Allergic conjunctivitis is a common problem that significantly impairs patients' quality of life. Whether air pollution serves as a risk factor for the development of allergic conjunctivitis remains elusive. In this paper, we assess the relationship between air pollutants and weather conditions with outpatient visits for allergic conjunctivitis. By using a time-series analysis based on the largest dataset ever assembled to date, we found that the number of outpatient visits for allergic conjunctivitis was significantly correlated with the levels of NO2, O3, and temperature, while its association with humidity was statistically marginal. No associations between PM10, PM2.5, SO2, or wind velocity and outpatient visits were seen. Subgroup analyses showed that sex seemed to modify the effects of humidity on outpatient visits for allergic conjunctivitis, but not for NO2, O3, or temperature. People younger than 40 were found to be susceptible to changes of all four parameters, while those older than 40 were only consistently affected by NO2 levels. Our findings revealed that higher levels of ambient NO2, O3, and temperature increase the chances of outpatient visits for allergic conjunctivitis. Ambient air pollution and weather changes may contribute to the worsening of allergic conjunctivitis.

The nuclear receptor coactivator amplified in breast cancer 1 (AIB1/SRC-3) has a well-defined role in steroid and growth factor signaling in cancer and normal epithelial cells. Less is known about its function in stromal cells, although AIB1/SRC-3 is up-regulated in tumor stroma and may, thus, contribute to tumor angiogenesis. Herein, we show that AIB1/SRC-3 depletion from cultured endothelial cells reduces their proliferation and motility in response to growth factors and prevents the formation of intact monolayers with tight junctions and of endothelial tubes. In AIB1/SRC-3(+/-) and (-/-) mice, the angiogenic responses to subcutaneous Matrigel implants was reduced by two-thirds, and exogenously added fibroblast growth factor (FGF) 2 did not overcome this deficiency. Furthermore, AIB1/SRC-3(+/-) and (-/-) mice showed similarly delayed healing of full-thickness excisional skin wounds, indicating that both alleles were required for proper tissue repair. Analysis of this defective wound healing showed reduced recruitment of inflammatory cells and macrophages, cytokine induction, and metalloprotease activity. Skin grafts from animals with different AIB1 genotypes and subsequent wounding of the grafts revealed that the defective healing was attributable to local factors and not to defective bone marrow responses. Indeed, wounds in AIB1(+/-) mice showed reduced expression of FGF10, FGFBP3, FGFR1, FGFR2b, and FGFR3, major local drivers of angiogenesis. We conclude that AIB1/SRC-3 modulates stromal cell responses via cross-talk with the FGF signaling pathway.

The aim of this study was to determine the transport and distribution characteristics of levofloxacin in the rat stomach and investigate the effects of combination treatment with rabeprazole. A total of 160 Wistar rats were randomly divided into four treatment groups: 50 mg/kg levofloxacin, 100 mg/kg levofloxacin, 50 mg/kg levofloxacin + rabeprazole and 100 mg/kg levofloxacin + rabeprazole. For two hours after intravenous administration, serum, gastric juice and stomach mucosa samples were collected at 15-min intervals, and the levofloxacin concentrations in all the samples were measured to determine the transport and distribution characteristics of levofloxacin in the rat stomach. In the 50 mg/kg levofloxacin and the 100 mg/kg levofloxacin groups, the drug concentration in the gastric juice gradually exceeded the serum concentration within 45-60 min of administration (P<0.05) and the drug concentrations in the gastric body and antrum were higher than those in the serum and the forestomach (P<0.05). At 15-30 min after administration, the drug concentrations in the gastric juice in the 50 mg/kg levofloxacin + rabeprazole and the 100 mg/kg levofloxacin + rabeprazole groups gradually exceeded the serum concentration (P<0.05). However, the levofloxacin concentration in the gastric body and in the antrum did not significantly differ between the two groups (P>0.05). The levofloxacin concentrations in each stomach region in the groups also treated with rabeprazole were higher than those treated with levofloxacin alone, but the differences were not significant. The levofloxacin transport fractions in the stomach in the 50 mg/kg levofloxacin, 100 mg/kg levofloxacin, 50 mg/kg levofloxacin + rabeprazole and 100 mg/kg levofloxacin + rabeprazole groups were 2.36, 2.52, 2.42 and 2.55, respectively, and no significant difference was identified. Levofloxacin may be actively transported in the rat stomach. The levofloxacin concentration in the gastric antrum exceeded that in the forestomach, and the local concentration increased with increasing dosage. Combining a proton pump inhibitor with levofloxacin has little effect on the concentration and distribution of levofloxacin in the stomach within 2 h.

We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China.

Emerging evidence has shown that both prostatic basal and luminal cells are able to initiate oncogenic transformation. However, despite the diversity of tumor-initiating cells, most prostate cancer cells express the androgen receptor (AR) and depend on androgens for their growth and expansion, implicating an essential role of androgen signaling in prostate tumorigenesis. Prostatic basal cells express p63 and are able to differentiate into luminal, neuroendocrine, and basal cells. Here, we directly assessed the essential role of androgen signaling in prostatic p63-expressing cell initiated oncogenic transformation and tumor formation. Using novel and relevant mouse models, we demonstrated that, with stabilized β-catenin expression, prostatic p63-expressing cells possess the ability to initiate oncogenic transformation and, in the presence of androgens, they further transdifferentiate into luminal-like tumor cells and develop adenocarcinomas. Castration prior to activating stabilized β-catenin sensitizes p63-expressing cells and increases their sensitivity to androgens, resulting in aggressive and fast growing tumor phenotypes. These findings are consistent with what have been observed in human prostate cancers, demonstrating an essential role for androgen signaling in prostate cancer initiation and progression. This study also provides fresh insight into developing new therapeutic strategies for better treating prostate cancer patients.

Steroid receptor coactivator 3 (SRC-3) is a multifunctional protein that plays an important role in malignancy of several cancers and in regulation of bacterial LPS-induced inflammation. However, the involvement of SRC-3 in allergic response remains unclear. Herein we used passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA) mouse models to assess the role of SRC-3 in allergic response.

Little is known about the cellular events promoting metastasis. We show that knockout of phospholipase D2 (PLD2), which generates the signaling lipid phosphatidic acid (PA), inhibits lung metastases in the mammary tumor virus (MMTV)-Neu transgenic mouse breast cancer model. PLD2 promotes local invasion through the regulation of the plasma membrane targeting of MT1-MMP and its associated invadopodia. A liposome pull-down screen identifies KIF5B, the heavy chain of the motor protein kinesin-1, as a new PA-binding protein. In vitro assays reveal that PA specifically and directly binds to the C terminus of KIF5B. The binding between PLD2-generated PA and KIF5B is required for the vesicular association of KIF5B, surface localization of MT1-MMP, invadopodia, and invasion in cancer cells. Taken together, these results identify a role of PLD2-generated PA in the regulation of kinesin-1 motor functions and breast cancer metastasis and suggest PLD2 as a potential therapeutic target for metastatic breast cancer.

Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth.

Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fatty acid metabolism by directly regulating carnitine/acyl-carnitine translocase (CACT) gene expression. Genetic deficiency of CACT in humans is accompanied by a constellation of metabolic and toxicity phenotypes including hypoketonemia, hypoglycemia, hyperammonemia, and impaired neurologic, cardiac and skeletal muscle performance, each of which is apparent in mice lacking SRC-3 expression. Consistent with human cases of CACT deficiency, dietary rescue with short chain fatty acids drastically attenuates the clinical hallmarks of the disease in mice devoid of SRC-3. Collectively, our results position SRC-3 as a key regulator of β-oxidation. Moreover, these findings allow us to consider platform coactivators such as the SRCs as potential contributors to syndromes such as CACT deficiency, previously considered as monogenic.

Pentachlorophenol (PCP) is highly toxic and persistent in soils. Bioreduction of PCP often co-occurs with varying concentrations of sulfate and nitrate in flooded paddy soils where each can act as an electron acceptor. Anaerobic soil microcosms were constructed to evaluate the influence of sulfate and nitrate amendments and their redox processes. Microcosms with varying sulfate and nitrate concentrations demonstrated an inhibitory effect on reductive dechlorination of PCP compared to an untreated control. Compared to nitrate, sulfate exhibited a more significant impact on PCP dechlorination, as evidenced by a lower maximum reaction rate and a longer time to reach the maximum reaction rate. Dechlorination of PCP was initiated at the ortho-position, and then at the para- and meta-positions to form 3-CP as the final product in all microcosms. Deep sequencing of microbial communities in the microcosms revealed a strong variation in bacterial taxon among treatments. Specialized microbial groups, such as the genus of Desulfovibrio responding to the addition of sulfate, had a potential to mediate the competitive microbial dechlorination of PCP. Our results provide an insight into the competitive microbial-mediated reductive dechlorination of PCP in natural flooded soil or sediment environments.

Reductive dechlorination is the primary pathway for environmental removal of pentachlorophenol (PCP) in soil under anaerobic condition. This process has been verified to be coupled with other soil redox processes of typical biogenic elements such as carbon, iron and sulfur. Meanwhile, biochar has received increasing interest in its potential for remediation of contaminated soil, with the effect seldom investigated under anaerobic environment. In this study, a 120-day anaerobic incubation experiment was conducted to investigate the effects of biochar on soil redox processes and thereby the reductive dechlorination of PCP under anaerobic condition. Biochar addition (1%, w/w) enhanced the dissimilatory iron reduction and sulfate reduction while simultaneously decreased the PCP reduction significantly. Instead, the production of methane was not affected by biochar. Interestingly, however, PCP reduction was promoted by biochar when microbial sulfate reduction was suppressed by addition of typical inhibitor molybdate. Together with Illumina sequencing data regarding analysis of soil bacteria and archaea responses, our results suggest that under anaerobic condition, the main competition mechanisms of these typical soil redox processes on the reductive dechlorination of PCP may be different in the presence of biochar. In particularly, the effect of biochar on sulfate reduction process is mainly through promoting the growth of sulfate reducer (Desulfobulbaceae and Desulfobacteraceae) but not as an electron shuttle. With the supplementary addition of molybdate, biochar application is suggested as an improved strategy for a better remediation results by coordinating the interaction between dechlorination and its coupled soil redox processes, with minimum production of toxic sulfur reducing substances and relatively small emission of greenhouse gas (CH4) while maximum removal of PCP.

Microbial ecological studies have been remarkably promoted by the high-throughput sequencing approach with explosive information of taxonomy and relative abundance. However, relative abundance does not reflect the quantity of the microbial community and the inter-sample differences among taxa. In this study, we refined and applied an integrated high-throughput absolute abundance quantification (iHAAQ) method to better characterize soil quantitative bacterial community through combining the relative abundance (by high-throughput sequencing) and total bacterial quantities (by quantitative PCR). The proposed iHAAQ method was validated by an internal reference strain EDL933 and a laboratory strain WG5. Application of the iHAAQ method to a soil phenanthrene biodegradation study showed that for some bacterial taxa, the changes of relative and absolute abundances were coincident, while for others the changes were opposite. With the addition of a microbial activity inhibitor (NaN3), the absolute abundances of soil bacterial taxa, including several dominant genera of Bacillus, Flavobacterium, and Paenibacillus, decreased significantly, but their relative abundances increased after 28 days of incubation. We conclude that the iHAAQ method can offer more comprehensive information to reflect the dynamics of soil bacterial community with both relative and absolute abundances than the relative abundance from high-throughput sequencing alone.

Endostar is a novel artificially-synthesized anti-angiogenesis drug, and has been approved for clinical use. Previous studies have indicated that patients with esophageal cancer could benefit from Endostar combined with chemotherapy or chemoradiotherapy. However, the most advantageous use of this drug remains to be elucidated. The role of autophagy in cancer treatment remains controversial. The results of the present study demonstrated that Endostar promotes autophagy activation, which is regulated via phosphorylation inhibition of the downstream signaling molecules of the vascular endothelial growth factor, AKT serine/threonine kinase and mechanistic target of rapamycin signaling pathways. Furthermore, inhibiting autophagy using the pharmacological inhibitor chloroquine facilitated the antiproliferative effect of Endostar and increased the number of apoptotic cells, compared with Endostar monotherapy. Taken together, the results of the present study suggest that autophagy activation induced by Endostar serves a protective role in human esophageal cancer treatment, and that autophagy inhibition promotes the antiproliferative role of Endostar. Therefore, the combination of Endostar with an autophagy inhibitor may be a novel prospective approach to improving the efficacy of Endostar for the treatment of patients with esophageal cancer.

Coastal ecosystems play significant ecological and economic roles but are threatened and facing decline. Microbes drive various biogeochemical processes in coastal ecosystems. Tidal flats are critical components of coastal ecosystems; however, the structure and function of microbial communities in tidal flats are poorly understood. Here we investigated the seasonal variations of bacterial communities along a tidal flat series (subtidal, intertidal and supratidal flats) and the factors affecting the variations. Bacterial community composition and diversity were analyzed over four seasons by 16S rRNA genes using the Ion Torrent PGM platform. Bacterial community composition differed significantly along the tidal flat series. Bacterial phylogenetic diversity increased while phylogenetic turnover decreased from subtidal to supratidal flats. Moreover, the bacterial community structure differed seasonally. Canonical correspondence analysis identified salinity as a major environmental factor structuring the microbial community in the sediment along the successional series. Meanwhile, temperature and nitrite concentration were major drivers of seasonal microbial changes. Despite major compositional shifts, nitrogen, methane and energy metabolisms predicted by PICRUSt were inhibited in the winter. Taken together, this study indicates that bacterial community structure changed along the successional tidal flat series and provides new insights on the characteristics of bacterial communities in coastal ecosystems.

No abstract available

Aberrant TGF‑β/Smad7 signaling has been reported to be an important mechanism underlying the pathogenesis of ulcerative colitis. Therefore, the present study aimed to investigate the effects of a number of potential anti‑colitis agents on intestinal epithelial permeability and the TGF‑β/Smad7 signaling pathway in an experimental model of colitis. A mouse model of colitis was first established before anti‑TNF‑α and 5‑aminosalicyclic acid (5‑ASA) were administered intraperitoneally and orally, respectively. Myeloperoxidase (MPO) activity, histological index (HI) of the colon and the disease activity index (DAI) scores were then detected in each mouse. Transmission electron microscopy (TEM), immunohistochemical and functional tests, including Evans blue (EB) and FITC‑dextran (FD‑4) staining, were used to evaluate intestinal mucosal permeability. The expression of epithelial phenotype markers E‑cadherin, occludin, zona occludens (ZO‑1), TGF‑β and Smad7 were measured. In addition, epithelial myosin light chain kinase (MLCK) expression and activity were measured. Anti‑TNF‑α and 5‑ASA treatments was both found to effectively reduce the DAI score and HI, whilst decreasing colonic MPO activity, plasma levels of FD‑4 and EB permeation of the intestine. Furthermore, anti‑TNF‑α and 5‑ASA treatments decreased MLCK expression and activity, reduced the expression of Smad7 in the small intestine epithelium, but increased the expression of TGF‑β. In mice with colitis, TEM revealed partial epithelial injury in the ileum, where the number of intercellular tight junctions and the expression levels of E‑cadherin, ZO‑1 and occludin were decreased, all of which were alleviated by anti‑TNF‑α and 5‑ASA treatment. In conclusion, anti‑TNF‑α and 5‑ASA both exerted protective effects on intestinal epithelial permeability in an experimental mouse model of colitis. The underlying mechanism may be mediated at least in part by the increase in TGF‑β expression and/or the reduction in Smad7 expression, which can inhibit epithelial MLCK activity and in turn reduce mucosal permeability during the pathogenesis of ulcerative colitis.

This randomized, open-label, multi-center phase 2 study (NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemotherapy in patients with esophageal squamous cell carcinoma after first-line chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with efficacy. The median OS in the sintilimab group was significantly improved compared with the chemotherapy group (median OS 7.2 vs.6.2 months; P = 0.032; HR = 0.70; 95% CI, 0.50-0.97). Incidence of treatment-related adverse events of grade 3-5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1%). Patients with high T-cell receptor (TCR) clonality and low molecular tumor burden index (mTBI) showed the longest median OS (15.0 months). Patients with NLR < 3 at 6 weeks post-treatment had a significantly prolonged median OS (16.6 months) compared with NLR ≥ 3. The results demonstrate a significant improvement in OS of sintilimab compared to chemotherapy as second-line treatment for advanced or metastatic ESCC.

The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage.

The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.

Cropland is a main source of global nitrogen pollution1,2. Mitigating nitrogen pollution from global croplands is a grand challenge because of the nature of non-point-source pollution from millions of farms and the constraints to implementing pollution-reduction measures, such as lack of financial resources and limited nitrogen-management knowledge of farmers3. Here we synthesize 1,521 field observations worldwide and identify 11 key measures that can reduce nitrogen losses from croplands to air and water by 30-70%, while increasing crop yield and nitrogen use efficiency (NUE) by 10-30% and 10-80%, respectively. Overall, adoption of this package of measures on global croplands would allow the production of 17 ± 3 Tg (1012 g) more crop nitrogen (20% increase) with 22 ± 4 Tg less nitrogen fertilizer used (21% reduction) and 26 ± 5 Tg less nitrogen pollution (32% reduction) to the environment for the considered base year of 2015. These changes could gain a global societal benefit of 476 ± 123 billion US dollars (USD) for food supply, human health, ecosystems and climate, with net mitigation costs of only 19 ± 5 billion USD, of which 15 ± 4 billion USD fertilizer saving offsets 44% of the gross mitigation cost. To mitigate nitrogen pollution from croplands in the future, innovative policies such as a nitrogen credit system (NCS) could be implemented to select, incentivize and, where necessary, subsidize the adoption of these measures.