Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry.

Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2ß, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2α and hTop2ß revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break. Herein, we synthesized an organoplatinum compound, etoplatin-N2ß, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2ß more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2ß are practically irreversible. Crystallographic analyses of hTop2ß complexed with DNA and etoplatin-N2ß demonstrate coordinate bond formation between Pt2+ and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt2+ coordination chemistry may allow for the development of potent inhibitors with protein conformation-dependent reversibility. This approach may be exploited to achieve isoform-specific targeting of human Top2s.

Regioselective synthesis and biological evaluation of N-substituted 2-aminoquinazolin-4-ones.

The reaction of methyl anthranilates with N-arylcyanamides in the presence of p-TsOH in t-BuOH under reflux afforded predominantly 3-arylquinazolin-4-ones. In contrast, the reaction of the same reactants with TMSCl in t-BuOH at 60 °C followed by the Dimroth rearrangement in aqueous ethanolic sodium hydroxide gave exclusively the regioisomers, 2-(N-arylamino)quinazolin-4-ones. The regioselective synthesis of N-aryl-substituted 2-aminoquinazolin-4-ones can be further applied to the synthesis of benzimidazo[2,1-b]quinazolin-12-ones.

Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA).

We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30% increased risk of lung cancer (OR 1.3, 95% CI 1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.

Exosomes from umbilical cord mesenchymal stromal cells promote the collagen production of fibroblasts from pelvic organ prolapse.

BACKGROUND: Pelvic organ prolapse (POP) involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity, and vaginal structure is an essential factor. In POP, the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions. The intricate etiology of POP and the prohibition of transvaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development. Human umbilical cord mesenchymal stromal cells (hucMSCs) present limitations, but their exosomes (hucMSC-Exo) are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling. AIM: To investigate the effects of hucMSC-Exo on the functions of primary vaginal fibroblasts and to elucidate the underlying mechanism involved. METHODS: Human vaginal wall collagen content was assessed by Masson's trichrome and Sirius blue staining. Gene expression differences in fibroblasts from patients with and without POP were assessed via RNA sequencing (RNA-seq). The effects of hucMSC-Exo on fibroblasts were determined via functional experiments in vitro. RNA-seq data from fibroblasts exposed to hucMSC-Exo and microRNA (miRNA) sequencing data from hucMSC-Exo were jointly analyzed to identify effective molecules. RESULTS: In POP, the vaginal wall exhibited abnormal collagen distribution and reduced fibroblast 1 quality and quantity. Treatment with 4 or 6 µg/mL hucMSC-Exo suppressed inflammation in POP group fibroblasts, stimulated primary fibroblast growth, and elevated collagen I (Col1) production in vitro. High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11 (MMP11) expression. CONCLUSION: HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression in vitro. Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression. HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.

[Carbon Reduction Analysis of Life Cycle Prediction Assessment of Hydrogen Fuel Cell Vehicles：Considering Regional Features and Vehicle Type Differences].

As one of the important paths for China to achieve the "dual carbon" strategy， developing hydrogen fuel cell vehicles is currently being promoted in various regions across the country， including passenger cars， coaches， and heavy-duty trucks. Quantifying the carbon reduction potential of hydrogen fuel cell vehicles for different vehicle types and regions has become a hot research topic. Using a life cycle assessment method that considers future vehicle fuel economy， power generation carbon emission factors， hydrogen production carbon emission factors， and regional differences in the scale and hydrogen production methods， this study quantitatively evaluated the life cycle carbon emissions of different types of vehicles， including fuel cell vehicles （FCV）， traditional fuel vehicles （ICEV）， and battery electric vehicles （BEV）. We compared and analyzed the carbon reduction potential of hydrogen fuel cell vehicles at different times and in different regions and conducted an uncertainty analysis on hydrogen consumption per hundred kilometers. The results showed that by 2025， the life cycle carbon emissions of hydrogen fuel cell coaches would decrease by 36.0% compared to that of traditional fuel coaches， but the reduction in carbon emissions for hydrogen fuel cell heavy-duty trucks was not significant. By 2035， as the hydrogen energy source structure in China continues to improve， the life cycle carbon emissions of hydrogen fuel cell heavy-duty trucks were predicted to decrease by 36.5% compared to that of traditional fuel heavy-duty trucks. The decarbonization potential was most significant for heavy-duty trucks compared to that of passenger cars and coaches. Taking the Beijing-Tianjin-Hebei demonstration group as an example in 2035， as the hydrogen consumption per hundred kilometers decreases by 20%， the carbon reduction potential of FCV passenger cars， coaches， and heavy-duty trucks would increase by 7.29%， 9.93%， and 19.57%， respectively. Therefore， it is recommended to prioritize the promotion of hydrogen fuel cell coaches in the short term， heavy-duty trucks in the long term， and passenger cars as a supplement. Promoting hydrogen fuel cell vehicles in different regions and stages will help advance the low-carbon development of the automotive industry in China.

Long-term treatment outcomes of transvaginal mesh surgery versus anterior-posterior colporrhaphy for pelvic organ prolapse.

BACKGROUND: In spite of rapid growth in the use of vaginally placed mesh in pelvic reconstructive surgery, there are few reports on the long-term efficacy and safety of mesh-augmented repairs. AIMS: To compare the long-term outcomes of modified pelvic floor reconstructive surgery with mesh (MPFR) versus traditional anterior-posterior colporrhaphy (APC) for the treatment of pelvic organ prolapse (POP). METHODS: This retrospective cohort study involved 158 women who underwent surgical management of prolapse with MPFR (n = 84) or APC (n = 74) in the period between January 2007 and June 2008. Main outcome measures included pelvic organ prolapse quantification measurement, Short Form-20 Pelvic Floor Distress Inventory (PFDI-20), Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ) questionnaires, perioperative outcomes, complications and a personal interview about urinary and sexual symptoms. Statistical analysis included comparison of means (Wilcoxon test or Student's t-test) and proportions (χ(2) test). RESULTS: Anatomical success rate for MPFR and APC was 88.1 versus 64.9% (P = 0.001), with a median follow-up of 55 versus 56 months (range 49-66 months, P = 0.341). Both operations significantly improved quality of life, and a greater improvement was seen in MPFR group than in APC group (P = 0.013). Complication rates did not differ significantly between the two groups. The mesh erosion rate was 3.6%. CONCLUSION: Modified pelvic floor reconstructive surgery with mesh had better anatomical and functional outcomes than APC at 4-5 years postoperation, as an alternative, cheap and effective treatment option to mesh kits for the management of POP.

[Life Cycle Prediction Assessment of Energy Saving and New Energy Vehicles for 2035].

The development of energy saving and new energy vehicles is an important technology path to reduce carbon emissions for the transportation industry. To quantitatively predict the life cycle carbon emissions of energy saving and new energy vehicles, this study used the life cycle assessment method and selected the fuel economy level, lightweight level, carbon emission factor of electricity structure, and carbon emission factor of hydrogen production as key performance parameters to establish inventories of internal combustion engine vehicles (ICEV), mild hybrid electrical vehicles (MHEV), heavy hybrid electrical vehicles (HEV), battery electrical vehicles (BEV), and fuel cell vehicles (FCV) based on automotive-related policy and technical routes. The sensitivity of carbon emission factors of electricity structure and different hydrogen production methods were analyzed and discussed. The results showed that the current life cycle carbon emissions (CO2 equivalent) of ICEV, MHEV, HEV, BEV, and FCV were 207.8, 195.2, 149.9, 113.3, and 204.7 g·km-1, respectively. By 2035, BEV and FCV were predicted to have a significant reduction of 69.1% and 49.3%, respectively, compared with ICEV. The carbon emission factor of electricity structure had the most significant influence on BEV life cycle carbon emissions. In terms of different hydrogen production methods of FCV, hydrogen demand should be mainly supplied by industrial hydrogen by-product purification in the short-term future, whereas hydrogen energy production by water electrolysis and hydrogen production from fossil energy combined with carbon capture, utilization, and storage technology should be used to meet the hydrogen demand of FCV in the long-term future, so as to achieve a significant improvement in the life cycle carbon reduction benefits of FCV.

Alexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability.

Alexander disease is a primary genetic disorder of astrocyte caused by dominant mutations in the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). While most of the disease-causing mutations described to date have been found in the conserved α-helical rod domain, some mutations are found in the C-terminal non-α-helical tail domain. Here, we compare five different mutations (N386I, S393I, S398F, S398Y and D417M14X) located in the C-terminal domain of GFAP on filament assembly properties in vitro and in transiently transfected cultured cells. All the mutations disrupted in vitro filament assembly. The mutations also affected the solubility and promoted filament aggregation of GFAP in transiently transfected MCF7, SW13 and U343MG cells. This correlated with the activation of the p38 stress-activated protein kinase and an increased association with the small heat shock protein (sHSP) chaperone, αB-crystallin. Of the mutants studied, D417M14X GFAP caused the most significant effects both upon filament assembly in vitro and in transiently transfected cells. This mutant also caused extensive filament aggregation coinciding with the sequestration of αB-crystallin and HSP27 as well as inhibition of the proteosome and activation of p38 kinase. Associated with these changes were an activation of caspase 3 and a significant decrease in astrocyte viability. We conclude that some mutations in the C-terminus of GFAP correlate with caspase 3 cleavage and the loss of cell viability, suggesting that these could be contributory factors in the development of Alexander disease.

[Life Cycle Assessment and Key Parameter Comparison of Hydrogen Fuel Cell Vehicles Power Systems].

Hydrogen fuel cell vehicles (HFCVs) are regarded as potential solutions to the problems of energy security and environmental pollution. To explore the energy consumption and pollutant emissions of fuel cell vehicle power systems, data inventories of an HFCV power system were established, and quantitative evaluation calculations and prediction analysis were carried out for fuel life cycle energy consumption and greenhouse gas emissions of Chinese fuel cell vehicles in 2030 based on the technology roadmap for new energy vehicles by modeling with GaBi software. The effects of different types of bipolar plates, different energy control strategies, and different hydrogen production methods on the environment were studied, with uncertainty analysis as the key parameter. The results showed that fossil energy consumption (ADPf), global warming potential (GWP, CO2 equivalent), and acidification potential (AP, SO2 equivalent) for the HFCV power system in the fuel life cycle were 1.35×105 MJ, 9108 kg, and 15.79 kg, respectively. The energy consumption and greenhouse gas emissions in the production of the power system were higher than those in the use stage, mainly because of the fuel cell stack and hydrogen storage tank. In the manufacturing process of metal bipolar plates, graphite composite bipolar plates, and graphite bipolar plates, graphite composite bipolar plates had the most comprehensive environmental benefits. Optimizing the energy control strategy will reduce hydrogen energy consumption. When the hydrogen energy consumption was reduced by 22.8%, the life cycle energy consumption and greenhouse gas emissions of the power system were reduced by 10.4% and 8.3%, respectively. For life cycle power systems, the use of hydrogen from electrolysis operated with water power reduced the GWP by approximately 39.6% relative to steam methane reforming. In contrast, the application of hydrogen from electrolysis operated with the Chinese electricity grid mix resulted in an increase in GWP of almost 53.7%. Measures to reduce fossil energy consumption and global warming potential in the life cycle of fuel cell vehicle powertrains include optimizing energy control strategies to reduce hydrogen energy consumption, scaling up the hydrogen production industry using water electrolysis for renewable energy power generation, and focusing on key technologies of fuel cell stacks to improve performance.

[Comparison outcomes of three surgical procedures in treatment of severe pelvic organ prolapse and analysis of risk factors for genital prolapse recurrence].

OBJECTIVE: To investigate clinical significance and application of modified pelvic floor reconstruction developed by Peking Union Medical College Hospital (MPFR) in treatment of severe pelvic organ prolapse (POP) by comparing the effectiveness, quality of postoperative sexual life, life satisfaction and risk factors for POP recurrence with the following two surgical procedures: traditional total vaginal hysterectomy with anterior-posterior colporrhaphy (TVH-APC) and total vaginal hysterectomy with lateral colporrhaphy and sacrospinous ligament fixation and vaginal bridge repair and episiotomy (TVH-LC-SSLF-VBR-EP). METHODS: Totally 173 patients with severe POP and at least two compartments defects of pelvic floor underwent surgeries in the study, 86 patients (group A) were treated by MPFR with polypropylene mesh application, 58 (group B) were treated by TVH-APC, and 29 patients (group C) were treated by TVH-LC-SSLF-VBR-EP. Peri-operative data and outcomes of postoperative courses at 6, 12, 18 months were collected and analyzed, in the meantime, the risk factors of recurrence were studied. RESULTS: (1) No statistical difference was observed among the above 3 groups in terms of length of operation, amount of blood loss, length of hospital stay, and morbidity after surgery (P > 0.05). (2) Cost hospitalization was (11 448 ± 3049) Yuan in group A, which was significantly higher than (7262 ± 1607) Yuan in group B and (7140 ± 1817) Yuan in group C (P < 0.05). (3) The length of vaginal cuff of (7.5 ± 1.4) cm in group A and (5.6 ± 1.1) cm in group C were significantly longer than (7.1 ± 0.6) cm in group B (P < 0.05). The width of vaginal cuff of (4.3 ± 0.3) cm in group A was larger than (3.4 ± 0.3) cm in group B and (3.3 ± 0.4) cm in group C (P < 0.05). (4) The recurrence rate at 12 months after surgery was 12.8% (11/86) in group A, which was similar with 17.2% (5/29) in group C (P > 0.05) and significantly less than 36.2% (21/58) in group B (P < 0.05). The rate of active sexual life of 16.3% (14/86) in group A was significantly higher than 1.7% (1/58) in group B and 0 in group C (P < 0.05). The index of life quality improvement at 12 months after surgery was 48 ± 12 in group A, which was no less than 53 ± 16 in group C (P > 0.05) and higher than 27 ± 9 in group B (P < 0.05). (5) Mesh rejection was observed in 6 patients in group A within 3 months after surgery, while the posterior vaginal wall was exclusively involved. No difference was found in urinary retention or urinary incontinence among three groups (P > 0.05). (6) The severe degree of POP, type of surgical procedure (TVT-APC), anterior compartment defect of pelvic floor, and early days of performing pelvic floor reconstruction surgeries were high risk factors for POP recurrence (P < 0.05). CONCLUSIONS: MPFR has a better curative effect and lower recurrence rate on patients with POP. It can help patients regain integrity of anatomical structure and functions of pelvic floor. TVH-LC-SSLF-VBR-EP is also effective.

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10-26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10-3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

[Analysis of 96 cases with cesarean scar pregnancy].

OBJECTIVE: To investigate the clinical manifestation, diagnosis, therapies and medical economics of cesarean scar pregnancy (CSP). METHODS: From Jan. 2005 to Dec. 2008, 96 patients with CSP treated in Obstetrics and Gynecology Hospital of Fudan University were studied retrospectively. Those cases were divided into 3 groups. Thirty-three patients were treated with methotrexate (MTX) 50 mg/m(2) intravenously guttae in group A. Among that 18 cases were treated with MTX, after 5-10 days they underwent dilation and curettage of uterus; 15 cases were given by dilation and curettage first if the level of serum human chorionic gonadotrophin-ß (ß-hCG) descent less than 30% in every 48 hours for 3 times after curettage, then MTX (50 mg/m(2)) intravenously guttae. Sixty patients were treated with MTX 100 mg bilateral uterine artery injection and embolization in group B. After 2 days, they underwent curettage. Group C: 3 patients were treated with laparotomy lesion excision. The following clinical parameters were compared, including blood loss (M), lesion diameter (x(-) ± s), blood ß-hCG level (M) before treatment, the number of cases with myometrial thickness anterior to the CSP ≤ 3 mm, the resistant index (RI) ≤ 0.5, expense (x(-) ± s), hospital days (x(-) ± s) in those 3 groups. The correlation of blood loss with lesion diameter and blood ß-hCG level was studied. RESULTS: (1) Clinical manifestation: bleeding loss were 20 ml in MTX + curettage of group A, 10 ml in curettage + MTX of group A, 12 ml in group B and 200 ml in group C. The volume of bleeding loss in group C was significantly higher than those in group A or group B (P < 0.01). The lesion diameter were (23 ± 15) mm in curettage + MTX of group A and (30 ± 14) mm of group B, which were higher than (16 ± 8) mm of MTX + curettage of group A (P < 0.01). The lesion diameter of (52 ± 7) mm in group C were significantly bigger than those in the other groups (P < 0.01). The level of blood ß-hCG levels were 21 592 U/L in MTX + curettage of group A, 979 U/L in curettage + MTX of group A, which reach statistical difference (P < 0.05). The level of blood ß-hCG levels were 11 312 U/L in group B and 101 U/L in group C. Among 28 cases with RI ≤ 0.5, there was 8 cases in group A (24%, 8/33), 18 cases in group B (30%, 18/60) and 2 cases in group C (2/3). Among 23 cases with myometrial thickness anterior to the CSP ≤ 3 mm, there was 21 cases in group B (35%, 21/60), which were significantly higher than 2 in group A (6%, 2/33) and none in group C (P < 0.05). The expense were (5578 ± 3679) yuan in MTX + curettage of group A and (5346 ± 2765) yuan in curettage + MTX of group, which did not reach statistical difference (P > 0.05). The expense were (7860 ± 2104) yuan in group B, which were significantly higher than those in group A and (5004 ± 421) yuan in group C (P < 0.05). The hospital days were (15 ± 8) days and (19 ± 14) days of group A, (16 ± 10) days in group B and (17 ± 8) days in group C, there was no significant difference among those treatments (P > 0.05). (2) Correlation: there was positive correlation between bleeding loss and lesion diameter (r = 0.31, P < 0.05) or blood ß-hCG level (r = 0.35, P < 0.05). CONCLUSIONS: MTX intravenously guttae, MTX uterine artery injection and embolization, and laparotomy lesion excision were all properly used in treatment of CSP. MTX uterine artery injection and embolization was recommended for those with big lesion, high ß-hCG level, less myometrial thickness anterior to the CSP or plentiful blood supply of the lesion but the expense might be high.

Retraction notice to "Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases" [Eur. J. Med. Chem. 190 (2020) 112074].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors. The authors regret to inform that they would like to withdraw this accepted article, due to serious errors in authorship, affiliations, material sources and supporting grant names/numbers. The authors sincerely apologize for these oversights and miscommunications the study caused.

Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases.

A series of thiochromeno[2,3-c]quinolin-12-one derivatives with various substitutions were synthesized and evaluated as topoisomerase (Topo) inhibitors. Six (8, 10, 12, 14, 19, and 26) of 23 compounds showed strong inhibitory activities against Topo-mediated DNA relaxation and proliferation of five human cell lines including breast (MDA-MB-231, MDA-MB-468 and MCF7), colorectal (HCT116) and non-small cell lung (H1299) cancers. Among these, compounds 14 and 26 exhibited full inhibitory activities against Topo I at 3 µM and Topo IIα at 1 µM. Cancer cells treated with 26 accumulated DNA damage and were arrested at the G2/M phase. With time, cells proceeded to apoptosis, as revealed by increased amounts of cells with fragmented DNA and cleavage of caspase-8 and -9. In contrast, normal breast epithelial cells showed low sensitivity to 26. Taken together, our study identifies 26 as a potent Topo dual-inhibitor with low toxicity to normal cells, and elucidates that the terminal amino group of N-2-aminoethylamino or N-3-aminopropylamino at the 6th position and 8,10-di-halogen substituents on thiochromeno[2,3-c]quinolin-12-one are critical for the Topo-inhibiting and cancer-killing activities.

Impact of cooking oil fume exposure and fume extractor use on lung cancer risk in non-smoking Han Chinese women.

Smoking tobacco is the major risk factor for developing lung cancer. However, most Han Chinese women with lung cancer are nonsmokers. Chinese cooking methods usually generate various carcinogens in fumes that may inevitably be inhaled by those who cook the food, most of whom are female. We investigated the associations of cooking habits and exposure to cooking fumes with lung cancer among non-smoking Han Chinese women. This study was conducted on 1,302 lung cancer cases and 1,302 matched healthy controls in Taiwan during 2002-2010. Two indices, "cooking time-years" and "fume extractor use ratio," were developed. The former was used to explore the relationship between cumulative exposure to cooking oil fumes and lung cancer; the latter was used to assess the impact of fume extractor use for different ratio-of-use groups. Using logistic models, we found a dose-response association between cooking fume exposure and lung cancer (odds ratios of 1, 1.63, 1.67, 2.14, and 3.17 across increasing levels of cooking time-years). However, long-term use of a fume extractor in cooking can reduce the risk of lung cancer by about 50%. Furthermore, we provide evidence that cooking habits, involving cooking methods and oil use, are associated with risk of lung cancer.

[Expression of androgen receptor in the vaginal wall and cardinal ligament of patients with pelvic organ prolapse].

OBJECTIVE: To evaluate the role of androgen and its receptor in the pathogenesis of prolapse of pelvic floor. METHODS: Specimens of right cardinal ligament and vaginal wall were collected from 38 patients with prolapse, aged (64 +/- 3) (45 - 79), all menopausal, and 23 women, aged (50 +/- 2)(45-57), with obstetric or gynecologic diseases other than prolapse (as controls), all undergoing total hysterectomy. The 38 prolapse patients were divided into 2 groups: Group > or = 60, aged (66 +/- 6), and Group < 60, aged (52 +/- 5). Western blotting and immunohistochemistry were used to detect the expression of androgen receptor (AR) in the tissues. Peripheral blood samples were collected from all patients to examine the levels of serum testosterone and sex hormone binding globulin (SHBG) by chemiluminescent labeling. RESULTS: There were no significant differences in the serum concentrations of testosterone and SHBG between the prolapse and the control groups. The AR positive rates in the cardinal ligament and vaginal wall tissues of the prolapse patients aged > or = 60 were (49 +/- 15)% and (49 +/- 10)% respectively, both not significantly different from those of the control group [(43 +/- 15)% and (42 +/- 3)% respectively, both P > 0.05]. ears, The AR expression rates in the tissues of cardinal ligament and vaginal wall of the prolapse patients were (42 +/- 3)% and (43 +/- 15)% respectively, both significantly higher than those of the control group [(29 +/- 7)% and (29 +/- 6)% respectively, both P < 0.001]. Western blotting showed that the positive rate of the AR with the relative molecular weight of 45 000 in the cardinal ligament of the prolapse group was 4.41%, significantly higher than that of the control group (2.1%, P = 0.02), however, the positive rate of the AR with the relative molecular weight of 45 000 in the vaginal wall tissue of the prolapse group was 3.34%, not significantly different from that of the control group (2.28%, P = 0.2). There were no significant differences in the in the straps of 110 000 and 90 000 detected by C-terminal polyantibodies of AR in the cardinal ligament and vaginal wall tissues between the prolapse patients and the control group (both P > 0.05). CONCLUSION: The increasing expression of AR in the tissue of vaginal wall and cardinal ligament of the prolapse patients with pelvic floor dysfunction may play an important role in the etiology of pelvic floor dysfunction.

Management of Urinary Incontinence before and after Total Pelvic Reconstruction for Advanced Pelvic Organ Prolapse with and without Incontinence.

BACKGROUND: The effectiveness of an anti-incontinence procedure concomitant with prolapse reconstruction for pelvic organ prolapse (POP) in preventing urinary incontinence (UI) after surgery remains controversial. Our study aimed to describe the incidence of pre- and postoperative UI for pelvic reconstructive surgery and evaluate the management of POP associated with UI. METHODS: A total of 329 patients who underwent total pelvic reconstruction between June 2009 and February 2015 at a single institution were identified. These patients were divided into two groups (Group A [Prolift reconstruction]: n = 190 and Group B [modified total pelvic reconstruction]: n = 139). Data regarding surgical procedures and patient demographic variables were recorded. Chi-square and Student's t-tests were used for two independent samples. RESULTS: A total of 115 patients presented with UI preoperatively. The average follow-up time was 46.5 months, with 20 patients lost to follow-up (6.1%). The cure rates of stress UI (SUI), urgency UI (UUI), and mixed UI (MUI) were 51% (30/59), 80% (16/20), and 48% (14/29), respectively. The cure rate of UUI after total pelvic reconstruction (80% [16/20]) was higher than that of SUI (50.8% [30/59], χ2 = 5.219, P = 0.03), and the cure rate of MUI (48%, 14/29) was the lowest. The cure rate of patients with UI symptoms postoperatively was lower than that of those with symptoms preoperatively (9.1% [28/309] vs. 16.2% [50/309], χ2 = 7.101, P = 0.01). There was no difference in the incidence of UI postoperatively between Groups A and B (P > 0.05). The cure rate of SUI in patients undergoing tension-free vaginal tape-obturator was not higher than that in those who did not undergo the procedure (42.9% [6/14] vs. 53.3% [24/45], χ2 = 0.469, P = 0.49). There were no differences in the cure rate for POP or UI between these two types of reconstructions (P > 0.05). CONCLUSIONS: No correlation between the incidence of UI and POP was identified. The results suggest that UI treatment should be performed after POP surgery for patients with both conditions.

Advanced glycation end products decrease collagen I levels in fibroblasts from the vaginal wall of patients with POP via the RAGE, MAPK and NF-κB pathways.

The present study was carried out to observe the impact of advanced glycation end products (AGEs) on collagen I derived from vaginal fibroblasts in the context of pelvic organ prolapse (POP), and explore the downstream effects on MAPK and nuclear factor-κB (NF-κB) signaling. After treating primary cultured human vaginal fibroblasts (HVFs) derived from POP and non-POP cases with AGEs, cell counting was carried out by sulforhodamine B. The expression levels of collagen I, receptor of advanced glycation end products (RAGE), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were detected by western blot analysis and PCR. RAGE, MAPK and NF-κB were molecularly and pharmacologically-inhibited by siRNA, SB203580 and PDTC, respectively, and downstream changes were detected by western blot analysis and PCR. Inhibition of HVF proliferation by AGEs occurred more readily in POP patients than that noted in the controls. After treatment with AGEs, collagen I levels decreased and MMP-1 levels increased to a greater extent in the HVFs of POP than that noted in the controls. During this same period, RAGE and TIMP-1 levels remained stable. Following treatment with AGEs and RAGE pathway inhibitors by siRNA, SB203580 and PDTC, the impact induced by AGEs was diminished. The inhibition of p-p38 MAPK alone was not able to block the promoting effect of AGEs on the levels of NF-κB, which suggests that AGEs may function through other pathways, as well as p-p38 MAPK. On the whole, this study demonstrated that AGEs inhibited HVF proliferation in POP cases and decreased the expression of collagen I through RAGE and/or p-p38 MAPK and NF-κB-p-p65 pathways. Our results provide important insights into the collagen I metabolism in HVFs in POP.

Midterm prospective comparison of vaginal repair with mesh vs Prolift system devices for prolapse.

OBJECTIVE: To compare midterm clinical outcome using modified pelvic floor reconstructive surgery with mesh (MPFR) vs Prolift devices for the treatment of pelvic organ prolapse (POP). STUDY DESIGN: This prospective observational cohort study involved 223 women with POP stages III-IV who were assigned to either MPFR (n=131) or Prolift device (n=92). Outcomes were analyzed at 6 and 12 months and the last follow-up visit postoperatively. Main outcome measures included pelvic organ prolapse quantification measurement, Short Form-20 Pelvic Floor Distress Inventory (PFDI-20), Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ) questionnaires, perioperative outcomes, complications, and a personal interview about urinary and sexual symptoms. Statistical analysis included comparison of means (Wilcoxon test or Student's t-test) and proportions (Chi-square test). Multivariate analysis was carried out using Cox proportional hazard model. RESULTS: At follow-up (median, 36 months; range, 17-58 months), anatomic success for MPFR and Prolift was 87.07% and 93.41%, respectively (P=0.1339). Both operations significantly improved quality of life, and PFDI-20 scores were lower in the Prolift group than the MPFR group (P=0.03). Complication rates did not differ significantly between the two groups and the prevalence of urinary symptoms decreased postoperatively in both groups. The cost of operation, however, was RMB ¥11,882.86 yuan for MPFR and ¥23,617.59yuan for Prolift (P=0.00). CONCLUSIONS: MPFR and Prolift had comparable anatomic outcomes, Prolift had better functional outcomes than MPFR, but MPFR is much cheaper than Prolift. MPFR is an alternative, cheap and effective surgical treatment option to mesh-kits for the management for POP.