births were included, among which 35,261 (8.3%) were preterm birth. Effect of each 10 μg/m3 increase of PM2.5 on preterm birth was most significant during the third trimester (HR, 1.06; 95%CI, 1.06–1.07), and also significant during the first trimester (HR, 1.04; 95%CI, 1.03–1.04), the second trimester (HR, 1.02; 95%CI, 1.02–1.02) and the entire pregnancy (HR, 1.06; 95%CI, 1.05–1.06). Compared with the lowest quartile of PM2.5, other quartiles increased the risk of preterm birth, and were most significant during the third trimester (HR, 1.87; 95%CI, 1.69–2.06). Subgroup analysis showed that compared with other subgroups, women who were older than 30 years, had low education level, worked as farmers, had male baby, had previous pregnancies, not live in coastal areas and pregnant in winter were more sensitive to PM2.5 exposure. Conclusions Ambient PM2.5 exposure during pregnancy played an important role in the pregnancy process and increased the risk of preterm birth.

Purpose Poly(lactic-co-glycolic acid) (PLGA) is widely used for drug delivery because of its biocompatibility, ability to solubilize a wide variety of drugs, and tunable degradation. However, achieving sub-100 nm nanoparticles (NPs), as might be desired for delivery via the enhanced permeability and retention effect, is extremely difficult via typical top-down emulsion approaches. Methods Here, we present a bottom-up synthesis method yielding PLGA/block copolymer hybrids (ie, "PolyDots"), consisting of hydrophobic PLGA chains entrapped within self-assembling poly(styrene-b-ethylene oxide) (PS-b-PEO) micelles. Results PolyDots exhibit average diameters

Purpose: HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins, is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities, or are unable to cross the blood–brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivo. Experimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo were assessed in non–tumor-bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient-derived GSC xenograft mouse glioma models. Results: Onalespib-mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII, and AKT, disrupted their downstream signaling, and decreased the proliferation, migration, angiogenesis, and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts. Conclusions: Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo, which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas. Clin Cancer Res; 23(20); 6215–26. ©2017 AACR.

Globally, one third of prevalent chronic hepatitis B (CHB) virus infection (HBV) occurred in China. Assessing the prevalence of CHB infesction and status of HBV-related services among pre-conception women will provide insight into risks of mother to child transmission (MTCT). A cross-sectional analysis of data from the National Free Pre-pregnancy Checkups (NFPC) program in 2010–2014 was conducted. A standardized questionnaire which collected demographic information and enzyme-linked immunosorbent assays (ELISA) which tested serological HBV markers were applied. A total of 16,051,850 rural women aged 15–49 years were included. 5.2% of women were infected with CHB, among whom, 28.6% were also hepatitis B e antigen (HBeAg) positive. The most CHB concentrated places were distributed in southeastern coastal provinces. Women born after 1992 did not experience a higher level of vaccine-induced immunity compared to those born before 1992. Nine in ten rural women with CHB were not aware of their HBV status and a very small proportion of women (0.22%) had received antiviral treatment. Our data demonstrated an overall high-intermediate burden of CHB. Heterogeneity of geographic distribution, high proportion of HBeAg, insufficient awareness of HBV status, and low access to HBV treatment are challenges for preventing the MTCT.

Obesity has been increasing worldwide. Data on obesity status among men of reproductive age are scarce. This study aimed to assess the national prevalence and trend of overweight and obesity among reproductive-age men in rural China. In the nationwide population-based study, data were obtained from the National Free Preconception Health Examination Project in rural China from 2010 to 2014. Weight and height were measured in 16 161 982 men aged 15–49 years and their female partners (15 997 739 participants aged 15–49 years) before conception, and body mass index (BMI) was calculated. We found that the prevalence of combined overweight and obesity among men was 33.8% (33.7–33.9%) according to Chinese criteria (BMI ≥ 24.0 kg/m2), the corresponding rates of obesity were 6.3% (6.2–6.4%; BMI ≥ 28.0 kg/m2), respectively. The prevalence varied in different ethnic groups, geographic regions, age, education and GDP levels, and increasing trend was observed over the 5-year study period. In addition, 45.8% of couples had at least one of them as overweight or obesity. About one third of men aged 15–49 years before conception in rural China are overweight or obese. Overweight/obesity clusters in families, which highlights the importance of family involvement of early prevention of obesity in China.

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system such as hippocampus, thalamus and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251 and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2. Funding Statement: This study was supported by the National Research and Development Project of 5 China (2020YFC0841100, 2020YFC0846400, 2020YFA0707600), CAMS Innovation Fund for Medical Sciences (2016-I2M-2-006, 2020-I2M-CoV19-012) and Major special Projects in Yunnan Province (Establishment of animal model of novel coronavirus infection and development of emergency vaccine). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All animal procedures were approved by the Institutional Animal Care and Use Committee of Institute of Medical Biology, Chinese Academy of Medical Science (ethics number: DWSP202002001).

Objective To investigate the effect of folic acid (FA) supplementation on the risks of preterm delivery (PTD) and small for gestational age births (SGA). Data sources Cohort studies were identified from MEDLINE, EMBASE, the Cochrane Library, CINAHL, and CBM from inception to January 2015. Participants and included studies Healthy women who want to get pregnancy or being pregnant. Main outcome measures PTD and SGA. Results The association of FA and PTD was significant when supplement initiated after pregnancy (RR = 0.68, 95%CI, 0.52–0.90), whereas no effect was founded if the initiation time was before conception (RR = 0.89, 95%CI, 0.80–1.01). The results for the association between FA supplementation and SGA showed significant protective effect: initiated before conception (RR = 0.70, 95%CI, 0.57–0.85) and initiated after conception (RR = 0.84, 95%CI, 0.81–0.89). Conclusion Folic acid supplementation is associated with a significant reduction on the risk of PTD when initiated after conception. It can also protect fetus from SGA.

Objectives. To provide prevalence and trends of underweight, overweight, and obesity among reproductive-age women and adolescent girls in rural China. Methods. We measured weight and height in 16 742 344 women aged 20 to 49 years and 178 556 girls aged 15 to 19 years from the National Free Preconception Health Examination Project between 2010 and 2014. Results. Among women, the prevalence of underweight was 7.8% (95% confidence interval [CI] = 7.7%, 7.9%), and overweight or obesity was 16.5% (95% CI = 16.4%, 16.6%; World Health Organization criteria). Among adolescents, prevalence of underweight was 6.0% (95% CI = 5.7%, 6.2%; Centers for Disease Control and Prevention criteria) and overweight or obesity was 8.3% (95% CI = 7.9% to 8.8%; International Obesity Task Force criteria). According to Chinese criteria, overweight and obesity prevalence was 24.8% (95% CI = 24.7%, 24.9%) for women and 17.2% (95% CI = 16.6%, 17.8%) for adolescents, and underweight prevalence was 2.9% (95% CI = 2.8%, 3.1%) for adolescents. Considerable disparities existed in prevalence and trends within subpopulations (age groups, parity, region, education levels, and socioeconomic status). Conclusions. Our results reveal coexisting underweight and overweight or obesity among rural women and adolescents of reproductive age, which requires public health attention.

Hypoxia induces reversible κ-opioid receptor (KOR) internalization similar to the internalization that is induced by KOR agonists. In the current study, we demonstrate that this KOR internalization is a protective mechanism via the β-arrestin specific pathway in an oxygen-glucose deprivation (OGD) model. Mouse neuroblastoma Neuro2A cells were stably transfected with mouse KOR-tdTomato fusion protein (N2A-mKOR-tdT cells). Various concentrations of salvinorin A (SA), a highly selective KOR agonist, were given in the presence and absence of norbinaltorphimine (norBNI), which is a KOR antagonist, or Dyngo-4a (internalization inhibitor) or API-2 (Akt/Protein kinase B signaling inhibitor-2). Various concentrations of SA and RB-64 (22-thiocyanatosalvinorin A, selective for the G protein signaling pathway) were administered both in normoxic and hypoxic conditions. Autophagosomes and ultrastructural components of cells were observed using transmission electron microscopy (TEM). Cell viability, severity of cell injury, and levels of proteins related to the Akt signaling pathway were evaluated using live cell counting (by Cell Counting Kit-8), the lactic acid dehydrogenase (LDH) release rate, and Western blot analysis, respectively. SA promoted cell survival and attenuated OGD-induced cell injury. The Akt signaling pathway is activated by SA. KOR internalization, when blocked by norBNI or Dyngo-4a, increased LDH release and decreased cell viability under OGD. Treatment with SA significantly inhibited autophagy, and the effects of SA on autophagy were reversed by API-2 pretreatment. RB-64 in a low concentration without β-arrestin recruitment did not reduce LDH release and increase cell viability as observed with SA. KOR internalization through β-arrestin activation is a protective mechanism against OGD. The Akt pathway might play a critical role in modulating these protective effects by inhibiting autophagy.

Background A mountain of evidence has shown that people’s physical and mental health can be affected by various air pollutions. Poor pregnancy outcomes are associated with exposure to air pollution. Therefore, this study aims to investigate the association between air pollutions (PM2.5, PM10, SO2, NO2, CO, and O3) and preterm birth/low birth weight in Guangdong province, China. Method All maternal data and birth data from January 1, 2014 to December 31, 2015 were selected from a National Free Pre-pregnancy Check-ups system, and the daily air quality data of Guangdong Province was collected from China National Environmental Monitoring Center. 1784 women with either preterm birth information (n = 687) or low birth weight information (n = 1097) were used as experimental group. Control group included 1766 women with healthy birth information. Logistic regression models were employed to evaluate the effects of air pollutants on the risk of preterm birth and low birth weight. Results The pollution levels of PM2.5, PM10, SO2, NO2, CO, and O3 in Guangdong province were all lower than the national air pollution concentrations. The concentrations of PM2.5, PM10, SO2, NO2 and CO had obvious seasonal trends with the highest in winter and the lowest in summer. O3 concentrations in September (65.72 μg/m3) and October (84.18 μg/m3) were relatively higher. After controlling for the impact of confounding factors, the increases in the risk of preterm birth were associated with each 10 μg/m3 increase in PM2.5 (OR 1.043, 95% CI 1.01–1.09) and PM10 (OR 1.039, 95% CI 1.01~1.14) during the first trimester and in PM2.5 (OR 1.038, 95% CI 1.01~1.12), PM10 (OR 1.024, 95% CI 1.02~1.09), SO2 (OR 1.081, 95% CI 1.01~1.29), and O3 (OR 1.016, 95% CI 1.004~1.35) during the third trimester. The increase in the risk of low birth weight was associated with PM2.5, PM10, NO2, and O3 in the first month and the last month. Conclusion This study provides further evidence for the relationships between air pollutions and preterm birth/low birth weight. Pregnant women are recommended to reduce or avoid exposure to air pollutions during pregnancy, especially in the early and late stages of pregnancy.

Background Epidemiological evidence on the association between long‐term exposure to ambient fine particulate matter (with an aerodynamic diameter ≤2.5 μm; PM 2.5 ) and hypertension is mixed. We investigated the long‐term association between ambient fine particles and hypertension in reproductive‐age adults. Methods and Results This analysis included 39 348 119 reproductive‐age (20–49 years) participants from the National Free Preconception Health Examination Project from April 22, 2010 to December 31, 2015 across China. The estimation of annual average ambient PM 2.5 concentrations for each community was realized through using satellite‐based spatial statistical models. Linear mixed models and 2‐level logistic regressions adjusted for potential confounders with natural cubic splines were used to investigate the shape of PM 2.5 –blood pressure and PM 2.5 ‐hypertension, respectively. The effect modification by sex, obesity, smoking status, age, diabetes mellitus, urbanity, race, and region was also taken into account. The concentration‐response relationship between PM 2.5 and hypertension was nonlinear, with a threshold concentration of 47.9 μg/m 3 . The odds ratio of hypertension related to a 10‐μg/m 3 increase in PM 2.5 above threshold was 1.010 (95% confidence interval, 1.007–1.012). A 10‐μg/m 3 increase in PM 2.5 above threshold corresponded to a 0.569 (95% confidence interval, 0.564–0.573) mm Hg elevation in systolic blood pressure and a 0.384 (95% confidence interval, 0.381–0.388) mm Hg elevation in diastolic blood pressure. There were 2.3% (95% confidence interval, 2.2%–2.4%) of the hypertension cases that could be attributed to PM 2.5 exposures in reproductive‐age adult populations. Conclusions Long‐term exposures to PM 2.5 above certain levels might increase population risk for hypertension and might be responsible for China's avoidable hypertension burden in reproductive‐age adults.

Purpose Poly(lactic-co-glycolic acid) (PLGA) is widely used for drug delivery because of its biocompatibility, ability to solubilize a wide variety of drugs, and tunable degradation. However, achieving sub-100 nm nanoparticles (NPs), as might be desired for delivery via the enhanced permeability and retention effect, is extremely difficult via typical top-down emulsion approaches. Methods Here, we present a bottom-up synthesis method yielding PLGA/block copolymer hybrids (ie, “PolyDots”), consisting of hydrophobic PLGA chains entrapped within self-assembling poly(styrene-b-ethylene oxide) (PS-b-PEO) micelles. Results PolyDots exhibit average diameters

Background Adequate sedation is important in the post-anesthesia care unit (PACU) following uvulopalatopharyngoplasty (UPPP) to ensure patient comfort and decrease the duration of mechanical ventilation (MV), PACU stay, and bleeding. This study aimed to compare dexmedetomidine and propofol as sedatives after UPPP in the PACU. Material/Methods We randomized 124 mechanically ventilated adults following UPPP who were managed in the PACU of the General Hospital of the Shenyang Military Region between January 2014 and June 2014, to receive either dexmedetomidine or propofol. The patients in the propofol group received an infusion of propofol (3 mg/kg/h) titrated up to 6 mg/kg/h to attain a Ramsay sedation score ≥4. The dexmedetomidine group patients received 1.0 μg/kg of dexmedetomidine over a period of 10 minutes and then 0.5 to 1.0 μg/kg/h infusion to maintain a Ramsay sedation score ≥4. Results Bispectral index (BIS) values were significantly lower in the dexmedetomidine group than in the propofol group at Ramsay sedation scores of 4 and 5. The mean times to spontaneous breathing, waking, and extubation were shorter in the dexmedetomidine group. Tramadol requirement was significantly reduced in the dexmedetomidine group (P

To examine the relationship between preconception blood pressure (BP) and the risk of preterm birth (PTB) using a historical cohort of reproductive-aged women and girls from a Chinese rural population.A historical cohort study established between 2010 and 2013 in People's Republic of China.Local family-planning service agencies and maternal-child care service centers.A total of 367,425 reproductive-aged women and girls who participated in the National Free Pre-pregnancy Checkups in 2010-2012 and subsequently had a live birth before October 2013.None.Incidence rates of PTB in reproductive-aged women and girls across preconception BP levels.Preterm births were defined as babies born alive at 28 to 37 weeks of pregnancy. Compared with the participants with a systolic BP of120 mm Hg, the multivariable-adjusted odds ratio (OR) for PTB was 0.99 (95% confidence interval [CI]: 0.95-1.03]), 1.21 (95% CI: 1.11-1.32), 1.47 (95% CI: 1.22-1.77), 1.80 (95% CI: 1.25-2.59), and 1.81 (95% CI: 1.20-2.73) for the participants with systolic BP of 120-129, 130-139, 140-149, 150-159, and ≥160 mm Hg, respectively. When the participants with normal BP were used as the reference, the adjusted OR for PTB was 1.04 (95% CI: 1.01-1.08), 1.38 (95% CI: 1.25-1.53), and 1.54 (95% CI: 1.21-1.97) for the participants with prehypertension, stage-1 hypertension, and stage-2 hypertension, respectively. In addition, isolated systolic and diastolic hypertension increased the risk of PTB by 55% and 30%, respectively.Our results indicated a strong linear and independent relationship between BP levels and the risk of PTB in Chinese reproductive-aged women and girls. Maternal hypertension before pregnancy can significantly increase the risk of PTB.

Background: Pre-gestational diabetes mellitus (pGDM) and elevated fasting blood glucose level are associated with increased risk of maternal, perinatal and neonatal morbidity and mortality. Only 30.1% of those with diabetes had been previously diagnosed in China. It was reported that nearly 50.0% of Chinese population is the rural population in the population census data in 2014. It has been verified the effects of glucose level during pregnancy on adverse pregnancy outcomes. However, data of the relationship between glucose level before pregnancy and its pregnancy outcomes is scarce. We investigated the epidemiology of reproductive-aged women in China, aiming to provide the data for the prevalence of pGDM and its association with pregnancy outcomes. Methods: Data are from a nationwide sample of women of reproductive age who participated in National Free Preconception Health Examination service in 31 provinces of rural China during 2010-16. Study population characteristics were presented as mean (SD) for continuous variables and number (percentages) for categorical variable, and analysis of variance and chi square test were used to test association between each level of blood glucose concentration, risk factors and adverse outcome. Findings: Of 7,094,807 registered women (age 20-49 years), 6,447,339 were included in analyses. The incidence of pGDM and IFG was 76,297 (1.18%) and 847,737 (13.15%), respectively. Only 917 (1.20%) women were aware that they had pGDM in rural China. Among women without previously diagnosed DM, there is a positive linear association between FPG levels and incidence of combined (counted when occurrence of any of the adverse outcome) and multiple adverse pregnancy outcome(counted when having ≥2 adverse outcomes at the same time) when FPG level was divided into 7 groups ( 10mmol/L). Interpretation: The awareness rate of pGDM prevalence in rural China is extremely low. The management of pGDM is unsatisfactory in women diagnosed with pGDM. PGDM is associated with an increased risk of adverse maternal, perinatal and neonatal outcomes across all levels of FPG. Further analysis is need to support decision on the cut-off point for increased risk of adverse outcome and target blood glucose level before pregnancy to achieve satisfactory outcome. Policy decision on adoption of an extensive screening of pGDM in prepregancy examination and strategies for pGDM and adverse pregnancy outcome control from a broader perspective require more evidence on cost-effectiveness of such approaches. Funding: The National Key Research and Development Program of Reproductive Health & Major Birth Defects Control and Prevention (Grant no. 2016YFC1000402); World Diabetes Foundation (Grant no. WDF14-908). National Natural Science Foundation (Grant no. 81402757) Declaration of Interest: We declare that we have no conflicts of interest. Ethical Approval: This study was approved by the Institutional Research Review Boards at NHFPC and Peking University First Hospital, and all participants provided written informed consent.

The reproductive-aged women have to face physiological and psychological challenges as long as they plan to conceive. However, most previous studies focused on depression and anxiety during pregnancy. This study aimed to investigate the association among preconception depression, anxiety, and social support of the Chinese reproductive-aged women. Nine-hundred five reproductive-aged women who planned to conceive for the first or second time in the next three months were recruited through the Maternity and Child Healthcare Hospital and Obstetrics and Gynecology Hospital from three provinces in China. Social Support Rating Scale, Self-Rating Depression Scale, and Self-Rating Anxiety Scale were used in this study. The hierarchical regression model was employed to examine the prediction effect of the three sub-dimensions of social support on preconception depression and anxiety. Of the reproductive-aged women, 25.86 and 13.04% had preconception depression and anxiety symptoms. Nearly all reproductive-aged women had moderate and high social support before pregnancy. The significant differences in depression and anxiety among different levels of occupation and monthly income were found. For depression and anxiety, objective support, support availability, and subjective support simultaneously entered into the model still could significantly explain 5.9 and 6.7% of variations after controlling for the demographic variables, respectively. According to this study, there were significant correlations among preconception depression, anxiety, and social support. And objective support, support availability, and subjective support could negatively predict preconception depression and anxiety. Attaching importance to the preconception mental health and social support can provide effective scientific support for helping women fully understand and effectively use the social resources, and scientifically prepare for pregnancy.

Alcohol solvents especially isopropanol were demonstrated for the first time to endow silver nanoclusters (AgNCs) in water with dramatically enhanced red fluorescence. More importantly, the specific iodide recognition capability of the AgNCs could thus be obtained towards a highly selective fluorimetric assay for detecting iodide ions in urine.

Previous studies indicated that parenting styles were important influencing factors for the development of children’s well-being. It is known that mass migration to the cities in China will affect family relations. However, few studies focused on the relationship between parenting styles and adolescents’ mental health in migrant families. Thus, this study aimed to investigate how parenting styles could affect adolescent’s social anxiety in migrant families. A total number of 1,345 adolescents in migrant families from four non-government-funded junior middle schools in Guangdong province formed the research sample. Parenting styles were measured using short-form of the Egna Minnen Betraffande Uppfostran, and social anxiety was evaluated using Social Anxiety Subscale of Self-Consciousness Scale. The results showed that emotional warmth, overprotection and rejection were significantly more often perceived from mothers than from fathers. Significant group differences between high social anxiety group and low social anxiety group were found in both father’s rearing styles and mother’s rearing styles. Furthermore, in migrant families, paternal emotional warmth could decrease adolescents’ social anxiety, whereas maternal overprotection could increase it.

With the gradual increase of global warming, the impact of extreme temperatures on health has become a focus of attention, however, its relationship with preterm birth remains unclear.To investigate the association between exposure to extreme temperatures and preterm birth.Temperature exposures and birth outcomes of 1,020,471 pregnant women from 132 cities in China were investigated. The pregnancy process was divided into different pregnancy periods. Study areas were divided into three categories (cold, medium, and hot areas) according to the local average temperature by cluster analysis. Average temperature data for each province used in the cluster analysis came from the China Statistical Yearbook 2013. Logistic regression was used to compare the effects of exposure to hot and cold conditions on the outcomes of pregnancy in different periods and regions.A total of 1,020,471 singleton births were included, of which 73,240(7.2%) were preterm births. Compared with moderate temperatures (5th to 95th percentile), heat exposure (95th percentile) in different periods of pregnancy increased the risk of preterm birth in hot areas. The most obvious increase was during the 3 months before pregnancy (odds ratio (OR)=1.229, 95% confidence interval (CI): 1.166-1.295). In contrast to heat exposure, cold exposure (5th percentile) in hot areas reduced the risk of preterm birth; the protective effect was most pronounced in the 3 months before pregnancy (OR=0.784, 95% CI: 0.734-0.832). In medium and cold areas cold exposure also reduced the risk of preterm birth. The effect of exposure to extreme ambient temperatures throughout the entire pregnancy on preterm birth was similar to those of the periods above.Acute and chronic exposure to extreme temperatures may affect the risk of preterm birth. Extreme heat is a risk factor for preterm birth and extreme cold is a protective factor.

Background The effect of second‐hand smoking, especially husband smoking, on wife's hypertension has not been well studied. The current study was aimed to assess the association of husband smoking with wife's hypertension among females aged 20 to 49 years. Methods and Results This study included 5 027 731 females along with their husbands from the National Free Pre‐pregnancy Checkup Projects conducted across 31 provinces in China in 2014. Smoking/passive smoking status was collected by a standard questionnaire and blood pressure was measured by an electronic device after 10 minutes rest. Odds ratios and their corresponding 95% CI s for female hypertension were estimated according to smoking status of husband and wife, husbands' smoking amount, and cumulative exposure to husband smoking. Compared with neither‐smoker group, the multivariable‐adjusted odds ratio for female hypertension was 1.28 (1.27–1.30), 1.53 (1.30–1.79), and 1.50 (1.36–1.67) in husband‐only, wife‐only, and mixed group, respectively. Furthermore, a higher risk of having hypertension was associated with amount and cumulative exposure of husband smoking. For example, compared with neither‐smoker, the multivariate‐adjusted odds ratio was 1.22 (1.19–1.25), 1.24 (1.21–1.26), 1.32 (1.26–1.37), 1.37 (1.34–1.41), and 1.75 (1.64–1.87) for females whose husband smoked 1 to 5, 6 to 10, 11 to 15, 16 to 20, and ≥21 cigarettes per day, respectively ( P for trend Conclusions There were associations of husband smoking with female hypertension prevalence. A family‐based smoking restriction strategy may reduce smoking in males and improve hypertension control in females.

Background Alcohol use occurs across the life span beginning in adolescence and continuing through adulthood. Ethanol (EtOH)-induced pathology varies with age and includes changes in neurogenesis, neurodegeneration, and glial cell activation. EtOH-induced changes in glial activation and immune activity are believed to contribute to EtOH-induced neuropathology. Recent studies indicate an emerging role of glial-derived neuroimmune molecules in alcohol abuse and addiction. Methods Adolescent and adult C57BL/6 mice were treated via gavage with 6 g/kg EtOH for 10 days, and tissue was harvested 1 day post treatment. We compared the effects of EtOH on chemokine and cytokine expression and astrocyte glial fibrillary acidic protein (GFAP) immunostaining and morphology in the hippocampus, cerebellum, and cerebral cortex. Results EtOH increased mRNA levels of the chemokine CCL2/MCP-1 in all 3 regions of adult mice relative to controls. The cytokine interleukin-6 (IL-6) was selectively increased only in the adult cerebellum. EtOH did not affect mRNA levels of the cytokine tumor necrosis factor-alpha (TNF-α) in any of these brain regions in adult animals. Interestingly, CCL2, IL-6, and TNF-α mRNA levels were not increased in the hippocampus, cerebellum, or cortex of adolescent mice. EtOH treatment of adult and adolescent mice resulted in increased GFAP immunostaining. Conclusions Collectively, these data indicate an age- and region-specific susceptibility to EtOH regulation of neuroinflammatory and addiction-related molecules as well as astrocyte phenotype. These studies may have important implications concerning differential alcohol-induced neuropathology and alcohol addiction across the life span.

Background China has historically been a highly endemic area for hepatitis B infection. Progress has been made in tackling the disease in infants and children, but infection rates remain high in adults, especially in rural areas. Current data on the prevalence of HBV in women of childbearing age is lacking. Objectives We analyzed the HBV serological status of women of childbearing age in rural China to provide data to inform the development of prevention and control measures for hepatitis B. Study design Questionnaires and serum samples have been collected from rural couples aged 20–49 years in 292 counties in 2014. ELISA methods were employed to detect serum HBV markers. Results From January to December 2014, 771,567 questionnaires and 764,460 blood samples were collected. Among these, 44,057 (5.76%) women tested positive for HBsAg and 100,519 (13.24%) tested positive for anti-HBc. In this sub group, 39,862 (39.66%) women also tested positive for HBsAg. There were 338,528 (41.67%) tested positive for anti-HBs and single anti-HBs presented in 259,800 (33.98%) women. In total, 385,140 (50.38%) tested negative for all HBV markers. Of the HBsAg positive participants, 12,520 (28.42%) were positive for both HBsAg and HBeAg, and therefore infectious although this declined with age (P Conclusions HBV prevalence among women of childbearing age in rural China has declined compared to the 2006 National study of women aged 15–59 years (5.76 vs. 6.73%), but remains high.

Chromatin modification through histone deacetylase inhibition has shown evidence of activity against malignancies. The mechanism of action of such agents are pleiotropic and potentially tumor specific. In this study, we studied the mechanisms of vorinostat-induced cellular effects in gliomas. The effects of vorinostat on proliferation, induction of apoptosis and cell cycle effects were studied in vitro (D54, U87 and U373 glioma cell lines). To gain additional insights into its effects on human gliomas, vorinostat-induced changes were examined ex vivo using a novel organotypic human glioma slice model. Vorinostat treatment resulted in increased p21 levels in all glioma cells tested in a p53 independent manner. In addition, cyclin B1 levels were transcriptionally downregulated and resulted in reduced kinase activity of the cyclin B1/cdk1 complex causing a G2 arrest. These effects were associated with a dose- and time-dependent inhibition of cellular proliferation and anchorage-independent growth in association with hyperacetylation of core histones and induction of apoptosis. Of particular significance, we demonstrate histone hyperacetylation and increased p21 levels in freshly resected human glioma specimens maintained as organotypic slice cultures and exposed to vorinostat similar to cell lines suggesting that human glioma can be targeted by this agent. Our data suggest that the effects of vorinostat are associated with modulation of cell cycle related proteins and activation of a G2 checkpoint along with induction of apoptosis. These effects are mediated by both transcriptional and post-translational mechanisms which provide potential options that can be exploited to develop new therapeutic approaches against gliomas.

T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORα and RORγt and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.