Inducible Fgf13 ablation alleviates cardiac fibrosis via regulation of microtubule stability.

Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, boasts significant potential for therapeutic intervention in cardiovascular dysfunctions. However, its impact on regulating fibrosis remains unexplored. This study aims to elucidate the role and mechanism of FGF13 on cardiac fibrosis. Here, we show that following transverse aortic constriction (TAC) surgery, interstitial fibrosis and collagen content increase in mice, along with reduced ejection fraction and fractional shortening, augmented heart mass. However, following Fgf13 deletion, interstitial fibrosis is decreased, ejection fraction and fractional shortening are increased, and heart mass is decreased, compared with those in the TAC group. Mechanistically, incubation of cardiac fibroblasts with transforming growth factor ß (TGFß) increases the expressions of types I and III collagen proteins, as well as α-smooth muscle actin (α-SMA) proteins, and enhances fibroblast proliferation and migration. In the absence of Fgf13, the expressions of these proteins are decreased, and fibroblast proliferation and migration are suppressed, compared with those in the TGFß-stimulated group. Overexpression of FGF13, but not FGF13 mutants defective in microtubule binding and stabilization, rescues the decrease in collagen and α-SMA protein and weakens the proliferation and migration function of the Fgf13 knockdown group. Furthermore, Fgf13 knockdown decreases ROCK protein expression via microtubule disruption. Collectively, cardiac Fgf13 knockdown protects the heart from fibrosis in response to haemodynamic stress by modulating microtubule stabilization and ROCK signaling pathway.

AURKA knockdown inhibits esophageal squamous cell carcinoma progression through ferroptosis.

Aurora kinase A, as a pro-carcinogenic in gastric cancer and glioma kinase, is enhanced in several human tumors. However, it's regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, this study aimed to investigate the expression status, functional roles, and molecular mechanisms of AURKA in ESCC development. AURKA expression was analyzed by the screening of the GEO database and detected using an immunohistochemical method. The biological function of AURKA on ESCC was evaluated in vitro and in vivo. Western blot assay, malondialdehyde (MDA), iron, and glutathione (GSH) kits were utilized to assess changes in ferroptosis. Database analysis results showed that AURKA was a differential gene in ESCC and was highly expressed in human ESCC tissues. Functionally, AURKA knockdown decreased ESCC cell proliferation, invasion, and metastasis both in vitro and in vivo. Moreover, when AURKA was knockdown, cells were more correctly blocked in the G2/M phase, and the ferroptosis-related MDA and Fe increased, whereas the GSH reduced. Consistently, Glutathione peroxidase 4 (GPX4) and solute carrier family 7a member 11 (SLC7A11) expression were downregulated by AURKA knockdown. However, ferroptosis inhibitor partially restore ESCC cell proliferation, invasion, and metastasis caused by AURKA knockdown. AURKA knockdown enhances ferroptosis and acts against cancer progression in ESCC. AURKA acts as a tumor-promoting gene and may serve as potential target for ESCC treatment.

Comparison of neoadjuvant immunotherapy versus routine neoadjuvant therapy for patients with locally advanced esophageal cancer: A systematic review and meta-analysis.

Background: The neoadjuvant use of immune checkpoint inhibitor combined with chemotherapy (nICT) or chemoradiotherapy (nICRT) in locally advanced esophageal cancer (EC) is currently an area of active ongoing research. Therefore, we carried out a comprehensive meta-analysis to compare the efficacy and safety of the new strategy with routine neoadjuvant strategy, which included neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT). Patients and methods: MEDLINE (via PubMed), Embase (via OVID), ISI Web of Science database and Cochrane Library were included. And, all of them were searched for eligible studies between January, 2000 and February, 2023. The pathological complete response (pCR) and major pathological response (MPR) were primary outcome of our study. The second outcome of interest was R0 resection rate. Odds ratio (OR) and associated 95% CI were used as the effect indicators comparing the safety and efficiency of the neoadjuvant immunotherapy with the routine neoadjuvant therapy. Fixed-effect model (Inverse Variance) or random-effect model (Mantel-Haenszel method) was performed depending on the statistically heterogeneity. Results: There were eight trials with 652 patients were included in our meta-analysis. The estimated pCR rate was higher in the neoadjuvant immunotherapy group (OR =1.86; 95% CI, 1.25-2.75; I2 = 32.8%, P=0.166). The different results were found in the esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) subgroups, the estimated OR was 2.35 (95%CI, 1.00-2.72; I2 = 30.9%, P=0.215) in the EAC subgroup, and 2.35 (95% CI, 1.20-4.54; I2 = 45.3%, P=0.161) in the ESCC subgroup, respectively. The neoadjuvant immunotherapy also showed the advantage in the MPR rates (OR =2.66; 95% CI, 1.69-4.19; I2 = 24.3%, P=0.252). There was no obvious difference between the neoadjuvant immunotherapy and routine neoadjuvant therapy with respect to surgical resection rate, R0 resection rate, surgical delay rate; while more treatment-related adverse events were observed for the neoadjuvant immunotherapy for pneumonitis/pneumonia (OR=3.46, 95% CI, 1.31-9.16; I2 = 67.3%, P=0.005) and thyroid dysfunction (OR=4.69, 95% CI, 1.53-14.36; I2 = 56.5%, P=0.032). Conclusion: The pooled correlations indicated that the neoadjuvant immunotherapy (both nICT and nICRT) could significantly increase the rates of pCR and MPR, compared with routine neoadjuvant therapy (both nCT and nCRT) in the treatment of locally advanced EC. The neoadjuvant immunotherapy and routine neoadjuvant therapy were with acceptable toxicity. However, randomized studies with larger groups of patients need to performed to confirm these results. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020155802.

A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo.

The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth.

[Effects of Extracellular Vesicles on the Drug Resistance of Lung Adenocarcinoma Cells by Modulating the ATP Binding Cassette Transporter G2].

Objective: To investigate the regulatory role of extracellular vesicles (EVs) carrying ATP binding cassette transporter G2 (ABCG2) on the drug resistance of lung adenocarcinoma cells and the relevant molecular mechanisms. Methods: A549 cells, human lung adenocarcinoma cells, were used to form cisplatin (or cis-Diaminedichloroplatinum, CDDP)-resistant lung adenocarcinoma cells, i.e., A549/CDDP cells. EVs from A549 and A549/CDDP cells were extracted by gradient centrifugation method and were hence named EVs 1 and EVs 2, respectively. The A549 cells were treated with EVs 1 and EVs 2 for 48 hours, and the cells were named A549-EVs 1 and A549-EVs 2 cells, respectively. A549/ ABCG2 cells were established by transfecting A549 cells with pCDNA3.1- ABCG2 recombinant plasmids. On the other hand, A549 cells transfected with empty vectors were named A549/pCDNA3.1 cells. MTT assay was conducted to calculate the 24-hour cell drug resistance index for CDDP. The ABCG2 gene expression in cells and EVs were assessed with real-time PCR. A549 and A549-EVs 2 cells were transplanted subcutaneously into nude mice, which were labeled the control group and the experimental group accordingly. After tumor formation, 3 mg/kg CDDP was intraperitoneally injected once a week for two times. The ABCG2 gene expression of subcutaneous transplanted tumor cells was examined by real-time PCR. The cell apoptosis rate of subcutaneous transplanted tumor cells was examined by flow cytometry. Results: Using the parental A549 cells as reference, the 24-h CDDP-resistance indexes of 549/CDDP, A549/ ABCG 2, A549/pCDNA3.1, A549-EVs 1, A549-EVs 2 cells were 7.17, 10.06, 1.02, 1.19 and 5.40, respectively. When comparing the ABCG2 gene expression levels in all cells and EVs, the findings were higher in A549/CDDP cells than those inA549 cells, higher in A549/ ABCG2 cells than those in A549/pCDNA3.1 or A549 cells, higher in EVs 2 than those in EVs 1, and higher in A549-EVs 2 than those in A549-EVs 1 cells ( P<0.01) . The volume of transplanted tumor and the ABCG2 gene expression level in the experimental group were higher than those in the control group, while the apoptosis rate was lower than that in the control group ( P<0.01). Conclusion: EVs carrying ABCG2 gene can regulate the drug resistance of lung adenocarcinoma cells.

Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies.

Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.

Long Non-coding RNAs LINC01679 as a Competitive Endogenous RNAs Inhibits the Development and Progression of Prostate Cancer via Regulating the miR-3150a-3p/SLC17A9 Axis.

Long non-coding RNAs (lncRNAs) have been indicated as the candidate factors to predict cancer prognosis. However, it is still unknown whether lncRNA combinations may be utilized for predicting overall survival (OS) of prostate cancer (PCa). The present work focused on selecting the potent OS-related lncRNA signature for PCa and studying its molecular mechanism to enhance the prognosis prediction accuracy. Differentially expressed lncRNAs (DElncRNAs) or differentially expressed genes (DEGs) were obtained based on TCGA database by R software "edgeR" package. lncRNAs or mRNAs significantly related to PCa were screened through univariate as well as multivariate Cox regression, for the construction of the risk model for prognosis prediction. Moreover, this constructed risk model was validated through ROC analysis, univariate regression, and Kaplan-Meier (KM) analysis. Additionally, we built a lncRNA-miRNA-mRNA ceRNA network through bioinformatics analysis. Colony formation, CCK-8, flow cytometry, scratch, and Transwell assays were performed based on PCa cells subjected to small interfering RNA (siRNA) targeting LINC01679/SLC17A9 and vector expressing LINC01679/SLC17A9 transfection. Thereafter, the ceRNA mechanism was clarified via qRT-PCR, Western blotting (WB), RNA pull-down, and luciferase reporter assays. Nude mouse tumor xenograft was established to examine LINC01679's oncogenicity within PCa cells. According to our results, LINC01679 depletion promoted cell proliferation, metastasis, tumor growth, and inhibited cell apoptosis in vivo and in vitro, which was also associated with poor survival. LINC01679 regulated miR-3150a-3p level by sponging it. Importantly, miR-3150a-3p overexpression was related to the increased proliferation and decreased apoptosis of PCa cells. Rescue assays suggested that miR-3150a-3p mimics rescued the repression on PCa progression mediated by LINC01679 upregulation, but SLC17A9 downregulation reversed the miR-3150a-3p inhibitor-mediated repression on PC progression. Importantly, SLC17A9 downregulation rescued the repression on PCa progression mediated by LINC01679 upregulation. LINC01679 and SLC17A9 are tightly associated with certain clinicopathological characteristics of PCa and its prognostic outcome. In addition, LINC01679 is the ceRNA that suppresses PCa development through modulating the miR-3150a-3p/SLC17A9 axis.

Patients with different types of arthritis may be at risk for major depression: results from the National Health and Nutrition Examination Survey 2007-2018.

BACKGROUND: Arthritis is one of the common causes of physical pain and disability, which often makes patients fall into major depression. However, the correlation between arthritis and major depression, and how different types of arthritis correspond to major depression remain to be explored. The purpose of this study is to explore the relationship between arthritis and major depression. METHODS: Arthritis status was reported by participants themselves, and the Patient Health Questionnaire-9 in National Health and Nutrition Examination Survey (NHANES) was used to evaluate major depression, logistic regression was used to evaluate the relationship between arthritis and major depression. RESULTS: We analyzed the data of 25,990 adults who participated in the NHANES from 2007 to 2018. Participants with major depression were more likely to be female, Hispanic, smoker, less educated, less recreational activities, poverty-to-income ratio <5, coronary heart disease, stroke, cancer or malignant tumor, diabetes, hypertension and higher body mass index (BMI). Arthritis was significantly correlated with major depression (25.4% vs. 44.9%; P<0.001), even after adjusting for gender, age, race, BMI, PIR, education, marriage, moderate recreational activities, smoking, history of coronary heart disease, stroke, cancer or malignant tumor, diabetes, and hypertension (OR =2.30, 95% CI, 2.06-2.56, P<0.001). Subgroup analysis showed that compared with degenerative arthritis, rheumatoid arthritis (RA), or other arthritis, psoriatic arthritis (PsA) had the greatest influence on major depression patients. CONCLUSIONS: All patients with arthritis, especially PsA, may have the risk of major depression. Psychological intervention necessary for patients with arthritis.

The HNF1A-AS1/miR-92a-3p axis affects the radiosensitivity of non-small cell lung cancer by competitively regulating the JNK pathway.

BACKGROUND: It has been widely reported that long non-coding RNAs (lncRNAs) could affect the varieties of tumor response to radiotherapy. LncRNA HNF1A-AS1 is transcribed from HNF1A gene cluster's antisense strand. This work focused on the mechanism of how HNF1A-AS1 participated in the radiosensitivity of non-small cell lung cancer (NSCLC). METHODS: The mRNA or protein expression of HNF1A-AS1, miR-92a-3p MAP2K4, and JNK in NSCLC cells and tissues was detected by qRT-PCR or western blotting. RNA immunoprecipitation (RIP) detection and luciferase reporting system were used to evaluate the relationship between HNFA-AS1 and miR-92a-3p or between miR-92a-3p and MAP2K4. Flow cytometry assays, colony formation, and MTT were performed to analyze the function changes in A549 and Calu-1 cells. The rescue experiment was also conducted to explore the underlying mechanisms. RESULTS: HNF1A-AS1 was investigated in NSCLC cells and tissues and highly related to the advanced pathological stage. HNF1A-AS1 bound with miR-92a-3p, which was downregulated in NSCLC. It showed that miR-92a-3p was negatively related to HNF1A-AS1. Knockdown of HNF1A-AS1 impacted most cell biological behaviors in NSCLC cells, including restricting the proliferation and aggravating apoptosis. Furthermore, knockdown of HNF1A-AS1 dramatically enhanced radiotherapy sensitivity of NSCLC. Moreover, miR-92a-3p was found to target MAP2K4 and could reduce MAP2K4 expression. Inhibition of HNF1A-AS1 elevated radiotherapy sensitivity and retarded the progression of NSCLC cells, followed by decreasing expression levels of MAP2K4. Besides, MAP2K4 mimic rescued the si-HNF1A-AS1 effects on the biological behavior of NSCLC cells. CONCLUSION: HNF1A-AS1 is highly expressed in NSCLC. MiR-92a-3p is the target gene of HNF1A-AS1 and involved in tumor progression by regulating the MAP2K4/JNK pathway. HNF1AS1/miR-92a-3p/MAP2K4 axis plays important roles in radiotherapy resistance of NSCLC.

Robotic and video-assisted lobectomy/segmentectomy for non-small cell lung cancer have similar perioperative outcomes: a systematic review and meta-analysis.

BACKGROUND: At present, the clinical conclusion that robotic-assisted thoracic surgery (RATS) and video-assisted thoracic surgery (VATS), which is better for patients with non-small cell lung cancer (NSCLC) is not clear. Therefore, this meta-analysis aimed to compare the perioperative outcomes between RATS and VATS for NSCLC. METHODS: The Population, Interventions, Comparators, Outcomes, and Study design (PICOS) framework was employed to develop the search strategy, and the findings was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched EMbase, The Cochrane Library, PubMed, Web of Science, CNKI, and Wan Fang Data to collect clinical studies about RATS vs. VATS for patients with NSCLC from inception to October 2019. The following outcomes were measured: rate of conversion to thoracotomy, postoperative complications, postoperative hospital mortality, lymph node dissection, hospitalization time, operating time, and postoperative drainage days. Estimation of potential publication bias was conducted by Begg's test and Egger's test. The Standardized Mean Difference (SMD) and Odds Ratio (OR) with 95% confidence intervals (CI) were pooled using Stata 15.0 software. RESULTS: A total of 18 studies involving 60,349 patients were included. Among them, 8,726 cases were in the RATS group, and 51,623 were in the VATS group. The results of meta-analysis showed that the operation time of RATS group was longer than that of VATS group (SMD=0.532, 95% CI: 0.391-0.674, P=0.000). And the further meta-analysis suggested that the incidence of postoperative complications was lower in patients who underwent RATS after 2015 (OR=0.848, 95% CI: 0.748-0.962, P=0.010). Meanwhile, there was no significant difference between both groups in postoperative hospitalization time (SMD=0.003, 95% CI: -0.104-0.110, P=0.957). In addition, more lymph nodes were retrieved in RATS group than VATS (SMD=0.308, 95% CI: 0.131-0.486, P=0.001). However, the conversion rate, retrieved lymph node station, days to tube removal and in-hospital mortality rate have no significant differences between both groups. DISCUSSION: The current meta-analysis indicates that the perioperative outcomes of RATS and VATS for NSCLC are equivalence. Due to the limited quantity and quality of included studies, the above conclusions still need to be verified by more high-quality studies.

Tumor- and Osteoblast-Derived Periostin in Prostate Cancer bone Metastases.

Exploring the biological function of periostin (POSTN) in prostate cancer (PCa) bone metastasis is of importance. It was observed that the expression of POSTN was high in PCa, especially highest in PCa metastasized to bone. In this study, we found that inhibiting POSTN in PCa cells could significantly alleviate PCa bone metastasis in vivo, suggesting POSTN is a promising therapeutic target. Since, due to the secreted expression of POSTN in osteoblasts and PCa, we hypothesized the positive feedback loop between osteoblasts and PCa mediated by POSTN in PCa bone metastasis. The in vitro experiments demonstrated that osteoblast-derived POSTN promoted PCa cell proliferation and invasion and PCa cell-derived POSTN promotes proliferation of osteoblasts. Furthermore, we found that POSTN regulated PCa and osteoblast function through integrin receptors. Finally, 18F-Alfatide II was used as the molecule probe of integrin αvß3 in PET-CT, revealing high intake in metastatic lesions. Our findings together indicate that targeting POSTN in PCa cells as well as in the osteoblastic may be an effective treatment for PCa bone metastasis.

Clinicopathological and prognostic value of circulating tumor cells in esophageal carcinoma: a meta-analysis.

BACKGROUND: The associations between circulating tumor cells (CTCs) in peripheral blood and prognosis of patients with esophageal carcinoma (EC) have been investigated by a number of studies, but the results are not consistent. Therefore, this study aimed to explore this controversial subject. METHODS: A literature database search was performed according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The risk ratio (RR), hazard ratio (HR) and their 95% confidence intervals (CIs) were retained as the effect measures. If necessary, subgroup analyses and metaregression should also be performed to clarify the heterogeneity. RESULTS: Thirty-three studies, containing 3,236 patients with EC, were included in this meta-analysis. The results showed that overall survival (OS) (HR =2.14; 95% CI, 1.73-2.65) and progression-free survival (PFS) (HR =2.29; 95% CI, 1.69-3.11) were worse in CTCs-positive patients. CTC positivity is also significantly associated with depth of infiltration (RR =1.42; 95% CI, 1.10-1.82, P=0.21) and tumor-node-metastasis (TNM) stage (RR =1.36; 95% CI, 1.09-1.69, P=0.22). However, there was no significant relationship between CTC-positive and distant metastasis (RR =1.58; 95% CI, 1.00-2.50, P=0.65). CONCLUSIONS: Detection of CTCs had prognostic value for EC patients. Positive CTC is associated with poor prognosis and some prognostic factors, such as depth of infiltration and TNM stage, but not related to metastasis.

Osimertinib for EGFR-mutant lung cancer with central nervous system metastases: a meta-analysis and systematic review.

BACKGROUND: Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is the only Food and Drug Administration-approved third-generation epidermal growth factor receptor (EGFR)TKI. Osimertinib is a cancer medicine that interferes with the growth and spread of cancer cells in the body. Osimertinib is used to treat a certain type of non-small cell lung cancer. We review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, activity of osimertinib penetrating blood-brain barrier and the efficacy of osimertinib. METHODS: Guided by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement, we conducted a systematic literature search in the databases PubMed, EMBASE, ISI Web of Science database on January 30, 2020, searching for studies investigating the osimertinib efficacy on patients with CNS metastases in EGFR-mutant non-small cell lung cancer (NSCLC). And Newcastle-Ottawa Scale (NOS) was used to assess the certainty in the evidence. RESULTS: The pooled results showed that the overall response rate (ORR) and disease control rate (DCR) were 70% and 92%, respectively, in patients with T790M mutations. The efficacy of osimertinib was confirmed by the median progression free survival (PFS). In untreated advanced EGFR-mutated NSCLC with CNS metastases patients, the pooled ORR and DCR of osimertinib were 71% and 93%, respectively. And the combined median PFS, achieved by osimertinib, was 12.21 months. Above data proved that osimertinib has well activity in disease control, especially in first line. CONCLUSIONS: This meta-analysis confirmed that in treatment-naive advanced NSCLC CNS metastases harboring EGFR-TKI-sensitizing mutations, Osimertinib showed impressive antitumor activity.

Update analysis on the association between Methionine synthase rs1805087 A/G variant and risk of prostate cancer.

Previous studies have investigated the association of the rs1805087 A/G variant of Methionine synthase gene with the susceptibility to prostate cancer (PCa). Nevertheless, the conclusions remain divergent. We performed a systemic analysis with odds ratios (ORs) and 95% confidence intervals (95% CIs) to assess Methionine synthase rs1805087 A/G variant and PCa risk. Furthermore, we utilized in silico analysis to investigate the relationship between Methionine synthase expression and the overall survival (OS) time. Totally, 10,666 PCa patients and 40,750 controls were included. We observed that Methionine synthase rs1805087 A/G variant is associated with an elevated risk of PCa (G-allele vs. A-allele: OR = 1.06, 95% CI = 1.01-1.11, P = 0.013; heterozygous model: OR = 1.08, 95% CI = 1.02-1.14, P = 0.009; dominant model: OR = 1.08, 95% CI = 1.02-1.14, P = 0.007). During stratified analysis, similar results were obtained in Asian populations, hospital-based, high quality studies and that with large sample size. Moreover, in silico analysis indicated the Methionine synthase expression is down-regulated in both young and old PCa subjects (P < 0.05). Compared with the normal subjects, the down-regulated expression of Methionine synthase was found in PCa cases with Gleason score 6 to 9. Our study showed that Methionine synthase rs1805087 A/G variant may be associated with susceptibility of PCa, especially in Asian populations, hospital-based studies and that with high quality and large sample size. Furthermore, Methionine synthase rs1805087 A/G variant may be related to the prognosis of PCa.

Association of C-reactive protein (CRP) rs1205 and rs2808630 variants and risk of cancer.

The correlation between rs1205, rs2808630 variants of C-reactive protein (CRP) gene and susceptibility of cancer has been assessed previously, but with conflicting results. We adopted odds ratios (ORs) with 95% confidence intervals (CIs), in silico tools and enzyme-linked immunosorbent assay (ELISA) analysis to evaluate this association. Totally, 10,614 cancer subjects and 33,294 controls were involved in the pooled analysis. When all the studies were pooled, no significant correlation was indicated between the two variants and cancer risk. However, in stratification analysis by ethnicity, we found that CRP rs1205 C>T polymorphism was associated with an elevated risk of cancer in Asians (T-allele vs. C-allele, OR = 1.20, 95% CI = 1.06-1.36, pheterogeneity = .226; TT vs. CC, OR = 1.48, 95% CI = 1.14-1.93, pheterogeneity = .089). Similar findings were observed for rs2808630 variant. In silico tools showed that lung adenocarcinoma participants with high CRP expression may have shorter overall survival time than low expression group. ELISA analysis indicated that CRP expression in prostate adenocarcinoma subjects with TT + TC genotypes was statistically higher than in those with CC genotypes. CRP rs1205 C>T and rs2808630 T>C polymorphism may be associated with cancer risk, especially for Asians.

Association between SOD2 V16A variant and urological cancer risk.

BACKGROUND: The correlation between superoxide dismutase 2 (SOD2) V16A variant and urological cancer susceptibility has been widely studied, however, with divergent results. RESULTS: Totally, 9,910 cancer patients and 11,239 control subjects were enrolled. V16A variant is associated with an increased susceptibility to urological cancer (A-allele vs. V-allele: OR = 1.06, 95% CI = 1.00 - 1.13, P = 0.047; AA+AV vs. VV: OR = 1.09, 95% CI = 1.02 - 1.16, P = 0.008), especially for prostate cancer (PCa). Serum SOD2 level of PCa patients with VV+VA genotypes was lower than in those with AA genotypes. SOD2 expression is downregulated in both prostate and bladder cancer, as compared to the control. Furthermore, SOD2 was found to be downregulated in more advanced PCa participants, as compared to the ones in early stages. PCa subjects with low SOD2 expression displayed a shorter disease-free survival (DFS) time compared to that of the high SOD2 expression counterparts. CONCLUSIONS: The SOD2 V16A variant may be associated with increased urological cancer susceptibility, especially for prostate cancer. METHODS: A pooled analysis utilizing odds ratios (ORs), in silico tools and ELISA was adopted to demonstrate this association. We also used immunohistochemical staining (IHS) to assess SOD2 expression.

Living Donor Liver Transplantation in Biliary Atresia Children with Pulmonary Hypertension.

OBJECTIVE: Though living donor liver transplantation (LDLT) is commonly performed for pediatric patients with biliary atresia (BA), pulmonary hypertension (PH) is seldom encountered or reported previously. The aim of this study is mainly to identify the prevalence of PH in pediatric patients undergoing liver transplantation and assess whether PH significantly augment the operative risk and evaluate the outcomes in this series of patients. DESIGN: Retrospectively cohort study. SETTING: Renji hospital, Shanghai, China. PARTICIPANTS: This study comprised 161 pediatric patients undergoing LDLT. INTERVENTIONS: Patient diagnosed of PH in preoperative examination was compared to those without PH in intra- or post- operative complications or outcomes. MEASUREMENTS AND MAIN RESULTS: We collected clinical records of LDLT surgery for pediatric patients during the year of 2016 in our hospital. Results suggested that pediatric patients undergoing LDLT had a substantial number of PH with a prevalence of 16.1% in this study. No significant difference was identified between two groups of patients regarding intraoperative outcomes and postoperative complications and mortality. CONCLUSION: LDLT is a safe procedure in a selected group of BA patients with PH, however, further long-term clinical investigations and mechanical researches are needed.

MMP-8 C-799 T, Lys460Thr, and Lys87Glu variants are not related to risk of cancer.

BACKGROUND: Several studies have focused on the relationship between MMP-8 variants and cancer risk, but they have been unsuccessful in drawing reliable conclusions. METHODS: We employed odds ratio (OR) together with 95% confidence interval (CI) to assess the correlation between MMP-8 C-799 T, Lys460Thr, and Lys87Glu polymorphisms and cancer risk. We further employed in silico tools to evaluate the effect of MMP-8 expression on cancer susceptibility and overall survival time. RESULTS: A total of 8140 patients with malignant carcinoma and 10,529 healthy individuals (control) were enrolled. Overall, the analysis showed that the relationship between three MMP-8 variants and cancer susceptibility was not significant (allelic contrast, C-799 T: OR = 0.98, 95% CI = 0.92-1.04, Pheterogeneity = 0.068; Lys460Thr: OR = 0.94, 95% CI = 0.67-1.32, Pheterogeneity = 0.905; Lys87Glu: OR = 1.05, 95% CI = 0.93-1.18, Pheterogeneity = 0.968). Similar results were observed in subgroup analysis by ethnicity, cancer type, and source of control. In silico analysis indicated that MMP-8 expression was elevated in bladder cancer tissue compared to that in the control. However, both the higher and lower MMP-8 expression groups did not show an impact on the overall survival time of the patients. CONCLUSIONS: MMP-8 C-799 T, Lys460Thr, and Lys87Glu variants are not participant with the susceptibility of cancer.

The association between three AXIN2 variants and cancer risk.

Plenty of epidemiological studies have assessed the effects of AXIN2 polymorphisms on the risk of developing cancer, but the available results were somewhat inconclusive. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilized to investigate the relationship between three AXIN2 variants (rs2240308 C/T, rs1133683 C/T, and rs4791171 A/G) and overall cancer susceptibility. In silico tools were undertaken to investigate the correlation of AXIN2 expression with cancer risk and survival time. Furthermore, we explored the serum expression of AXIN2 by enzyme-linked immunosorbent assay. A total of 4167 cancer patients and 3515 control subjects were evaluated. The overall results demonstrated that there was no major association of these polymorphisms on cancer risk. However, stratified analysis by cancer type showed evidence that rs2240308 C/T polymorphism had a lower risk in lung cancer (OR, 0.76; 95% CI, 0.63-0.92; Pheterogeneity = 0.865) and prostate cancer (OR, 0.54; 95% CI, 0.35-0.84; Pheterogeneity = 0.088) by heterozygote comparison. Similar results were indicated in Asian descendants and population-based studies. In silico analysis showed evidence that AXIN2 expressions in lung cancer and prostate cancer were lower than that in normal counterpart. High expression of AXIN2 may have longer overall survival time than low expression group for lung cancer participants. In addition, individuals who were CC/TC carriers had a higher serum expression level than TT carriers. In conclusion, this pooled analysis suggested that AXIN2 rs2240308 C/T variant may decrease both lung and prostate cancer susceptibility, particularly in Asian descendants and population-based studies. Future large scale and well-designed research are required to validate these effects in more detail.