Tetrabromobisphenol-A/S and their derivatives in surface particulates from workshop floors of three representative e-waste recycling sites in China.

Surface particulates collected from the workshop floors of three major e-waste recycling sites (Taizhou, Qingyuan, and Guiyu) in China were analyzed for tetrabromobisphenol A/S (TBBPA/S) and their derivatives to investigate the environmental pollution caused by e-waste recycling activities. Mean concentrations of total TBBPA/S analogs in surface particulates were 31,471-116,059 ng/g dry weight (dw). TBBPA, TBBPA-BGE, and TBBPA-BDBPE were the most frequently detected in particulates with average concentration ranges of 17,929-78,406, 5601-15,842, and 5929-21,383 ng/g dw, respectively. Meanwhile, TBBPA, TBBPA-BGE, and TBBPA-BDBPE were the most abundant TBBPA/S analogs, accounting for around 96% of the total. The composition profiles of TBBPA/S analogs differed significantly among three e-waste sites. Similarly, principal component analysis uncovered different pollution patterns among different sites. The discrepancy in the profiles of TBBPA/S analogs largely relied on the e-waste types recycled in different areas. E-waste recycling led to the release of TBBPA/S analogs, and TBBPA/S analogs produced differentiation during migration from source (surface particulates) to nearby soil. More researches are necessary to find a definite relationship between pollution status and e-waste types and study differentiation behavior of TBBPA/S analogs in migration and diffusion from source to environmental medium.

Inactivation of the tumor suppressor gene Apc synergizes with H. pylori to induce DNA damage in murine gastric stem and progenitor cells.

Helicobacter pylori infection is a major risk factor for the development of gastric cancer. The bacteria reside in close proximity to gastric surface mucous as well as stem and progenitor cells. Here, we take advantage of wild-type and genetically engineered murine gastric organoids and organoid-derived monolayers to study the cellular targets of H. pylori-induced DNA damage and replication stress and to explore possible interactions with preexisting gastric cancer driver mutations. We find using alkaline comet assay, single-molecule DNA fiber assays, and immunofluorescence microscopy of DNA repair foci that H. pylori induces transcription-dependent DNA damage in actively replicating, Leucine-rich-repeat containing G-Protein-Coupled Receptor 5 (Lgr5)-positive antral stem and progenitor cells and their Troy-positive corpus counterparts, but not in other gastric epithelial lineages. Infection-dependent DNA damage is aggravated by Apc inactivation, but not by Trp53 or Smad4 loss, or Erbb2 overexpression. Our data suggest that H. pylori induces DNA damage in stem and progenitor cells, especially in settings of hyperproliferation due to constitutively active Wnt signaling.

Unveiling the pH-Dependent Yields of H2O2 and OH by Aqueous-Phase Ozonolysis of m-Cresol in the Atmosphere.

Hydrogen peroxide (H2O2) and hydroxyl radical (OH) are important oxidants in the atmospheric aqueous phase such as cloud droplets and deliquescent aerosol particles, playing a significant role in the chemical transformation of organic and inorganic pollutants in the atmosphere. Atmospheric aqueous-phase chemistry has been considered to be a source of H2O2 and OH. However, our understanding of the mechanisms of their formation in atmospheric waters is still incomplete. Here, we show that the aqueous-phase reaction of dissolved ozone (O3) with substituted phenols such as m-cresol represents an important source of H2O2 and OH exhibiting pH-dependent yields. Intriguingly, the formation of H2O2 through the ring-opening mechanism is strongly promoted under lower pH conditions (pH 2.5-3.5), while higher pH favors the ring-retaining pathways yielding OH. The rate constant of the reaction of O3 with m-cresol increases with increasing pH. The reaction products formed during the ozonolysis of m-cresol are analyzed by an Orbitrap mass spectrometer, and reaction pathways are suggested based on the identified product compounds. This study indicates that aqueous-phase ozonolysis of phenolic compounds might be an alternative source of H2O2 and OH in the cloud, rain, and liquid water of aerosol particles; thus, it should be considered in future model studies.

Mycobacterial infection aggravates Helicobacter pylori-induced gastric preneoplastic pathology by redirection of de novo induced Treg cells.

The two human pathogens Helicobacter pylori and Mycobacterium tuberculosis (Mtb) co-exist in many geographical areas of the world. Here, using a co-infection model of H. pylori and the Mtb relative M. bovis bacillus Calmette-Guérin (BCG), we show that both bacteria affect the colonization and immune control of the respective other pathogen. Co-occurring M. bovis boosts gastric Th1 responses and H. pylori control and aggravates gastric immunopathology. H. pylori in the stomach compromises immune control of M. bovis in the liver and spleen. Prior antibiotic H. pylori eradication or M. bovis-specific immunization reverses the effects of H. pylori. Mechanistically, the mutual effects can be attributed to the redirection of regulatory T cells (Treg cells) to sites of M. bovis infection. Reversal of Treg cell redirection by CXCR3 blockade restores M. bovis control. In conclusion, the simultaneous presence of both pathogens exacerbates the problems associated with each individual infection alone and should possibly be factored into treatment decisions.

PDGFR-ß inhibitor slows tumor growth but increases metastasis in combined radiotherapy and Endostar therapy.

BACKGROUND: Pericytes are pivotal mural cells of blood vessels and play an essential role in coordinating the function of endothelial cells. Previous studies demonstrated that Endostar, a novel endostatin targeting endothelial cells, can enhance the effect of radiotherapy (RT). The present study addressed whether inhibiting pericytes could potentially improve the efficacy of combined RT and Endostar therapy. METHODS: Platelet-derived growth factor beta-receptor inhibitor (CP673451) was chosen to inhibit pericytes and RT (12 Gy) was delivered. Lewis lung carcinoma-bearing C57BL/6 mice were randomized into 3 groups: RT, RT + Endo, and RT + Endo + CP673451. Subsequently, tumor microvessel density (MVD), pericyte coverage, tumor hypoxia, and lung metastasis were monitored at different time points following different therapies. RESULTS: Compared to the other two groups, RT + Endo + CP673451 treatment markedly inhibited tumor growth with no improvement in the overall survival. Further analyses clarified that in comparison to RT alone, RT + Endo significantly reduced the tumor MVD, with a greater decrease noted in the RT + Endo + CP673451 group. However, additional CP673451 accentuated tumor hypoxia and enhanced the pulmonary metastasis in the combined RT and Endostar treatment. CONCLUSIONS: Tumor growth can be further suppressed by pericyte inhibitor; however, metastases are potentially enhanced. More in-depth studies are warranted to confirm the potential benefits and risks of anti-pericyte therapy.

Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study.

OBJECTIVES: Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. MATERIALS AND METHODS: EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. RESULTS: Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. CONCLUSIONS: WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment.

Bevacizumab radiosensitizes non-small cell lung cancer xenografts by inhibiting DNA double-strand break repair in endothelial cells.

The aims of this study were to evaluate the effects of biweekly bevacizumab administration on a tumor microenvironment and to investigate the mechanisms of radiosensitization that were induced by it. Briefly, bevacizumab was administered intravenously to Balb/c nude mice bearing non-small cell lung cancer (NSCLC) H1975 xenografts; in addition, bevacizumab was added to NSCLC or endothelial cells (ECs) in vitro, followed by irradiation (IR). The anti-tumor efficacy, anti-angiogenic efficacy and repair of DNA double-strand breaks (DSBs) were evaluated. The activation of signaling pathways was determined using immunoprecipitation (IP) and WB analyses. Finally, biweekly bevacizumab administration inhibited the growth of H1975 xenografts and induced vascular normalization periodically. Bevacizumab more significantly increased cellular DSB and EC apoptosis when administered 1 h prior to 12 Gy/1f IR than when administered 5 days prior to IR, thereby inhibiting tumor angiogenesis and growth. In vitro, bevacizumab more effectively increased DSBs and apoptosis prior to IR and inhibited the clonogenic survival of ECs but not NSCLC cells. Using IP and WB analyses, we confirmed that bevacizumab can directly inhibit the phosphorylation of components of the VEGR2/PI3K/Akt/DNA-PKcs signaling pathway that are induced by IR in ECs. In conclusion, bevacizumab radiosensitizes NSCLC xenografts mainly by inhibiting DSB repair in ECs rather than by inducing vascular normalization.

The association between TGF-ß1 polymorphisms and radiation pneumonia in lung cancer patients treated with definitive radiotherapy: a meta-analysis.

BACKGROUND: Previous studies investigating the association between TGF-ß1 polymorphisms and Radiation Pneumonia (RP) risk have provided inconsistent results. The aim of our study was to assess the association between the TGF-ß1 genes C509T, G915C and T869C polymorphisms and risk of RP in lung cancer patients treated with definitive radiotherapy. METHODS: Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases for studies published before September 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for TGF-ß1 polymorphisms and RP were calculated in a fixed-effects model or a random-effects model when appropriate. RESULTS: Ultimately, each 7 studies were found to be eligible for meta-analyses of C509T, G915C and T869C, respectively. Our analysis suggested that the variant genotypes of T869C were associated with a significantly increased RP risk in dominant model (OR = 0.59, 95% CI = 0.45-0.79) and CT vs. TT model (OR = 0.47, 95% CI = 0.32-0.69). In the subgroup analyses by ethnicity/country, a significantly increased risk was observed among Caucasians. For C509T and G915C polymorphism, no obvious associations were found for all genetic models. CONCLUSION: This meta-analysis suggests that T869C polymorphism of TGF-ß1 may be associated with RP risk only in Caucasians, and there may be no association between C509T and G915C polymorphism and RP risk.

Enhanced radioresponse with a novel recombinant human endostatin protein via tumor vasculature remodeling: experimental and clinical evidence.

PURPOSE: This study aimed to examine the effect of the novel recombinant human endostatin (rh-Endo) protein on tumor vasculature, and to explore and evaluate the optimal scheduling of rh-Endo and radiotherapy (RT). METHODS: Tumor-perfusion parameters and hypoxia were monitored after rh-Endo treatment in 10 non-small cell lung-cancer (NSCLC) patients. Eight-week female C57BL/6J mice were randomized to receive rh-Endo or control (saline) once daily for 12 days when Lewis lung carcinoma (LLC) reached approximately 100-150 mm(3). On planned days, tumors were measured for cell apoptosis, microvessel density, pericytes, blood-vessel morphology, and tumor hypoxia. The tumor response under different combinations of rh-Endo and RT schedules was evaluated. RESULTS: Tumor hypoxia was significantly reduced 5 days after rh-Endo in NSCLC patients, and a similar result was found in the LLC mouse model. The anti-tumor effect was markedly enhanced when RT was administered within the remodeling period compared to any other treatment schedule. rh-Endo treatment remodeled the tumor vasculature after 5 days by reducing microvessel density and increasing pericytic coverage of the vessel endothelium. CONCLUSION: This study demonstrated decreased hypoxia in animals and patients upon rh-Endo treatment, which also enhanced the radioresponse within the vasculature-remodeling period. The optimal clinical combination of rh-Endo and RT warrants further investigation.