Once-daily upadacitinib versus placebo in adults with extensive non-segmental vitiligo: a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study.

Background: Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. Methods: This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6 mg (UPA6), upadacitinib 11 mg (UPA11), upadacitinib 22 mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Findings: Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n = 49), UPA11 (n = 47), UPA22 (n = 43), or PBO (n = 46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was -7.60 (95% CI -22.18 to 6.97; p = 0.3037) for UPA6, -21.27 (95% CI -36.02 to -6.52; p = 0.0051) for UPA11, and -19.60 (95% CI -35.04 to -4.16; p = 0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was -7.45 (95% CI -16.86 to 1.96; p = 0.1198) for UPA6, -10.84 (95% CI -20.37 to -1.32; p = 0.0259) for UPA11 and -14.27 (95% CI -24.24 to -4.30; p = 0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n = 1)] and non-fatal ischemic stroke [UPA11 (n = 1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Interpretation: Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15 mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. Funding: AbbVie Inc.

Delivery of exogenous miR-19b by Wharton's Jelly Mesenchymal Stem Cells attenuates transplanted kidney ischemia/reperfusion injury by regulating cellular metabolism.

Renal ischemia-reperfusion injury (IRI) frequently occurs following kidney transplantation, and exosomes derived from umbilical cord mesenchymal stem cells (WJ-MSC-Exos) have shown promise in treating IRI in transplanted kidneys. Our study delved into the potential mechanism of WJ-MSC-Exos in ameliorating IRI in transplanted kidneys, revealing that miR-19b is abundantly present in WJ-MSC-Exos. Both in vivo and in vitro experiments demonstrated that the absence of miR-19b abolished the protective effects of WJ-MSC-Exos against renal IRI. Mechanistically, miR-19b suppressed glycogen synthase kinase-3ß (GSK3ß) expression, thereby stabilizing PDXK protein through direct binding. Treatment with WJ-MSC-Exos led to reduced PDXK levels and enhanced pyridoxine accumulation, ultimately mitigating IRI in transplanted kidneys and I/R-induced HK2 cell apoptosis. These findings elucidate the underlying mechanism of WJ-MSC-Exos in alleviating IRI in transplanted kidneys, unveiling novel therapeutic targets for post-kidney transplantation IRI and providing a solid theoretical foundation for the clinical application of WJ-MSC-Exos in IRI treatment post-transplantation.

Enantioconvergent Reductive C(sp)-C(sp3 ) Cross-Coupling to Access Chiral α-Alkynyl Phosphonates Under Dual Nickel/Photoredox Catalysis.

Transition-metal-catalyzed asymmetric carbon-carbon bond formation to forge phosphonates with an α-chiral carbon center through C(sp3 )-C(sp3 ) and C(sp2 )-C(sp3 ) couplings has been successful. However, the enantioselective C(sp)-C(sp3 ) coupling has not yet been disclosed. Reported herein is an unprecedented enantioconvergent cross-coupling of alkynyl bromides and α-bromo phosphonates to deliver chiral α-alkynyl phosphonates.

Poor outcomes of proliferative glomerulonephritis with monoclonal IgG deposits in renal allografts: a retrospective multicenter study.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) in renal allografts is a rare, renal-limited disease. No study has reported the long-term outcomes and prognostic features of PGNMID in renal allografts in the Chinese population. METHODS: We retrospectively included transplant patients diagnosed with PGNMID who underwent renal allograft biopsy at three transplant centers from April 2012 to July 2020. We observed the clinicopathologic features, explored the long-term graft survival, and investigated the characteristics associated with the prognosis. RESULTS: A total of 13 transplant patients with PGNMID were included, out of 3821 biopsies. The mean follow-up time was 55 months since kidney transplantation (KTx). At diagnosis, all patients presented with proteinuria (100%) and most of them with hematuria (92%). IgG3κ (69%) was the main immunofluorescence (IF) subtype. The median graft survival of the total cohort was 17 months from diagnosis and 49 months from kidney transplantation. During follow-up, 9 patients needed dialysis and 2 out of 9 patients who progressed to dialysis died of infection. Primary membranoproliferative glomerulonephritis (MPGN) (P = 0.014) and MPGN pattern at diagnostic biopsy (P < 0.001) were associated with a higher risk of graft loss. CONCLUSIONS: The long-term outcome of allograft PGNMID was relatively poor in the Chinese population. Primary MPGN and MPGN pattern in renal allograft were associated with  poor outcomes.

Phosphate ions functionalized spinel iron cobaltite derived from metal organic framework gel for high-performance asymmetric supercapacitors.

Spinel iron cobaltite (FeCo2O4) with high theoretical capacity is a promising positive electrode material for building high-performance supercapacitors. However, its inherent poor conductivity and deficient electrochemical active sites hinder the improvement of its electrochemical kinetics behavior. Herein, phosphate ions modified FeCo2O4 is obtained in the presence of oxygen vacancies (P-FeCo2O4-x) by a simple metal organic framework gel-derived strategy. Phosphate ions added on the surface of P-FeCo2O4-x greatly enhances its surface activity, thus prompting the faster charge storage kinetics of the electrode material. Due to its ample electrochemical active sites and rapid ion diffusion and electron mobility, the optimized P-FeCo2O4-x electrode delivers a superior specific capacity of 1568.8 F g-1 (784.4 C g-1) at a current density of 1 A/g and has an excellent cycling stability with 93.3 % initial capacity retention ratio after 5000 cycles. More impressively, the assembled asymmetric supercapacitor consisting of P-FeCo2O4-x and activated carbon which act as positive and negative electrode materials, respectively displays a favorable energy density of 60.2 Wh kg-1 at a power density of 800 W kg-1 and has a long cycling lifespan. These results demonstrate the potential importance of modifying the surface of spinel cobaltite with phosphate ions and incorporating oxygen defects in it as a facile strategy for enhancing the electrochemical kinetics of electrode materials.

Metagenomic Next-Generation Sequencing Reveals the Profile of Viral Infections in Kidney Transplant Recipients During the COVID-19 Pandemic.

Background: To study the clinical application of metagenomic next-generation sequencing (mNGS) in the detection of viral infections in kidney transplant recipients (KTRs) during the COVID-19 pandemic. Methods: Using mNGS technology, 50 human fluid samples of KTRs were detected, including 20 bronchoalveolar lavage fluid (BALF) samples, 21 urine samples and 9 blood samples. The detected nucleic acid sequences were compared and analyzed with the existing viral nucleic acid sequences in the database, and the virus infection spectrum of KTRs was drawn. Results: The viral nucleic acids of 15 types of viruses were detected in 96.00% (48/50) of the samples, of which 11 types of viruses were in BALF (95.00%, 19/20), and the dominant viruses were torque teno virus (TTV) (65.00%; 13/20), cytomegalovirus (CMV) (45.00%; 9/20) and human alphaherpesvirus 1 (25.00%; 5/20). 12 viruses (95.24%, 20/21) were detected in the urine, and the dominant viruses were TTV (52.38%; 11/21), JC polyomavirus (52.38%; 11/21), BK polyomavirus (42.86%; 9/21), CMV (33.33%; 7/21) and human betaherpesvirus 6B (28.57%; 6/21). 7 viruses were detected in the blood (100.00%, 9/9), and the dominant virus was TTV (100.00%; 9/9). Four rare viruses were detected in BALF and urine, including WU polyomavirus, primate bocaparvovirus 1, simian virus 12, and volepox virus. Further analysis showed that TTV infection with high reads indicated a higher risk of acute rejection (P < 0.05). Conclusions: mNGS detection reveals the rich virus spectrum of infected KTRs, and improves the detection rate of rare viruses. TTV may be a new biomarker for predicting rejection.

Modular and Facile Access to Chiral α-Aryl Phosphates via Dual Nickel- and Photoredox-Catalyzed Reductive Cross-Coupling.

Chiral phosphine-containing skeletons are important motifs in bioactive natural products, pharmaceuticals, chiral catalysts, and ligands. Herein, we report a general and modular platform to access chiral α-aryl phosphorus compounds via a Ni/photoredox-catalyzed enantioconvergent reductive cross-coupling between α-bromophosphates and aryl iodides. This dual catalytic regime exhibited high efficiency and good functional group compacity. A wide variety of substrates bearing a diverse set of functional groups could be converted into chiral phosphates in good to excellent yields and enantioselectivities. The utility of the method was also demonstrated by the development of a new phosphine ligand and the synthesis of enzyme inhibitor derivatives. The detailed mechanistic studies supported a radical chain process and revealed a unique distinction compared with traditional reductive cross-coupling.

Exosomes Secreted by Mesenchymal Stem Cells Induce Immune Tolerance to Mouse Kidney Transplantation via Transporting LncRNA DANCR.

Mesenchymal stem cells induce kidney transplant tolerance by increasing regulatory T (Treg) cells. Bone marrow mesenchymal stem cell exosomes (BMMSC-Ex) promote Treg cell differentiation. Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is expressed in BMMSCs and can be encapsulated in exosomes. We aimed to explore the role of DANCR in BMMSC-Ex in immune tolerance after kidney transplantation and related mechanism. The isogenic/allograft kidney transplantation mouse model was established, and levels of serum creatinine (SCr) were determined. Hematoxylin-eosin staining was conducted to detect the inflammation, and immunohistochemistry was performed to detect the infiltration of CD4+ T cells. Levels of IFN-γ, IL-17, and IL-2 were examined by ELISA. Flow cytometry was conducted to determine Treg cells. In the allograft group, the inflammatory response was severe, CD4+ T cell infiltration, SCr levels, and plasma rejection-related factors were up-regulated, while injection of BMMSC-Ex reversed the results. BMMSC-Ex increased Treg cells in kidney transplantation mice. Interference with DANCR reversed the promoting effect of BMMSC-Ex on Treg cell differentiation. DANCR bound to SIRT1, promoted ubiquitination and accelerated its degradation. The injection of BMMSC-Ex (after interference with DANCR) promoted SIRT1 levels, inflammatory response, CD4+ T cell infiltration, SCr levels, and plasma rejection related factors' expression, while Treg cells were decreased. LncRNA DANCR in BMMSC-Ex promoted Treg cell differentiation and induced immune tolerance of kidney transplantation by down-regulating SIRT1 expression in CD4+ T cells.

Optimal one-stage design and analysis for efficacy expansion in Phase I oncology trials.

BACKGROUND: Contemporary Phase I oncology trials often include efficacy expansion in various tumor indications post dose finding. Preliminary anti-tumor activity from efficacy expansion can aid Go/No-Go decision for Phase 2 or Phase 3 initiation. Tumor cohorts in efficacy expansion are commonly analyzed independently in practice, which are often underpowered due to small sample size. Pooled analysis is also sometimes conducted, but it ignores the heterogeneity of the anti-tumor activity across cohorts. METHODS: We propose an optimal one-stage design and analysis strategy for the efficacy expansion to assess whether the treatment is effective. Allowing heterogeneous anti-tumor effects across tumor cohorts, inactive cohorts are pruned, and the potentially active cohorts are pooled together to gain study power. For a prospective design with a target power, the total sample size across all cohorts is minimized; or for an ad hoc analysis with pre-specified sample size for each cohort, the pruning criteria are optimized to achieve maximum power. The global type I error is controlled after proper multiplicity adjustment, and a penalty adjusted significance level is used for the pooled test. RESULTS: Simulation studies show that the proposed optimal design has desirable operating characteristics in increasing the overall power and detecting more true positive tumor cohorts. CONCLUSION: The proposed optimal design and analysis strategy provides a practical approach to design and analyze heterogeneous efficacy expansion cohorts in a basket setting with global type I and type II error being controlled.

Uncovering the microbiota in renal cell carcinoma tissue using 16S rRNA gene sequencing.

INTRODUCTION: Increasing evidence indicates an important role of microbiota in cancer development and progression, while little is known about the correlation between microbiota and renal cell carcinoma (RCC). Thus, we performed this study to profile the intratumoral microbiota possibly associated with RCC. MATERIALS AND METHODS: Paired RCC and adjacent normal tissue samples were collected from 24 patients with RCC. V3-V4 variable region of microbial 16S rRNA gene was sequenced using Illumina MiSeq. Sequencing reads were processed using QIIME. Differentially abundant bacterial taxa between groups were identified by LEfSe, and their potential functions were inferred by PICRUSt. RESULTS: Decreased species diversity was presented in RCC tissues (Simpson index, P = 0.0340), and the composition of the bacterial community in RCC tissues was significantly distinct from that in normal tissues (unweighted UniFrac distance, P = 0.026; weighted UniFrac distance, P = 0.017). Compared with normal tissues, 25 taxa increased and 47 reduced taxa were identified in RCC tissues. Among these taxa, the class Chloroplast (AUC = 0.91, P < 0.0001) and the order Streptophyta (AUC = 0.89, P < 0.0001) showed high indication accuracy to discriminate RCC tissues from normal tissues. Furthermore, nine altered pathways were identified in RCC tissues to reveal the potential microbial function. CONCLUSIONS: Our results have uncovered the presence of distinct microbiota in RCC and adjacent normal tissues and provided a better understanding of the possible role of the intratumoral microbiota in RCC. Further studies are required to confirm our results and determine the real correlation between microbiota and RCC.

Catalpol inhibits the proliferation, migration and metastasis of HCC cells by regulating miR­140­5p expression.

Hepatocellular carcinoma (HCC) is a frequent malignant tumor. Catalpol is a Chinese medicine extract with a number of pharmacologically active properties. The present study aimed to investigate the effects and mechanisms of catalpol in HCC. HCC cells were treated with catalpol in the presence or absence of microRNA (miR)­140­5p inhibitor, and assays to determine cell viability, proliferation, invasion and migration were performed. Reverse transcription­quantitative PCR and western blotting were performed to determine the mRNA and protein expression levels of miR­140­5p, vimentin, N­Cadherin and E­Cadherin. Moreover, cells were treated with catalpol in the absence or presence of transforming growth factor (TGF)­ß1, and the cell morphology was observed under a microscope. The results demonstrated that catalpol inhibited cell proliferation, invasion and migration, and decreased the expression levels of vimentin and N­cadherin, but increased the expression levels of E­cadherin and miR­140­5p. Catalpol inhibited morphological changes in epithelial­mesenchymal transformation (EMT) of cells induced by TGF­ß1. Following inhibition of miR­140­5p expression, the proliferation, invasion and migration of HCC cells were promoted, E­cadherin expression was decreased, and the levels of vimentin and N­cadherin were increased. The miR­140­5p inhibitor effectively reversed the inhibitory effect of catalpol on cell proliferation, invasion and migration. Thus, the results suggested that the antitumor potential of catalpol in HCC may be exerted by regulating the expression of miR­140­5p to inhibit proliferation, invasion, migration and EMT of HCC cells.

What is the optimum systemic treatment for advanced/metastatic renal cell carcinoma of favourable, intermediate and poor risk, respectively? A systematic review and network meta-analysis.

PURPOSE: The optimum systemic therapies for advanced/metastatic renal cell carcinoma (RCC) of favourable, intermediate and poor risk have not been established. We aimed to compare and rank the effects associated with systemic therapies in the first-line setting. METHODS: We searched PubMed, Cochrane databases, Web of Science and ClinicalTrials.gov for randomised controlled trials (RCT) published up to February 2020 of all available treatments for advanced/metastatic RCC. Analysis was done on a Bayesian framework. RESULTS: 15 unique RCTs including 8995 patients were identified. For advanced/metastatic RCC of favourable risk, avelumab plus axitinib was associated with a significantly higher improvement in progression-free survival (PFS) than sunitinib (HR 0.57, 95% CI 0.34 to 0.96). For intermediate-risk patients, cabozantinib, nivolumab plus ipilimumab, pembrolizumab plus axitinib and avelumab plus axitinib were associated with significantly higher improvement in PFS than sunitinib (HR 0.63, 95% CI 0.44 to 0.97; HR 0.66, 95% CI 0.53 to 0.81; HR 0.58, 95% CI 0.44 to 0.80; HR 0.62, 95% CI 0.47 to 0.83, respectively); pembrolizumab plus axitinib and nivolumab plus ipilimumab were associated with significantly higher improvement in overall survival (OS) than sunitinib (HR 0.53, 95% CI 0.34 to 0.81; HR 0.66, 95% CI 0.50 to 0.87, respectively). For poor-risk patients, nivolumab plus ipilimumab and pembrolizumab plus axitinib were associated with significantly higher improvement in PFS than sunitinib (HR 0.57, 95% CI 0.43 to 0.76; HR 0.48, 95% CI 0.30 to 0.82, respectively); nivolumab plus ipilimumab and pembrolizumab plus axitinib were significantly more efficacious for OS than sunitinib (HR 0.57, 95% CI 0.39 to 0.883; HR 0.43, 95% CI 0.23 to 0.80, respectively). For OS, there were 81% and 78% probabilities that pembrolizumab plus axitinib was the best option for intermediate-risk and poor-risk patients, respectively. CONCLUSION: Avelumab plus axitinib might be the optimum treatment for advanced/metastatic RCC of favourable risk. Pembrolizumab plus axitinib might be the optimum treatment for intermediate-risk and poor-risk patients.

Microstructures of the spermatic cord with three-dimensional reconstruction of sections of the cord and application to varicocele.

The aim of the study was to investigate the micro-structures of the spermatic cord using histological examination with three-dimensional (3D) reconstruction of the serial tissue sections of the cord for clinical application in microscopic varicocelectomy. Human spermatic cord specimens obtained from 13 adult male cadavers were used to prepare serial transverse sections. The sections were stained to allow observation of the spermatic cord microstructures. The 3D reconstruction was performed with digitized serial sections by Mimics software. The microscopic varicocelectomy was performed based on the anatomical results of 3D reconstruction of the spermatic cord. The results showed the number of small spermatic veins, large spermatic veins, arteries, lymphatics or nerves were not markedly different between the subinguinal and inguinal regions or between the right and left sperm cord. The number of medium spermatic veins in the subinguinal region was obviously higher than at the inguinal level. The internal spermatic vessels and the vas deferens together with other associated vessels within the cremaster were separately enclosed by two thin and translucent sheaths, the internal spermatic fascia and the vas deferens fascia. We conclude that internal spermatic vessels and the vas deferens together with the associated neurovascular vessels are wrapped by two distinct sheaths separating them from the surrounding tissues. Microscopic varicocelectomy based on the anatomical results of 3D reconstruction of the spermatic cord is feasible. ABBREVIATIONS: 3D: three-dimensional; ISF: internal spermatic fascia; ESF: external spermatic fascia; MHIV: High inguinal microsurgical varicocelectomy; MSIV: subinguinal microsurgical varicocelectomy; CAAD: computer-assisted anatomic dissection; HE: hematoxylin-eosin.

Role of immune checkpoint inhibitor-based therapies for metastatic renal cell carcinoma in the first-line setting: A Bayesian network analysis.

BACKGROUND: Several novel immune checkpoint inhibitor (ICI)-based treatments exhibited promising survival benefits for metastatic renal cell carcinoma (mRCC), yet there is no current guidance regarding the optimum first-line regimen. We performed this network analysis to compare the efficacy and safety of all available treatments for mRCC. METHODS: A systematic search of literature was conducted up to April 30, 2019, and the analysis was done on a Bayesian fixed-effect model. FINDINGS: Twenty-five randomized clinical trials (RCTs) involving 13,010 patients were included in this study. The results showed that for overall survival, pembrolizumab plus axitinib (hazard ratio [HR]: 0.53; 95% credible interval [CrI]: 0.38-0.73) and nivolumab plus ipilimumab (HR: 0.63; 95% CrI: 0.50-0.79) were significantly more effective than sunitinib, and pembrolizumab plus axitinib was probably (68%) to be the best choice. For progression-free survival, cabozantinib (HR: 0.66; 95% CrI: 0.46-0.94), pembrolizumab plus axitinib (HR: 0.69; 95% CrI: 0.57-0.84), avelumab plus axitinib (HR: 0.69; 95% CrI: 0.56-0.85), nivolumab plus ipilimumab (HR: 0.82; 95% CrI: 0.68-0.99), and atezolizumab plus bevacizumab (HR: 0.86; 95% CrI: 0.74-0.99) were statistically superior to sunitinib, and cabozantinib was likely (43%) to be the preferred options. Nivolumab plus ipilimumab (OR: 0.50; 95% CrI: 0.28-0.84), and atezolizumab plus bevacizumab (OR: 0.56; 95% CrI: 0.36-0.83) were associated with significantly lower rate of high-grade adverse events than sunitinib. INTERPRETATION: Our findings demonstrate that pembrolizumab plus axitinib might be the best treatment for mRCC, while nivolumab plus ipilimumab has the most favorable balance between efficacy and acceptability, and may provide new guidance to make treatment decisions. FUND: This research was supported by the Henan Provincial Scientific and Technological Research Project (Grant No. 192102310036).

miR-191 secreted by platelet-derived microvesicles induced apoptosis of renal tubular epithelial cells and participated in renal ischemia-reperfusion injury via inhibiting CBS.

In this study, we aimed to reveal the role of miR-191 in apoptosis of renal tubular epithelial cells and in the involvement of renal ischemia-reperfusion injury. Renal transplantation rat model was established. miR-191 and Cystathionine-ß-synthase (CBS) were measured by qRT-PCR and Western blot. The regulation of miR-191 on CBS was detected by luciferase reporter assay. We found miR-191 expression in platelets and platelet microvesicles (P-MVs) of patients and model rats was significantly upregulated than that of health and normal rats. Also, mRNA and protein levels of CBS in renal tissues of patients were significantly downregulated than that of health and normal rats. We also found that P-MVs could transfer miR-191 to HK-2 cells. Luciferase reporter assay showed that CBS was a direct target of miR-191. In addition, we proved that P-MVs-secreted miR-191 inhibited CBS expression in HK-2 cells, and P-MVs-secreted miR-191 promoted HK-2 cell apoptosis via CBS. Finally, we verified the trends of CBS expressions, HK-2 cell apoptosis and apoptosis-related proteins in vivo were similar as the trends in vitro. Therefore, CBS was a direct target of miR-191, and miR-191 could transfer to HK-2 cells via P-MVs to decrease the expression of CBS, thus to promote cell apoptosis and renal IR injury.

Effects of levosimendan on mortality in patients undergoing cardiac surgery: A systematic review and meta-analysis.

PURPOSE: We sought to determine the impact of levosimendan on mortality following cardiac surgery based on large-scale randomized controlled trials (RCTs). METHODS: We searched PubMed, Web of Science, Cochrane databases, and ClinicalTrials.gov for RCTs published up to December 2017, on levosimendan for patients undergoing cardiac surgery. RESULTS: A total of 25 RCTs enrolling 2960 patients met the inclusion criteria; data from 15 placebo-controlled randomized trials were included for meta-analysis. Pooled analysis showed that the all-cause mortality rate was 6.4% (71 of 1106) in the levosimendan group and 8.4% (93 of 1108) in the placebo group (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.55-1.04; P = 0.09). There were no significant differences between the two groups in the rates of myocardial infarction (OR: 0.91; 95% CI, 0.68-1.21; P = 0.52), serious adverse events (OR: 0.84; 95% CI, 0.66-1.07; P = 0.17), hypotension (OR: 1.69; 95% CI, 0.94-3.03; P = 0.08), and low cardiac output syndrome (OR: 0.47; 95% CI, 0.22-1.02; P = 0.05). CONCLUSION: Levosimendan did not result in a reduction in mortality in adult cardiac surgery patients. Well designed, adequately powered, multicenter trials are necessary to determine the role of levosimendan in adult cardiac surgery.

Micro-vesicles derived from human Wharton's Jelly mesenchymal stromal cells mitigate renal ischemia-reperfusion injury in rats after cardiac death renal transplantation.

The purpose of the present study was to investigate the possible therapeutic effects of the human Wharton-Jelly mesenchymal stromal cells derived micro-vesicles (hWJMSCs-MVs) on renal ischemia-reperfusion injury (IRI) after cardiac death (CD) renal transplantation in rats. MVs were injected intravenously in rats immediately after renal transplantation. The animals were sacrificed at 24 h, 48 h, 1 and 2 weeks post-transplantation. ELISA was used to determine the von Willebrand Factor (vWF), tumor necrosis factor (TNF)-α, and interleukin (IL)-10 levels in the serum. Tubular cell proliferation and apoptosis were identified by Ki67 immunostaining and TUNEL assay. Renal fibrosis was assessed by Masson's tri-chrome straining and alpha-smooth muscle actin (α-SMA) staining. The infiltration of inflammatory cells was detected by CD68+ staining. The transforming growth factor (TGF)-ß, hepatocyte growth factor (HGF), and α-SMA expression in the kidney was measured by Western blot. After renal transplantation, the rats treated with hWJMSCs-MVs improved survival rate and renal function. Moreover, MVs mitigated renal cell apoptosis, enhanced proliferation, and alleviated inflammation at the first 48 h. In the late period, abrogation of renal fibrosis was observed in the MVs group. MVs also could decrease the number of CD68+ macrophages in the kidney. Furthermore, MVs decreased the protein expression levels of α-SMA and TGF-ß1 and increased the protein expression level of HGF at any point (24 h, 48 h, 1 or 2 weeks). The administration of MVs immediately after renal transplantation could ameliorate IRI in both the acute and chronic stage.

BM-MSCs-derived microvesicles promote allogeneic kidney graft survival through enhancing micro-146a expression of dendritic cells.

OBJECTIVE: Microvesicles (MVs) are plasmalemmal vesicles that are released from various cells and regarded as a mediator of intermolecular communication. In present study, we aimed to evaluate the therapeutic efficacy of the bone marrow mesenchymal stem cells (BM-MSCs)-derived MVs in the mice kidney transplant model and explored the underlying mechanism. METHODS: BM-MSCs were isolated from C57BL/6 mice and identified using flow cytometry. In vivo allogenic kidney transplantation model of mice was performed between C57BL/6 mice (recipient) and BALB/c mice (donor). Recipient-type BM-MSC (0.1ml) or equal volume of medium as a control was injected i.v. 24h after kidney transplantation. Serum was collected for creatinine concentration detection at 14 d after transplantation. Dendritic cells (DCs) phenotype and miR-146a expression level in plant was identified. Immature DCs (iDCs) and mature DCs (mDCs) were derived from monocytes. MVs were separated from BM-MSCs. RESULTS: BM-MSCs positive for CD29 (95.8%) and CD44 (94.7%) were cultured and confirmed to prolong the allogenic kidney graft survival in mice. Importantly, the expression of miR-146a increased significantly in DCs of BM-MSCs-treated allogenic kidney. Moreover, both BM-MSCs and MVs derived from BM-MSCs enhanced miR-146a expression in iDCs and mDCs in vitro. Furthermore, MVs substantially reduced IL-12 mRNA expression and IL-12 production of mDCs whereas this action was reversed by miR-146a silencing. MiR-146a silencing also abrogated the MVs-induced decrease in serum creatinine, reduction of immature DCs phenotype in transplant and increase in miR-146a expression level. CONCLUSION: In summary, our data suggested that the BM-MSCs-derived MVs improved allogenic kidney transplantation survival through inhibiting DCs maturity by miR-146a.

LncRNA ZEB2-AS1 promotes bladder cancer cell proliferation and inhibits apoptosis by regulating miR-27b.

BACKGROUND: The aim of this study was to explore the role of lncRNA zinc finger E-box binding homeobox 2 antisense RNA 1 (ZEB2-AS1), as a new tumor-associated lncRNA, in bladder cancer (BC) pathogenesis. METHODS: BC tissues and tumor-adjacent normal bladder tissues were collected for detection of the expression profile of ZEB2-AS1 and miR-27b in BC. The endogenous expression of ZEB2-AS1 and miR-27b was modulated by the recombinant expression vector in vitro. The interaction between ZEB2-AS1 and miR-27b was identified by luciferase report gene assays and RNA immunoprecipitation (RIP) assays. The proliferation and apoptosis of BC cells was determined using CCK-8 assays and flow cytometric analysis. RESULTS: The expression of ZEB2-AS1 was significantly increased in both BC tissues and BC cells (J82, 5637, T24); while miR-27b was down-regulated in BC tissues. More importantly, ZEB2-AS1 was significantly negative correlated with miR-27b expression in BC tissues (R2=0.1688, P<0.05). ZEB2-AS1 silencing inhibited BC cell proliferation and promoted apoptosis. Further studies confirmed that miR-27b was negatively regulated by ZEB2-AS1 in BC cells 5637 and T24, and the effects of ZEB2-AS1 on BC cells was mediated by miR-27b. CONCLUSION: Our data provided strong evidence that ZEB2-AS1 promoted tumorigenesis and development of BC through down-regulating tumor-suppressive miR-27b.