Leukocyte Telomere Length and the Risk of Prostate Cancer and Benign Prostatic Hyperplasia: Insights From UK Biobank and Mendelian Randomization Study.

BACKGROUND: Previous observational studies have been controversial regarding the association of leukocyte telomere length (LTL) with prostate cancer (PCa) and benign prostatic hyperplasia (BPH). METHODS: First, we conducted an observational study utilizing UK Biobank data. The correlation between LTL and the risk of PCa and BPH was evaluated via multivariate-adjusted logistic regression. Then, we conducted a 2-sample Mendelian randomization to examine causal links between LTL (472 174 individuals) and PCa as well as BPH. To verify the reliability of the primary analysis, we conducted a second analysis and sensitivity analyses. RESULTS: In the UK Biobank study, individuals in the longer quartiles of LTL were observed to have a higher risk of PCa (1.155-fold to 1.349-fold, all p < .001) and BPH (1.119-fold to 1.212-fold, all p < .001) compared to those in the lowest quartile in multivariate-adjusted logistic regression. We observed that genetically predicted longer LTL resulted in a 1.427-fold risk of PCa (odds ratio [OR] = 1.427, 95% confidence interval [CI] = 1.197-1.702, p < .001) and 1.539-fold risk of BPH (OR = 1.539, 95% CI = 1.387-1.707, p < .001) in the primary analysis. In the second analysis, the results also indicated that longer LTL increased the genetic liability to both PCa (OR = 1.338, 95% CI = 1.189-1.507, p < .001) and BPH (OR = 1.006, 95% CI = 1.003-1.008, p < .001). Sensitivity analyses also supported the reliability of the results. CONCLUSIONS: Our study provides convincing evidence supporting that longer LTL increases the risk of PCa and BPH in European individuals. Large-scale studies are needed to elucidate the potential mechanisms of LTL in PCa and BPH occurrence.

The causal effect of metabolic syndrome and its components on benign prostatic hyperplasia: A univariable and multivariable Mendelian randomization study.

BACKGROUND: Previous observational studies have indicated that metabolic abnormalities are associated with benign prostatic hyperplasia (BPH). The limitations of the research methodology of observational studies do not allow causal inference to be drawn; however, Mendelian randomization (MR) can clarify this. METHODS: Using summary-level data from genome-wide association studies, we conducted a two-sample MR study to examine the causality of the metabolic syndrome (MetS) and its components on BPH (26,358 BPH cases and 110,070 controls). The random-effects inverse-variance weighted was employed as the primary method for MR analyses. RESULTS: We observed that genetically predicted waist circumference (WC) (odds ratio [OR] = 1.236, 95% confidence interval [CI]: 1.034-1.478, p = 0.020) and diastolic blood pressure (DBP) (OR = 1.011, 95% CI: 1.002-1.020, p = 0.020) were significantly positively associated with BPH risk. We did not identify a causal effect of MetS (OR = 0.975, 95% CI: 0.922-1.031, p = 0.375), systolic blood pressure (OR = 1.004, 95% CI: 0.999-1.008, p = 0.115), triglycerides (OR = 1.016, 95% CI: 0.932-1.109, p = 0.712), high-density lipoprotein (OR = 1.005, 95% CI: 0.930-1.086, p = 0.907), and fasting blood glucose (OR = 1.037, 95% CI: 0.874-1.322, p = 0.678) on BPH. In the multivariable MR analysis, we observed that the risk effect of DBP (OR = 1.013, 95% CI: 1.000-1.026, p = 0.047) on BPH persisted after conditioning with WC (OR = 1.132, 95% CI: 0.946-1.356, p = 0.177). CONCLUSIONS: Our study provides genetic evidence supporting the causal effect of DBP on BPH, although the effect of WC needs to be further validated.

[Research progress on mechanism and preventive measures of retrograde ejaculation after benign prostatic hyperplasia surgery].

Benign prostatic hyperplasia (BPH) is a common disease in middle-aged and elderly men. It's first-line therapy is drugs. But with the progression of the disease or side effects of drugs, surgical treatment will become a better choice. However, either transurethral resection of the prostate, the standard procedure, or enucleation or resection of the prostate based on various laser platforms or plasma technologies cause a high incidence of retrograde ejaculation in their postoperative follow-up. In the past, retrograde ejaculation was usually regarded as the cost of benign prostatic hyperplasia surgery. In recent years, with the continuous improvement of surgical skills and the emergence of new techniques, retrograde ejaculation has aroused the attention of clinicians. This article mainly introduces the mechanism of retrograde ejaculation after benign prostatic hyperplasia surgery and the methods to reduce the incidence of retrograde ejaculation after surgery. These methods mainly include various modified surgery, as well as novel minimally invasive techniques such as prostate embolization and prostatic urethral lift.

Ultrathin fluoroacrylic coating wrapped microporous non-woven fabrics as efficient air filtration membranes.

Ultrathin fluoroacrylic emulsion coating wrapped effective microporous non-woven air filtration membranes of 0.2 µm thickness were made for PPE masks with up to 99.9% filtration efficiencies for both 0.3 µm NaCl aerosol particles and oily DEHS aerosols. An ultrasonic dip-coating process was applied for the controllable formation of a nano-protrusion morphology on the fiber surface.

The Efficacy and Safety of Dingkun Pill in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective: Dingkun Pill (DKP) is a proprietary Chinese medicine that has been utilized for patients with gynecological diseases, and its clinical application has been widely accepted in China. However, the effects of DKP on reproduction and metabolism in women with polycystic ovary syndrome (PCOS) have never been systematically evaluated. Our objective was to evaluate the efficacy and safety of DKP in treating reproductive and metabolic abnormalities with PCOS. Methods: We searched in PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, VIP Database, and Chinese Biomedical Literature Database up until January 2022 to identify randomized controlled trials (RCTs). The methodological quality of the included RCTs was estimated using the Cochrane collaboration risk-of-bias instrument, and the meta-analysis was performed using RevMan. Results: A total of 22 RCTs (including 1994 participants) were identified. DKP, combined with ovulation-inducing drugs (OID) or combined oral contraceptives (COC) was superior to OID or COC alone in improving the pregnancy rate (relative risk (RR) 1.84, 95% CI 1.62 to 2.11 and RR 1.38, 95% CI 1.16 to 1.64, respectively), ovulation rate (RR 1.38, 95% CI 1.03 to 1.84 and RR 1.23, 95% CI 1.11 to 1.37, respectively), endometrial thickness (weighted mean difference (WMD) 2.50, 95% CI 1.91 to 3.09 and WMD 0.62, 95% CI 0.08 to 1.16, respectively), luteinizing hormone (WMD -1.93, 95% CI -2.80 to-.07 and WMD -1.79, 95% CI -2.66 to-0.92, respectively), and testosterone (standardized mean difference (SMD) -2.12, 95% CI -3.01 to-1.24 and SMD -1.21, 95% CI -1.64 to-0.78, respectively). DKP combined with COC led to a greater improvement in homeostasis model assessment-ß (WMD 20.42, 95% CI 16.85 to 23.98) when compared with COC alone. There was a significant difference between DKP and COC in terms of decreasing total cholesterol (WMD -0.37, 95% CI -0.72 to-0.02), triacylglycerol (WMD -0.85, 95% CI -1.50 to-0.20), and free fatty acid (WMD -130.00, 95% CI -217.56 to-42.22). However, DKP did not affect the follicle stimulating hormone, fasting blood glucose, fasting insulin, body mass index, waist-to-hip ratio, high-density lipoprotein cholesterol, or low-density lipoprotein cholesterol. Adverse reactions were more common in COC alone compared to DKP and COC in combination (RR 0.22, 95% CI 0.07 to 0.63). Conclusion: DKP shows promise in modifying reproductive and metabolic parameters in patients with PCOS and may be used as a primary choice in conventional or complementary therapies for PCOS. The quality of the evidence analyzed was suboptimal, and therefore, our results should be interpreted cautiously. More prospective large-scale and well-designed RCTs, as well as longer intervention durations are required in the future to draw more reliable conclusions.

Requirement of a putative mitochondrial GTPase, GemA, for azole susceptibility, virulence, and cell wall integrity in Aspergillus fumigatus.

Drug resistance in fungal pathogens is a new challenge in clinical aspergillosis treatment. Mitochondria as dynamic organelles are involved in numerous biological processes in fungi, including drug resistance. However, little is known about the mechanism underlying mitochondrial regulation of the response of fungal pathogens to antifungal drugs. Here, we showed that a putative mitochondrial GTPase, GemA, a yeast Gem1 homolog, is crucial for the azole response and cell wall integrity in the opportunistic pathogen Aspergillus fumigatus. The fluorescence observation showed that GFP-labeled GemA is located in mitochondria, and loss of gemA results in aberrant giant mitochondrial morphology and abnormal mitochondrial membrane potential. Moreover, a ΔgemA mutant attenuates fungal virulence in the Galleria mellonella model of aspergillosis. Furthermore, gemA loss increases resistance to azoles and terbinafine but not to amphotericin B. Of note, RNA-seq combined with RT-qPCR showed that a series of drug efflux pumps were upregulated in the gemA deletion mutant. Deleting mdr1 or inhibiting the expression of drug efflux pumps can partially decrease the resistance to azoles resulting from the gemA mutant, implying that GemA influences azole response by affecting the expression of drug efflux pumps. Importantly, the ΔgemA mutant is susceptible to the cell wall-perturbing reagent CR, but not to CFW, and this defect can be partly rescued by hyperosmotic stress. TEM revealed that the cell wall of ΔgemA was thicker than that of the WT strain, demonstrating that GemA plays a role in cell wall composition and integrity. Collectively, we identified a putative mitochondrial GTPase, GemA, which is critical for hyphal growth, virulence, azole susceptibility, and cell wall integrity and acts by affecting mitochondrial function.

GIV is a promising novel poor prognostic factor in liver hepatocellular carcinoma.

Numerous studies have implicated Gα-interacting, vesicle-associated protein (GIV) in the development and metastasis of various cancers. However, its role remains unclear in liver hepatocellular carcinoma (LIHC). We aimed to demonstrate the relationship between GIV and LIHC based on The Cancer Genome Atlas database. We use the Gene Expression Profiling Interactive Analysis and UALCAN to explore the expression of GIV and the survive analysis of GIV in patients with LIHC, genetic alteration analysis, immune infiltration analysis, functional enrichment, protein-protein interaction network analyses, and transcription factor targets of GIV-correlated genes and GIV-interacting genes were performed this study. GIV expression was significantly elevated in LIHC tissues. Remarkable correlation was established between GIV expression and LIHC pathological stage. Low expression of GIV in tumor tissues had a better prognosis than GIV-high expression. GIV alteration frequency was 1.44% in patients with LIHC. GIV-unaltered patients had better survival than GIV-altered ones. Moreover, GIV expression level in LIHC significantly correlated with the infiltration level of immune cells and cancer-associated fibroblasts. The functions of differentially expressed GIVs are associated with the cell cycle pathway. Our data imply that E2F4, E2F1, MYC, and MYCN are key transcription factors for GIV-correlated genes and GIV-interacted genes. GIV may be an adverse prognostic factor for patients with LIHC; it also can be a potential therapeutic target against LIHC. Further studies are required to validate our findings.

Lactobacillus plantarum ZJUIDS14 alleviates non-alcoholic fatty liver disease in mice in association with modulation in the gut microbiota.

This present study was designed to explore the protective role of Lactobacillus plantarum ZJUIDS14 against Non-alcoholic Fatty Liver Disease (NAFLD) in a high-fat-diet (HFD)-induced C57BL/6 mice model. The probiotic (109 CFU/every other day) was administered by oral gavage for 12 weeks. We found that L. plantarum ZJUIDS14 intervention significantly alleviated HFD related hepatic steatosis, liver damage, insulin resistance, and increased hepatic expression of peroxisome proliferator activated receptor α (PPAR-α) while stimulating the activation of AMP-activated protein kinase (AMPK). Furthermore, L. plantarum ZJUIDS14 improved mitochondrial function as reflected by an increase in dynamin related protein 1 (DRP1) and a decrease of proteins associated with oxidative phosphorylation (OXPHOS) after the treatment. Additionally, mice from the L. plantarum ZJUIDS14 group had a restored intestinal flora and homeostasis involving Coprostanoligenes group, Ruminococcaceae UCG-014, Allobaculum, Ruminiclostridium 1, and Roseburia. Meanwhile, these five genera exhibited a significant (negative or positive) association with ileum inflammation mRNA levels and SCFA contents, by Spearman's correlation analysis. In general, our data demonstrated that L. plantarum ZJUIDS14 mitigates hepatic steatosis and liver damage induced by HFD. Specifically, they strengthened the integrity of the intestinal barrier, regulated gut microbiota, and improved mitochondrial function. Our data provide an experimental basis for L. plantarum ZJUIDS14 as a promising candidate to prevent NAFLD.

Participatory and Transdisciplinary Studies of Brucella Infection in Humans and Animals in Yunnan Province, China-Lessons Learned.

Brucellosis is an important zoonosis occurring globally. In addition to the risk for disease in humans, the disease causes production losses, since the disease in livestock is characterized by abortion and other reproductive failures. The disease is a public health concern in China, but no information is available on knowledge, perception and awareness of potential risk groups such as farmers, butchers and animal health workers; yet successful control requires compliance of those affected groups to be effective. Following the principles of the Ecohealth approach, emphasis was given to participation of all relevant stakeholders, use of qualitative and quantitative tools, and cross-sectorial collaboration. Data collection included on-farm questionnaires (N = 192) and collection of bulk milk samples of goat (N = 40), cattle (N = 45) and buffalo (N = 41) from farms, as well as serum samples (N = 228) from humans. Milk samples were tested with an ELISA for presence of antibodies, while a serum agglutination test was used for human samples. Qualitative work included 17 focus group discussion (FGD) with villagers and 47 in-depth interviews (IDI) with village animal health workers, doctors, and butchers, focused on knowledge, perception and awareness on zoonoses including brucellosis. Results from questionnaires indicate that abortions are a common problem; cattle with abortion history are kept for further insemination and the milk still consumed or sold. Antibodies against Brucella were detected in cows' (5/45) and goats' (1/40) milk samples, and in human samples (5/126) in Yiliang, while in Mangshi, all buffalo (N = 41) and humans (N = 102) were negative. FGD and IDI results showed an alarmingly low knowledge and awareness on zoonoses; particularly, low awareness about brucellosis was noted, even among the professional groups. Collaboration between village animal health workers and doctors was uncommon. No confirmed brucellosis cases were found in retrospective investigation of hospital and veterinary stations. This study demonstrates the presence of brucellosis in livestock and humans in Yunnan, indicating a non-negligible risk for humans. It is also made apparent that there is a need for increased awareness among both farmers and professionals in order to reduce the risk of zoonotic transmissions.

High TRAF3IP3 Level Predicts Poor Prognosis of Patients with Gliomas.

BACKGROUND: Tumor necrosis factor receptor-related factor 3 (TRAF3) interacting protein 3 (TRAF3IP3) is involved in the development of immune tissues and the immune response of the body. Downregulated expression of TRAF3IP3 in malignant melanoma can inhibit tumor growth. The role of TRAF3IP3 in glioma is unknown. METHODS: We used the Wilcoxon rank sum test to compare the expression of TRAF3IP3 in glioma and normal tissues based on The Cancer Genome Atlas and Genotype Tissue Expression. Logistics regression was used to evaluate the relationship between TRAF3IP3 and clinicopathologic characters. Gene set enrichment analysis and single-sample gene set enrichment analysis were conducted to annotate biological function of TRAF3IP3. We used Kaplan-Meier and Cox regression to evaluate the prognostic value of TRAF3IP3. RESULTS: We downloaded RNA-seq data of 670 gliomas and 1157 normal tissues. TRAF3IP3 was highly expressed in gliomas (P < 0.001). High expression of TRAF3IP3 and higher World Health Organization grade (odds ratio [OR], 3.57 [2.42-5.34 CI]; P < 0.001), wild-type isocitrate dehydrogenase status (OR, 4.79 [3.40-6.83 CI]; P < 0.001), 1p/19q non-codeletion (OR, 15.32 [9.23-27.01 CI]; P < 0.001), mutant epidermal growth factor receptor status (OR, 2.77 [1.65-4.81 CI]; P < 0.001), worse histologic type (OR, 3.64 [2.48-5.43 CI]; P < 0.001) and worse primary therapy outcome (OR, 2.29 [1.47-3.61 CI]; P < 0.001) were significantly correlated. Six signaling pathways were significantly enriched in the TRAF3IP3 high-expression phenotype group, including JAK-STAT, interferon-γ, apoptosis, P53, programmed cell death protein 1, and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). High expression of TRAF3IP3 was associated with worse progression-free survival (hazard ratio [HR], 2.39 (1.39-3.01); P < 0.001), disease-free survival (HR, 3.02 (2.27-4.01); P < 0.001) and overall survival (HR, 2.87 (2.20-3.75); P < 0.001). CONCLUSIONS: TRAF3IP3 play an important role in the occurrence and development of glioma and may be a potential biomarker for the prognosis of glioma.

Bile acid metabolism and liver fibrosis following treatment with bifid triple viable capsules in nonalcoholic fatty liver disease.

PURPOSE: This study investigated liver enzymes, bile acid metabolism, and liver fibrosis in nonalcoholic fatty liver disease (NAFLD) to evaluate the therapeutic effects of microecological preparations on fatty liver. METHODS: Liver enzymes, liver fibrosis, and bile acids were assessed in 40 healthy volunteers and 124 NAFLD patients. All patients were retested for liver enzymes, bile acids, and liver fibrosis after two months of bifid triple viable capsule therapy. Results: (1) Prior to treatment, alanine aminotransferase, aspartate aminotransferase, glutamyl transpeptidase, FibroScan liver stiffness, total bile acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, and taurolithocholic acid increased with the severity of NAFLD (P<0.05). Primary/secondary bile acids increased in patients compared to healthy controls; free/conjugated bile acids decreased (P<0.05). (2) We detected a positive correlation between total bile acid, cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, taurolithocholic acid, tauroursodeoxycholic acid, and FibroScan liver stiffness. (3) Following treatment, liver enzymes decreased. Bile acids were impacted by decreasing primary/secondary bile acids and increasing free/conjugated bile acids. Improvements were observed in the fibrosis of mild fatty liver. No effects were observed for moderate and severe fatty liver. CONCLUSIONS: Liver enzymes, bile acids, and liver fibrosis were correlated with the severity of NAFLD. There were positive correlations between bile acids and liver fibrosis. Bifid triple viable capsules could decrease liver enzymes and impact bile acid metabolism but failed to effectively improve liver fibrosis.

The relation of microsatellite instability to expression of hTERT in human gastric carcinoma.

OBJECTIVE: To investigate the role of microsatellite instability (MSI) in the pathogenesis of gastric carcinoma and its relationship with the expression of hTERT gene. METHODS: 75 cases of gastric carcinoma and paired normal control tissues were included in this study. MSI of BAT-25, BAT-26, D5S346, D17S250 and D2S1235 were detected by PCR, native polyacrylamide gel electrophoresis, and silver staining while the expression of hTERT was localized by immunohistochemistry at the same time. RESULTS: MSI positive rates of BAT-25, BAT-26, D5S346, D17S250 and D2S123 were 14.7%, 12.00%, 26.67%, 16% and 21.3%. MSI was obviously related with lymph node metastasis and pathologic stages respectively (P<0.05), but not with age, gender, histologic type, or infiltration depth (P>0.05). hTERT was not expressed in normal gastric mucosa, but in intestinal metaplasia, dysplasia, and gastric carcinoma. The positive rate of hTERT was 76% (57/75) in 75 cases of gastric carcinoma tissues. The expression of hTERT was obviously related to histological type (P<0.05), but not to age, gender, lymph node metastasis, depth of invasion, or staging, respectively (P>0.05). The positive rate was higher in poorly differentiated cases than in moderately and well differentiated cases (P<0.05). MSI accounted for 28.1% of 57 hTERT positive cases while MSI accounted for 72.2% in 18 hTERT negative cases. Spearman rank correlation analysis showed that MSI was negatively related to hTERT expression (r=0.387, P=0.001). CONCLUSION: MSI may play an important role in the pathogenesis and progression of gastric carcinoma by affecting the expression of TERT gene.

Multiple Roles of WNT5A in Breast Cancer.

Breast cancer is one of the most common malignant tumors of women. Modern combinatorial therapeutic regimens can reduce patient tumor burdens to undetectable levels, yet in many cases these tumors will relapse. Understanding of breast cancer biology, developing more potent therapeutic approaches, and overcoming resistance are of great importance. WNT5A is a non-canonical signaling member of the WNT family. Its role in breast cancer still remains unclear. Most of the evidence shows that WNT5A is a suppressor in breast cancer and loss of its expression is associated with poor prognosis, while some evidence suggests the tumorigenicity of WNT5A. WNT signaling molecules are potent targets for treatment of cancer. Therefore, understanding the role of WNT5A in breast cancer may provide new ideas and methods for breast cancer treatment. We review the evidence concerning WNT5A and breast cancer involving the signaling pathways and the molecular-targeted therapy of WNT5A. Our results show that the role WNT5A plays depends on the availability of key receptors and intercellular interactions among different cell types.

Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy.

PURPOSE: Insulin-like growth factor 1 receptor (IGF-IR) has been implicated in the pathogenesis of ovarian cancer. Ganitumab is an investigational, fully human monoclonal antibody against IGF-IR. Here, we explore the therapeutic potential of ganitumab for the treatment of ovarian cancer. EXPERIMENTAL DESIGN: The effects of ganitumab were tested in vitro against a panel of 23 established ovarian cancer cell lines. The ability of ganitumab to inhibit IGF-I-, IGF-II-, and insulin-mediated signaling was examined in vitro and in tumor xenografts using ovarian cancer models displaying IGF-IR/PI3K/AKT pathway activation by two distinct mechanisms, PTEN loss and IGF-II overexpression. Drug interactions between ganitumab and cisplatin, carboplatin, or paclitaxel were studied in vitro and in vivo. RESULTS: In vitro, growth inhibition varied significantly among individual ovarian cancer cell lines. IGF-II mRNA and phospho-IGF-IR protein expression were quantitatively correlated with response to ganitumab, and PTEN mutations conferred resistance to ganitumab. Ganitumab potently inhibited baseline and IGF-I-, IGF-II-, and insulin-induced IGF-IR and IGF-IR/insulin hybrid receptor signaling in vitro and in vivo. Synergistic and additive drug interactions were seen for ganitumab and carboplatin or paclitaxel in vitro. Furthermore, ganitumab significantly increased the efficacy of cisplatin in ovarian cancer xenograft models in vivo. CONCLUSIONS: These observations provide a biologic rationale to test ganitumab as a single agent or in combination with carboplatin/cisplatin and paclitaxel in patients with ovarian cancer. Moreover, assessment of tumor expression of IGF-II, phospho-IGF-IR, or PTEN status may help select patients with ovarian cancer who are most likely to benefit from ganitumab. Clin Cancer Res; 20(11); 2947-58. ©2014 AACR.

Nonsteroidal anti-inflammatory drug use and the risk of melanoma: a meta-analysis.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have emerged as potential chemopreventive agents for melanoma. However, the clinical studies have provided contradictory results as to whether NSAIDs reduce the risk of melanoma. Our aim was to assess this association through a detailed meta-analysis of the studies on the subject published in the peer-reviewed literature. Relevant studies were identified by searching PubMed, EMBASE and Web of Science electronic databases up to July 2012. Reference lists from retrieved articles were also reviewed. Pooled relative risk (RR) estimates and corresponding 95% confidence intervals (CIs) were calculated using the fixed-effects or the random-effects models on the basis of heterogeneity analysis. Subgroup analyses were carried out where data were available. Ten studies involving 490 322 participants contributed to the meta-analysis. The summary RR estimate on the basis of all studies did not indicate that overall NSAIDs use significantly decreases the risk of melanoma (RR=0.94; 95% CI, 0.86-1.03). The use of neither aspirin (RR=0.96; 95% CI, 0.89-1.03) nor nonaspirin NSAIDs (RR=1.05; 95% CI, 0.96-1.14) was associated with the risk of melanoma. Similar results were obtained in the subgroup analyses of cohort studies (RR=1.03; 95% CI, 0.95-1.13), high-intensity NSAID use (the highest dose of NSAID use reported by included studies, RR=1.05; 95% CI, 0.79-1.40), and long-term NSAID use (longest duration of NSAID use reported by included studies, RR=0.87; 95% CI, 0.66-1.14). However, a slight reduction in the risk of melanoma by taking NSAIDs was observed in case-control studies (RR=0.86; 95% CI, 0.80-0.93). In conclusion, the results of our meta-analysis did not indicate that the use of NSAIDs or aspirin is associated with the risk of melanoma. More and in-depth research should focus on those problems in the future.

Oral bisphosphonates and the risk of colorectal cancer: a meta-analysis.

AIM: : To conduct a meta-analysis on the relationship between the usage of bisphosphonates and the risk of colorectal cancer. METHODS: We searched PUBMED and EMBASE for studies assessing colorectal cancer incidence or prevalence in bisphosphonate users versus nonusers that were published before August 2012. We used the STATA software to calculate the pooled odds ratios (OR) and 95% confidence interval (CI) for the risk of colorectal cancer associated with exposure to bisphosphonates using a random-effects model. RESULTS: Eight studies met our inclusion criteria, which comprised 5 cohort studies and 3 case-control studies, with a total of 22,291 colorectal cancer cases. The usage of bisphosphonates was associated with a statistically significant decrease in colorectal cancer risk, with a pooled OR of 0.89 (95% CI, 0.80-0.99). A statistically significant decrease in the risk of colorectal cancer was observed in the long-term exposure groups (pooled OR, 0.73; 95% CI, 0.57-0.93). CONCLUSIONS: These results indicate that the decrease in risk of colorectal cancer may be associated with the usage of bisphosphonates. More studies are needed to confirm the relationship.

Activity of the fibroblast growth factor receptor inhibitors dovitinib (TKI258) and NVP-BGJ398 in human endometrial cancer cells.

The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P = 0.073 and P = 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection.

[Effects of human cytomegalovirus on the cell cycle of duct epithelial cell cultures of human salivary gland in vitro and relative mechanism].

OBJECTIVE: To investigate the effects of human cytomegalovirus (HCMV) on the cell cycle of duct epithelial cell cultures of human salivary gland (HSG) in vitro and relative mechanism. METHODS: HSG was cultured in vitro. Reverse transcriptase polymerase chain reaction (RT-PCR) and nest-RT-PCR were used respectively to investigate ie1/ie2 transcription in HSG infected by human cytomegalovirus(HCMV). The effects of HCMV on the cell cycle of HSG were studied by flow cytometry in vitro. The expression of cyclin D1 in HSG infected by HCMV was detected by Western blotting. RESULTS: HCMV iel/ie2 transcription could be detected in HSG infected by HCMV. HCMV arrested productively infected cells in G1 stage. And cyclin D1 was down-regulated in HCMV infected HSG. CONCLUSION: HCMV inhibits proliferation of HSG by affecting G1/S check point and down-regulating cyclin D1 in vitro.

Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer.

PURPOSE: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. EXPERIMENTAL DESIGN: We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. RESULTS: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00-2.24, P = 0.052). CONCLUSIONS: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer.

[Expression of Toll-like receptors in human bone marrow mesenchymal stem cells].

The aim of this study was to explore the characteristics of Toll-like receptor expression in mesenchymal stem cells derived from bone marrow of healthy donor (BM-MSCs). BM-MSCs were isolated from bone marrow of healthy donor by Ficoll method. Expressions of CD34, CD45, HLA-DR, CD44 and CD71 in BM-MSCs were detected by flow cytometry. CD71 in BM-MSCs was assayed by immunocytochemistry. The adipocyte and osteoblast induction of BM-MSCs were detected by alizarin red stain and oil red stain respectively. TLR 1 - 10 mRNA levels in BM-MSCs were evaluated by semiquantitative RT-PCR. The results showed that expressions of CD34, CD45 and HLA-DR in BM-MSC were negative while the expressions of CD44 and CD71 were positive. CD71 in BM-MSCs was positive. After induced by osteoblast and adipocyte inductor, BM-MSCs were positive for alizarin red staining and oil red staining respectively. All of TLR 1 - 10 mRNA were found in BM-MSCs with high expression levels of TLR2, TLR3, TLR4, TLR7, TLR8, TLR9 and low expression levels of TLR1, TLR5, TLR6, TLR10. In conclusion, different levels of TLR 1 - 10 mRNA were expressed in BM-MSCs of healthy donor.