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Retinoblastoma (Rb) accounts for 3% of all childhood cancers. It is the most common intraocular malignant tumor with a highly aggressive and metastatic phenotype. Gaining a more comprehensive understanding of the molecular mechanisms underlying the proliferation, metastasis, migration, invasive apoptosis, and autophagy processes associated with this cancer would facilitate the design of therapeutic modalities and the identification of novel tumor markers. Recent investigations have shown the contribution of circular RNAs (circRNAs) in the evolution of Rb. Several circRNAs, including circ_0000034, circ_0000527, circ_0075804, circ_0099198, circFAM158A, and circVAPA, promote the progression and metastasis of Rb. However, some circRNAs, such as circ_0001649, circMKLN1, and circTET1, play a tumor suppressive role. In this regard, circRNAs can regulate cancer-developing processes including cell proliferation, apoptosis, migration, invasion, and tumor growth. This review summarizes the functional roles of circRNAs in Rb and their potential clinical applications for diagnosis and prognosis, and provides a comprehensive understanding of the role of circRNAs in the pathophysiology of Rb. [ABSTRACT FROM AUTHOR]

To report a case of secondary bilateral choroiditis in a patient with primary Sjögren's syndrome(pSS). Case report. A 69-year-old woman visited our hospital for consultation due to decreased visual acuity in both eyes for 1 month. At the first visit, best corrected visual acuity (BCVA) was 0.2 and 0.3 in her right and left eyes, respectively. Intraocular pressure values were 15 mmHg and 16 mmHg in her right and left eyes, respectively. Examination revealed edema of the eyelids and conjunctiva,and corneal fluorescence staining was positive. No inflammation in the anterior chamber or vitreous opacities were observed. Bilateral multiple retinal detachments were observed on the posterior fundus, and optical coherence tomography revealed bilateral multiple areas of retinal neuroepithelial detachment, choroidal thickening, and choroidal folds. No abnormal fluorescence leakage was observed on fundus fluorescein angiography or indocyanine green angiography. In addition, systematic manifestations included recurrent bilateral parotid gland enlargement. Labial gland biopsy revealed dilated glandular ducts, scattered interstitial glands, and lymphocytic foci. Salivary gland scintigraphy revealed severe impairment of glandular excretory function. Moreover, blood tests for anti-Ro/SSA and anti-La/SSBantibodies were positive. The patient was diagnosed with primary Sjögren's syndrome. After 2 months treatment with oral prednisolone acetate combined with hydroxychloroquine, her BCVAimproved to 0.8 and 1.0 in the right and left eyes, respectively. The fundus also recovered to normal, and no recurrence was observed during the 1-year follow-up period. The current case highlights that pSS, which usually manifests with dry eye and keratoconjunctivitis, may manifest with chronic choroiditis in both eyes as well. Based on our experience with this case, patients with clinically suspected bilateral choroiditis should be evaluated for pSS. [ABSTRACT FROM AUTHOR]

Abstract: cAMP is a key modulator for glucose-dependent insulin secretion (GDIS). Members of the phosphodiesterase (PDEs) gene family regulate intracellular levels of cAMP by hydrolyzing cAMP to the corresponding inactive 5′AMP derivative. These studies examined the expression and function of all 18 cAMP-specific PDEs in the rat insulinoma derived INS-1 (832/13) cell and isolated rat islets using quantitative PCR and siRNA-mediated gene-specific knockdown. PDE1C, PDE3B, PDE4C, PDE8B, PDE10A, and PDE11A were significantly expressed in rat islets and INS-1 (832/13) cells at the mRNA level. PDE1C, PDE10A and PDE11A were also expressed in brain, along with PDE3B, PDE4C and PDE8B which were also highly expressed in liver, and PDE3B was present in adipose tissue and PDE4C in skeletal muscle. siRNA mediated knockdown of PDE1C, PDE3B, PDE8B and PDE4C, but not PDE10A and PDE11A, significantly enhanced GDIS in rat INS-1 (832/13) cells. Also, selective inhibitors of PDE3 (trequinsin) and PDE4 (roflumilast and L-826,141) significantly augmented GDIS in both INS-1 (832/13) cells and rat islets. The combination of PDE3 and PDE4 selective inhibitors demonstrate that these enzymes comprise a significant proportion of the cAMP metabolizing activity in INS-1 cells and rat islets. [Copyright &y& Elsevier]

Background: To investigate the epidemiological, clinical characteristics and outcomes of diabetes in pregnancy (DIP).Methods: This single-center, retrospective study included 16,974 pregnant women hospitalized during 2018-2019. Among them, 2860 DIP patients were grouped according to diabetes type, glycemic status, and insulin use. Multivariate logistic regression analysis was conducted.Results: The incidence of DIP [17.10%; pregestational diabetes mellitus (PGDM), 2.00% (type I, 0.08%; type 2, 1.92%); gestational diabetes mellitus (GDM), 14.85% (GDM A1, 13.58%; GDM A2, 1.27%)] increased annually. Premature birth, congenital anomalies, large for gestational age (LGA), neonatal asphyxia, neonatal intensive care unit transfer, hypertension, and puerperal infection were more common in DIP than in healthy pregnancies. The most common comorbidities/complications were hypertension, thyroid dysfunction, cervical incompetence, intrahepatic cholestasis, premature membrane rupture, oligo/polyhydramnios, and fetal distress. GDM incidence at ages ≥35 and ≥ 45 years was 1.91 and 3.26 times that at age < 35 years, respectively. If only women with high-risk factors were screened, 34.8% GDM cases would be missed. The proportion of insulin use was 14.06% (PGDM, 55%; GDM, 8.53%). Mean gestational age at peak insulin dose in DIP was 32.87 ± 5.46 weeks. Peak insulin doses in PGDM and GDM were 3.67 and 2 times the initial doses, respectively. The risks of LGA, premature birth, cesarean section, and neonatal hypoglycemia in PGDM were 1.845, 1.533, 1.797, and 1.368 times of those in GDM, respectively. The risks of premature birth and neonatal hypoglycemia in women with poor glycemic control were 1.504 and 1.558 times of those in women with good control, respectively.Conclusions: The incidence of adverse outcomes in DIP is high. [ABSTRACT FROM AUTHOR]

To explore the long-term safety and benefit of umbilical cord mesenchymal stromal cell (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). In the primary completion of this trial (ClinicalTrials.gov identifier: NCT01374854), the authors randomized patients (n = 21 per group) to either SCT or standard care (control) and previously reported effects on insulin secretion. The authors report about the incidence of chronic diabetes complications (primary endpoint) after 8 years of follow-up. The authors also report on secondary endpoints, safety, islet function and metabolic control. Data were obtained from 14 of 21 patients in the SCT group and 15 of 21 patients in the control group who completed follow-up. At 8 years, the incidence of peripheral neuropathy was 7.1% (one of 14) in the SCT group versus 46.7% (seven of 15) in the control group (P = 0.017). The incidence of diabetic nephropathy was 7.1% (one of 14) in the SCT group versus 40.0% (six of 15) in the control group (P = 0.039). The incidence of retinopathy was 7.1% (one of 14) in the SCT group versus 33.3% (five of 15) in the control group (P = 0.081). Two patients (two of 14, 14.3%) in the SCT group and 11 patients (11 of 15, 73.3%) in the control group developed at least one complication (P = 0.001). One and six patients in the SCT group and control group, respectively, had at least two complications (P = 0.039). No malignancies were reported in the treated group. Co-transplantation of umbilical cord MSCs and aBM-MNCs in patients with established T1D was associated with reduced incidence of chronic diabetes complications. [ABSTRACT FROM AUTHOR]

To evaluate the feasibility of serum sCD30 for prediction of acute graft rejection, we analyzed clinical data of 231 patients, whose serum levels of sCD30 were detected by ELISA before and after transplantation. They were divided into three groups: acute rejection group (AR, n = 49), uncomplicated course group (UC, n = 171) and delayed graft function group (DGF, n = 11). Preoperative sCD30 levels of three groups were 183±74, 177±82 and 168±53 U/ml, respectively (P=0.82). Significant decrease of sCD30 was detected in three groups on day 5 and 10 post-transplantation respectively (52 ±30 and 9±5 U/ml respectively, P< 0.001). Compared with Group UC and DGF, patients of Group AR had higher sCD30 values on day 5 post-transplantation (92±27 U/ml vs. 41±20 U/ml and 48± 18 U/ml, P<<0.001). However, sCD30 levels on day 10 post-transplantation were virtually similar in patients of three groups (P=0.43). Receiver operating characteristic (ROC) curve demonstrated that sCD30 level on day 5 post-transplantation could differentiate patients who subsequently suffered acute allograft rejection from others (area under ROC curve 0.95). According to ROC curve, 65 U/ml may be the optimal operational cut-off level to predict impending graft rejection (specificity 91.8%, sensitivity 87.1%). Measurement of soluble CD30 on day 5 post-transplantation might offer a noninvasive means to recognize patients at risk of impending acute graft rejection during early post-transplantation period. [ABSTRACT FROM AUTHOR]

Background: Gestational diabetes mellitus (GDM), a common endocrine disorder with rising prevalence in pregnancy, has been reported to be associated with alteration of gut microbiota in recent years. However, the role of gut microbiome in GDM physiopathology remains unclear. This pilot study aims to characterize the alteration of gut microbiota in GDM on species-level resolution and evaluate the relationship with occurrence of GDM. Methods: An analysis based on 16S rRNA microarray was performed on fecal samples obtained from 30 women with GDM and 28 healthy pregnant women. Results: We found 54 and 141 differentially abundant taxa between GDM and control group at the genus and the species level respectively. Among GDM patients, Peptostreptococcus anaerobius was inversely correlated with fasting glucose while certain species (e.g., Aureimonas altamirensis, Kosakonia cowanii) were positively correlated with fasting glucose. Conclusions: This study suggests that there are large amounts of differentially abundant taxa between GDM and control group at the genus and the species level. Some of these taxa were correlated with blood glucose level and might be used as biomarkers for diagnoses and therapeutic targets for probiotics or synbiotics. [ABSTRACT FROM AUTHOR]

The high-temperature reliability of nano-Ag pastes on bare Cu substrates is of great significance in power electronics. Although Cu metallization in sintered joints is susceptible to oxidation in air, methods to inhibit the oxidation under high temperatures are rarely studied. In this paper, a SiC–Cu interconnection with an average shear strength of 161.7 MPa was fabricated using nano-Ag paste by a two-step sintering process. The microstructure of the sintered silver was investigated by the transmitted Kikuchi diffraction (TKD) technique, and the formation of robust joints was attributed to the low porosity, fine gain size and high density of twins. Pores in the sintered silver were isolated, which effectively impeded the penetration of oxygen and growth of Cu oxide during high-temperature thermal storage. Two kinds of failure mechanisms were determined: the growth of a Cu 2 O band and the evolution of a dense sintered layer. Overall, we propose a sintering method for SiC–Cu interconnections that could guarantee long-term service at 200 °C and short-term service at 300 °C in air. • Robust SiC–Cu interconnection was prepared via nano-Ag paste by a two-step sintering process. According to transmitted Kikuchi diffraction observation, the superior mechanical strength is attributed to the low porosity, fine grain sizes and high density of twins in sintered silver. • Instead of spreading on the whole substrate, the Cu oxide initiated at the edge of joints and grew along the horizontal direction of cross-section of joints. Healing porosity of sintered nano-Ag effectively inhibited the penetration of oxygen and enhanced the high-temperature reliability of SiC–Cu interconnection. • The evolution of dense sintered layer and loose microstructure is the main reason for the strength degradation of joints aged at 200 °C for more than 100 h. And this was contributed to the extensive diffusion of Cu atoms from substrate and Ag atoms from sintered Ag matrix. [ABSTRACT FROM AUTHOR]

Background: Hypoxia is a major cause of beta cell death and dysfunction after transplantation. The aim of this study was to investigate the effect of exosomes derived from mesenchymal stem cells (MSCs) on beta cells under hypoxic conditions and the potential underlying mechanisms. Methods: Exosomes were isolated from the conditioned medium of human umbilical cord MSCs and identified by WB, NTA, and transmission electron microscopy. Beta cells (βTC-6) were cultured in serum-free medium in the presence or absence of exosomes under 2% oxygen conditions. Cell viability and apoptosis were analysed with a CCK-8 assay and a flow cytometry-based annexin V-FITC/PI apoptosis detection kit, respectively. Endoplasmic reticulum stress (ER stress) proteins and apoptosis-related proteins were detected by the WB method. MiRNAs contained in MSC exosomes were determined by Illumina HiSeq, and treatment with specific miRNA mimics or inhibitors of the most abundant miRNAs was used to reveal the underlying mechanism of exosomes. Results: Exosomes derived from MSC-conditioned culture medium were 40–100 nm in diameter and expressed the exosome markers CD9, CD63, CD81, HSP70, and Flotillin 1, as well as the MSC markers CD73, CD90, and CD105. Hypoxia significantly induced beta cell apoptosis, while MSC exosomes remarkably improved beta cell survival. The WB results showed that ER stress-related proteins, including GRP78, GRP94, p-eIF2α and CHOP, and the apoptosis-related proteins cleaved caspase 3 and PARP, were upregulated under hypoxic conditions but were inhibited by MSC exosomes. Moreover, the p38 MAPK signalling pathway was activated by hypoxia and was inhibited by MSC exosomes. The Illumina HiSeq results show that MSC exosomes were rich in miR-21, let-7 g, miR-1246, miR-381, and miR-100. After transfection with miRNA mimics, the viability of beta cells under hypoxia was increased significantly by miR-21 mimic, and the p38 MAPK and ER stress-related proteins in beta cells were downregulated. These changes were reversed after exosomes were pretreated with miR-21 inhibitor. Conclusions: Exosomes derived from MSCs could protect beta cells against apoptosis induced by hypoxia, largely by carrying miR-21, alleviating ER stress and inhibiting p38 MAPK signalling. This result indicated that MSC exosomes might improve encapsulated islet survival and benefit diabetes patients. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have vastly expanded our view of RNA world in intracellular signal regulating networks. Here, we functionally characterized a normally highly expressed miRNA, miR-30a-5p (MIMAT0000087), which exhibits downregulated expression profiles in prostate cancer samples. MiR-30a-5p knockdown and overexpression in PC-3 cell line alters cell proliferation supporting a tumour suppressor role. We also discovered that PCLAF is the direct target of miR-30a-5p. Notably, PC-3 cell proliferation is inhibited by miR-30a-5p/PCLAF axis. miR-30a-5p represents a novel molecule of functionally important miRNAs which may shed light on the novel therapeutic targets for prostate cancer. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a common malignancy among women and the leading cause of female cancer mortality worldwide. In recent years, increasing evidence has shown that long non-coding RNAs (lncRNAs) can act as competing endogenous RNAs (ceRNAs) in human cancer and that they are involved in many biological processes, including proliferation, migration, apoptosis and invasion. In the present study, the biological function and molecular mechanism of ataxin 8 opposite strand (ATXN8OS) in BC tissue and cell lines were investigated. It was found that ATXN8OS was markedly up-regulated in BC tissue and cell lines, and that its level of overexpression was inversely linked with the overall survival rate of patients with BC. Knockdown of ATXN8OS inhibited proliferation, viability and invasion in the human MCF7 and MDA-MB-231 BC cell lines. In addition, microRNA-204 (miR-204) was negatively associated with the expression of ATXN8OS in BC tissues and cell lines. A luciferase assay demonstrated a direct binding site for miR-204 within ATXN8OS, and inhibition of miR-204 stimulated the tumour-promoting effect of ATXN8OS on BC cells. In conclusion, the present study suggested that ATXN8OS acts as a tumour promoter by sequestering miR-204 during the development of BC, therefore providing a mechanistic insight which may facilitate the diagnosis and treatment of BC. [ABSTRACT FROM AUTHOR]

Reticulon‐4 (RTN4), a reticulon family protein localized in the endoplasmic reticulum, is reported to be involved in multiple physiological processes like neuroendocrine secretion and membrane trafficking in neuroendocrine cells. Previous studies have presented a great potential of RTN4 for the treatment of autoimmune‐mediated demyelinating diseases and spinal cord injury regeneration. While interaction with Bcl‐2 and Bcl‐2‐like family in apoptosis modulation implicated its possible role in various human cancers. However, the investigation of this gene in prostate cancer is mainly ignored. Here in our current study, we focused on its role in prostate cancer and found that RTN4 DNA copy numbers were higher in prostate cancer than normal prostate gland while its RNA and protein expressions were relatively lower. Chromosomal neighbor gene EML6 had similar expression patterns with RTN4 in prostate cancer tissues and cell lines, and further research found that they could be both targeted by miR‐148a‐3p. Lentivirus‐mediated RTN4 overexpression potently inhibited DU145 and LNCaP cells proliferation. Cell cycle was blocked in G2/M phase and significant cell senescence was observed in RTN4 overexpressed prostate cancer cells. Finally, interaction networks in the normal prostate gland and cancer tissues further revealed that RTN4 maybe phosphorylated by MAPKAPK2 and FYN at tyrosine 591 and serine 107, respectively. All these results implied that RTN4 might somehow participate in prostate tumor progression, and this elicits possibility to develop or identify selective agents targeting RTN4 for prostate cancer therapy. Our results showed that reticulon‐4 (RTN4) was downregulated and targeted by miR‐148a‐3p, and inhibited prostate cancer cell proliferation by inducing cell cycle arrest and senescence, suggesting that RTN4 may be an important molecular event linked to prostate cancer. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of Serenoa repens among patients with benign prostatic hyperplasia (lower urinary tract symptoms/benign prostatic hyperplasia [LUTS/BPH]) in China.Methods: We conducted a double blind, placebo-controlled study of 354 patients with LUTS/BPH from 19 institutions, to evaluate the efficacy and safety of Serenoa repens. Participants were randomly assigned (1:1) into the Serenoa repens extract (320 mg) or placebo groups for 24 weeks. Primary efficacy parameters were changes in International Prostate Symptom Score and peak urinary flow from baseline to each assessment. Secondary efficacy parameters included improvement of storage symptom and voiding symptom scores, prostate volume, urinary frequency, and total prostate-specific antigen level. Other parameters assessed were quality of life score, a four-item male sexual function questionnaire score, and International Index of Erectile Function score across the consecutive double-blind visits.Results: Statistically significant improvement in the peak urinary flow, International Prostate Symptom Score, scores of storage symptoms and voiding symptoms, quality of life score, four-item male sexual function questionnaire score, and International Index of Erectile Function score were observed in the Serenoa repens extract group compared with those in the placebo group (P <.05). Two (1.18%) of 169 patients in the placebo group and 3 (1.89) of 159 patients in the Serenoa repens extract group experienced 1 or more adverse events.Conclusion: The Serenoa repens extract was effective, safe, well-tolerated, and clinically and statistically superior to placebo in the target LUTS/BPH population. [ABSTRACT FROM AUTHOR]

Purpose: We intend to investigate the association between tacrolimus-induced new-onset diabetes after transplantation (NODAT) and polymorphisms of CYP3A4, CYP3A5, ATP-binding cassette transporter sub-family C member 8 (ABCC8), and glucokinase (GCK) in renal transplant recipients.Methods: Polymorphisms of CYP3A4 *18B, CYP3A5 *3, ABCC8 T-3C, and GCK G-30A were genotyped in 169 renal transplant recipients. Trough concentrations of tacrolimus were detected by an ELISA kit. The relative materials were collected in all patients and volunteers. The association of NODAT and polymorphisms was analyzed.Results: CYP3A4 *18B and GCK G-30A were related to NODAT (p < 0.05). The lower concentration/dose or fasting serum glucose was in CYP3A4 *1/*1 carriers than that in *18B/*18B carriers in all the renal transplant recipients (p < 0.05), respectively. Genotype of ABCC8 T-3C was associated with fasting serum glucose in both NODAT and non-NODAT patients (p < 0.05). Furthermore, family history of DM (OR = 3.734, p = 0.002), concentration/dose above 70 ([ng/mL]/[mg/kg]) (OR = 2.154, p = 0.034) and GCK G-30A (OR = 2.272, p = 0.026) were independently correlated with the incidence of NODAT in logistic regression.Conclusions: The polymorphisms of CYP3A4 *18B and GCK G-30A were related to NODAT induced by tacrolimus. [ABSTRACT FROM AUTHOR]

In this study, we developed fluorescent dual pH and oxygen sensors loaded in multi-well plates for in-situ and high-throughput monitoring of oxygen respiration and extracellular acidification during microbial cell growth for understanding metabolism. Biocompatible PHEMA-co-PAM materials were used as the hydrogel matrix. A polymerizable oxygen probe (OS2) derived from PtTFPP and a polymerizable pH probe (S2) derived from fluorescein were chemically conjugated into the matrix to solve the problem of the probe leaching from the matrix. Gels were allowed to cure directly on the bottom of 96-well plates at room-temperature via redox polymerization. The influence of matrix’s composition on the sensing behaviors was investigated to optimize hydrogels with enough robustness for repeatable use with good sensitivity. Responses of the dual sensing hydrogels to dissolved oxygen (DO) and pH were studied. These dual oxygen-pH sensing plates were successfully used for microbial cell-based screening assays, which are based on the measurement of fluorescence intensity changes induced by cellular oxygen consumption and pH changes during microbial growth. This method may provide a real-time monitoring of cellular respiration, acidification, and a rapid kinetic assessment of multiple samples for cell viability as well as high-throughput drug screening. All of these assays can be carried out by a conventional plate reader. [ABSTRACT FROM AUTHOR]

Purpose: To exploit the intravoxel incoherent motion (IVIM) diffusion-weighted (DW) MRI when evaluating the therapeutic response of gastrointestinal stromal tumors (GIST) to Imatinib in a mouse model. Materials and Methods: Mice with xenografts bearing cells from the GIST-T1 cell line were randomly divided into a treated group receiving Imatinib and a control group. DWMRI scans with 14 b-values (0–1500 s/mm2) were performed before and after treatment (days 1, 3 and 7). IVIM related parameters perfusion fractions (fp) and perfusion-related diffusion coefficients (D*) and the conventional apparent diffusion coefficients (ADC) were calculated by fitting the DWMRI signal decay. The mean changes from baseline to each post-treatment time point for each measurement (ΔADC, Δfp and ΔD*) were calculated. The differences of mean changes between the two groups were tested for statistical significance. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans. Results: Increases in ADC of the treated group were higher than those of the control group after treatment, whereas statistical significances were not observed. Compared to the control group, D* in the treated group decreased significantly (ΔD*treated = -41%, -49%, and -49% with P = 0.0001, 0.0001 and 0.0001), and fp increased significantly (Δfptreated = 79%, 82% and 110%, with P = 0.001, 0.0001 and P = 0.0007) on days 1, 3 and 7 after treatment. Histopathological analyses demonstrated different tumor tissue characteristics between the treated and control groups. Conclusion: IVIM measurements may serve as more sensitive imaging biomarkers than ADC when assessing GIST response to Imatinib as early as one day after treatment. [ABSTRACT FROM AUTHOR]

Objective: To determine the safety and effects on insulin secretion of umbilical cord (UC) mesenchymal stromal cells (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D).Research Design and Methods: Between January 2009 and December 2010, 42 patients with T1D were randomized (n = 21/group) to either SCT (1.1 × 10(6)/kg UC-MSC, 106.8 × 10(6)/kg aBM-MNC through supraselective pancreatic artery cannulation) or standard care (control). Patients were followed for 1 year at 3-month intervals. The primary end point was C-peptide area under the curve (AUC(C-Pep)) during an oral glucose tolerance test at 1 year. Additional end points were safety and tolerability of the procedure, metabolic control, and quality of life.Results: The treatment was well tolerated. At 1 year, metabolic measures improved in treated patients: AUCC-Pep increased 105.7% (6.6 ± 6.1 to 13.6 ± 8.1 pmol/mL/180 min, P = 0.00012) in 20 of 21 responders, whereas it decreased 7.7% in control subjects (8.4 ± 6.8 to 7.7 ± 4.5 pmol/mL/180 min, P = 0.013 vs. SCT); insulin area under the curve increased 49.3% (1,477.8 ± 1,012.8 to 2,205.5 ± 1,194.0 mmol/mL/180 min, P = 0.01), whereas it decreased 5.7% in control subjects (1,517.7 ± 630.2 to 1,431.7 ± 441.6 mmol/mL/180 min, P = 0.027 vs. SCT). HbA1c decreased 12.6% (8.6 ± 0.81% [70.0 ± 7.1 mmol/mol] to 7.5 ± 1.0% [58.0 ± 8.6 mmol/mol], P < 0.01) in the treated group, whereas it increased 1.2% in the control group (8.7 ± 0.9% [72.0 ± 7.5 mmol/mol] to 8.8 ± 0.9% [73 ± 7.5 mmol/mol], P < 0.01 vs. SCT). Fasting glycemia decreased 24.4% (200.0 ± 51.1 to 151.2 ± 22.1 mg/dL, P < 0.002) and 4.3% in control subjects (192.4 ± 35.3 to 184.2 ± 34.3 mg/dL, P < 0.042). Daily insulin requirements decreased 29.2% in only the treated group (0.9 ± 0.2 to 0.6 ± 0.2 IU/day/kg, P = 0.001), with no change found in control subjects (0.9 ± 0.2 to 0.9 ± 0.2 IU/day/kg, P < 0.01 vs. SCT).Conclusions: Transplantation of UC-MSC and aBM-MNC was safe and associated with moderate improvement of metabolic measures in patients with established T1D. [ABSTRACT FROM AUTHOR]

Objective This study aimed to investigate the role of the Notch1/Delta-like 4 signaling pathway and its relationship with T helper 17 (Th17) cells in the peripheral transplantation immune of renal transplant recipients. Methods Fifty-two kidney transplant recipients in our hospital were selected and divided into the acute rejection group (AR), renal tubular necrosis (ATN) group, and stable renal function group, according to their postoperative recovery. Flow cytometry was used to detect the expression of Notch1 and Delta-like 4 in peripheral lymphocytes and the presence of Th17 cells in the kidney of transplant recipients. Results The expression levels of Notch1 and Delta-like 4 and level of Th17 cells among the three groups before surgery and at postoperative day 1 showed no significant differences (P > 0.05). At 3, 7, and 14 d after surgery, these three factors in the AR group were significantly higher than in the stable renal function group (P < 0.01) and ATN group (P < 0.01), where the levels in the latter two groups were similar. Upon the occurrence of acute rejection, the Notch1 and Delta-like 4 expression and Th17 cell ratio were significantly increased (P < 0.01) but gradually decreased after anti-rejection therapy. Notch1 and Delta-like 4 were significantly positively correlated with Th17 cells (r = 0.893, P < 0.01 and r = 0.893, P < 0.01, respectively). Conclusion The detection of Notch1 and Delta-like 4 expression in peripheral blood lymphocytes of renal transplant recipients can serve as a positive indicator for evaluating the diagnosis and treatment efficacy of the AR reaction. [ABSTRACT FROM AUTHOR]

Diabetes is a significant risk factor for thrombosis. The present study aimed at assessing coagulability, platelet reactivity, and thrombogenicity of the diabetic female Zucker Diabetic Fatty (ZDF) rat model and its relevance in studying antithrombotic mechanisms. Materials and Methods The basal coagulant state in ZDF rats was evaluated by clotting times, thromboelastography, and thrombin generation assay. A 14-day treatment with dapagliflozin in ZDF rats was pursued to investigate if glycemic control can improve coagulability. Thrombus formation in the Arterio-Venous (A-V) shunt model and the FeCl3-induced arterial thrombosis model was studied, with the antithrombotic effect of apixaban in the former model further investigated. Results ZDF rats exhibited significantly shortened clotting times, enhanced thrombin generation, and decreased fibrinolysis at baseline. Effective glycemic control achieved with dapagliflozin did not improve any of these parameters. ZDF rats displayed accelerated thrombus formation and were amenable to apixaban treatment in the A-V shunt model albeit with less sensitivity than normal rats. ZDF rats exhibited less platelet aggregation in response to ADP, collagen and PAR-4, and attenuated thrombotic response in the FeCl3 model. Conclusions ZDF rats are at a chronic hypercoagulable and hypofibrinolytic state yet with compromised platelet reactivity. They display accelerated and attenuated thrombosis in the A-V shunt and FeCl3 model of thrombosis, respectively. Results shed new light on the pathophysiology of the ZDF rat model and illustrate its potential value in translational research on anticoagulant agents in diabetics. Caution needs to be exerted in utilizing this model in assessing antiplatelet mechanisms in diabetes-associated atherothrombosis. [ABSTRACT FROM AUTHOR]

Background: The mechanisms by which tamoxifen inhibits breast tumor growth are not completely understood. Partial agonist antiestrogens such as tamoxifen may cause the estrogen receptor (ER) to interact with genes different from those activated by ER bound to estradiol. Doming is a property often associated with, and considered a marker of, differentiation in mammary epithelial cells in culture. This study compared the ability of pure and partial agonist antiestrogens to stimulate doming. Materials and methods: MCF-7 cells grown in medium with 10% calf serum were treated with antiestrogens. Domes were counted in three rows (width of the 4× field) across the flask. Results: Three partial agonist antiestrogens [4-hydroxytamoxifen (OHT), H1285 and RU 39,411] caused dome formation. None of the pure antiestrogens tested (ICI 164,384, ICI 182,780 and RU 58,668) caused doming. Doming was stimulated in a dose-dependent manner starting at 1 nM OHT with maximum stimulation at 10-100 nM. Estradiol did not stimulate doming, but blocked doming at 1%-10% of the OHT concentration. Trichostatin A (TSA) reduced the level of estrogen receptor alpha (ERα) and adding it 24 h before adding OHT prevented dome formation. Conclusions: OHT and the other partial agonist antiestrogens appear to act through the ER to stimulate doming. The ability of tamoxifen to induce a marker of differentiation may play a role in its inhibition of breast tumors. If so, then the fact that other partial agonist antiestrogens share this ability, but that pure antiestrogens lack it, may be an important consideration in developing new antiestrogens for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Genome-wide association studies (GWAS) are useful in studying the complex pathways underlying diseases such as atherosclerosis; however, additional testing is often necessary to identify the disease causal genes linked to GWAS loci. We used siRNA-mediated gene knockdown in primary human hepatocytes (PHuH) to identify potential GWAS causal genes affecting the hepatic secretion of apolipoprotein B (ApoB), ApoA1, and proprotein convertase subtilisin/kexin type 9. Materials and methods: Candidate causal genes within GWAS loci affecting human plasma levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides were identified from the literature; 191 genes were selected from 74 loci. A functional siRNA screen was performed using PHuH. Results: Four genes: poly (ADP-ribose) polymerases member 10, haptoglobin, fucosyltransferase 1, and lysophosphatidic acid receptor 2 were identified and confirmed. Knocking down these genes reduced cell-associated and secreted ApoB levels. Conclusion: Modification of these four genes may affect plasma lipids through modulation of ApoB secretion. [Copyright &y& Elsevier]

Context: Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease.Objective: To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor.Design, Setting, and Patients: One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed.Intervention: Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs.Main Outcome Measures: The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events.Results: Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02)Conclusion: Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year.Trial Registration: clinicaltrials.gov Identifier: NCT00658073. [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy and safety of high-power holmium: yttrium aluminum-garnet (Ho:YAG) laser lithotripsy for multitract modified minimally invasive percutaneous nephrolithotomy (MPCNL) in the treatment of patients with large staghorn renal calculi. Methods: A randomized, prospective study was conducted. Two-hundred seventy-three consecutive patients (291 renal units) with large staghorn renal calculi were randomized to undergo multitract MPCNL with 30-W low-power or 70-W high-power Ho:YAG laser lithotripsy. Both groups were compared in terms of perioperative findings and postoperative outcomes, including procedure time, stone-free rate, length of hospital stay, transfusion rates, renal function recovery, and other complications. Results: The average patient age was 49.2 years (range 22-73) and mean stone size was 5.54 ± 0.7 cm. The 2 groups had some comparable perioperative findings and outcome, including tracts required per operated renal unit (n), blood loss, postoperative fever, postoperative hospital stay, stone-free rate, and improvement of operated renal function. The operation time in the high-power group was significantly shorter than that in the low-power group (129.20 ± 17.2 vs 105.18 ± 14.2, P <.01). Conclusion: A combination of multitract MPCNL and high-power Ho:YAG laser lithotripsy can greatly decrease the operative time without increasing the intraoperative complications or delaying postoperative renal function recovery when compared with low-power Ho:YAG laser lithotripsy. [ABSTRACT FROM AUTHOR]

Background: Renal ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal allograft. This study aimed at investigating the effects ofmesenchymal stem cells (MSC) on ischemia/reperfusion (I/R) injury and the underlying mechanisms in a rat model. Methods: Renal ischemia was produced by clamping the right renal vessels for 60 min after the left kidney was removed. Immediately after visual confirmation of reflow, 1 × 106 MSC were administered by intravenous injection, followed by reperfusion for 24 h. The kidney functions, tissue malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels were evaluated. Histopathological examinations were also performed. Results: MSC infusion significantly improved kidney function as indicated by lower urea and creatinine levels in the MSC compared to the vehicle group (p < 0.05). I/R-induced reduction in renal tissue SOD enzyme activity and GSH-Px was significantly improved by MSC (p < 0.05). Treatment with MSC also resulted in significant reduction in renal tissue MDA levels that were increased by renal I/R injury (p < 0.05). At histological examination, the kidneys of MSC-treated rats showed a fairly normal morphology. Conclusions: MSC protects the kidneys against I/R injury at least via their antioxidant effects. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The TRAP/Mediator complex serves as a coactivator for many transcriptional activators, including nuclear receptors such as the thyroid hormone receptor (TR) that targets the TRAP220 subunit. The critical but selective function of TRAP220 is evidenced by the embryonic lethal phenotype of Trap220-/- mice and by the observation that Trap220-/- fibroblasts (isolated before embryonic death) are impaired in specific nuclear receptor-dependent pathways. Here we have used a biochemical and genetic approach to understand the basis of specificity in TRAP220 function. We show that Trap220-/- cells possess a TRAP/Mediator complex that is relatively intact and compromised in its ability to support TR-dependent, but not VP16-dependent, transcription in vitro. Transfection studies using TRAP220 mutants revealed that the N terminus of TRAP220 is necessary and sufficient for stable association with the TRAP/Mediator complex and, further, that TRAP220- dependent TR function in transfected cells requires both of the NR boxes that contain the LXXLL motif implicated in nuclear receptor binding. Similarly, an analysis of isolated TRAP/Mediator complexes with mutations in either or both of the two NR boxes confirmed a critical role for them in in vitro coactivator function. The implications of these observations are discussed in terms of our present understanding of coactivator function. [ABSTRACT FROM AUTHOR]

A vesicovaginal fistula with vagina obstruction associated with vaginal calculi is an extremely rare medical condition. We report a giant primary vaginal calculus resulting from vesicovaginal fistula with partial vaginal outlet obstruction secondary to perineum trauma and surgery in a 12-year-old girl. Episiotomy was performed and the adhesive labia minora was split. After the removal of a giant calculus in the vagina, approximately 8 cm in diameter, the fistula tract was completely excised, followed by the repair of the vesicovagina fistula and the vagina. The patient was symptom-free at 6-month follow-up examination. [ABSTRACT FROM AUTHOR]