ARID1A regulates R-loop associated DNA replication stress.

ARID1A is a core DNA-binding subunit of the BAF chromatin remodeling complex, and is lost in up to 7% of all cancers. The frequency of ARID1A loss increases in certain cancer types, such as clear cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeling complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.

Synergistic photothermal-photodynamic-chemotherapy toward breast cancer based on a liposome-coated core-shell AuNS@NMOFs nanocomposite encapsulated with gambogic acid.

A multifunctional nanoplatform with core-shell structure was constructed in one-pot for the synergistic photothermal, photodynamic, and chemotherapy against breast cancer. In the presence of gambogic acid (GA) as the heat-shock protein 90 (HSP90) inhibitor and the gold nanostars (AuNS) as the photothermal reagent, the assembly of Zr4+ with tetrakis (4-carboxyphenyl) porphyrin (TCPP) gave rise to the nanocomposite AuNS@ZrTCPP-GA (AZG), which in turn, further coated with PEGylated liposome (LP) to enhance the stability and biocompatibility, and consequently the antitumor effect of the particle. Upon cellular uptake, the nanoscale metal - organic framework (NMOF) of ZrTCPP in the resulted AuNS@ZrTCPP-GA@LP (AZGL) could be slowly degraded in the weak acidic tumor microenvironment to release AuNS, Zr4+, TCPP, and GA to exert the synergistic treatment of tumors via the combination of AuNS-mediated mild photothermal therapy (PTT) and TCPP-mediated photodynamic therapy (PDT). The introduction of GA serves to reduce the thermal resistance of the cell to re-sensitize PTT and the constructed nanoplatform demonstrated remarkable anti-tumor activity in vitro and in vivo. Our work highlights a facile strategy to prepare a pH-dissociable nanoplatform for the effective synergistic treatment of breast cancer.

[Comparison of respiratory diseases and symptoms among school-age children in areas with different levels of air pollution].

OBJECTIVE: To compare the differences of children's health in different area, and to confirm if the prevalence of respiratory diseases and symptoms among children are closely associated with the air pollution. METHODS: A cross-sectional study was conducted in an urban area A and a suburban area B with different levels of air pollution in Beijing. Using a cluster sampling method, we recruited 4 564 children from 3 primary schools in urban A and 4 primary schools in suburban B. Respiratory symptoms were investigated using an international standardized questionnaire including characteristics of children, living conditions, respiratory diseases and symptoms and situation of parents. The concentrations of air pollutants for recent five years were obtained from Reports on the Quality of the Beijing Environment. SPSS 16.0 was used to analyze data. RESULTS: The prevalence of cough, persistent cough, phlegm, persistent phlegm, wheeze and asthma in A area were higher than those in B area [(62.2% vs. 59.9%), (6.3% vs. 3.1%), (42.4% vs. 37.4%),(3.6% vs. 2.4%),(13.3% vs. 9.9%)and(9.5% vs. 5.4%)]. Except for cough, cough with cold, cough without cold, the prevalence of respiratory diseases and symptoms in A area were significantly higher than those in B area (P<0.05). Logistic regression analysis showed the prevalence of persistent cough, phlegm without cold, asthma in A area were significantly higher than those in B area (P<0.05). CONCLUSION: Respiratory diseases and symptoms among school-age children were closely associated with the level of air pollution.

[Concentrations of fine particulate matters and ultrafine particles and influenced factors during winter in an area of Beijing].

OBJECTIVE: To study the concentrations of fine particulate matters and ultrafine particles and influenced factors during winter in an area of Beijing. METHODS: Real-time monitoring of particles' mass and number concentrations were conducted in an area of Beijing from February 7(th) to 27(th), 2013. At the same time, the meteorological data were also collected from the Beijing meteorological website. Differences of the particles' mass and number concentrations during different periods were analyzed using Mann-Whitney U test. Meanwhile, the influenced factors were also analyzed. RESULTS: The mean concentrations of fine particulate matters and ultrafine particles were (157.2 ± 142.8) µg/m³ and (25 018 ± 9 309) particles/cm³, respectively. The particles' number and mass concentrations in haze days were 1.27 times and 2.91 times higher than those in non-haze days, respectively. The mass concentrations of fine particulate matters in the self-monitoring site were higher than those in the nearest central monitoring sites, and the hourly-average concentrations of particles were significantly consistent with those at the commuter times. Meanwhile, the setting off of fireworks/firecrackers during the Spring Festival could lead to short-term increases of the particles' number and mass concentrations. When the wind speed was low and the related humidity was high, the concentrations of particulate matters were relatively high, and the mass concentrations of fine particulate matters were lagged about 1-2 d. CONCLUSION: The level of the particulate matters in this area was high. Heavy traffic, setting off of fireworks/firecrackers and meteorological factors may be some of the main factors affecting the concentrations of the particulate matters in this area. Among those factors, the effect of setting off of fireworks/firecrackers didn't last long and the effect of the meteorological factors had a hysteresis effect.

Surface Functional Modification by Ti3 C2 Tx MXene on PLLA Nanofibers for Optimizing Neural Stem Cell Engineering.

Optimizing cell substrates by surface modification of neural stem cells (NSCs), for efficient and oriented neurogenesis, represents a promising strategy for treating neurological diseases. However, developing substrates with the advanced surface functionality, conductivity, and biocompatibility required for practical application is still challenging. Here, Ti3 C2 Tx MXene is introduced as a coating nanomaterial for aligned poly(l-lactide) (PLLA) nanofibers (M-ANF) to enhance NSC neurogenesis and simultaneously tailor the cell growth direction. Ti3 C2 Tx MXene treatment provides a superior conductivity substrate with a surface rich in functional groups, hydrophilicity, and roughness, which can provide biochemical and physical cues to support NSC adhesion and proliferation. Moreover, Ti3 C2 Tx MXene coating significantly promotes NSC differentiation into both neurons and astrocytes. Interestingly, Ti3 C2 Tx MXene acts synergistically with the alignment of nanofibers to promote the growth of neurites, indicating enhanced maturation of these neurons. RNA sequencing analysis further reveals the molecular mechanism by which Ti3 C2 Tx MXene modulates the fate of NSCs. Notably, surface modification by Ti3 C2 Tx MXene mitigates the in vivo foreign body response to implanted PLLA nanofibers. This study confirms that Ti3 C2 Tx MXene provides multiple advantages for decorating the aligned PLLA nanofibers to cooperatively improve neural regeneration.

Absence of association between N-acetyltransferase 2 acetylator status and colorectal cancer susceptibility: based on evidence from 40 studies.

BACKGROUND AND OBJECTIVES: N-Acetyltransferase (NAT) 2 is an important enzyme involved in the metabolism of different xenobiotics, including potential carcinogens, whose phenotypes were reported to be related to individual susceptibility to colorectal cancer (CRC). However, the results remain conflicting. To assess the relationship between NAT2 phenotypes and CRC risk, we performed this meta-analysis. METHODS: A comprehensive literature search was conducted to identify all case-control or cohort studies of NAT2 acetylator status on the susceptibility of CRC by searching of PubMed and EMBASE, up to May 20, 2011. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. RESULTS: A total of over 40,000 subjects from 40 published literatures were identified by searching the databases. No significantly elevated CRC risk in individuals with NAT2 slow acetylators compared with fast acetylators was found when all studies pooled (OR = 0.95, 95% CI: 0.87-1.04, I(2) = 52.6%). While three studies contributed to the source of heterogeneity were removed, there was still null result observed (OR = 0.96, 95% CI: 0.90-1.03, P = 0.17 for heterogeneity, I(2) = 17.8%). In addition, we failed to detect any associations in the stratified analyses by race, sex, source of controls, smoking status, genotyping methods or tumor localization. No publication bias was observed in this study. CONCLUSIONS: This meta-analysis suggests that the NAT2 phenotypes may not be associated with colorectal cancer development.