Cellular senescence and metabolic reprogramming model based on bulk/single-cell RNA sequencing reveals PTGER4 as a therapeutic target for ccRCC.

Clear cell renal cell carcinoma (ccRCC) is the prevailing histological subtype of renal cell carcinoma and has unique metabolic reprogramming during its occurrence and development. Cell senescence is one of the newly identified tumor characteristics. However, there is a dearth of methodical and all-encompassing investigations regarding the correlation between the broad-ranging alterations in metabolic processes associated with aging and ccRCC. We utilized a range of analytical methodologies, such as protein‒protein interaction network analysis and least absolute shrinkage and selection operator (LASSO) regression analysis, to form and validate a risk score model known as the senescence-metabolism-related risk model (SeMRM). Our study demonstrated that SeMRM could more precisely predict the OS of ccRCC patients than the clinical prognostic markers in use. By utilizing two distinct datasets of ccRCC, ICGC-KIRC (the International Cancer Genome Consortium) and GSE29609, as well as a single-cell dataset (GSE156632) and real patient clinical information, and further confirmed the relationship between the senescence-metabolism-related risk score (SeMRS) and ccRCC patient progression. It is worth noting that patients who were classified into different subgroups based on the SeMRS exhibited notable variations in metabolic activity, immune microenvironment, immune cell type transformation, mutant landscape, and drug responsiveness. We also demonstrated that PTGER4, a key gene in SeMRM, regulated ccRCC cell proliferation, lipid levels and the cell cycle in vivo and in vitro. Together, the utilization of SeMRM has the potential to function as a dependable clinical characteristic to increase the accuracy of prognostic assessment for patients diagnosed with ccRCC, thereby facilitating the selection of suitable treatment strategies.

Metabolic reprogramming based on RNA sequencing of gemcitabine-resistant cells reveals the FASN gene as a therapeutic for bladder cancer.

Bladder cancer (BLCA) is the most frequent malignant tumor of the genitourinary system. Postoperative chemotherapy drug perfusion and chemotherapy are important means for the treatment of BLCA. However, once drug resistance occurs, BLCA develops rapidly after recurrence. BLCA cells rely on unique metabolic rewriting to maintain their growth and proliferation. However, the relationship between the metabolic pattern changes and drug resistance in BLCA is unclear. At present, this problem lacks systematic research. In our research, we identified and analyzed resistance- and metabolism-related differentially expressed genes (RM-DEGs) based on RNA sequencing of a gemcitabine-resistant BLCA cell line and metabolic-related genes (MRGs). Then, we established a drug resistance- and metabolism-related model (RM-RM) through regression analysis to predict the overall survival of BLCA. We also confirmed that RM-RM had a significant correlation with tumor metabolism, gene mutations, tumor microenvironment, and adverse drug reactions. Patients with a high drug resistance- and metabolism-related risk score (RM-RS) showed more active lipid synthesis than those with a low RM-RS. Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect.

A case report of anti-GAD65 antibody-positive autoimmune encephalitis in children associated with autoimmune polyendocrine syndrome type-II and literature review.

Background: Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients, including stiff person syndrome, cerebellar ataxia, refractory epilepsy, and limbic and extra limbic encephalitis. While there are few case reports and research on anti-GAD65 antibody-associated encephalitis in adults, such cases are extremely rare in pediatric cases. Methods: For the first time, we report a case of anti-GAD65-positive autoimmune encephalitis associated with autoimmune polyendocrine syndrome (APS) type II. We reviewed previously published pediatric cases of anti-GAD65 autoimmune encephalitis to discuss their clinical features, laboratory tests, imaging findings, EEG patterns, and prognosis. Case presentation: An 8-year-old, male child presented to the outpatient department after experiencing generalized convulsions for twenty days. The child was admitted for epilepsy and had received oral sodium valproate (500 mg/day) in another center, where investigations such as USG abdomen and MRI brain revealed no abnormalities, however, had abnormal EEG with diffuse mixed activity in the left anterior middle prefrontal temporal region. On the follow-up day, a repeat blood test showed a very low serum drug concentration of sodium valproate hence the dose was increased to 750 mg/day. Then, the child experienced adverse effects including increased sleep, thirst, and poor appetite, prompting the parents to discontinue the medication. A repeat MRI showed increased signals on FLAIR sequences in the right hippocampus hence admitted for further management. The child's past history included a diagnosis of hypothyroidism at the age of 4, and receiving levothyroxine 75 mcg once daily. His parents are healthy with no history of any similar neurological, autoimmune, or genetic diseases, but his uncle had a history of epilepsy. At presentation, he had uncontrolled blood glucose levels with elevated HbA1c levels. Additionally, the serum and CSF autoantibodies were positive against the anti-GAD65 antibody with the titer of 1:100 and 1:32 respectively. The patient was managed with a mixed type of insulin regimen and received first-line immunotherapy (intravenous immunoglobulin, IVIG) for five consecutive days, followed by oral prednisone and sodium valproate as an antiepileptic drug. Upon achieving a favorable clinical outcome, the patient was discharged with oral medications. Results: Among the 15 pediatric patients reported in this literature, nine presented with limbic encephalitis (LE), three with extralimbic encephalitis (ELE), and three with a combination of limbic and extralimbic encephalitis. Most of these cases exhibited T2-W FLAIR hyperintensities primarily localized to the temporal lobes in the early phase, progressing to hippocampal sclerosis/atrophy in the later phase on MRI. EEG commonly showed slow or spike waves on frontotemporal lobes with epileptic discharges. Prognostic factors varied among patients, with some experiencing persistent refractory seizures, type-1 diabetes mellitus (T1DM), persistent memory impairment, persistent disability requiring full assistance, and, in severe cases, death. Conclusion: Our findings suggest that anti-GAD65 antibody-positive autoimmune encephalitis patients may concurrently present with other APS. Our unique case presented with multiple endocrine syndromes and represents the first reported occurrence in children. Early diagnosis and timely initiation of immunotherapy are crucial for improving clinical symptoms and reducing the likelihood of relapses or permanent disabilities. Therefore, emphasis should be placed on prompt diagnosis and appropriate treatment implementation to achieve better patient outcomes.

Fatty Acid Oxidation Mediated by Malonyl-CoA Decarboxylase Represses Renal Cell Carcinoma Progression.

Fatty acid metabolism reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Increased lipid storage supports ccRCC progression, highlighting the importance of understanding the molecular mechanisms driving altered fatty acid synthesis in tumors. Here, we identified that malonyl-CoA decarboxylase (MLYCD), a key regulator of fatty acid anabolism, was downregulated in ccRCC, and low expression correlated with poor prognosis in patients. Restoring MLYCD expression in ccRCC cells decreased the content of malonyl CoA, which blocked de novo fatty acid synthesis and promoted fatty acid translocation into mitochondria for oxidation. Inhibition of lipid droplet accumulation induced by MLYCD-mediated fatty acid oxidation disrupted endoplasmic reticulum and mitochondrial homeostasis, increased reactive oxygen species levels, and induced ferroptosis. Moreover, overexpressing MLYCD reduced tumor growth and reversed resistance to sunitinib in vitro and in vivo. Mechanistically, HIF2α inhibited MLYCD translation by upregulating expression of eIF4G3 microexons. Together, this study demonstrates that fatty acid catabolism mediated by MLYCD disrupts lipid homeostasis to repress ccRCC progression. Activating MLYCD-mediated fatty acid metabolism could be a promising therapeutic strategy for treating ccRCC. SIGNIFICANCE: MLYCD deficiency facilitates fatty acid synthesis and lipid droplet accumulation to drive progression of renal cell carcinoma, indicating inducing MYLCD as a potential approach to reprogram fatty acid metabolism in kidney cancer.

Co-Effects of Hydrological Conditions and Industrial Activities on the Distribution of Heavy Metal Pollution in Taipu River, China.

In Taipu River, after being transformed from a drainage channel to a drinking water supply river in 1995, heavy metals that have accumulated in sediments have become an environmental issue. Herein, we collected sediments of Taipu River in 2018, 2020, and 2021 and analyzed the distribution of Sb, As, Cd, Cu, Pb, Cr, and Zn to identify their sources. The results revealed that the mean concentrations of heavy metals were above the background values, except for Cr and As. During the non-flood season, the midstream of Taipu River becomes a heavy metal hotspot, with their concentrations 2-5 times higher than those in upstream sediment. There were significant correlations (r = 0.79-0.99) among drainage, precipitation and flow rate, which indicated that drainage caused by both the opening of Taipu Gate and precipitation control the flow rate and, then, possibly influenced the distribution of heavy metals. Moreover, three sources (industrial sources, particle deposition sources, and natural sources) were characterized as the determinants for the accumulation of heavy metal by the Positive Matrix Factorization model, with the contribution rates of 41.7%, 32.9%, and 25.4%, respectively. It is recommended that the influence of hydrological conditions and industrial activities should be a key consideration when developing regulations for the management of heavy metals in rivers.

The efficacy and safety of Longmu Tang granule for the treatment of atopic dermatitis: study protocol for a single-centred, double-blinded, randomised, placebo-controlled trial.

BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing skin disease that has long-term physical and mental health impacts on children with this condition. Current treatments mainly include anti-inflammatory, antibacterial, and anti-allergic interventions, systemic therapy, and recently emerging target-focused agents. However, these treatments have limited effectiveness and unwanted side effects. The use of traditional Chinese medicine (TCM) in the treatment of AD has a long history, with promising efficacies, low toxicity, and improvements in the quality of life of patients with AD. Longmu Tang granule, a TCM, has been used to effectively treat AD since 2008 through doctors' prescriptions. To scientifically evaluate the clinical efficacy and safety of Longmu Tang granule, we proposed to launch a single-centred, double-blinded, randomised, placebo-controlled trial. METHODS: In this single-centred, double-blinded, randomised, placebo-controlled clinical trial conducted at Xiyuan Hospital of China Academy of Chinese Medical Sciences, a total of 60 participants will be randomly assigned (1:1) to receive the Longmu Tang granule or placebo granule for 8 weeks. The primary outcome will be evaluated using the index of Scoring Atopic Dermatitis. The secondary outcomes will be evaluated using the Children's Dermatology Life Quality Index and the number cancellation test. The mechanistic evidence will be the serum levels of inflammatory cytokines, including immunoglobulin E, tumour necrosis factor-α, interleukin-1, and interleukin-6. DISCUSSION: The results of this trial will provide evidence of the efficacy and safety of the Longmu Tang granule and prove its anti-inflammatory action in patients with AD. TRIAL REGISTRATION: Chinese Clinical Trial Registry Chictr.org ID: ChiCTR2100041591 . Registered on 1 January 2021.

A Metabolism-Related Gene Landscape Predicts Prostate Cancer Recurrence and Treatment Response.

Background: Prostate cancer (PCa) is the most common malignant tumor in men. Although clinical treatments of PCa have made great progress in recent decades, once tolerance to treatments occurs, the disease progresses rapidly after recurrence. PCa exhibits a unique metabolic rewriting that changes from initial neoplasia to advanced neoplasia. However, systematic and comprehensive studies on the relationship of changes in the metabolic landscape of PCa with tumor recurrence and treatment response are lacking. We aimed to construct a metabolism-related gene landscape that predicts PCa recurrence and treatment response. Methods: In the present study, we used differentially expressed gene analysis, protein-protein interaction (PPI) networks, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression to construct and verify a metabolism-related risk model (MRM) to predict the disease-free survival (DFS) and response to treatment for PCa patients. Results: The MRM predicted patient survival more accurately than the current clinical prognostic indicators. By using two independent PCa datasets (International Cancer Genome Consortium (ICGC) PCa and Taylor) and actual patients to test the model, we also confirmed that the metabolism-related risk score (MRS) was strongly related to PCa progression. Notably, patients in different MRS subgroups had significant differences in metabolic activity, mutant landscape, immune microenvironment, and drug sensitivity. Patients in the high-MRS group were more sensitive to immunotherapy and endocrine therapy, while patients in the low-MRS group were more sensitive to chemotherapy. Conclusions: We developed an MRM, which might act as a clinical feature to more accurately assess prognosis and guide the selection of appropriate treatment for PCa patients. It is promising for further application in clinical practice.

Incidence of Newly Diagnosed Type 1 Diabetes Mellitus in Children and Adolescents in Henan Province of China from 2017 to 2020: A Retrospective Multicenter Study Based on Hospitalization Data

Objective: The incidence of type 1 diabetes mellitus (T1DM) is rapidly increasing worldwide. However, the incidence in Henan Province of China has been unknown for more than two decades. This study aimed to estimate the incidence of T1DM in the 0.5-14.9 years age group in Henan Province of China from 2017 to 2020. Methods: A retrospective analysis of hospital registration data from 18 cities in Henan Province, China, identified 1726 patients (843 males, 883 females) between 0.5-14.9 years of age with newly diagnosed T1DM in Henan Province from January 1st, 2017, to December 31st, 2020, covering more than 19 million children years at risk. Results: The crude incidence of T1DM per 100 000 person years for the 0.5-14.9 years age group in the Henan Province of China was 2.19 [95% confidence interval (CI): 1.99, 2.40], with a peak in the 10-14.9 years age group. The rate ratio of females to males was 1.32 (95% CI: 1.20, 1.45) in the 0.5-14.9 years age group. The incidence rate was higher in females than males in the 5-9.9 years age group (p<0.01) and the 10-14.9 years age group (p<0.01). The seasonality of the incidence was different from that in previous reports, with the lowest incidence in the spring. Conclusion: The incidence of T1DM in the 0.5-14.9 years age group in Henan Province was still among the lowest reported globally, but was in line with other incidence rates reported from China.

Perioperative outcomes of intracorporeal robot-assisted radical cystectomy versus open radical cystectomy: A systematic review and meta-analysis of comparative studies.

PURPOSE: To systematically review studies comparing the perioperative outcomes of intracorporeal robot-assisted radical cystectomy (iRARC) and open radical cystectomy (ORC). METHODS: Systematic searches of PubMed, Web of Science and the Cochrane Library were performed in June 2020. Studies with data comparing iRARC and ORC were included in our review, and a pooled meta-analysis was completed. RESULTS: In total, 8 studies (7 prospective studies, 1 retrospective study) comparing 1193 patients were included for our review and meta-analysis. Compared with ORC, iRARC demonstrated lower estimated blood loss (weighted mean difference (WMD): -449.25; 95% CI -566.47 - -332.03; p < 0.01), lower blood transfusion rates (OR: 0.31; 95% CI 0.22 - 0.46; p < 0.01), and lower postoperative complication rates with Clavien-Dindo grades III-IV (30 days: OR: 0.65; 95% CI 0.47 - 0.90; p = 0.01; 90 days: OR: 0.72; 95% CI 0.53 - 0.98; p = 0.04), but a longer operative time (WMD: 78.82; 95% CI 52.77 - 104.87; P < 0.01). Furthermore, there was no significant difference between iRARC and ORC in terms of postoperative complication rates with Clavien-Dindo grades Ⅰ-Ⅱ (30 days: OR: 0.71; 95% CI 0.36 - 1.40; p = 0.32; 90 days: OR: 0.98; 95% CI 0.74 - 1.30; p = 0.89), length of stay (WMD: -1.18; 95% CI -3.33 - -2.07; p = 0.06) and positive surgical margins (OR: 0.78; 95% CI 0.0.45 - 1.36; p = 0.38). CONCLUSION: iRARC was associated with a significantly lower estimated blood loss and a lower blood transfusion rate and major postoperative complication rate than ORC.

UBAC2 promotes bladder cancer proliferation through BCRC-3/miRNA-182-5p/p27 axis.

Emerging evidences have demonstrated that ubiquitin-associated domain-containing protein 2 (UBAC2) is closely related to the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of UBAC2 in bladder cancer (BC) development have not been defined. In this study, we found that both UBAC2 mRNA and protein levels were upregulated in BC tissues and cell lines, and knockdown of UBAC2 inhibited BC cells proliferation both in vitro and in vivo. Meanwhile, Kaplan-Meier survival plots of 406 BC cases from TCGA database showed that higher expression of UBAC2 in BC patients was associated with lower survival rate. Mechanistic studies revealed that knockdown of UBAC2 increased the expression of p27 by posttranscriptional regulation. Our previous study indicated that circular RNA BCRC-3 (BCRC-3) promoted the expression of p27 through interacting with miR-182-5p, and reversed miR-182-5p-induced inhibition of p27 3'UTR activity. In the present study, we found that UBAC2 could bind to BCRC-3, and subsequently affected the interaction of BCRC-3 with miR-182-5p to inhibit the expression of p27. Furthermore, knockdown of BCRC-3 partly reversed the upregulation of p27 expression induced by knockdown of UBAC2. Our findings highlight a novel mechanism of UBAC2 in regulating p27 through affecting the function of BCRC-3, and provide a research basis for the diagnostic and therapeutic application of BC.

Lasers versus bipolar technology in the transurethral treatment of benign prostatic enlargement: a systematic review and meta-analysis of comparative studies.

PURPOSE: To systematically review studies comparing the overall efficacy and safety of lasers and bipolar technology for the transurethral treatment of benign prostatic enlargement (BPE). METHODS: A systematic review of the literature was completed in February 2018. Studies with comparative data between different lasers and bipolar technologies (enucleation or resection) were included in this review. A meta-analysis was performed using STATA 14.0, and subgroup analyses were also performed regarding the type of laser (holmium, thulium, green light and diode). RESULTS: 27 studies with 31 published articles (4382 patients) were selected for the meta-analysis. Compared with bipolar technology, lasers demonstrated shorter catheterization duration (standardized mean difference (SMD): 1.44; 95% CI 1.07-1.81; p < 0.001) and shorter hospital stay (SMD: 1.16; 95% CI 0.83-1.49; p < 0.001), and a smaller drop in hemoglobin (Hb) level (SMD: 0.86; 95% CI 0.47-1.26; p < 0.001). However, significant heterogeneity was detected in the studies and statistical significance was lost on sub-analyses. Furthermore, there were no significant differences between lasers and bipolar technology in the maximum flow rate (Qmax) and international prostate symptom score (IPSS) at a minimum of 3 months after treatment. Complications, including urethral stricture, urinary incontinence, urinary tract infection, re-catheterization and blood transfusion, did not significantly differ between lasers and bipolar technology. CONCLUSION: Early efficacy and safety profiles were comparable between bipolar and laser treatments. Differences were observed in terms of smaller reduction in Hb, shorter catheterization duration and shorter hospital stay in favor of lasers. However, the smaller reduction in Hb, with lasers, did not translate into reduced transfusion requirements. Furthermore, there was significant heterogeneity in the studies and, in subgroup analyses, the differences were not statistically significant.

Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6-methyladenosine of Notch1.

BACKGROUND: N6-methyladenosine (m6A) emerges as one of the most important modification of RNA. Bladder cancer is a common cancer type in developed countries, and hundreds of thousands of bladder cancer patients die every year. MATERIALS AND METHODS: There are various cells in bladder tumor bulk, and a small population cells defined as tumor initiating cells (TIC) have self-renewal and differentiation capacities. Bladder TICs drive bladder tumorigenesis and metastasis, and their activities are fine regulated. However, the role of N6-methyladenosine in bladder TIC self-renewal is unknown. RESULTS: Here, we found a decrease of N6-methyladenosine in bladder tumors and bladder TICs. N6-methyladenosine levels are related to clinical severity and outcome. Mettl14 is lowly expressed in bladder cancer and bladder TICs. Mettl14 knockout promotes the proliferation, self-renewal, metastasis and tumor initiating capacity of bladder TICs, and Mettl14 overexpression exerts an opposite role. Mettl14 and m6A modification participate in the RNA stability of Notch1 mRNA. Notch1 m6A modification inhibits its RNA stability. Notch1 plays an essential role in bladder tumorigenesis and bladder TIC self-renewal. CONCLUSION: This work reveals a novel role of Mettl14 and N6-methyladenosine in bladder tumorigenesis and bladder TICs, adding new layers for bladder TIC regulation and N6-methyladenosine function.

circGprc5a Promoted Bladder Oncogenesis and Metastasis through Gprc5a-Targeting Peptide.

Bladder cancer is a serious cancer in the world, especially in advanced countries. Bladder cancer stem cells (CSCs) drive bladder tumorigenesis and metastasis. Circular RNAs (circRNAs) are involved in many biological processes, but their roles in bladder oncogenesis and bladder CSCs are unclear. Here, we identified that circGprc5a is upregulated in bladder tumors and CSCs. circGpr5a knockdown impairs the self-renewal and metastasis of bladder CSCs, and its overexpression exerts an opposite role. circGpr5a has peptide-coding potential and functions through a peptide-dependent manner. circGprc5a-peptide binds to Gprc5a, a surface protein highly expressed in bladder CSCs. Gprc5a knockout inhibits the bladder CSC self-renewal and metastasis. circGprc5a-peptide-Gprc5a can be utilized to target bladder cancer and bladder CSCs.

MKP2 inhibits TGF-ß1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway.

Epithelial-to-mesenchymal transition (EMT) is a phenotypic conversion that plays a crucial role in renal fibrosis leading to chronic renal failure. Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate the MAP kinase pathway involved in transforming growth factor-ß1 (TGF-ß1)-induced EMT. However, the function of MKP2 in the regulation of EMT and the underlying mechanisms are still largely unknown. In the present study, we detected the expression of MKP2 in an animal model of renal fibrosis and evaluated the potential role of MKP2 in tubular EMT induced by TGF-ß1. We found that the expression of MKP2 was up-regulated in the tubular epithelial of unilateral ureter obstruction rats. Meanwhile, we also demonstrated that TGF-ß1 up-regulated MKP2 expression in NRK-52E cells during their EMT phenotype acquisition. Importantly, overexpression of MKP2 inhibited c-Jun amino terminal kinase (JNK) signaling and partially reversed EMT induced by TGF-ß1. Moreover, reducing MKP2 expression enhanced JNK phosphorylation, promoted the E-cadherin suppression and induced α-SMA expression and fibronectin secretion in response to TGF-ß1, which could be rescued by a JNK inhibitor. These results provide the first evidence that MKP2 is a negative feedback molecule induced by TGF-ß1, and MKP2 overexpression inhibits TGF-ß1-induced EMT through the JNK signaling pathway. MKP2 could be a promising target to be used in gene therapy for renal fibrosis.

MicroRNA-212 inhibits the proliferation, migration and invasion of renal cell carcinoma by targeting X-linked inhibitor of apoptosis protein (XIAP).

MicroRNAs have been found to be critical regulator of cancer cell biology. MicroRNA-212 (miR-212) was identified to be a critical cancer-associated microRNA playing either oncogenic functions or tumor suppressive roles in different types of human cancers. In this study, we found that the level of miR-212 in renal cell carcinoma (RCC) tissues was significantly lower than that in adjacent non-tumor tissues. Decreased level of miR-212 was associated with advanced T stage and TNM stage of RCC. The expression of miR-212 was decreased in RCC cell lines as compared with the HK-2 cell line. Overexpression of miR-212 inhibited cell viability, proliferation, migration and invasion of CAKI-2 cells. Knockdown of miR-212 increased cell viability and proliferation, migration and invasion of ACHN cells. In vivo experiments showed that miR-212 inhibited the proliferation and promoted the apoptosis of ACHN cells in nude mice and thus inhibited the in vivo tumor growth of CAKI-2 cells. Furthermore, we confirmed that X-linked inhibitor of apoptosis protein (XIAP) was the downstream target of miR-212. The expression level of miR-212 was negatively correlated with XIAP expression in RCC tissues. Moreover, XIAP mediated the tumor suppressive roles of miR-212 in RCC. Finally, we demonstrated that the aberrant expression of miR-212 and XIAP was evidently correlated with poor prognosis of RCC patients. In all, miR-212 can act as a prognostic biomarker for RCC patients and inhibits the growth and metastasis of RCC cells by inhibiting XIAP.

NDRG2 knockdown promotes fibrosis in renal tubular epithelial cells through TGF-ß1/Smad3 pathway.

Renal fibrosis is a common pathological pathway of various chronic kidney diseases progressing to end-stage renal disease and is characterized by tubular atrophy, fibroblast/myofibroblast activation and excessive deposition of extracellular matrix (ECM). N-Myc downstream-regulated gene-2 (NDRG2) is reported to be associated with liver fibrosis in rats. However, the biological function of NDRG2 in renal fibrosis remains unclear. Therefore, we investigate the effect of NDRG2 on renal fibrosis and the underlying mechanism of NDRG2 in TGF-ß1-induced renal tubular epithelial cells (HK-2). Our results show that TGF-ß1 down-regulates NDRG2 mRNA and protein expression in HK-2 cells. Moreover, NDRG2 knockdown dramatically reduces the TGF-ß1-induced protein and mRNA of E-cadherin and increases the TGF-ß1-induced protein and mRNA expression level of α-SMA, Vimentin, Snail, Col-I, Col-III and FN; this is reversed by NDRG2 overexpression. Furthermore, NDRG2 silencing significantly increases the phosphorylation level of Smad3 (p-Smad3), which is decreased by NDRG2 overexpression, although these have no effect on the protein expression of p-Smad2 and Smad7. In addition, SIS3, a specific inhibitor of Smad3 phosphorylation, partly reverses the effect of NDRG2 knockdown on the protein and mRNA expression of epithelial-mesenchymal transition (EMT) markers and ECM components in TGF-ß1-induced HK-2 cells. Taken together, our results indicate that NDRG2 knockdown promotes renal fibrosis through its effect on the protein and mRNA expression of EMT markers and ECM components by regulating the downstream Smad3 signaling pathway in renal tubular epithelial cells. Modulation of NDRG2 expression might provide a new therapy for renal fibrosis.

MiR-218 impedes IL-6-induced prostate cancer cell proliferation and invasion via suppression of LGR4 expression.

Prostate cancer is the most common solid-organ malignancy and the second leading cause of cancer-related death in males. The oncogenic effect of leucine-rich repeat-containing G protein-coupled receptor (LGR) 4 has been recognized in the formation of various types of cancers, yet its regulatory mechanism in prostate cancer is still not fully understood. Previous study has shown that LGR4 may be a new responsive gene of interleukin-6 (IL-6) in cancer progression. In the present study, we established the LNCaP-IL-6+ cell subline by long-term incubation with a low concentration of IL-6 and explored the regulatory role of miR-218, a tumor-suppressing miRNA, in IL-6-induced LGR4 expression and LNCaP-IL-6+ cell proliferation and invasion. The results showed that miR-218 expression was gradually decreased and IL-6 expression was gradually increased in the process of prostate cancer progression from normal prostate, benign prostatic hyperplasia to prostate cancer, and from LNCaP to LNCaP-IL-6+ cells. Notably, we also found that miR-218 inhibited the expression of cell cycle regulatory protein cyclin A1 and invasion-related matrix metalloproteinase-9 protein induced by IL-6, and impeded the accelerative effect of IL-6 on LNCaP-IL-6+ cell proliferation, cell cycle progression and cell invasion. Moreover, our results confirmed that miR-218 directly targets LGR4 and modulated the PI3K/Akt and Wnt/ß-catenin pathways in the LNCaP-IL-6+ cells. Taken together, these data clearly demonstrated the involvement of the miR-218/LGR4 regulatory pathway in IL-6-induced cell proliferation and invasion in LNCaP-IL-6+ cells via PI3K/Akt and Wnt/ß-catenin signaling, providing new insight into therapeutics for inflammation-induced prostate cancer.

Introducing the Quill™ device for modified sleeve circumcision with subcutaneous suture: a retrospective study of 70 cases.

OBJECTIVE: The purpose of the study was to evaluate the safety and feasibility of treatment for male circumcision using modified sleeve circumcision and subcuticular suture with the Quill™ device. METHODS: From May 2011 to March 2012, 70 consecutive cases of male circumcision were performed using an alternative technique with the Quill™ device by a single surgeon in our institution. The inclusion and exclusion criteria for the selection process of this procedure were the same as for conventional circumcision. We evaluated the indications and perioperative outcomes. The circumcisions were performed as day-case procedures under local anesthesia. RESULTS: All patients were followed up for a minimum of 3-6 months. The ages ranged from 8 to 68 (mean = 27.0 years, SD = 10). The indications for surgery were either cosmetic (n = 16, 22.9%) or medical [redundant prepuce (n = 36, 51.4%), phimosis (n = 5, 7.1%), paraphimosis (n = 2, 2.9%), balanoposthitis (n = 9, 12.9%), melanoma (n = 1, 1.4%), and condyloma acuminata (n = 1, 1.4%)] (n = 54, 77.1%). The mean operation time in this group was 29 min (19-38 min) when the Quill™ device was used. In all, 3 cases developed complications (4.3%). The final cosmetic result was satisfactory for both the patients and their spouses or parents. CONCLUSION: This study showed that modified sleeve circumcision and subcuticular suture were safe and reliable surgical methods of circumcision that provide a better cosmetic result.

Urinary Emmprin, matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 as potential biomarkers in children with ureteropelvic junction narrowing on conservative treatment.

BACKGROUND: Rapid diagnosis and initiation of the treatment on congenital obstructive nephropathy are important for young children to slow down renal injury. The aim of our study was to investigate the role of urinary extracellular matrix metalloproteinase inducer (Emmprin), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in the long-term follow-up of children with ureteropelvic junction (UPJ) narrowing on conservative treatment. METHODS: The study included 40 children with non-obstructed hydronephrosis due to unilateral UPJ narrowing who were treated conservatively and followed up for 24 months. Voided urine samples were collected at diagnosis and at 3, 9, 15 and 24 months of follow-up, respectively. Three enzymes concentrations were measured in urine. RESULTS: During the follow-up, 25 children showed renal function stabilization (non-obstructed group) and 15 children renal function deterioration (obstructed group). In the non-obstructed group, a comparison between urine three enzymes levels at the last follow-up and at baseline showed no significant differences (all P > 0.05). Glomerular filtration rate (GFR) and split renal function (SRF) showed similar trends. In the obstructed group, a comparison between the three enzymes levels at diagnosis and at basal condition showed a significant increase (all P < 0.01). But GFR and SRF showed a marked reduction at diagnosis (all P < 0.001). Receiver operator characteristic (ROC) analyses revealed a better diagnostic profile for uEmmprin, uMMP-9 and uTIMP-1 in identifying children with abnormal SRF (<40%) at 24 months of follow-up [area under the curve (AUC) 0.877, 0.727 and 0.823, respectively]. CONCLUSIONS: Urinary Emmprin, MMP-9 and TIMP-1 may be noninvasive potential biomarkers that could be used for long-term follow-up of children with UPJ narrowing on conservative treatment to determine those who might develop obstruction.