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Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles.Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining.We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423GA (p.Leu141=) and c.839+5GA variants impaired the normal splicing of TBX6 messenger RNA, c.422TC (p.Leu141Pro) and c.745GA (p.Val249Met) led to decreased protein expression, c.10CT (p.Pro4Ser) and c.400GA (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356GA (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance.Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.

Müllerian anomaly (M.A.) is a group of congenital anatomic abnormalities caused by aberrations of the development process of the Müllerian duct. M.A. can either be isolated or be involved in Mendelian syndromes, such as Dandy-Walker syndrome, Holt-Oram syndrome and Bardet-Biedl syndrome, which are often associated with both uterus and kidney malformations. In this study, we applied a genotype-first approach to analyze the whole-exome sequencing data of 492 patients with M.A. Six potential pathogenic variants were found in five genes previously related to female urogenital deformities (PKD1, SON, SALL1, BMPR1B, ITGA8), which are partially overlapping with our patients' phenotypes. We further identified eight incidental findings in seven genes related to Mendelian syndromes without known association with reproductive anomalies (TEK, COL11A1, ANKRD11, LEMD3, DLG5, SPTB, BMP2), which represent potential phenotype expansions of these genes.

With the rapid increase in sea cucumber aquaculture productions, numerous environmental pollution challenges have emerged in China. It is necessary to implement Cleaner Production (CP) assessment in sea cucumber aquaculture industry to facilitate sustainable development. CP indicator system could be a useful reference resource for enterprises to implement CP strategy and select appropriate CP technologies. Therefore, a CP indicator system was established for the first time in sea cucumber aquaculture industry and the suitability of production area as a first-grade indicator was first incorporated into the CP assessment framework in this study. Two enterprises as case studies in Dalian, China, were selected, and a synthetic assessment model was developed using Delphi method, analytic hierarchy process, and fuzzy comprehensive evaluation method. The results show that two enterprises are at a CP average level while that of enterprise X is higher than that of enterprise Y. Moreover, the detailed CP improvement measures for two enterprises were proposed based on the assessment results. The works in this study could provide a useful reference to implement CP in sea cucumber aquaculture industry and other aquaculture industries in China.

To investigate the artificial vaginal microecological features in patients who underwent laparoscopic peritoneal vaginoplasty. 54 cases of patients with artificial vagina after laparoscopic peritoneal vaginoplasty were included in this study. Microecosystem evaluation was performed. Artificial vaginal functional tests and biopsy from vaginal walls were performed. After laparoscopic peritoneal vaginoplasty, the artificial vaginal flora intensity was level II∼III (88.9%); the vaginal flora diversity was level II∼III (72.2%); the predominant vaginal bacteria were gram-positive macrobacillus (27.8%); approximately 57.4% of the patients had vaginal pH ≤ 4.5; there was no pathogenic bateria or other pathogens; dysbiosis accounted for 53.7% of the patients (64.5% of the patients who had the vaginoplasty operation less than 2 years ago exhibited dysbiosis; 39.1% of the patients who had the operation at least 2 years ago exhibited dysbiosis). Vaginal dysbiosis is common after laparoscopic peritoneal vaginoplasty. However, as time goes by, the artificial vaginal microecological condition gradually becomes normal. Evaluation of vaginal microenvironment after laparoscopic peritoneal vaginoplasty might play an important role in reproductive tract infection prevention and neovagina health care.

Environmental pollution caused by aquaculture production has become an increasing problem in China. In the present study, life cycle assessment (LCA) was used to evaluate and analyze the environmental impact of sea cucumber (Apostichopus japonicas) production in Dalian as an example for Chinese aquaculture cleaner production (CP) research. The production process included three stages: feeding, farming, and processing. In addition, to analyze the key factors that influence the environmental performance, the feeding stage was divided into breeding and culturing phases; the farming stage was divided into planting and harvesting phases; and the processing stage comprised sorting, stewing, salting, and freezing phases. The popular LCA software tool GaBi and the CML-2001 method for a problem-oriented approach to LCA were used to calculate the environmental impact at each stage and phase of the sea cucumber production process. The results showed that the normalization results of LCA in the three stages were 1.21 E−08 yr, 2.44 E−10 yr, and 1.11 E−09 yr, respectively. The feeding stage had the greatest environmental impact, because high levels of electricity, fossil fuel, and water are required to maintain the culturing water temperature and oxygen status for juvenile sea cucumbers. Moreover, from the analysis of the LCA normalization results in each phase, we found that the marine aquatic ecotoxicity potential (MAETP) was the largest contributor to the environmental impact, with electricity use, water requirements, and fossil fuel consumption as the key factors that affected the results. Improvement measures toward CP in each stage were proposed, such as energy substitution (nuclear energy, natural gas, or solar-energy), water reduction (microecologics), and bio-waste management (bio-waste recycling). These measures will provide a reference for policy makers and enterprise managers to enact strategies to improve the sustainability of Chinese aquaculture.

Background Cervical cancer (CC) is one of the leading causes of mortality worldwide. Previously, we reported that blueberry extract constrains the growth of CC. Raspberry is a widely consumed fruit that exhibits antitumor properties against several cancer types but little is known about its direct effect on CC. This study was designed to investigate the potential antitumor effect of raspberry extract (RE) on CC cells and to elucidate the possible mechanisms behind it. Materials and methods Clonogenic survival assay and caspase-3 activity kits were used to evaluate the effects of RE on cell survival, proliferation, and apoptosis of a widely used CC cell line, HeLa. Possible molecular mechanisms were investigated using reverse transcription-polymerase chain reaction. Results The percentage of colonies and optic density value of HeLa cells decreased in the presence of RE in comparison to controls. Relative caspase-3 activity in cancer cells increased in the presence of RE in comparison to controls. The antitumor effect displayed on HeLa cells by RE was associated with the increased expression of antiproliferative molecule P53 and the increased expression of pro-apoptotic molecule tumor necrosis factor receptor superfamily member 6 (FAS). Conclusion RE displays anticancer activity against CC HeLa cells. The mechanism behind this is by up-regulation of anti-proliferative molecule P53 and pro-apoptotic molecule FAS.

The textile industry has a high environmental impact, discharging significant amounts of industrial water, consuming high levels of energy, and emitting vast amounts of air pollutants. To meet the requirement of sustainable manufacturing, we built a system-oriented improved design framework based on life cycle assessment (LCA) for an existing polyester–cotton production system to reduce the environmental impacts of the production process. LCA was used to identify candidates for best available technology (BAT) development. The effect of the BATs on environmental, economic, and product performance was evaluated. LCA identified that polyester–cotton production exerted the greatest environmental impacts on marine aquatic ecotoxicity potential, global warming potential, and abiotic depletion. The printing and dyeing stages of the production process were the most damaging to the environment. Six BATs were proposed and all were feasible with clear economic and environmental benefits, as the resource depletion, ecological influence, and human health values were reduced by 50.13, 50.08, and 7.65%, respectively, compared with the existing process. In addition, the quality of the products, such as color fastness and color shade, was greatly improved. We suggest that future studies should also take into consideration the distribution and use stage using accurate and representative original data, to further improve the sustainability of the production process. Human health, fertilizer leakage, land use, and pesticides should also be taken into account within the life cycle of textiles.

Objective To evaluate the outcomes of laparoscope-assisted peritoneal vaginoplasty for the treatment of congenital vaginal atresia. Methods A retrospective study enrolled patients diagnosed with congenital vaginal atresia who were treated with one of two different laparoscope-assisted peritoneal vaginoplasty techniques (named Luohu-one and Luohu-two) between October 31, 2001 and December 31, 2014. Operative time, intraoperative bleeding volume, surgical difficulty, complications, and post-procedure sexual satisfaction were reported. Results Data were collected for 620 patients. The Luohu-one procedure was used in the treatment of 145 patients, while 475 patients were treated with the Luohu-two procedure. In 5 (0.8%) patients, it was necessary to perform a sigmoid colon vaginoplasty. During surgery, 16 patients experienced a rectal injury, among whom, 9 patients experienced a rectal–vaginal fistula. Follow-up data extending to 7 years were available for 285 patients. Of these 285 patients, 231 agreed to report details of their sexual experiences. In total, 222 (96.1%) patients reported being very satisfied with their vaginal conditions and sex life. The Luohu-two procedure demonstrated shorter operative and recovery time, and reduced intraoperative bleeding. However, both procedures demonstrated satisfactory results. Conclusion Laparoscope-assisted peritoneal vaginoplasty demonstrated good safety and effectiveness in the treatment of patients with congenital vaginal atresia.

China has proposed to use ethanol instead of methyl tert-butyl ether (MTBE) as a gasoline additive, with full compliance planned for 2020. At present, previous studies on gasoline additive focus almost exclusively on effects of fuel performance and engine, however, the environmental impact production and use of additives cannot be ignored. Herein, we use the life cycle assessment (LCA) method, the environmental effects of E10 (10% maize ethanol and 90% gasoline, v/v) and M10 (10% MTBE and 90% gasoline, v/v) were evaluated and compared. Quantifying the net environmental benefits of implementing this national policy from a life cycle perspective. The results showed that the environmental impact of E10 was 15.4% lower than that of M10. Thus, replacing MTBE with ethanol reduces the total environmental impact. However, there were some negative environmental impacts such as waste solids and water use. Finally, we propose further improvements to make E10 more environmentally friendly.

Interleukin-33 (IL-33), a damage-associated molecular pattern molecule, is a cytokine within the IL-1 interleukin family that binds to the plasma membrane receptor suppression of tumorigenicity 2 on numerous cell types. IL-33 has been extensively studied in its role in autoimmune diseases, host responses to pathogens and allergens, and has been associated with tumorigenic effects in cancer research. The present study was performed to investigate the effects of IL-33 on colon cancer cells, based off the previous data that have demonstrated an anti-tumor effect of IL-33 on pancreatic cancer cells. The effects of IL-33 on proliferation, cell survival and apoptosis on human HCT-116 colon cancer cells were examined using clonogenic survival assays, proliferation and caspase-3 activity kits, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and immunocytochemistry. It was determined that the HCT-116 cells demonstrated an notable decrease in optical density value upon incubation with IL-33, along with a decrease in the number of colonies, compared with the controls. It was further determined that the anti-proliferative effect of IL-33 on HCT-116 cells was associated with downregulation of the pro-proliferative molecules cyclin B, cyclin D and cyclin dependent kinase 2. An apoptosis-inducing effect of IL-33 on HCT-116 cells was associated with downregulation of the anti-apoptotic molecules Flice-like inhibitory protein and B-cell lymphoma 2. Taken together, the results indicated that IL-33 inhibits the growth of colon cancer by suppressing cellular proliferation, whilst simultaneously promoting apoptosis.

Background IL-9 is a pleiotropic cytokine produced mainly by Th9 cells. IL-9 may have an anti-proliferative role in murine melanoma, however, its effect on human melanoma is unknown. Methods We examined the effects of IL-9 on proliferation and apoptosis in four human melanoma cell lines, HTB-65, HTB-72, CRL-11147, and SK-Mel-5. Clonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining and caspase-3 activity assay were used to assess proliferation and apoptosis, as appropriate. Results We found that IL-9 decreased the percentage of colonies of HTB-72 and SK-Mel-5 cells but not that of HTB-65 or CRL-11147 cells. PCNA mRNA, PCNA+ cells, PCNA staining intensity, and the OD value of HTB-72 melanoma cells were consistently decreased in the present of IL-9. IL-9 also increased TUNEL+ cells and the relative caspase-3 activity in HTB-72 melanoma cells. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. The anti-proliferative effect of IL-9 on HTB-72 cells correlated with higher expression of anti-proliferative molecule p21. Its pro-apoptotic effect on HTB-72 cells correlated with higher expression of the pro-apoptotic molecule TRAIL. Conclusions IL-9 inhibits melanoma HTB-72 cell growth by upregulation of p21 and TRAIL. Understanding the interactions between IL-9 and melanoma may help direct strategies for cytokine-based immunotherapy development. J. Surg. Oncol. 2015 111:969–974. © 2015 Wiley Periodicals, Inc.

Ovarian cancer is the leading cause of cancer‑ associated mortality in the female reproductive system. Interleukin (IL)‑33 and its receptor IL 1 receptor like 1 (also termed ST2) are expressed by many cell types including epithelial cells. The role of IL‑33 in the pathogenesis of neoplasia remains controversial. The authors previously demonstrated that IL‑33 inhibits the growth of pancreatic cancer cells. The present study was performed to explore if IL‑33 has any direct effects on ovarian cancer cells. A clonogenic survival assay, immunohistochemistry (IHC), proliferation kit and caspase‑3 activity kit were all used to evaluate the direct effects of IL‑33 on cell proliferation and apoptosis of a widely studied ovarian cancer cell line, A2780. The possible molecular mechanisms were further evaluated with reverse transcription‑polymerase chain reaction and IHC. It was demonstrated that the percentage of colonies and the optical density value of cancer cells were all increased in the presence of IL‑33; however, the relative caspase‑3 activity in cancer cells was decreased in the presence of IL‑33. Molecular mechanism studies revealed that the pro‑proliferative effect of IL‑33 on cancer cells was associated with decreased levels of p27, and the anti‑apoptotic effect of IL‑33 was associated with levels of Fas cell surface death receptor (Fas) and tumor necrosis factor‑related apoptosis‑inducing ligand receptor 1 (TRAILR1). Therefore, IL‑33 promoted proliferation and inhibited apoptosis of ovarian cancer cells by downregulation of p27, Fas and TRAILR1. Contrary to previous studies demonstrating an anti‑tumor effort in pancreatic cancer, the results of the present study indicated that IL‑33 exhibited a significant onco‑promoting effect on ovarian cancer. Accordingly, the inhibition of IL‑33 may be a promising therapeutic strategy for ovarian cancer.

IL-33 is a member of the IL-1 family of cytokines, and no study has been performed to address its direct anti-tumor effect. This study is designed to investigate whether IL-33 has any direct effect on pancreatic cancer. Clonogenic survival assay, immunohistochemistry, TUNEL staining, proliferation, caspase-3 activity kits and RT-PCR were used to evaluate the effects of IL-33 on cell survival, proliferation and apoptosis of a pancreatic cancer cell line, MIA PaCa-2. We found that the percentage of colonies of MIA PaCa-2 cells, PCNA+ cells and the OD value of cancer cells were all decreased in the presence of IL-33. TUNEL+ cells and the relative caspase-3 activity in cancer cells were increased in the presence of IL-33. We further found that its anti-proliferative effect on cancer cells correlated with downregulation of pro-proliferative molecules cdk2 and cdk4 and upregulation of anti-proliferative molecules p15, p21 and p53. Its pro-apoptotic effect correlated with downregulation of anti-apoptotic molecule FLIP and upregulation of pro-apoptotic molecule TRAIL. These results suggest that IL-33 presents significant anti-tumor effects by inhibition of proliferation and induction of apoptosis of MIA PaCa-2 pancreatic cancer cells. Thus, strength of IL-33/ST2 signal pathway might be a promising way to treat pancreatic cancer.

IL-9 is a pleiotropic cytokine produced mainly by Th9 cells. IL-9 may have an anti-proliferative role in murine melanoma, however, its effect on human melanoma is unknown.We examined the effects of IL-9 on proliferation and apoptosis in four human melanoma cell lines, HTB-65, HTB-72, CRL-11147, and SK-Mel-5. Clonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining and caspase-3 activity assay were used to assess proliferation and apoptosis, as appropriate.We found that IL-9 decreased the percentage of colonies of HTB-72 and SK-Mel-5 cells but not that of HTB-65 or CRL-11147 cells. PCNA mRNA, PCNA+ cells, PCNA staining intensity, and the OD value of HTB-72 melanoma cells were consistently decreased in the present of IL-9. IL-9 also increased TUNEL+ cells and the relative caspase-3 activity in HTB-72 melanoma cells. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. The anti-proliferative effect of IL-9 on HTB-72 cells correlated with higher expression of anti-proliferative molecule p21. Its pro-apoptotic effect on HTB-72 cells correlated with higher expression of the pro-apoptotic molecule TRAIL.IL-9 inhibits melanoma HTB-72 cell growth by upregulation of p21 and TRAIL. Understanding the interactions between IL-9 and melanoma may help direct strategies for cytokine-based immunotherapy development.

Radiation therapy plays a critical role in women with advanced-stage cervical cancer worldwide, particularly in developing countries, and most of the time it may be the only available treatment. The efficacy of radiation largely depends on the radiosensitivity of the tumor. The high radiation dose associated with therapy for cervical cancer may have severe side-effects and low-dose radiation has little effect on cervical cancer. A safe and effective radiosensitizing agent is required to allow reduction of radiation doses used and of side-effects associated with radiation for cervical cancer. In recent years, great knowledge has been gained about the effects of apoptosis, cyclo-oxygenases, angiogenesis, hypoxia and temperature on radiation, making it possible to manipulate the radiation response of cervical cancer to achieve a better treatment outcome. In this mini review, some of these factors associated with the radiosensitivity of cervical cancer are discussed.

Interleukin-35 (IL-35), an IL-12 cytokine family member, mediates the immune inhibitory function of regulatory T cells (Treg). We assayed the presence of IL-35 in paraffin-embedded human pancreas cancer (PCAN) and unexpectedly found IL-35 was expressed mainly by epithelial derived PCAN cells, but not by Treg. We further examined the expression and effect of exogenous IL-35 in human PCAN cell lines and found IL-35 promoted growth and inhibited apoptosis in PCAN cell lines. IL-35 induced proliferation correlated with an increase in cyclin B, cyclin D, cdk2, and cdk4 and a decrease in p27 expression, while inhibition of apoptosis was associated with an increase in Bcl-2 and a decrease in TRAILR1. We conclude IL-35 is produced by PCAN in vivo and promotes PCAN cell line growth in vitro. These results might indicate an important new role for IL-35 as an autocrine growth factor in PCAN growth.