[A birth cohort study of the association between prenatal serum bisphenol A concentration and infant neurobehavior development].

Objective: To explore the association between maternal bisphenol A (BPA) exposure during pregnancy and neurobehavioral development in infant. Methods: Participants were from the Ma'anshan Birth Cohort, which was established from October 2008 to October 2010 based on four municipal medical and health institutions in Ma'anshan. High-performance liquid chromatography-tandem mass spectrometry was applied for the determination of serum BPA concentration in 1 783 pregnant women sampled at their first filing, and during 2.97 to 28.1 months age of the infants. Neurobehavioral development were assessed by 0-6-year-old pediatric examination table of neuropsychological development. Generalized linear model was used to analyze the association between serum BPA levels during pregnancy and infants' neurobehavioral development. Results: A total of 931 mother-child pairs had complete data on serum BPA detection during pregnancy and assessment of infants' neurobehavioral development status. The age of pregnant women at their first filing was (26.67±3.45) years old, and the M (P25,P75) of serum BPA concentration (ng/ml) was 0.23 (0.11, 0.52), with a detection rate of 84.1% (783/931). The age of infants was (13.18±5.46) months, and 53.5% (498) were boys. The developmental quotient scores of large motor, fine motor, adaptive ability, language ability and social behaviors of infants were (97.88±16.32), (97.16±15.35), (99.64±15.47), (95.3±16.04) and (98.95±14.76) points, respectively. Generalized linear model showed that after adjusting for factors such as delivery mode, feeding mode, family per capita monthly income, preterm delivery, gender, maternal age, residence, pre-pregnancy body mass index and residence time, serum BPA level in pregnancy was negatively associated with infant's development of social behavior [ß (95%CI):-2.42 (-4.71, -0.12)]. The post-stratification analysis by infant age revealed that the serum BPA level in pregnancy was only negatively associated with the development of language and social behavior developmental quotient scores in infants between the ages of 12 and 18 months, with ß (95%CI) about -6.66 (-13.06, -0.25) and -7.401 (-12.97, -1.83), respectively. Conclusion: BPA exposure during pregnancy affects language and social behavior development in infants, and the detection window is between 12 and 18 months old of the infant.

Oncogenes expand during evolution to withstand somatic amplification.

Background: Cancer-related genes are under intense evolutionary pressure. We conjectured that gene size is an important determinant of amplification propensity for oncogenes and thus cancer susceptibility and therefore could be subject to natural selection. Patients and methods: Gene information, including size and genomic locations, of all protein-coding genes were downloaded from Ensembl (release 87). Quantification of gene amplification was based on Genomic Identification of Significant Targets in Cancer scores obtained from available The Cancer Genome Atlas studies. Results: Oncogenes are larger in size as compared with non-cancer genes (mean size: 92.1 kb versus 61.4 kb; P < 0.0001) in the human genome, which is contributed by both increased total exon size (mean size: 4.6 kb versus 3.4 kb; P < 0.0001) and higher intronic content (mean %: 84.8 versus 78.0; P < 0.01). Such non-random size distribution and intronic composition are conserved in mouse and Drosophila (all P < 0.0001). Stratification by gene age indicated that young oncogenes have been subject to a stronger evolutionary pressure for gene expansion than their non-cancer counterparts. Pan-cancer analysis demonstrated that larger oncogenes were amplified to a lesser extent. Tumor-suppressor genes also moved toward small oncogenes in the course of evolution. Conclusions: Oncogenes expand in size whereas tumor-suppressor genes move closer to small oncogenes in the course of evolution to withstand oncogenic somatic amplification. Our findings have shed new light on the previously unappreciated influence of gene size on oncogene amplification and elucidated how cancers have shaped our genome to its present configuration.

[Association between early pregnancy bisphenol A exposure and sleep problems among preschool children].

Objective: To analyze the association between maternal bisphenol A exposure during early pregnancy and sleep problems among preschool children. Methods: Research subjects were from one of the sub-cohorts(Ma'anshan Cohort) of the China-Anhui Birth Cohort Study (C-ABCS) in Ma'anshan city. The basic situation of pregnant women and sleep information of preschool children were investigated. We selected preschool children whose mother's maternal serum bisphenol A concentrations of the first trimester had been already detected between December 2012 to Januray 2014. 1 259 pairs of mothers and children were included. The concentrations of bisphenol A exposure during early pregnancy were divided into low, medium and high exposure groups according to 25(th) percentile (P(25)) and 75(th) percentile (P(75)) levels. Multivariate multinomial logistic regression model was used to analyze the association between maternal bisphenol A exposure during early pregnancy and sleep-related problems in preschool children. Results: The P(50) (P(25)-P(75)) of serum bisphenol A exposure level during early pregnancy was 0.231 (0.106-0.512) ng/ml. The sleep-related problems scores of 1 259 preschool children were (16.43±3.82) points. The occasional sleep-related problems were detected about 47.8% (602 cases) and frequent sleep-related problems were detected about 18.3% (230 cases). After the adjustment of the confounding factors such as children's gender, age, BMI, sleep position (lying down, sleeping on one's back), the length of time to sleep and the length of sleep at night, in comparison with bisphenol A low exposure group, the OR (95%CI) value of preschool children with occasional sleep-related problems in maternal bisphenol A high exposure group during early pregnancy was 1.44 (1.01-2.06). After the gender stratification, the results showed that in comparison with bisphenol A low exposure group, the OR (95%CI) value of preschool girls with occasional sleep-related problems in maternal bisphenol A medium and high exposure group during early pregnancy were 1.61 (1.05-2.46) and 2.40 (1.42-4.04), respectively. The OR (95%CI) value of preschool girls with frequent sleep-related problems in maternal bisphenol A high exposure group during early pregnancy was 2.64 (1.34-5.17). However, in boys, there was no statistically significant association between maternal bisphenol A exposure during early pregnancy and sleep-related problems (P>0.05). Conclusion: Maternal bisphenol A exposure during early pregnancy might be related to sleep-related problems in preschool children.

Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial.

BACKGROUND: Previous animal and clinical studies showed that nitrous oxide may produce long-term analgesia. The aim of this study was to evaluate the effect of nitrous oxide in preventing chronic postsurgical pain. We also explored whether methylenetetrahydrofolate reductase gene polymorphisms (1298A>C, 667C>T) would enhance nitrous oxide analgesia. METHODS: We conducted a telephone interview at 12 months after surgery on 2924 (41.1%) patients enrolled in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia-II trial. Pain at the wound site was recorded using the modified brief pain inventory and the neuropathic pain questionnaire. General health status was measured using the EQ-5D questionnaire. Genotyping was performed in a subset of 674 Asian patients in Hong Kong. RESULTS: At 12 months after surgery, 356 (12.2%) patients reported chronic postsurgical pain at the wound site and 112 (3.8%) patients had severe pain and required regular analgesic interventions. Nitrous oxide did not affect the rate of chronic postsurgical pain (11.8% nitrous oxide group; 12.5% no nitrous oxide group), relative risk (95% confidence intervals): 0.94 (0.75-1.17), P=0.57. However, in a planned subgroup analysis, nitrous oxide reduced the risk of chronic postsurgical pain in Asian patients, relative risk (95% confidence intervals): 0.70 (0.50-0.98), P=0.031. Patients who were homozygous for either gene polymorphism and who received nitrous oxide during surgery were less likely to report chronic postsurgical pain. CONCLUSIONS: Nitrous oxide administration had no impact on chronic postsurgical pain, but benefits may still be possible in Asian patients and patients with variants in methylenetetrahydrofolate reductase gene. CLINICAL TRIAL REGISTRATION: NCT00430989.

Intrarectal administration of mCRAMP-encoding plasmid reverses exacerbated colitis in Cnlp(-/-) mice.

Cathelicidin is a pleiotropic host defense peptide secreted by epithelial and immune cells. Whether endogenous cathelicidin is protective against ulcerative colitis, however, is unclear. Here we sought to delineate the role of endogenous murine cathelicidin (mCRAMP) and the therapeutic efficacy of intrarectal administration of mCRAMP-encoding plasmid in ulcerative colitis using dextran sulfate sodium (DSS)-challenged cathelicidin-knockout (Cnlp(-/-)) mice as a model. Cnlp(-/-) mice had more severe symptoms and mucosal disruption than the wild-type mice in response to DSS challenge. The tissue levels of interleukin-1ß and tumor necrosis factor-α, myeloperoxidase activity and the number of apoptotic cells were increased in the colon of DSS-challenged Cnlp(-/-) mice. Moreover, mucus secretion and mucin gene expression were impaired in Cnlp(-/-) mice. All these abnormalities were reversed by the intrarectal administration of mCRAMP or mCRAMP-encoding plasmid. Taken together, endogenous cathelicidin may protect against ulcerative colitis through modulation of inflammation and mucus secretion.

Cathelicidin protects against Helicobacter pylori colonization and the associated gastritis in mice.

Cathelicidin, an antimicrobial peptide of the innate immune system, has been shown to modulate microbial growth, wound healing and inflammation. However, whether cathelicidin controls Helicobacter pylori infection in vivo remains unexplored. This study sought to elucidate the role of endogenous and exogenous mouse cathelicidin (CRAMP) in the protection against H. pylori infection and the associated gastritis in mice. Results showed that genetic ablation of CRAMP in mice significantly increased the susceptibility of H. pylori colonization and the associated gastritis as compared with the wild-type control. Furthermore, replenishment with exogenous CRAMP, delivered via a bioengineered CRAMP-secreting strain of Lactococcus lactis, reduced H. pylori density in the stomach as well as the associated inflammatory cell infiltration and cytokine production. Collectively, these findings indicate that cathelicidin protects against H. pylori infection and its associated gastritis in vivo. Our study also demonstrates the feasibility of using the transformed food-grade bacteria to deliver cathelicidin, which may have potential clinical applications in the treatment of H. pylori infection in humans.

MicroRNA dysregulation in colorectal cancer: a clinical perspective.

Recent researches have shed light on the biological importance of microRNAs (miRNAs) in colorectal cancer (CRC) genesis, progression and response to treatments. The potential utility of miRNAs in the preclinical stage have been explored and investigated. In this review, we explored the literature and reviewed the cutting edge progress in the discovery of noninvasive plasma and faecal miRNAs for CRC early diagnosis, as well as their measurability and predictability. We also discussed the utility of miRNAs as novel prognostic and predictive markers, and their association with CRC clinical phenotypes including recurrence, metastasis and therapeutic outcomes. Finally, we summarised miRNA-related single-nucleotide polymorphisms and their potential influence on sporadic CRC susceptibility and therapeutic response. In conclusion, the use of miRNAs as biomarker for CRC is still in its infancy and need further characterisation and evaluation.

Specific immunotherapy suppresses Th2 responses via modulating TIM1/TIM4 interaction on dendritic cells.

BACKGROUND: Specific immunotherapy (SIT) is the only curable remedy for allergic disorders currently; however, the underlying mechanism is not fully understood yet. This study aimed to elucidate the mechanism of SIT on suppressing TIM4 (T cell immunoglobulin mucin domain molecule 4) expression in dendritic cells (DCs) and modulating the skewed T helper 2 (Th2) responses in patients with airway allergy. METHODS: Twenty patients with allergic rhinitis (AR) were treated with SIT for 3 months. Before and after SIT, the expression of TIM4 in peripheral DC and TIM1 in Th2 cells was examined. The role of Fc gamma receptor (FcgammaR) I and II in modulating the expression of TIM4 in DCs was investigated. RESULTS: The interaction of TIM1/TIM4 played a critical role in sustaining the polarization status of Th2 cells in AR patients. Cross-linking FcgammaRI by antigen/IgG complexes increased the production of TIM4 by dendritic cells via upregulating tumor necrosis factor-alpha in DCs. Exposure to microbial products promoted the expression of FcgammaRI in DCs that further increased the expression of TIM4. Exposure to specific antigens alone upregulated the expression of FcgammaRII in DCs, that suppressed the expression of TIM4. CONCLUSIONS: We conclude that SIT suppresses the skewed Th2 responses via disrupting the interaction of TIM1/TIM4 in antigen-specific Th2 cells.

Bone morphogenetic protein signalling is required for the anti-mitogenic effect of the proteasome inhibitor MG-132 on colon cancer cells.

BACKGROUND AND PURPOSE: Inhibition of proteasome has been emerging as a promising approach in pathway-directed cancer therapy. Bone morphogenetic protein (BMP) signalling, which is known to be regulated by the ubiquitin-proteasome pathway in osteoblasts, plays a crucial role in the suppression of gastrointestinal carcinogenesis. Here we sought to elucidate the anti-mitogenic effect of a proteasome inhibitor in relation to BMP signalling in colon cancer. EXPERIMENTAL APPROACH: The effects of the proteasome inhibitor MG-132 on proliferation of SW1116 and HT-29 colon cancer cells were determined by [(3)H]-thymidine incorporation and colony-formation assay. The involvement of BMP signalling in the action of MG-132 was elucidated by western blot, real-time PCR, immunofluorescence and RNA interference. KEY RESULTS: MG-132 significantly suppressed the proliferation of colon cancer SW1116 and HT-29 cells. In this regard, MG-132 activated BMP signalling and this was manifested as an increase in Smad1/5/8 phosphorylation and upregulation of p21(Waf1/Cip1) and p27(Kip1) expression. Knockdown of BMP receptor II abolished Smad1/5/8 phosphorylation, the induction of p21(Waf1/Cip1) and p27(Kip1) and inhibition of cell proliferation induced by MG-132. Further analysis revealed that MG-132 upregulated the expression of BMP1 and BMP2, which are secreted members of the BMP superfamily. Moreover, the expression of Smad6, an intracellular inhibitor of BMP signalling, was suppressed by MG-132. CONCLUSIONS AND IMPLICATIONS: These findings suggest that inhibition of proteasome suppresses the proliferation of colon cancer cells via activation of BMP signalling. They also demonstrate a novel aspect of proteasome function in the regulation of colon cancer cell proliferation.

[Exposure to bisphenol A during maternal pregnancy and the emotional and behavioral impact on their preschool children].

Objective: To explore the long-term effects of maternal pregnancy bisphenol A (BPA) exposure on emotional and behavioral problems appeared in their preschool children. Methods: The study sample was a subset of the China-Anhui Birth Cohort Study (C-ABCS). A unified questionnaire was used to collect basic information on both pregnant women and their children. Free BPA concentration in maternal serum was determined by high-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS). The parent-report version of the Strengths and Difficulties Questionnaire (SDQ) was used to estimate the emotional and behavioral problems in preschool children. A total of 1 713 pairs of mothers and children were included in this study. Association between BPA exposure during pregnancy and the emotional and behavioral problems in preschool children was evaluated with multinomial logistic regression model. Results: Prevalence rates in 1 713 preschool children appeared as: 6.48% of emotional problems, 8.11% for conduct problems, 8.35% for hyperactivity/inattention, 2.86% for peer problems, 11.38% for prosocial behaviors and 7.94% for total difficulties. Subjects were divided according to the degrees of exposure and the results showed as: low exposure group (≤0.120 ng/ml), medium exposure group (0.120

Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Heart and lung transplantation is a high-risk procedure requiring intensive immunosuppressive therapy for preventing organ rejection. Alemtuzumab, a CD52-specific monoclonal antibody, is increasingly used for induction therapy compared with conventional agents. However, there has been no systematic review comparing its efficacy with traditional therapeutic drugs. METHODS: PubMed and EMBASE were searched to October 1, 2017, for articles on alemtuzumab in cardiothoracic transplant surgery. Of the 433 studies retrieved, 8 were included in the final meta-analysis. RESULTS: In lung transplantation, alemtuzumab use was associated with lower odds of acute cellular rejection compared with antithymocyte globulin (odds ratio [OR], 0.21; 95% CI, 0.11-0.40; P < .001), lower acute rejection rates (OR, 0.12; 95% CI, 0.03-0.55; P < .01), and infection rates (OR, 0.69; 95% CI, 0.35-1.36; P = .33) when compared with basiliximab. Multivariate meta-regression analysis found that mean age, male sex, single lung transplant, double lung transplant, cytomegalovirus or Epstein-Barr virus status, idiopathic pulmonary fibrosis, cystic fibrosis, and mean ischemic time did not significantly influence acute rejection outcomes. For heart transplantation, alemtuzumab use was associated with lower acute rejection rates when compared with tacrolimus (OR, 0.44; 95% CI, 0.30-0.66; P < .001). CONCLUSIONS: Alemtuzumab use was associated with lower rejection rates when compared with conventional induction therapy agents (antithymocyte globulin, basiliximab, and tacrolimus) in heart and lung transplantation. However, this was based on observational studies. Randomized controlled trials are needed to verify its clinical use.

WITHDRAWN: Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis.

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Transplant Proc. 2018; 50 (10):3739-3747, https://doi.org/10.1016/j.transproceed.2018.08.018. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

TEAD1/4 exerts oncogenic role and is negatively regulated by miR-4269 in gastric tumorigenesis.

TEA domain (TEAD) transcription factors are key components of the Hippo-YAP1 signaling pathway, but their functional role and regulatory mechanisms remain unclear. This study aims to comprehensively explore the expression pattern and functional role of TEAD family in gastric carcinogenesis and investigate its regulation by microRNAs (miRNAs). The mRNA and protein expression of TEAD family were examined by quantitative reverse transcription-PCR (qRT-PCR) and western blot. Their functional roles were determined by in vitro and in vivo studies. The clinicopathological association of TEAD4 in gastric cancer (GC) was studied using immunohistochemistry on tissue microarray. The prediction of miRNAs, which potentially target TEAD1/4, was performed by TargetScan and miRDB. The regulation of TEAD1/4 by miRNAs was confirmed by qRT-PCR, western blot and luciferase assays. TEAD1/4 were overexpressed in GC cell lines and primary GC tissues. Knockdown of TEAD1/4 induced a significant anticancer effect in vitro and in vivo. TEAD1 was confirmed to be a direct target of miR-377-3p and miR-4269, while TEAD4 was negatively regulated by miR-1343-3p and miR-4269. Among them, miR-4269 was the most effective inhibitor of TEAD1/4. Ectopic expression of these miRNAs substantiated their tumor-suppressive effects. In primary GC tumors, downregulation of miR-4269 was associated with poor disease-specific survival and showed a negative correlation with TEAD4. TEAD1 and TEAD4 are oncogenic factors, whose aberrant activation are, in part, mediated by the silence of miR-377-3p, miR-1343-3p and miR-4269. For the first time, the nuclear accumulated TEAD4 and downregulated miR-4269 are proposed to serve as novel prognostic biomarkers in GC.

Disruption of NCOA2 by recurrent fusion with LACTB2 in colorectal cancer.

Whole-genome and transcriptome sequencing were used to discover novel gene fusions in a case of colon cancer. A tumor-specific LACTB2-NCOA2 fusion originating from intra-chromosomal rearrangement of chromosome 8 was identified at both DNA and RNA levels. Unlike conventional oncogenic chimeric proteins, the fusion product lacks functional domain from respective genes, indicative of an amorphic rearrangement. This chimeric LACTB2-NCOA2 transcript was detected in 6 out of 99 (6.1%) colorectal cancer (CRC) cases, where NCOA2 was significantly downregulated. Enforced expression of wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impaired the pro-tumorigenic phenotypes of CRC cells, whereas knockdown of endogenous NCOA2 in normal colonocytes had opposite effects. Mechanistically, NCOA2 inhibited Wnt/ß-catenin signaling through simultaneously upregulating inhibitors and downregulating stimulators of Wnt/ß-catenin pathway. Collectively, our data supports that NCOA2 is a novel negative growth regulatory gene repressing the Wnt/ß-catenin pathway in CRC, where recurrent fusion with LACTB2 contributes to its disruption.

Selection of Phlebotomus papatasi (Diptera: Psychodidae) lines susceptible and refractory to Leishmania major infection.

Variation in susceptibility to infection with cultured promastigotes of Leishmania major was detected among 3 different geographic strains (ISRAEL, EGYPT, and INDIA) of the sand fly Phlebotomus papatasi. The ISRAEL strain showed the greatest susceptibility and was chosen for subsequent genetic selection experiments. After 13 generations of genetic selection in this strain, a stable refractory line was obtained in which only 7.5% of the insects could be infected. A highly susceptible line was also obtained in 5 generations of selection. Infection rates in the susceptible line were stabilized at about 94%. A description of the selection process and characteristics of the 2 lines are given.