Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Hysteroscopic Fenestration with Precise Incision of the Cavity Septum: A Novel Minimally Invasive Surgery of Complete Septate Uterus with Double Cervix.

STUDY OBJECTIVE: This study aimed to develop and describe a novel surgical procedure that involves hysteroscopic fenestration with precise incision of the complete uterine septum and double cervix preservation after magnetic resonance imaging (MRI) evaluation in patients and to evaluate its efficacy. DESIGN: A prospective consecutive clinical study. SETTING: A university teaching hospital. PATIENTS: Twenty-four patients with complete septate uterus and double cervix. INTERVENTIONS: Three-dimensional reconstruction of uterus was performed with pelvic MRI and three-dimensional SPACE sequence scanning. Hysteroscopic fenestration with precise incision of the cavity septum and double cervix preservation was performed in patients. Three months after operation, follow-up pelvic MRI and second-look hysteroscopy were performed conventionally. MEASUREMENTS AND MAIN RESULTS: Operating time, blood loss, operative complications, MRI and hysteroscopic changes of uterus, symptoms improvement, and reproductive outcomes were assessed. The surgery was successfully completed without any intraoperative complications in all patients. Operating time was 21.71 ± 8.28 minutes (range, 10-40 minutes) and blood loss was 9.92 ± 7.14 mL (range, 5-30 mL). Postoperative MRI showed the uterine anteroposterior diameter (3.66 cm vs 3.92 cm; p <.05) was increased. Postoperative MRI and the second-look hysteroscopy showed the cavity shape and uterine volume were expanded to the normal. Symptoms of dysmenorrhea, abnormal uterine bleeding, and dyspareunia were ameliorated after the surgery in 70% of patients (7 of 10), 60% of patients (3 of 5), and 1 patient, respectively. The preoperative spontaneous abortion rate was 80% (4 of 5) and the postoperative spontaneous abortion rate was 11.11% (1 of 9). After the surgery, there were 2 ongoing pregnancies and 6 pregnancies ended in term births. Two live births were delivered by cesarean section and 4 by vaginal delivery without cervical incompetence during pregnancy. CONCLUSIONS: Hysteroscopic fenestration with precise incision of the uterine septum and double cervix preservation is an effective surgical procedure.

The Effects of circ_000558/miR-1225-5p/ARL4C on Regulating the Proliferation of Renal Cell Carcinoma Cells.

Renal cell carcinoma (RCC) is one of the top ten tumors over the world. RCC is not sensitive to radiotherapy and chemotherapy. Therefore, it is necessary to find new targets for the treatment. CircRNAs are a special type of noncoding RNAs, which play important roles in many types of cancer. In this study, we found circ_000558 was upregulated in RCC cells, and it elevated the proliferation ability of RCC cells. The relationship between miR-1225-5p and circ_000558 or ARL4C was predicted via circBank and circular RNA interactome and confirmed by dual-luciferase reporter assay. Then, the effects of circ_000558/miR-1225-5p/ARL4C on RCC cell proliferation and apoptosis were assessed by CCK-8 assay. The results revealed that the knockdown of ARL4C significantly reduced RCC cell proliferation and overexpression of circ_000558 could significantly induce RCC cell proliferation after miR-1225-5p treatment further promoted the inhibitory ability of ARL4C knockdown. Overall, our study suggested that circ_000558/miR-1225-5p/ARL4C network was related to the RCC cell proliferation. This finding could provide new targets for the treatment and prognosis of RCC.

Transient Receptor Potential Channel 1 Potentially Serves as a Biomarker Indicating T/TNM Stages and Predicting Long-Term Prognosis in Patients With Renal Cell Carcinoma.

Background: Transient receptor potential channel 1 (TRPC1) regulates the progression of several cancers, but its clinical implication in renal cell carcinoma (RCC) has not been explored yet. This study aimed to investigate the correlation of TRPC1 with clinical characteristics and prognosis in patients with RCC. Methods: Totally, 177 patients with primary RCC who received surgical resection were retrospectively screened. Their tumor and paired adjacent tissue specimens were retrieved to assess TRPC1 mRNA expression using RT-qPCR and TRPC1 protein expression using immunohistochemistry (IHC). Results: Both TRPC1 IHC score and TRPC1 mRNA expression were elevated in RCC tissue than in adjacent tissue (both P < 0.001). Meanwhile, both TRPC1 IHC score and TRPC1 mRNA expression in tumor were associated with higher T stage (both P = 0.02) and TNM stage (P = 0.009, P = 0.003, respectively). However, no correlation was found in tumor TRPC1 IHC score or TRPC1 mRNA expression with other tumor properties (all P > 0.05). Besides, the 3-, 5-, and 7-year overall survival (OS) were 81.4, 68.6, and 60.2%, respectively in patients with high tumor TRPC1 protein, while they were 89.3, 82.7, and 76.7%, respectively in patients with low tumor TRPC1 protein. High (vs. low) TRPC1 protein in the tumor was associated with shorter OS (P = 0.017), while high (vs. low) TRPC1 mRNA in the tumor was not correlated with OS (P = 0.144). By the forward stepwise method, TRPC1 protein expression independently predicted poor OS (P = 0.01, hazard ratio = 2.052). Conclusion: TRPC1 serves as a potential biomarker reflecting tumor features and long-term survival profile in patients with RCC.

CRMP4 CpG Hypermethylation Predicts Upgrading to Gleason Score ≥ 8 in Prostate Cancer.

Background: This study determined the predictive value of CRMP4 promoter methylation in prostate tissues collected by core needle biopsies for a postoperative upgrade of Gleason Score (GS) to ≥8 in patients with low-risk PCa. Method: A retrospective analysis of the clinical data was conducted from 631 patients diagnosed with low-risk PCa by core needle biopsy at multiple centers and then underwent Radical Prostatectomy (RP) from 2014-2019. Specimens were collected by core needle biopsy to detect CRMP4 promoter methylation. The pathologic factors correlated with the postoperative GS upgrade to ≥8 were analyzed by logistic regression. The cut-off value for CRMP4 promoter methylation in the prostate tissues collected by core needle biopsy was estimated from the ROC curve in patients with a postoperative GS upgrade to ≥8. Result: Multivariate logistic regression showed that prostate volume, number of positive cores, and CRMP4 promoter methylation were predictive factors for a GS upgrade to ≥8 (OR: 0.94, 95% CI: 0.91-0.98, P=0.003; OR: 3.16, 95% CI: 1.81-5.53, P<0.001; and OR: 1.43, 95% CI: 1.32-1.55, P<0.001, respectively). The positive predictive rate was 85.2%, the negative predictive rate was 99.3%, and the overall predictive rate was 97.9%. When the CRMP4 promoter methylation rate was >18.00%, the low-risk PCa patients were more likely to escalate to high-risk patients. The predictive sensitivity and specificity were 86.9% and 98.8%, respectively. The area under the ROC curve (AUC) was 0.929 (95% CI: 0.883-0.976; P<0.001). The biochemical recurrence (BCR)-free survival, progression-free survival (PFS), and cancer-specific survival (CSS) were worse in patients with CRMP4 methylation >18.0% and postoperative GS upgrade to ≥8 than in patients without an upgrade (P ≤ 0.002). Conclusion: A CRMP4 promoter methylation rate >18.00% in prostate cancer tissues indicated that patients were more likely to escalate from low-to-high risk after undergoing an RP. We recommend determining CRMP4 promoter methylation before RP for low-risk PCa patients.

CTSV (cathepsin V) promotes bladder cancer progression by increasing NF-κB activity.

Chronic inflammation is positively associated with the development of urinary bladder cancer. However, its detailed regulatory mechanism remains elusive. The quantitative real-time polymerase chain reaction was used to measure mRNA levels of relative genes. The protein levels were monitored by western blotting. Cell proliferation and viability were evaluated by the cell counting Kit 8 (CCK8) and colony formation assays, respectively. The dual-luciferase reporter assay was performed to assay the transcriptional activity. In vivo experiments were implemented in nude mice as well. The TCGA database analysis suggested that the aberrant expression of cathepsin V (CTSV) was related to a poor outcome in bladder cancer patients. CTSV boosted the inflammation reaction, which facilitated the development of bladder cancer. The overexpression of CTSV increased the proliferation and viability of bladder cancer cells. On the contrary, the deletion of CTSV significantly inhibited the proliferation and viability of bladder cancer cells. The tumor repression resulting from CTSV deficiency in vitro was also verified in vivo. Moreover, multiple cancer-associated luciferase screening showed that the overexpression of CTSV triggered the inflammatory signaling pathway, which could be restored by introducing the NF-κB inhibitor. CTSV is upregulated and promotes proliferation through the NF-κB pathway in bladder cancer and may be a potential target in inflammation-associated bladder cancer.

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Genome-Wide Association of Kidney Traits in Hispanics/Latinos Using Dense Imputed Whole-Genome Sequencing Data: The Hispanic Community Health Study/Study of Latinos.

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low-frequency and ancestry-specific variants. METHODS: This study used imputed whole-genome sequencing from the Trans-Omics for Precision Medicine project to identify novel loci for estimated glomerular filtration rate and urine albumin-to-creatinine ratio in up to 12 207 Hispanics/Latinos. Replication was performed in the Women's Health Initiative and the UK Biobank when variants were available. RESULTS: Two low-frequency intronic variants were associated with estimated glomerular filtration rate (rs58720902 at AQR, minor allele frequency=0.01, P=1.6×10-8) or urine albumin-to-creatinine ratio (rs527493184 at ZBTB16, minor allele frequency=0.002, P=1.1×10-8). An additional variant at PRNT (rs2422935, minor allele frequency=0.54, P=2.89×10-8) was significantly associated with estimated glomerular filtration rate in meta-analysis with replication samples. We also identified 2 known loci for urine albumin-to-creatinine ratio (BCL2L11 rs116907128, P=5.6×10-8 and HBB rs344, P=9.3×10-11) and validated 8 loci for urine albumin-to-creatinine ratio previously identified in the UK Biobank. CONCLUSIONS: Our study shows gains in gene discovery when using dense imputation from multi-ethnic whole-genome sequencing data in admixed Hispanics/Latinos. It also highlights limitations in genetic research of kidney traits, including the lack of suitable replication samples for variants that are more common in non-European ancestry and those at low frequency in populations.

Long non-coding RNA NEAT1 promotes bladder progression through regulating miR-410 mediated HMGB1.

LncRNA NEAT1 is reported as a crucial oncogene in multiple cancers. But, its biological role in bladder cancer is barely understood. Therefore, we concentrated on the function and role of NEAT1 in bladder cancer. Firstly, NEAT1 expression in bladder cancer cells was determined and it was displayed NEAT1 was significant elevated. NEAT1 was knockdown and overexpressed in T24 and J82 cells. Then it was indicated that NEAT1 silence greatly inhibited bladder cancer cell proliferation with an increased ratio of apoptotic cells and severe cell cycle arrest. Overexpression of NEAT1 exhibited a reversed process in bladder cancer cells. Additionally, in vivo experiments were employed using establishment of nude mice models. NEAT1 knockdown inhibited bladder cancer growth while increase of NEAT1 promoted bladder cancer development in vivo. By employing the bioinformatics analysis, we speculated that miR-410 was as a downstream target of NEAT1. Then, the targeting association between them was proved in our research and we implicated miR-410 was dramatically restrained in bladder cancer cells. Meanwhile, it was exhibited that miR-410 was negatively regulated by NEAT1. Apart from these, HMGB1 was speculated as a downstream target of miR-410. Dual-luciferase reporter assay was used to prove the correlation between miR-410 and HMGB1. Up-regulation of miR-410 restrained HMGB1 levels and NEAT1 can regulate HMGB1 level via sponging miR-410. To sum up, we implied NEAT1/miR-410/HMGB1 axis participated in bladder cancer.

MEG3 interacted with miR-494 to repress bladder cancer progression through targeting PTEN.

The long noncoding RNA MEG3 is a significant tumor-suppressive gene in various tumors. But its biological role in bladder cancer remains uninvestigated. Herein, the biological mechanism of MEG3 in bladder cancer pathogenesis was explored. First, the expression of MEG3 in bladder cancer cells was examined, and we found that it was significantly reduced. In addition, in bladder cancer cells, we observed htat miR-494 was increased. Then, MEG3 was overexpressed in UMUC3 and SW780 cells and it could negatively modulate miR-494 expression. Bladder cancer cell proliferation was repressed, cell apoptosis was triggered and meanwhile, the cell cycle was remarkably arrested by the overexpression of MEG3. Moreover, the increase of MEG3 suppressed bladder cancer cell migration and invasion capacity. MEG3 can sponge miR-494 and the binding sites between them were confirmed by carrying out a series of functional assays. Furthermore, PTEN was speculated as a putative target of miR-494. Meanwhile, we found that miR-494 inhibitors induced PTEN. Finally, in vivo assays were conducted to prove that MEG3 can restrain bladder tumor growth by modulating miR-494 and PTEN. In conclusion, it was suggested MEG3 can interact with miR-494 to regulate PTEN in bladder cancer development.

MicroRNA-30a-3p functions as a tumor suppressor in renal cell carcinoma by targeting WNT2.

The expression and function of microRNA (miR)-30a-3p in several types of human cancer have been explored. However, the biological function of miR-30a-3p in renal cell carcinoma (RCC) remains largely unknown. In this study, we demonstrate that expression of miR-30a-3p is down-regulated in RCC tissues compared to adjacent normal tissues. Furthermore, ectopic expression of miR-30a-3p significantly suppressed the proliferation, migration, and invasion of a human RCC cell line in vitro, while miR-30a-3p inhibited tumor growth in vivo as well. TargetScan software identified Wnt2 as a potential direct target of miR-30a-3p. To confirm this relationship, Wnt2 was ectopically expressed. The effects of miR-30a-3p on RCC cell proliferation and invasion were subsequently restored. Therefore, the results of this study support an anti-tumor role for miR-30a-3p in RCC progression which is potentially mediated via Wnt2.

Certain BCG-reactive responses are associated with bladder cancer prognosis.

A subset of bladder patients does not respond to BCG treatment effectively and the underlying reason behind this observation is currently unclear. CD4+ T cells are composed of various subsets that each expresses a distinctive set of cytokines and can potently shift the immune response toward various directions. In this study, we examined the CD4+ T-cell cytokine response in bladder cancer patients toward BCG stimulation. We found that bladder cancer patients presented a variety of responses toward BCG, with no uniform characteristics. Those patients with high IFN-γ and IL-21 expression in CD4+ T cells presented significantly better prognosis than patients with low cytokine secretion in CD4+ T cells. Tumor-infiltrating CD4+ T cells were significantly less potent in expressing IFN-γ, IL-4, and IL-17, and more potent in expressing IL-10 than circulating CD4+ T cells. In addition, we found no difference in CD80, CD86, or MHC II expression by macrophages from patients with different IFN-γ and IL-21 levels. However, the secretion of IL-12, a Th1-skewing cytokine, was released at significantly higher level by macrophages from patients with high IFN-γ or high IL-21 secretion. We also identified that modulating monocytes/macrophages by GM-CSF-mediated polarization resulted in significantly elevated expression of IFN-γ and IL-21 from CD4+ T cells. Overall, these results suggested that the specific types of responses mounted by CD4+ T cells were critical to the final outcome of bladder cancer patients and can be influenced by monocyte/macrophage polarization.

MicroRNA-142-5p promotes cell growth and migration in renal cell carcinoma by targeting BTG3.

PURPOSE: Some microRNA (miRNA) levels have been found to be dysregulated in cancer patients, suggesting the potential usefulness of miRNAs in cancer therapies. The purpose of this study was to investigate the expression of miR-142-5p in human renal cell carcinoma (RCC) and its potential role in tumor growth and metastasis. METHODS: The expression level of miR-142-5p in human RCC tissue and cell lines was determined by quantitative reverse transcription polymerase chain reaction analysis. MTT, colony formation, Transwell, and cell cycle assays were performed to explore the potential functions of miR-142-5p in human RCC cells. The potential target gene of miR-142-5p was identified and confirmed via luciferase reporter assays. RESULTS: miR-142-5p expression was elevated in RCC tissues and cell lines. Overexpression of miR-142-5p significantly promoted cell proliferation and colony formation and could prevent G1 phase arrest among RCC 786-O cells. Meanwhile, the migration potential of 786-O cells was greater than that of control cells. BTG3 was identified as a direct target of miR-142-5p, and re-expression of BTG3 reversed the miR-142-5p-induced cell proliferation. CONCLUSION: miR-142-5p promoted the proliferation and migration of RCC cells by targeting BTG3. With this potential onco-miRNA role in the progression of RCC, miR-142-5p may be a therapeutic target for the treatment of RCC.

Downregulation of miR-193a-3p inhibits cell growth and migration in renal cell carcinoma by targeting PTEN.

Although miR-193a-3p has been found to be dysregulated in variety of human tumors, little is known about its role in renal cell carcinoma. This study was designed to investigate the function and underlying mechanism of miR-193a-3p in human renal cell carcinoma tissues and cell lines. Here, we demonstrated that the expression of miR-193-3p was increased in renal cell carcinoma tissues and cell lines. In addition, knockdown of miR-193a-3p significantly inhibited cell proliferation and colony formation and induced cells into G1 phase arrest. Meanwhile, the migration potential of 786-O cells was also decreased compared to control group. Furthermore, we identified PTEN as a direct and functional target of miR-193a-3p, at least partly responsible for promoting tumor effect of miR-193a-3p in renal cell carcinoma. Taken together, the findings indicated for the first time that miR-193a-3p functions as a tumor-promoting microRNA by directly targeting PTEN in renal cell carcinoma.

Diagnosis and treatment of cervical papillary squamous cell carcinoma with unknown depth of stromal invasion.

OBJECTIVE: To evaluate the diagnosis and treatment of papillary squamous cell carcinoma (PSCC) of the uterine cervix with unknown depth of stromal invasion. METHODS: In a retrospective study, the diagnostic and treatment strategies after colposcopy-guided biopsy sampling were assessed among patients seen at a university hospital in Shanghai, China, in 2008-2015. RESULTS: Among 55 patients, 29 with clinically visible lesions underwent radical hysterectomy; the final pathologic diagnosis was invasive squamous cell carcinoma in all patients. Of these patients, eight had undergone loop electrosurgical excision procedure (LEEP) and two had undergone a second biopsy sampling before radical hysterectomy was performed. Of the 26 patients with no clinically visible lesions, 17 had cervical lesions as confirmed by medical imaging and 12 of these patients underwent LEEP. The pathologic examination showed lesions of varying severity but no cancer in situ. The remaining five patients underwent radical hysterectomy; one of these patients was found to have micro-invasive cancer. CONCLUSION: Patients with PSCC with unknown depth of stromal invasion and clinically visible lesions receive radical hysterectomy rather than undergoing a second biopsy sampling or LEEP. Less invasive surgery is recommended for patients with no clinically visible lesions.

Prospective Study of CRMP4 Promoter Methylation in Prostate Biopsies as a Predictor For Lymph Node Metastases.

Background: For patients with prostate cancer (PCa), the presence of pelvic lymph node metastasis (LNM) is a strong predictor of poor outcome. However, the approaches with promising sensitivity and specificity to detect LNM are still lacking. We investigated the value of collapsin response mediator protein 4 (CRMP4) promoter methylation in biopsies as a predictor for LNM. Methods: CRMP4 promoter methylation at two previously identified CpG sites was determined in 80 case-matched biopsy samples (the training set) using bisulfite pyrosequencing. The predictive cutoff value was independently validated using cohort I of 339 PCa patients (Southern China) and cohort II of 328 case patients (Germany, across China). Mann-Whitney U test, the receiver operating characteristic curve, McNemar's test, and logistic regression were used to assess data. All statistical tests were two-sided. Results: In the training set, CRMP4 promoter methylation (≥15.0% methylated) was statistically significantly associated with LNM (P < 001). Successful validations were achieved in both cohorts I and II (sensitivity = 92.3%, 95% confidence interval [CI] = 79.3 to 97.9, and sensitivity = 92.2%, 95% CI = 81.1 to 97.8, respectively; specificity = 92.7%, 95% CI = 80.2 to 99.1, and specificity = 91.3%, 95% CI = 87.4 to 94.4, respectively). The sensitivity of CRMP4 promoter methylation is superior to conventional MRI (cohort I: 92.3% vs 26.2%, P < 001; cohort II: 92.2% vs 33.3%, P < 001). CRMP4 promoter methylation is an independent predictor of LNM (cohort I: hazard ratio [HR] = 8.35, 95% CI = 5.64 to 12.35, P < 001; cohort II: HR = 12.46, 95% CI = 5.82 to 26.70, P < 001) in a multivariable analysis model. Conclusion: CRMP4 promoter methylation in diagnostic biopsies could be a robust biomarker for LNM in PCa.

Expression of Tiam1 and Rac1 proteins in renal cell carcinoma and its clinical-pathological features.

PURPOSE: To explore the connections between Tiam1 and Rac1 expression in renal cell carcinoma (RCC), and its pathological type, grading, invasion and metastasis. METHODS: Tiam1 and Rac1 expression was measured in 60 specimens of RCC (including 42 clear cell cases, 12 papillary cases, and 6 chromophobe cases) and a 10-specimen control group using quantum dots IHC labeling, complete with clinical and pathological records, dated 2008 to 2014, were taken from the archives of the Department of Pathology, People's Hospital of Wuhan University. The expressions of Tiam1 and Rac1 proteins in specimens were measured using immunohistochemical (IHC) and quantum dots-labeling methods to examine their relationships to the clinical and pathological characteristics of RCC. The HIPAS-1000 software was used to quantitatively analyze on the results to obtain absorbance and positive area ratio (PAR) values, and SPSS 15.0 was used to perform single-factor analysis of variance and q verification. Spearman's rank correlation test is used to verify the correlation between absorbance and PAR of the two proteins. RESULTS: 1. QDs IHC staining. Tiam1 and Rac1 expression is high in RCC, and low in surrounding tissues (P<0.05). 2. Expression levels of both proteins show no correlation with patient sex, age, or tumor size (P>0.05), yet correlate with the differentiation, stage, and lymphatic metastasis of tumors (P<0.05). Spearman's test shows a positive correlation between the expression levels of Tiam1 and Rac1 in RCC tissues (r=0.425, P<0.05). CONCLUSION: 1. Abnormal Tiam1 and Rac1 expression may be an early molecular event in RCC, suggesting they are carcinogens related to proto-oncogenes. 2. Tiam1 and Rac1 expression levels correlate with the differentiation, stage, and lymphatic metastasis of RCC, suggesting they play important roles in its invasion and metastasis. 3. The expression levels of Tiam1 and Rac1 are positively correlated within RCC, suggesting a synergy between the two in controlling its pathogenesis and development.

Astragalus membranaceus ameliorates renal interstitial fibrosis by inhibiting tubular epithelial-mesenchymal transition in vivo and in vitro.

Epithelial-mesenchymal transition (EMT) induces the progression of renal tubulointerstitial fibrosis. Astragalus membranaceus (AM) is a traditional Chinese herbal medicine that has been demonstrated to exert anti-inflammatory and anti-cancer effects, in addition to protecting and supporting the immune system. The present study investigated the effects of AM on renal fibrosis. A mouse model of unilateral ureteral obstruction (UUO) was established and treated with various concentrations of AM (100, 200 or 400 mg/kg/day). Interstitial fibrosis markedly increased in the UUO mice. AM significantly reduced the obstruction-induced upregulation of α-smooth muscle actin (α-SMA) and downregulation of E-cadherin in the kidneys of the UUO mice (P<0.05). Furthermore, AM treatment significantly inhibited the induction of EMT and the deposition of extracellular matrix. In addition, a transforming growth factor (TGF)-ß1-stimulated murine renal proximal tubule cell line (NRK-52E) was treated with various concentrations of AM (10, 20, and 40 µg/ml). E-cadherin expression levels significantly decreased and those of α-SMA significantly increased in NRK-52E cells stimulated with TGF-ß1 in vitro (P<0.05). Co-treatment with AM reversed these effects (P<0.05), and AM treatment reduced TGF-ß1-induced expression and Smad2/3 phosphorylation (P<0.05). These results suggested that AM antagonizes tubular EMT by inhibiting the Smad signaling pathway.

Subcostal Port Placement for Lateral Transperitoneoscopic Adrenalectomy: Assessment of Surgical Efficacy.

The purpose of this study was to evaluate the safety and efficacy of the modified lateral transperitoneal (MLTP) approach in comparison with the traditional lateral transperitoneal (LTP) and lateral retroperitoneal (LRP) approach. From January 2008 to December 2012, 287 patients underwent laparoscopic adrenalectomy, and the MLTP, LTP and LRP approaches were used in 93, 96 and 98 patients. The patients' demographics and surgical outcomes from the three approaches were reviewed and compared. There were no significant differences in the general demographic or postoperative recovery variables among the three groups. However, the average volume of blood lost was lower for the MLTP group than for the other two groups. Additionally, the average operative time was significantly shorter in the MLTP group than in the LTP group and slightly shorter than in the LRP group, but the differences were not statistically significant. This study shows that the MLTP approach is a safe and effective procedure which is associated with shorter operative time and lower volumes of blood loss.

Role of microRNA-27a in down-regulation of angiogenic factor AGGF1 under hypoxia associated with high-grade bladder urothelial carcinoma.

Hypoxia stimulates angiogenesis under a variety of pathological conditions, including malignant tumors by inducing expression of angiogenic factors such as VEGFA. Surprisingly, here we report significant association between down-regulation of a new angiogenic factor AGGF1 and high-grade urothelial carcinoma. The proportion of strong AGGF1 expression cases was significantly lower in the high-grade urothelial carcinoma group than that in the low-grade urothelial carcinoma group (P=1.40×10(-5)) or than that in the normal urothelium tissue group (P=2.11×10(-4)). We hypothesized that tumor hypoxia was responsible for differential expression of the AGGF1 protein in low- and high-grade urothelial carcinomas, and therefore investigated the molecular regulatory mechanism for AGGF1 expression under hypoxia. Under hypoxic conditions, AGGF1 protein levels declined without any change in mRNA levels and protein stability. Hypoxia-induced down-regulation of AGGF1 was mediated by miR-27a. Overexpression of miR-27a suppressed AGGF1 expression through translational inhibition, but not by RNA degradation. Moreover, the hypoxia-induced decrease of AGGF1 expression disappeared after miR-27a expression was inhibited. Furthermore, down-regulation of AGGF1 reduced hypoxia-induced apoptosis in cancer cells. Taken together, the results of this study indicate that (1) hypoxia down-regulates expression of the AGGF1 protein, but not AGGF1 mRNA, by inducing expression of miR-27a; (2) Down-regulation of AGGF1 had an apparent protective role for cancer cells under hypoxia; (3) Down-regulation of the AGGF1 protein confers a significant risk of high-grade human urothelial bladder carcinoma.