Correlation between tumor budding and the long-term follow-up outcomes after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND: The effect of tumor budding (TB) on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) after endoscopic submucosal dissection (ESD) remains unclear. We evaluated the long-term outcomes of patients with superficial ESCC after ESD and the risk factors of TB for the long-term prognosis. METHODS: We conducted a retrospective study in a Chinese hospital. All patients with ESCC treated by ESD and reported TB were included consecutively. Comparative analyses were conducted in three parts: specimen analysis, follow-up analyses of unmatched patients, and propensity score-matched (PSM) patients. Cox proportional hazard regression models were constructed to identify risk factors for overall survival and recurrence-free survival (RFS). RESULTS: A total of 437 patients were enrolled [154 TB and 283 no tumor budding (NTB)], and 258 patients (52 TB and 206 NTB) were included in the follow-up analysis. Results showed that the invasion depth, differentiation type, and positive vascular invasion (all p < 0.001) of the TB group were significantly different from the NTB group. The all-cause mortality and the median RFS time between the two groups were comparable. RFS rate at 5 years were 84.6% and 80.6%, respectively (p = 0.43). Cox analyses identified that having other cancers but not TB, as a risk factor independently associated with overall survival and RFS after ESD. CONCLUSION: TB tends to be associated with invasion depth, differentiation type, and positive vascular invasion. However, it might not affect the long-term outcomes of patients with superficial ESCC after ESD when other high-risk factors are negative.

CircRNA Hsa_circ_0120175 Promotes Ovarian Cancer Tumorigenesis and Predicts a Poor Prognosis.

BACKGROUND: Circular RNA is a type of non-coding RNA that is commonly found in eukaryotic genomes. They play an essential role in the biological processes of cell proliferation and cell apoptosis involved in normal development and abnormal tumorigenesis. In this study, we examined whether that the circular RNA GENE hsa_circ_0120175 is substantially expressed in epithelial ovarian cancer, and then explored whether hsa_circ_0120175 plays an important role in the occurrence and development of ovarian cancer. METHODS: A total of 40 patients with ovarian cancer were included in this study, and tissue samples were collected from both ovarian cancer tissues and paracancer tissues. The levels of hsa_circ_0120175 expression were determined using qRT-PCR in both varian cancer cells and tissues. This study assessed the impact of hsa_circ_0120175 on cellular proliferation, migration, and invasion using various in vitro assays with cultured ovarian carcinoma cells. RESULTS: Hsa_circ_0120175 was highly expressed in both human tissues and ovarian cancer cells. In ovarian cancer patients, the expression level of hsa_circ_0120175 was significantly different among The International Federation of Gynecology and Obstetrics (FIGO) stages (p = 0.03), and the difference was statistically significant. Multivariate Cox regression analysis showed that lymph node metastasis was independently related to Overall Survival (OS), and the difference was statistically significant (p = 0.033). In vitro, decreasing hsa_circ_0120175 significantly reduced ovarian carcinoma cell proliferation, migration, and invasion (p < 0.05). CONCLUSIONS: Hsa_circ_0120175 has the potential to serve as a biomarker for diagnosing and treating ovarian carcinoma. This is because it promotes cellular proliferation, migration, and invasion in epithelial ovarian carcinoma.

METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/ß-Catenin Axis.

Epithelial ovarian cancer (EOC) ranks third in the incidence of gynecological malignancies. m6A methylation as RNA modification plays a crucial role in the evolution, migration, and invasion of various tumors. However, the role of m6A methylation in ovarian cancer (OC) only recently has begun to be appreciated. Therefore, we used various bioinformatic methods to screen the public GEO datasets of epithelial ovarian cancer (EOC) for m6A methylation-related regulators. We identified methyltransferase 16 (METTL16) that was dramatically downregulated in EOC as such a regulator. We also identified metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a known target lncRNA of METTL16, in these five GEO datasets. RT-qPCR and immunohistochemical staining confirmed that compared with the normal ovarian tissues and cells, METTL16 was significantly downregulated, while lncRNA MALAT1 was significantly upregulated, in 30 EOC tissues of our own validation cohorts and EOC cell lines, revealing a negative correlation between METTL16 and lncRNA MALAT1. Moreover, our analysis unveiled a correlation between downregulated METTL16 and the known adverse prognostic factors of EOC patients in our own cohorts. The CCK-8, EdU, scratch wound healing, and transwell invasion assays revealed that METTL16 significantly suppressed the proliferating, migrating, and invading abilities of OC cells. The inhibitory effects of METTL16 on the in vivo tumor growth of EOC cells were measured by subcutaneous tumor formation assay in mice. Furthermore, the RIP, RNA stability assay, western blotting, and cytoimmunofluorescence staining showed that METTL16 hindered the growth of EOC cells through promoting the degradation of MALAT1 by binding that, in turn, upregulates ß-catenin protein and promotes nuclear transport of ß-catenin protein in EOC cells. This study suggests that METTL16 acts as a tumor suppressor gene of EOC by achieving its inhibitory function on the malignant progression of EOC through the METTL16/MALAT1/ß-catenin axis that are new targets for EOC diagnosis and therapy.

Serum soluble TREM2 is an independent biomarker associated with coronary heart disease.

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a unique receptor expressed by macrophages in atherosclerotic plaque and is involved in the progression of atherosclerosis. Whether serum soluble TREM2 (sTREM2) levels has a relationship with coronary heart disease (CHD) remains unclear. METHODS: The cross-sectional study included 86 patients with CHD and 86 controls matched with age and sex. Demographic information, medication history, and laboratory data were collected. sTREM2 concentrations were detected by enzyme-linked immunosorbent assay. We compared the sTREM2 levels in two groups and constructed stepwise linear regression analysis for factors related to the sTREM2 level in patients with CHD; we further used the logistic regression model to evaluate the relationship between sTREM2 and CHD. The diagnostic value of sTREM2 and other biomarkers in CHD was evaluated by the receiver operating characteristic curve (ROC). RESULTS: The serum level of sTREM2 in CHD patients is higher than that in controls. In CHD patients, the stepwise linear regression analysis found that sTREM2 levels were correlated with triglyceride (TG), high-density lipoprotein cholesterols (HDL-C), apolipoprotein B (ApoB) and smoking status. Logistic regression models showed that sTREM2 was associated independently with CHD after adjusted confounders. The ROC curve showed a sensitivity of 59.3% and specificity of 81.4% with an area under the curve of 0.781 (95% CI: 0.711-0.852) for the diagnosis of CHD with serum sTREM2 at a cut-off value of > 1104.894 pg/ml, indicating a higher diagnostic value than high sensitivity C reaction protein (hs-CRP) and apolipoprotein B (ApoB). CONCLUSION: In this study, we provide evidence that sTREM2 levels are elevated in CHD patients and are associated with various cardiovascular risk factors. Additionally, sTREM2 demonstrates better diagnostic performance compared to traditional indicators in identifying CHD. These findings suggest that sTREM2 may serve as a potential biomarker for coronary heart disease.

True hermaphroditism with sex cord tumor with annular tubules (SCTAT): a rare case report and review of the literature.

BACKGROUND: True hermaphroditism is a rare condition. It is defined as the presence of both testicular and ovarian tissues in the same individual. Sex cord tumour with annular tubules (SCTAT) is a rare stromal tumour of the sex cord that occurs mostly in the ovaries. CASE PRESENTATION: A 16-year-old girl presented to the gynaecology department with primary amenorrhea. Gynaecological examination revealed an enlarged clitoris that looked like a small penis. The chromosome karyotype was chimaera. The postoperative pathology confirmed true hermaphroditism with SCTAT. The patient underwent hormonal replacement after an operation and had no evidence of recurrence for 6 months. CONCLUSION: Cases of true hermaphroditism with SCTAT are extremely rare conditions. Surgery and hormonal replacement are important for improving the prognosis of such patients.

Clinical Significance of Methyltransferase-like 16 Expression in Epithelial Ovarian Cancer.

OBJECTIVE: To detect methyltransferase-like (METTL) 16 expression in epithelial ovarian cancer (EOC) by immunohistochemistry (IHC), and its relationship with clinicohistopathological parameters and prognosis. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Gynaecology and Pathology, The First Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), from February to June 2022. METHODOLOGY: METTL16 expression in 115 EOC patients was evaluated by IHC. According to the immunoreactive score (IRS), scores <6 represented low expressions and ≥6 high expressions. Clinicopathologic data and follow-up information were collected for statistical evaluation. RESULTS: METTL16 expression decreased in EOC (p = 0.001) and affected the poor prognosis of EOC patients. Low METTL16 patients expression had significantly higher frequencies of advanced FIGO stage, low grade, more lymph node metastasis, high CA125 levels, bilateral disease, distant metastasis, and high frequency of neural/vascular invasion compared to high METTL16 patients (p ≤0.001, <0.001, <0.001, 0.017, 0.027, <0.001, and 0.010, respectively). The survival analysis showed that the overall survival (p <0.0001) as well as the disease-free survival (p <0.0001) were remarkably shorter in low METTL16 patients compared to high METTL16 patients, suggesting worse survival. CONCLUSION: There was a clear association between the expression of METTL16, poor prognostic factors, and lower survival of EOC patients, suggesting that it might exert a vital effect on the malignant progression / prognosis of EOC. KEY WORDS: Epithelial ovarian cancer (EOC), METTL16, Immunohistochemistry, Prognosis.

Evaluation of the clinical effectiveness of modified sacrospinous ligament fixation via the anterior vaginal wall path for pelvic organ prolapse: A feasibility report based on 50 patients.

Objective: To describe the surgical techniques and short-term outcomes for 50 cases of modified sacrospinous ligament fixation via the anterior vaginal wall path for pelvic organ prolapse. Methods: 100 patients with pelvic organ prolapse (stage III or stage IV based on POP-Q staging) from January 2018 to January 2020 were retrospectively analyzed. Among them, 50 patients received modified sacrospinous ligament fixation via the anterior vaginal wall path for pelvic organ prolapse (mSSLF group), while the other 50 patients received pelvic reconstruction using T4 mesh (T4 group). Operative time, blood loss, postoperative POP-Q score, length of the hospital stay, complications, and postoperative pain were compared between the two groups. Results: The duration of the operation in mSSLF group was (50 ± 15.2 min), which was shorter than that of the T4 group (60 ± 14.8 min) (p = 0.02). No intraoperative complications were reported from the mSSLF group, whereas one vascular injury occurred in the T4 group. In both groups, postoperative pain and painful intercourse was significantly lower in the mSSLF group than in the SSLF group (p < 0.001). The exposed mesh rate was lower than T4 group. Conclusions: The rates of intraoperative complications, postoperative pain and mesh erosion were significantly lower than those of the T4 group, but there was no significant difference in the efficacy and safety of the treatment of pelvic organ prolapse. So mSSLF may be a feasible technique to manage severe prolapse, with promising short-term efficacy and safety.

Single-port laparoscopic sacrospinous ligament suspension via the natural vaginal cavity (SvNOTES) for pelvic prolapse: The first feasibility study.

Objective: This study aims to investigate the feasibility and short-term efficacy of single-port laparoscopic-assisted transvaginal natural cavity endoscopic sacrospinous ligament suspensions (SvNOTES). Methods: A total of 30 patients diagnosed with anterior or/and middle pelvic organ prolapse Stages III and IV underwent natural vaginal cavity (SvNOTES), and 30 patients who underwent conventional sacrospinous ligament (SSLF) were used as a control group. The operation time, blood loss, postoperative POP-Q score, length of hospital stay, and complications were compared between the two groups. Results: The operation time for SvNOTE was (60 ± 13) min, which was longer than (30 ± 15) min for SSLF (P = 0.04). However, the bleeding amount in SvNOTE was 29.44 ± 2.56, significantly lower than that in the SSLF group (80 ± 10; P = 0.02), and the postoperative hospital stay in the SvNOTE group was (4 ± 2) days, longer than (3 ± 1) days in SSLF (P = 0.02). However, there were no intraoperative complications in the SvNOTE group, whereas one ureteral injury occurred in the SSLF group; in addition, the postoperative POP-Q score was significantly better in the SvNOTE group than that in the SSLF group with increasing time (P < 0.001). Conclusion: Compared with SSLF, single-port laparoscopic sacrospinous ligament suspension via the natural vaginal cavity is visualized, greatly improving the success rate of sacrospinous ligament fixation, with less blood loss and fewer complications, arguably a safer and minimally invasive surgical approach.

HIF-1α Regulated WTAP Overexpression Promoting the Warburg Effect of Ovarian Cancer by m6A-Dependent Manner.

N6-methyladenosine (m6A) RNA methylation has been determined to execute crucial functions in tumorigenesis and cancer development. WT1-associated protein (WTAP) has an important "writer" role in m6A modification, and it is also a nuclear protein that colocalizes with splicing factors and plays a critical role in cell function and cancer progression. However, little is known about the role of WTAP in ovarian cancer (OC) and its mechanisms. In this study, we found for the first time that hypoxia-inducible factor (HIF)-1α could positively regulate increased expression of WTAP under hypoxia. And further results revealed that WTAP expression was closely associated with the clinicopathological features of OC, and high expression of WTAP predicted low survival rate in patients with OC. In addition, cell proliferation and invasive capacity were significantly reduced after knockdown of WTAP expression in OC cells. However, cell proliferation and invasive ability were significantly enhanced after overexpression of WTAP. Additionally, we find that WTAP interacts with DGCR8 (a crucial chip protein) to regulate the expression of microRNA-200 (miR-200) in an m6A-dependent way. Further experiments showed that the key glycolysis enzyme HK2 could be positively regulated by miR-200, which significantly affected the intracellular Warburg effect. In conclusion, this is considered uncovered that upregulation of WTAP expression by HIF-1α intercedes with miRNA processing, accelerates the Warburg impact, and advances the event and advancement of tumor, thus giving a novel viewpoint on m6A adjustment in OC movement.

Analysis of Short-Term Efficacy of Gasless Single-Port Laparoscopic Inguinal Lymphadenectomy Through Vulva Incision for Vulvar Cancer.

Objective: To investigate the feasibility and short-term efficacy of gasless single-port laparoscopic inguinal lymphadenectomy through vulva incision (VEIL-V). Methods: The data of 9 patients diagnosed as vulvar squamous cell carcinoma who underwent single-port laparoscopic inguinal lymph node dissection through vulvectomy incision were retrospectively analyzed. And 13 patients who underwent laparoscopic inguinal lymph node dissection through lower abdominal subcutaneous approach as the control group (VEIL-H). The operation time, blood loss, numbers of unilateral lymph nodes, hospitalization time, and complications between the two groups were compared. Results: The operation time of VEIL-V was 56.11 ± 5.94 min, which were shorter than that of VEIL-H (74.62 ± 5.50 min; P = 0.013). Bleeding amount in the VEIL-H was 29.44 ± 2.56, which was significantly lower than that of the VEIL-H group (43.08 ± 4.14 ml; P = 0.021). In the two groups, the numbers of unilateral lymph nodes harvested were similar. The differences in the postoperative hospital stay, skin, and lymphatic complications were not statistically significant. Conclusion: Compared with VEIL-H, gasless single-port laparoscopic inguinal lymphadenectomy through vulva incision reduces the difficulty of operation with shorter operation time, and less blood loss, which can be a safe and mini-invasive surgical approach.

Krüppel-like factor 14 deletion in myeloid cells accelerates atherosclerotic lesion development.

AIMS: Atherosclerosis is the dominant pathologic basis of many cardiovascular diseases. Large genome-wide association studies have identified that single-nucleotide polymorphisms proximal to Krüppel-like factor 14 (KLF14), a member of the zinc finger family of transcription factors, are associated with higher cardiovascular risks. Macrophage dysfunction contributes to atherosclerosis development and has been recognized as a potential therapeutic target for treating many cardiovascular diseases. Herein, we address the biologic function of KLF14 in macrophages and its role during the development of atherosclerosis. METHODS AND RESULTS: KLF14 expression was markedly decreased in cholesterol loaded foam cells, and overexpression of KLF14 significantly increased cholesterol efflux and inhibited the inflammatory response in macrophages. We generated myeloid cell-selective Klf14 knockout (Klf14LysM) mice in the ApoE-/- background for the atherosclerosis study. Klf14LysMApoE-/- and litter-mate control mice (Klf14fl/flApoE-/-) were placed on the Western Diet for 12 weeks to induce atherosclerosis. Macrophage Klf14 deficiency resulted in increased atherosclerosis development without affecting the plasma lipid profiles. Klf14-deficient peritoneal macrophages showed significantly reduced cholesterol efflux resulting in increased lipid accumulation and exacerbated inflammatory response. Mechanistically, KLF14 upregulates the expression of a key cholesterol efflux transporter, ABCA1 (ATP-binding cassette transporter A1), while it suppresses the expression of several critical components of the inflammatory cascade. In macrophages, activation of KLF14 by its activator, perhexiline, a drug clinically used to treat angina, significantly inhibited the inflammatory response and increased cholesterol efflux in a KLF14-dependent manner in macrophages without triggering hepatic lipogenesis. CONCLUSIONS: This study provides insights into the anti-atherosclerotic effects of myeloid KLF14 through promoting cholesterol efflux and suppressing the inflammatory response. Activation of KLF14 may represent a potential new therapeutic approach to prevent or treat atherosclerosis.

Phospholipid nanoparticles: Therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation.

BACKGROUND: Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Cholesterol crystals (CCs) induce inflammation in atherosclerosis and are associated with unstable plaques and poor prognosis, but no drug can remove CCs in the clinic currently. METHODS: We generated a phospholipid-based and high-density lipoprotein (HDL)-like nanoparticle, miNano, and determined CC-dissolving capacity, cholesterol efflux property, and anti-inflammation effects of miNano in vitro. Both normal C57BL/6J and Apoe-deficient mice were used to explore the accumulation of miNano in atherosclerotic plaques. The efficacy and safety of miNano administration to treat atherosclerosis were evaluated in the Ldlr-deficient atherosclerosis model. The CC-dissolving capacity of miNano was also detected using human atherosclerotic plaques ex vivo. FINDINGS: We found that miNano bound to and dissolved CCs efficiently in vitro, and miNano accumulated in atherosclerotic plaques, co-localized with CCs and macrophages in vivo. Administration of miNano inhibited atherosclerosis and improved plaque stability by reducing CCs and macrophages in Ldlr-deficient mice with favorable safety profiles. In macrophages, miNano prevented foam cell formation by enhancing cholesterol efflux and suppressed inflammatory responses via inhibiting TLR4-NF-κB pathway. Finally, in an ex vivo experiment, miNano effectively dissolved CCs in human aortic atherosclerotic plaques. INTERPRETATION: Together, our work finds that phospholipid-based and HDL-like nanoparticle, miNano, has the potential to treat atherosclerosis by targeting CCs and stabilizing plaques. FUNDING: This work was supported by the National Institutes of Health HL134569, HL109916, HL136231, and HL137214 to Y.E.C, HL138139 to J.Z., R21NS111191 to A.S., by the American Heart Association 15SDG24470155, Grant Awards (U068144 from Bio-interfaces and G024404 from M-BRISC) at the University of Michigan to Y.G., by the American Heart Association 19PRE34400017 and Rackham Helen Wu award to M.Y., NIH T32 GM07767 to K. H., Barbour Fellowship to D.L.

Improvements in High-Density Lipoprotein Quantity and Quality Contribute to the Cardiovascular Benefits by Anti-tumor Necrosis Factor Therapies in Rheumatoid Arthritis: A Systemic Review and Meta-Analysis.

Objective: Inflammation plays important role in atherosclerotic cardiovascular diseases (CVDs), but the interaction between the inflammation and lipid profile is largely unrevealed in humans. Patients with rheumatoid arthritis (RA) suffer from a higher risk of CVDs. Decreased total cholesterol (TC) and high-density lipoprotein (HDL) were prevalent in patients with RA. Anti-tumor necrosis factor (TNF) therapies relieve disease activity and decrease CVDs risk in RA, but their comprehensive effects on the lipid profile are unclear. This study aims to investigate the changes in blood lipid profile along time in the patients with RA accepting anti-TNF therapies by meta-analysis. Methods: The MEDLINE, the Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for eligible literature. Data of lipids were classified into short-, mid-, and long-term according to treatment duration. Meta-analyses were performed to compare the lipid levels before and after treatments. Results: A total of 44 records and 3,935 patients were included in the meta-analyses. Anti-TNF therapies were associated with significant increase in TC [mean difference (MD): +0.14, +0.23, and +0.26 mmol/l, respectively] and HDL (MD): +0.11, +0.12, and +0.11 mmol/l, respectively) in the short-, mid-, and long-term; anti-TNF therapies were associated with increased low-density lipoprotein (LDL) (MD: +0.06 mmol/l) and apolipoprotein A1 (ApoA1) (MD: +0.07 g/l) in the short-term, but not in the mid-term and long-term; triglyceride (TG) and apolipoprotein B (ApoB) do not change significantly in all the periods; proatherosclerotic indexes (TC/HDL, ApoB/ApoA1, and LDL/HDL) tend to decrease in the short- and mid-term, but return to baseline in the long-term after TNF inhibition. Conclusion: Anti-TNF therapies were related to a long-term raised HDL level, which, together with evidence of improved HDL function, may contribute partially to the decreased CVDs risk by TNF inhibition.

New Insight Into Metformin-Induced Cholesterol-Lowering Effect Crosstalk Between Glucose and Cholesterol Homeostasis via ChREBP (Carbohydrate-Responsive Element-Binding Protein)-Mediated PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Regulation.

[Figure: see text].

The microRNA212 regulated PEA15 promotes ovarian cancer progression by inhibiting of apoptosis.

PEA15 (Proliferation And Apoptosis Adaptor) is a 15kDa multifunctional phosphoprotein involved in various essential biological processes such as proliferation and apoptosis of cancer cells. Previous studies have demonstrated that PEA15 can promote the progression of many malignancies. In the present study, the expression of PEA15 in ovarian cancer and normal tissues analyzed in several databases and PEA15 was found to be significantly up-regulated in OC tissues compared to normal tissues. Immunochemical assays performed using 171 OC tissue specimens proved that the expression of PEA15 was remarkably positively correlated with the FIGO stage and associated with histologic subgroups of ovarian cancer. IHC assay for the two phosphorylation sites of PEA15 S116 and S104 was also performed. PEA15 high expression predicted a poor prognosis in OC patients analysed from K-M plot dataset. In addition, we proved knockdown of PEA15 inhibits OC cell proliferation and induces cell apoptosis by Bcl2 downregulation and Bax and cleaved Caspase-3 upregulation. Overexpression of PEA15 promotes the proliferative capacity of OC cells. Moreover, this study first discovered PEA15 expression in OC can be negatively regulated by microRNA212. Overexpression of miR-212 in ovarian cancer cells could cause downregulated the expression of PEA15 expression. Overexpression of miR-212 was found to exerted similar effects on the proliferation, and apoptosis of the ovarian cancer cells as that of PEA15 suppression. Additionally, overexpression of PEA15could at least partially abolished the effects of miR-212 on the proliferation, and apoptosis of ovarian cancer cells. In conclusion, our findings revealed PEA15 appears as a novel predictive biomarker, thus providing a valuable therapeutic target in OC treatment strategy.

Effects of metformin on blood lipid profiles in nondiabetic adults: a meta-analysis of randomized controlled trials.

PURPOSE: To evaluate the effects of metformin on serum lipid profiles in nondiabetic adults through a comprehensive meta-analysis. METHODS: In the present meta-analysis, randomized and controlled trials were collected by searching PubMed, Embase, and Cochrane Libraries from inception to April 2019. Compared with placebos, the effects of metformin treatment on lipid profiles in nondiabetic adults were evaluated. RESULTS: Forty-seven studies from 45 articles including 5731 participants were enrolled. Pooled results showed that metformin had significant effects on total cholesterol (mean change -6.57 mg/dl; 95% CI -9.66, -3.47; P = 0.000) and LDL-c (mean change -4.69 mg/dl; 95% CI -7.38, -2.00; P = 0.001), but insignificant effects on HDL-c (mean change -4.33 mg/dl; 95% CI -9.62, 0.96; P = 0.109) and triglyceride (mean change -0.85 mg/dl; 95% CI -0.36, 2.06; P = 0.169). Significant heterogeneities were found for all lipid profiles (HDL-c = 85.5%; LDL-c = 59.9%; total cholesterol = 75.3% and triglyceride = 67.1%). Different from the pooled data, in a subgroup analysis, the effect of metformin on triglyceride in patients with polycystic ovarian syndrome (PCOS) was significant with a mean reduction of 8.15 mg/dl. In addition, sensitivity analysis showed that the pooled effects of metformin on serum lipid profiles were stable. Publication bias derived from funnel plots or Begg's tests (P = 0.933, 0.860, 0.904, and 0.567 for HDL-c, LDL-c, total cholesterol, and triglyceride, respectively) was not significant. CONCLUSION: This meta-analysis revealed that metformin could reduce total cholesterol and LDL-c in nondiabetic adults. In addition, metformin might exert a triglyceride-lowering effect in nondiabetics with PCOS status.

Downregulation of Proline Hydroxylase 2 and Upregulation of Hypoxia-Inducible Factor 1α are Associated with Endometrial Cancer Aggressiveness.

INTRODUCTION: Proline hydroxylase 2 (PHD2) is involved in tumorigenesis. This study aimed to examine PHD2 and hypoxia-inducible factor 1α (HIF-1α) expression in different endometrial tissues and explore the correlations between PHD2 and HIF-1α expression with clinicopathological characteristics of endometrial cancer. METHODS: We collected 50 tissue sections of endometrial adenocarcinoma, 30 of atypical endometrial hyperplasia, and 30 of control normal endometrium. The expression of PHD2 was detected by PCR, Western blot, and immunohistochemical analysis. RESULTS: PHD2 mRNA and protein levels reduced in endometrial cancer tissues compared to normal endometrium (p<0.05). In contrast, HIF-1α expression levels increased in endometrial cancer tissues compared to normal endometrium (p<0.05). In addition, PHD2 and HIF-1α levels were correlated with lymphovascular stromal invasion (LVSI), postoperative FIGO stage, and lymph node metastasis of endometrial cancer (p<0.05). CONCLUSION: Our findings suggest that reduced expression of PHD2 and increased expression of HIF-1α are associated with endometrial cancer aggressiveness. PHD2 might be a novel biomarker and a potential target for endometrial cancer management.

Sodium/calcium overload and Sirt1/Nrf2/OH-1 pathway are critical events in mercuric chloride-induced nephrotoxicity.

Mercury (Hg), a significant toxic metal for nephrotoxicity, can be found in food (vegetable and seafood) and drinking water by contamination. Oxidative stress is involved in inorganic Hg-induced nephrotoxicity, but the Sirtuin1 (Sirt1)/Nrf2/OH-1 pathway and sodium (Na)/calcium (Ca) ions actions in mercuric chloride (HgCl2)-induced nephrotoxicity remains unclear to date. In this study, Kunming mice were treated HgCl2 (5 mg/kg) for 24 h to evaluate potential mechanism. Here, along with Sirt1 activation, pale kidney, hisologic conditions, typical apoptotic changes and TUNEL positive nuclei were observed under acute HgCl2 exposure. Specifically, although HgCl2 increased the expression of Nrf2, Keap1, OH-1 and NQO1, the mRNA levels of GSS, GCLC and GCLM showed no significant alterations in mice kidney. Moreover, mice exposed to HgCl2 decreased the concentrations of Mg, K, P, Mn, Fe, Zn, and elevated Na, Ca, Cu and Se in kidney. It was also observed that HgCl2 suppressed the ATPases (Na+-K+-ATPase, Ca2+-ATPase, Mg2+-ATPase and Ca2+-Mg2+-ATPase) activities and decreased the mRNA levels of Atp1a1, Atp1a2 in the kidney. Further study showed that HgCl2 elevated Na+ concentrations by markedly increased the mRNA levels of Na+ transporter. The present study revealed that HgCl2 induced Sirt1/Nrf2/OH-1 pathway activation while did not inhibit apoptosis in kidney of mice. Additionally, HgCl2 regulates Na+ concentrations, which might create secondary disorders in absorption and excretion of other ions. Altogether we assume that Sirt1/Nrf2/Na+/Ca2+ pathway might be a potential therapeutic target for treating acute HgCl2 induced nephrotoxicity.

Short-term effect of a negative colonoscopy in patients with functional constipation.

The yield of colonoscopy for neoplasia among patients with chronic constipation is very low. However, a negative colonoscopy may benefit these patients by decreasing anxiety and thereby alleviating constipation symptoms. We performed a prospective study to characterize the effect of a negative colonoscopy in patients with functional constipation. Seventy-five patients with chronic constipation were enrolled, and 69 patients were diagnosed with functional constipation through the Rome III criteria. After excluding patients whose constipation symptoms were affected by medications (e.g., laxatives, prokinetics), 45 patients were included in the study. Among the 45 patients, the average health-related anxiety score decreased from 21.0 to 15.6 at 1 week after colonoscopy (P < 0.01). Sustained improvement was observed in anxiety scores at 1 month (14.0), 2 months (12.4), and 6 months (11.2). Mean constipation symptom score was also decreased at 1 week (8.7), 1 month (8.0), 2 months (7.6), and 6 months (6.8) compared with the precolonoscopy period (11.5; P < 0.01). These results suggest that a negative colonoscopy in patients with functional constipation is associated with a decline in health-related anxiety and constipation symptom scores. (Registration number: ChiCTR-OOh-16008488).

Non-destructive 3D Microtomography of Cerebral Angioarchitecture Changes Following Ischemic Stroke in Rats Using Synchrotron Radiation.

A better understanding of functional changes in the cerebral microvasculature following ischemic injury is essential to elucidate the pathogenesis of stroke. Up to now, the simultaneous depiction and stereological analysis of 3D micro-architectural changes of brain vasculature with network disorders remains a technical challenge. We aimed to explore the three dimensional (3D) microstructural changes of microvasculature in the rat brain on 4, 6 hours, 3 and 18 days post-ischemia using synchrotron radiation micro-computed tomography (SRµCT) with a per pixel size of 5.2 µm. The plasticity of angioarchitecture was distinctly visualized. Quantitative assessments of time-related trends after focal ischemia, including number of branches, number of nodes, and frequency distribution of vessel diameter, reached a peak at 6 h and significantly decreased at 3 days and initiated to form cavities. The detected pathological changes were also proven by histological tests. We depicted a novel methodology for the 3D analysis of vascular repair in ischemic injury, both qualitatively and quantitatively. Cerebral angioarchitecture sustained 3D remodeling and modification during the healing process. The results might provide a deeper insight into the compensatory mechanisms of microvasculature after injury, suggesting that SRµCT is able to provide a potential new platform for deepening imaging pathological changes in complicated angioarchitecture and evaluating potential therapeutic targets for stroke.