Association Between Phthalate Exposure in Pregnancy and Gestational Diabetes: A Chinese Cross-Sectional Study.

OBJECTIVE: The present study aims to explore the association between phthalate exposure and the risk of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: A total of 11 plasticizer metabolites were measured in patient morning urine using high-performance liquid chromatography. Furthermore, fasting blood glucose and fasting insulin were detected in first-trimester blood samples. The chemical concentration was described using the median, the metabolite concentration difference between the GDM and control groups was compared using the bootstrap method, and the correlations of the fasting blood glucose, fasting insulin, insulin resistance index, and phthalic acid ester (PAE) metabolites were analyzed using Spearman correlation analysis. The multivariate logistic regression model and predictive probability map were performed to help assess the linearity and nature of any dose-response relationship. RESULTS: Of the 224 women recruited for the present study, 200 met the inclusion criteria. Their measured outcomes and biomonitoring data were examined for the presence of chemicals. The results showed that the patients in the GDM group had higher mono-(2-ethylhexyl) phthalate (MEHP) and methylerythritol cyclophosphane concentrations in their bodies than the patients in the control group. Statistically significant MEHP-GDM associations were also observed (P < 0.001). The GDM and MEHP dose-response relationships were different among pregnant women aged <35 years and those aged >35 years (P < 0.001). Furthermore, gestational age >28 weeks exhibited similar changes to those aged ≤28 weeks (P = 0.059). CONCLUSION: The findings of the present study add to the growing body of evidence supporting phthalate exposure as a GDM risk factor.

TTK predicts triple positive breast cancer prognosis and regulates tumor proliferation and invasion.

This study was conducted to investigate the expression of the spindle assembly checkpoint kinase tyrosine/threonine kinase (TTK) in triple positive breast cancer (TPBC) and its effect on TPBC cells. We analyzed the status of TTK in 69 TPBC samples using immunohistochemistry. The correlation between TTK and clinicopathological parameters was analyzed using a chi-squared test. The prognostic value of TTK was evaluated using Kaplan-Meier survival curves. We analyzed the role of TTK in the invasion and proliferation of TPBC cells in vitro and in vivo. The mean age of the 69 patients with TPBC enrolled in this study was 53 years (range: 29-86 years). TTK expression was positively correlated with tumor size (p=0.034), p53 status (p=0.023), TNM stage ([p=0.023), and Ki-67 index (p<0.001). The Kaplan-Meier curves revealed that TTK expression was correlated with poor disease-free survival (p=0.001) and overall survival (p=0.050). Multivariate proportional hazard regression analyses showed that TTK and TNM staging were significant independent predictors of disease-free survival (p=0.007 and p=0.034, respectively). Additionally, TTK knockdown inhibited the invasion and proliferation of the BT474 TPBC cell line. The findings of this study indicate that TTK overexpression is associated with cancer progression and prognosis in patients with TPBC, whereas TTK knockdown inhibits the invasion and proliferation of TPBC cells. Thus, TTK might serve as a prognostic marker for TPBC.

ER stress mediated­autophagy contributes to neurological dysfunction in traumatic brain injury via the ATF6 UPR signaling pathway.

A major public health problem, traumatic brain injury (TBI) can cause severe neurological impairment. Although autophagy is closely associated with the pathogenesis of TBI, the role of autophagy in neurological deficits is unclear. The purpose of the present study was to investigate the molecular mechanisms of endoplasmic reticulum (ER) stress­induced autophagy and its detrimental effects on neurological outcomes following TBI. A rat model of TBI was established by controlled cortical impact. ER stress activation, autophagy induction and autophagic flux dysfunction were examined in the damaged hippocampus post­TBI. Pharmacological inhibition of ER stress significantly blocked post­traumatic autophagy activation, as evidenced by decreased conversion of microtubule­associated protein 1 light chain 3 (LC3)­I to LC3­II and Beclin­1 expression levels in the hippocampus region. Short hairpin RNA­mediated activating transcription factor 6 knockdown significantly prevented ER stress­mediated autophagy stimulation via targeting essential autophagic genes, including autophagy related (ATG)3, ATG9 and ATG12. Furthermore, neurological scores, foot fault test and Morris water maze were used to evaluate the neurological functions of TBI rats. The results revealed that the blockage of ER stress or autophagy attenuated TBI­induced traumatic damage and functional outcomes. In conclusion, these findings provided new insights into the molecular mechanisms of ER stress­induced autophagy and demonstrated its potential role in neurological deficiency following TBI.

Aristocratic human papillomavirus drove cervical cancer: a study of the therapeutic potential of the combination of interferon with zinc.

Human papillomavirus (HPV) infection is related to cancer growth of vaginal, cervical, vulva, penile, anogenital, and non-genital oropharyngeal sites. HPV, as a sexually transmitted virus, infects all sexes similarly but with more significant pathological risks in women. This accounts for high mortality due to late detection and poor prognosis. The initial development and eventual progress of this cancer type depend entirely on three main oncogenes E5, E6 and E7, constitutively expressed to lead to carcinogenesis. Despite an opportunity for pharmacological therapy, there is still a shortage of medical treatment that may remove HPV from infected lesions. This study offers a concise summary of the nature of the issue and the current status of work on potential lead molecules and therapeutic approaches that show the capacity of HPV therapies to counteract the roles of deregulation of E5, E6, and E7.

Establishment and validation of a nomogram to predict the risk of ovarian metastasis in gastric cancer: Based on a large cohort.

BACKGROUND: Ovarian metastasis is a special type of distant metastasis unique to female patients with gastric cancer. The pathogenesis of ovarian metastasis is incompletely understood, and the treatment options are controversial. Few studies have predicted the risk of ovarian metastasis. It is not clear which type of gastric cancer is more likely to metastasize to the ovary. A prediction model based on risk factors is needed to improve the rate of detection and diagnosis. AIM: To analyze risk factors of ovarian metastasis in female patients with gastric cancer and establish a nomogram to predict the probability of occurrence based on different clinicopathological features. METHODS: A retrospective cohort of 1696 female patients with gastric cancer between January 2006 and December 2017 were included in a single center, and patients with distant metastasis other than ovary and peritoneum metastasis were excluded. Potential risk factors for ovarian metastasis were analyzed using univariate and multivariable logistic regression. Independent risk factors were chosen to construct a nomogram which received internal validation. RESULTS: Ovarian metastasis occurred in 83 of 1696 female patients. Univariate analysis showed that age, Lauren type, whether the primary lesion contained signet-ring cells, vascular tumor emboli, T stage, N stage, the expression of estrogen receptor, the expression of progesterone receptor, serum carbohydrate antigen 125 and the neutrophil-to-lymphocyte ratio were risk factors for ovarian metastasis of gastric cancer (all P < 0.05). Multivariate analysis showed that age ≤ 50 years, Lauren typing of non-intestinal, gastric cancer lesions containing signet-ring cell components, N stage > N2, positive expression of estrogen receptor, serum carbohydrate antigen 125 > 35 U/mL, and a neutrophil-to-lymphocyte ratio > 2.16 were independent risk factors (all P < 0.05). The independent risk factors were constructed into a nomogram model using R language software. The consistency index after continuous correction was 0.840 [95% confidence interval: (0.774-0.906)]. After the internal self-sampling (Bootstrap) test, the calibration curve of the model was obtained with an average absolute error of 0.007. The receiver operating characteristic curve of the obtained model was drawn. The area under the curve was 0.867, the maximal Youden index was 0.613, the corresponding sensitivity was 0.794, and the specificity was 0.819. CONCLUSION: The nomogram model performed well in the prediction of ovarian metastasis. Attention should be paid to the possibility of ovarian metastasis in high-risk populations during re-examination, to ensure early detection and treatment.

Regulation of MYB mediated cisplatin resistance of ovarian cancer cells involves miR-21-wnt signaling axis.

c-MYB has been reported to be elevated in few cancers, including in ovarian cancer. It influences resistance to cisplatin but the details are not very well understood. The objective of this study was to further evaluate role of c-MYB in ovarian cancer's cisplatin resistance. To elucidate the underlying mechanism of cisplatin resistance in ovarian cancer, we focused on the epigenetic regulation by miRNAs. Two cell lines, ES2 and OVCAR3, were used as the model systems. C-MYB expression was either up-regulated or silenced and the resulting effect on cisplatin resistance evaluated, along with the mechanistic role of miR-21, through transfections with pre/anti-miRNAs. An in vivo cisplatin resistance model was also employed to verify findings. High c-MYB correlated with increased miR-21. High c-MYB also resulted in induction of EMT and increased resistance against cisplatin which was attenuated by anti-miR-200s. c-MYB decreased ß-catenin phosphorylation and thus activated wnt signaling. Silencing of c-MYB resulted in reduced miR-21 levels, reduced EMT, reduced cisplatin IC-50s and increased ß-catenin phosphorylation. In an in vivo mice model of cisplatin resistance, c-MYB overexpressing ES2 xenografts were more aggressive than their control counterparts. These c-MYB overexpressing ES xenografts were significantly more resistant to cisplatin but could be sensitized to cisplatin by anti-miR-21. Our results provide a novel mechanism of cisplatin resistance by c-MYB which involves an essential role of miR-21.

Comparing PET/MRI with PET/CT for Pretreatment Staging of Gastric Cancer.

18F-FDG PET/MRI has been applied to the diagnosis and preoperative staging in various tumor types; however, reports using PET/MRI in gastric cancer are rare because of motion artifacts. We investigated the value of PET/MRI for preoperative staging compared with PET/CT in gastric cancer (GC). Thirty patients with confirmed GC underwent PET/CT and PET/MRI. TNM staging for each patient was determined from the PET/MRI and PET/CT images. The diagnostic performance of PET/MRI and PET/CT was calculated compared with the pathologic TNM stage. The two methods were compared using statistical analyses. The accuracy for T staging between PET/MRI and PET/CT was 76.9% vs. 57.7%, respectively. In T1 and T4a staging, the sensitivity and specificity for PET/MRI vs. PET/CT was 1.0 vs. 0.6 and 1.0 vs. 0.8, respectively. The area under the curve (AUC) for PET/MRI vs. PET/CT was 1.00 vs. 0.78 in the T1 stage, 0.73 vs. 0.66 in the T2 stage, 0.72 vs. 0.57 in the T3 stage, and 0.86 vs. 0.83 in the T4 stage. The accuracy for N staging of PET/MRI vs. PET/CT was 53.9% vs. 34.0%, and that for N0 vs. N+ was 85.0% vs. 77.0%. The sensitivity for PET/MRI in N3 staging was 0.67 and 0 for PET/CT. There was a statistically significant difference in the AUC for N1 staging (PET/MRI vs. PET/CT, 0.63 vs. 0.53, p = 0.03). SUVmax/ADC positively correlated with tumor volume and Ki-67. PET/MRI performs more accurately in TNM staging compared with PET/CT and is optimal for accurate N staging. SUVmax/ADC has positive correlations with tumor volume and Ki-67.

Predictive factors for lymph node metastasis and defining a subgroup treatable for laparoscopic lymph node dissection after endoscopic submucosal dissection in poorly differentiated early gastric cancer.

AIM: To investigate the predictive factors of lymph node metastasis (LNM) in poorly differentiated early gastric cancer (EGC); to guide the individual application of a combination of endoscopic submucosal dissection (ESD) and laparoscopic lymph node dissection (LLND) in a suitable subgroup of patients with poorly differentiated EGC. METHODS: We retrospectively analyzed 138 patients with poorly differentiated EGC who underwent gastrectomy with lymphadenectomy between January 1990 and December 2015. The association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. Odds ratios (OR) with 95% confidence interval (95%CI) were calculated. We further examined the relationship between the positive number of the significant predictive factors and the LNM rate. RESULTS: The tumor diameter (OR = 13.438, 95%CI: 1.773-25.673, P = 0.029), lymphatic vessel involvement (LVI) (OR = 38.521, 95%CI: 1.975-68.212, P = 0.015) and depth of invasion (OR = 14.981, 95%CI: 1.617-52.844, P = 0.024) were found to be independent risk factors for LNM by multivariate analysis. For the 138 patients diagnosed with poorly differentiated EGC, 21 (15.2%) had LNM. For patients with one, two and three of the risk factors, the LNM rates were 7.7%, 47.6% and 64.3%, respectively. LNM was not found in 77 patients that did not have one or more of the three risk factors. CONCLUSION: ESD might be sufficient treatment for intramucosal poorly differentiated EGC if the tumor is less than or equal to 2 cm in size and when LVI is absent upon postoperative histological examination. ESD with LLND may lead to the elimination of unnecessary gastrectomy in poorly differentiated EGC.

Timing of surgery after neoadjuvant chemotherapy for gastric cancer: Impact on outcomes.

AIM: To evaluate whether the neoadjuvant chemotherapy (NACT)-surgery interval time significantly impacts the pathological complete response (pCR) rate and long-term survival. METHODS: One hundred and seventy-six patients with gastric cancer undergoing NACT and a planned gastrectomy at the Chinese PLA General Hospital were selected from January 2011 to January 2017. Univariate and multivariable analyses were used to investigate the impact of NACT-surgery interval time (< 4 wk, 4-6 wk, and > 6 wk) on pCR rate and overall survival (OS). RESULTS: The NACT-surgery interval time and clinician T stage were independent predictors of pCR. The interval time > 6 wk was associated with a 74% higher odds of pCR as compared with an interval time of 4-6 wk (P = 0.044), while the odds ratio (OR) of clinical T3vs clinical T4 stage for pCR was 2.90 (95%CI: 1.04-8.01, P = 0.041). In Cox regression analysis of long-term survival, post-neoadjuvant therapy pathological N (ypN) stage significantly impacted OS (N0vs N3: HR = 0.16, 95%CI: 0.37-0.70, P = 0.015; N1vs N3: HR = 0.14, 95%CI: 0.02-0.81, P = 0.029) and disease-free survival (DFS) (N0vs N3: HR = 0.11, 95%CI: 0.24-0.52, P = 0.005; N1vs N3: HR = 0.17, 95%CI: 0.02-0.71, P = 0.020). The surgical procedure also had a positive impact on OS and DFS. The hazard ratio of distal gastrectomy vs total gastrectomy was 0.12 (95%CI: 0.33-0.42, P = 0.001) for OS, and 0.13 (95%CI: 0.36-0.44, P = 0.001) for DFS. CONCLUSION: The NACT-surgery interval time is associated with pCR but has no impact on survival, and an interval time > 6 wk has a relatively high odds of pCR.

Comparison between laparoscopic and open surgery for large gastrointestinal stromal tumors: A meta-analysis.

AIM: To investigate whether laparoscopic surgery is as safe and feasible as open resection for patients with larger gastrointestinal stromal tumors (GISTs) (≥ 5 cm). METHODS: A systematic search of PubMed, EMBASE, Web of Science and the Cochrane Library database was performed. Relevant studies of laparoscopic and open surgery for GISTs of > 5 cm published before December 2016 were identified from these databases. The quality of the studies was assessed by the Newcastle-Ottawa Quality Assessment Scale. The tumor size, operation time, blood loss, postoperative hospital stay, complication rate, and disease-free survival rate were assessed. The software Stata (version 12.0) was used for the meta-analysis. RESULTS: Five clinical trials comprising 209 patients with GISTs of similar larger sizes were evaluated. The pooled analysis of 100 patients in the laparoscopic resection group and 109 patients in the open resection group demonstrated that laparoscopic surgery was significantly associated with a shorter postoperative hospital stay (P < 0.001) and less blood loss (P = 0.002). Moreover, there were no statistically significant differences in the operation time (P = 0.38), postoperative complication rate (P = 0.88), or disease-free survival rate (P = 0.20) between two groups. CONCLUSION: Our findings revealed that for patients with large GISTs of comparable sizes, laparoscopic surgery did not significantly influence the operation factors or clinical outcomes compared with open surgery. This suggests that laparoscopic resection is as acceptable as open surgery for treatment of large gastric GISTs.

RNAi-mediated inhibition of Lgr5 leads to decreased angiogenesis in gastric cancer.

Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is a novel gastric cancer marker. However, it is unclear whether it can play roles in tumor angiogenesis. In this study, we aim to investigate the role of Lgr5 on gastric cancer angiogenesis. Lgr5, VEGF expression levels and microvessel density (MVD) were detected in tumor tissue. Then, Lgr5 mRNA was downregulated by small interference RNA technique. Western blotting and real-time quantitative PCR (qRT-PCR) were performed to detect the expression of Lgr5 and VEGF protein and mRNA in Lgr5 siRNA-transfected gastric cancer cells. The effect of silencing Lgr5 on angiogenesis was examined by assessing human umbilical vein endothelia cell (HUVEC) capillary tube formation. The results indicated that Lgr5 expression was upregulated in gastric cancer and positively correlated with VEGF (r=0.305, P=0.001) and MVD (r=0.312, P=0.001). Silencing of Lgr5 expression resulted in suppression of VEGF mRNA and protein (all P=0.001). Moreover, when HUVECs were stimulated with conditioned medium from Lgr5 siRNA-transfected gastric cancer cells, tube formation was significantly decreased (2.51 ± 0.19 mm/mm2) compared with the treatment with regular cell culture medium (DMEM) (7.34 ± 0.30 mm/mm2) or medium from control siRNA-transfected cells (7.18 ± 0.33 mm/mm2) (all P=0.001). In conclusion, Lgr5 plays important roles in angiogenesis. Lgr5-specific siRNA could be designed into an effective therapeutic agent to inhibit gastric cancer angiogenesis.

Systematic review of anastomotic leakage rate according to an international grading system following anterior resection for rectal cancer.

BACKGROUND: A generally acceptable definition and a severity grading system for anastomotic leakages (ALs) following rectal resection were not available until 2010, when the International Study Group of Rectal Cancer (ISGRC) proposed a definition and a grading system for AL. METHODS: A search for published data was performed using the MEDLINE database (2000 to December 5, 2012) to perform a systematic review of the studies that described AL, grade AL according to the grading system, pool data, and determine the average rate of AL for each grade after anterior resection (AR) for rectal cancer. RESULTS: A total of 930 abstracts were retrieved; 40 articles on AR, 25 articles on low AR (LAR), and 5 articles on ultralow AR (ULAR) were included in the review and analysis. The pooled overall AL rate of AR was 8.58% (2,085/24,288); the rate of the asymptomatic leakage (Grade A) was 2.57%, that of AL that required active intervention without relaparotomy (Grade B) was 2.37%, and that of AL that required relaparotomy (Grade C) was 5.40%. The pooled rate of AL that required relaparotomy was higher in AR (5.40%) than in LAR (4.70%) and in ULAR (1.81%), which could be attributed to the higher rate of protective defunctioning stoma in LAR (40.72%) and ULAR (63.44%) compared with that in AR (30.11%). CONCLUSIONS: The new grading system is simple that the ALs of each grade can be easily extracted from past publications, therefore likely to be accepted and applied in future studies.

A functional variant of NEDD4L is associated with obesity and related phenotypes in a Han population of Southern China.

NEDD4L is a candidate gene for hypertension, both functionally and genetically. Recently, studies showed evidence for the association of NEDD4L with obesity, a key intermediate phenotype in hypertension. To further investigate the relationship between NEDD4L and body mass-related phenotypes, we genotyped three common variants (rs2288774, rs3865418 and rs4149601) in a population-based study of 892 unrelated Han Cantonese using the Sequenom MALDI-TOF-MS platform. Allele frequencies and genotype distribution were calculated in lean controls and overweight/obese cases and analyzed for association by the Chi-squared test and Logistic regression. Linear regression analysis was used to analyze the effect of individual genotypes on quantitative traits. Multivariate analyses demonstrated that the minor allele of rs4149601(A = 20.9%) was associated with a 2.60 kg, 2.78 cm and 0.97 kg/m2 decrease per allele copy in weight, waist and BMI, respectively. Carriers of this allele also had a significant lower risk of overweight/obesity (p < 0.0001, OR = 0.52, 95% CI: 0.37-0.74) as compared to non-carriers. However, no significant association between genotypes at rs2288774 and rs3865418 and covariate-adjusted overweight/obesity or any related phenotypes was observed. These results suggested that the functional variant of NEDD4L, rs4149601, may be associated with obesity and related phenotypes, and further genetic and functional studies are required to understand its role in the manifestation of obesity.