Search

CXC Chemokine Receptor 3 (CXCR3) is functionally pleiotropic and not only plays an important role in chemotaxis, but also participates in T cell differentiation and may play a critical role in inducing and maintaining immune tolerance. These observations are particularly critical for autoimmune cholangitis in which CXCR3 positive T cells are found around the portal areas of both humans and mouse models of primary biliary cholangitis (PBC). Herein, we investigated the role of CXCR3 in the pathogenesis of autoimmune cholangitis. We have taken advantage of a unique CXCR3 knockout dnTGFβRII mouse to focus on the role of CXCR3, both by direct observation of its influence on the natural course of disease, as well as through adoptive transfer studies into Rag−/− mice. We report herein that not only do CXCR3 deficient mice develop an exacerbation of autoimmune cholangitis associated with an expanded effector memory T cell number, but also selective adoptive transfer of CXCR3 deficient CD8 + T cells induces autoimmune cholangitis. In addition, gene microarray analysis of CXCR3 deficient CD8 + T cells reveal an intense pro-inflammatory profile. Our data suggests that the altered gene profiles induced by CXCR3 deficiency promotes autoimmune cholangitis through pathogenic CD8 + T cells. These data have significance for human PBC and other autoimmune liver diseases in which therapeutic intervention might be directed to chemokines and/or their receptors. [ABSTRACT FROM AUTHOR]

Background & Aims Response-guided therapy has been confirmed to be an effective strategy for the treatment of chronic hepatitis C in the pegylated interferon (PegIFN) era, but no randomized trial utilizing this strategy has been conducted in chronic hepatitis B. Methods In this open-label, multicenter, randomized trial, HBeAg positive patients were treated with PegIFN (180 μg/week) for 24 weeks. Early responders (HBsAg <1500 IU/ml and HBV DNA <10 5 copies/ml at week 24) received PegIFN for a further 24 weeks (arm A), while non-early responders were randomized to PegIFN for another 24 weeks (arm B), another 72 weeks (arm C) or PegIFN for another 72 weeks plus adefovir for 36 weeks (arm D). The primary endpoint was the change of quantitative HBsAg from baseline to the end of follow-up (EOF). Results For non-early responders, 96-week PegIFN monotherapy did not lead to a greater reduction of HBsAg from baseline to EOF, compared with 48-week PegIFN (−0.71 vs. −0.67 log 10 IU/ml, P = 0.407). The rate of HBeAg seroconversion with HBV DNA <2000 IU/ml at EOF were similar for arms B, C and D (17.9%, 23.9% and 25.0% respectively). For patients with HBsAg <1500 IU/ml or HBV DNA <10 5 copies/ml at week 24, 38.4% and 37.0% achieved HBeAg seroconversion with HBV DNA <2000 IU/ml at EOF respectively. Conclusions Patients with HBsAg <1500 IU/ml or HBV DNA <10 5 copies/ml at week 24 would benefit from continued PegIFN treatment. Extending the duration of PegIFN with or without adding adefovir did not show superiority over 48 weeks PegIFN monotherapy. Lay summary Extending the duration of pegylated interferon (PegIFN) alfa-2a is not recommended in HBeAg positive patients as treatment extension beyond 48 weeks did not show convincing benefit. Patients who achieved HBsAg <1500 IU/ml or HBV DNA <10 5 copies/ml after 24-week PegIFNα-2a showed satisfactory outcome after the withdrawal of finite PegIFNα-2a treatment. Clinical Trial Number: NCT01086085. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B ( CHB) is a worldwide public health problem which represents an enormous economic and social burden. Convincing evidence has shown that persistent active viral replication is an independent predictor of disease progression. Therefore, sustained suppression of HBV replication is the cornerstone for preventing the progression of disease and prolonging survival in patients with CHB. Pivotal clinical trials and real-world studies show that nucleos(t)ide analogues ( NAs) are potent suppressors of HBV DNA replication with very good safety profiles. Although 1-year treatment with NAs only results in a modest rate of HBeAg seroconversion, extended treatment could increase this rate. Profound suppression of HBV DNA can result in histological improvement and a clinical benefit with a decrease in disease progression in patients with compensated or decompensated cirrhosis. Treatment must be begun with a highly potent and low resistant regimen to obtain long-term suppression of viral replication. An alternative solution may be a roadmap approach in which an inexpensive antiviral drug is started and another drug is added-on or switched-to if there is a suboptimal on-treatment decrease in HBV DNA. Clinical evidence has shown that once HBV DNA is suppressed and long-term HBeAg seroconversion is achieved, NAs can be stopped. In summary, high antiviral efficacy, excellent tolerance, extensive applicability, clearly proven histological improvement and long-term clinical benefit all make NAs the preferred choice for the management of CHB in most patients. [ABSTRACT FROM AUTHOR]

Background: Parthenogenetic embryonic stem cells (PESCs) may have future utilities in cell replacement therapies since they are closely related to the female from which the activated oocyte was obtained. Furthermore, the avoidance of parthenogenetic development in mammals provides the most compelling rationale for the evolution of genomic imprinting, and the biological process of parthenogenesis raises complex issues regarding differential gene expression.Methods and Results: We describe here homozygous rhesus monkey PESCs derived from a spontaneously duplicated, haploid oocyte genome. Since the effect of homozygosity on PESCs pluripotency and differentiation potential is unknown, we assessed the similarities and differences in pluripotency markers and developmental potential by in vitro and in vivo differentiation of homozygous and heterozygous PESCs. To understand the differences in gene expression regulation between parthenogenetic and biparental embryonic stem cells (ESCs), we conducted microarray analysis of genome-wide mRNA profiles of primate PESCs and ESCs derived from fertilized embryos using the Affymetrix Rhesus Macaque Genome array. Several known paternally imprinted genes were in the highly down-regulated group in PESCs compared with ESCs. Furthermore, allele-specific expression analysis of other genes whose expression is also down-regulated in PESCs, led to the identification of one novel imprinted gene, inositol polyphosphate-5-phosphatase F (INPP5F), which was exclusively expressed from a paternal allele.Conclusion: Our findings suggest that PESCs could be used as a model for studying genomic imprinting, and in the discovery of novel imprinted genes. [ABSTRACT FROM AUTHOR]

Cervical cancer is one of the most common cancers that threaten women's lives, and its early screening is of great significance for the prevention and treatment of cervical diseases. Pathologically, the accurate segmentation of cervical cells plays a crucial role in the diagnosis of cervical cancer. However, the frequent presence of adherent or overlapping cervical cells in Pap smear images makes separating them individually a difficult task. Currently, there are few studies on the segmentation of adherent cervical cells, and the existing methods commonly suffer from low segmentation accuracy and complex design processes. To address the above problems, we propose a novel star-convex polygon-based convolutional neural network with an encoder-decoder structure, called SPCNet. The model accomplishes the segmentation of adherent cells relying on three steps: automatic feature extraction, star-convex polygon detection, and non-maximal suppression (NMS). Concretely, a new residual-based attentional embedding (RAE) block is suggested for image feature extraction. It fuses the deep features from the attention-based convolutional layers with the shallow features from the original image through the residual connection, enhancing the network's ability to extract the abundant image features. And then, a polygon-based adaptive NMS (PA-NMS) algorithm is adopted to screen the generated polygon proposals and further achieve the accurate detection of adherent cells, thus allowing the network to completely segment the cell instances in Pap smear images. Finally, the effectiveness of our method is evaluated on three independent datasets. Extensive experimental results demonstrate that the method obtains superior segmentation performance compared to other well-established algorithms. [ABSTRACT FROM AUTHOR]

Objective To examine the effects of cytochrome P450 3A4 ( CYP3A4 ), cytochrome P450 3A5 ( CYP3A5 ) and ATP-binding cassette sub-family B member 1 ( ABCB1 ) genetic polymorphisms on carbamazepine (CBZ) plasma concentrations in Chinese patients with epilepsy using CBZ as monotherapy and bitherapy with phenytoin (PHT), phenobarbital (PB), or valproic acid (VPA). Methods Eighty-eight Chinese patients with epilepsy were recruited from Xiangya Hospital Central South University, of whom 66 patients were placed in the CBZ monotherapy group, 10 patients were placed in the CBZ bitherapy group combined with one enzyme-inducing anti-seizure medications (PHT or PB), and 12 patients were placed in the CBZ bitherapy group combined with VPA. Carbamazepine and carbamazepine-10,11-epoxide (CBZ-E) plasma concentration of these patients were measured. In addition, the genetic polymorphisms of rs4646440 and rs2242480 in the CYP3A4 gene, rs15524 and rs776746 in the CYP3A5 gene, and rs1045642, rs2032582, rs10234411 and rs1128503 in the ABCB1 gene of the cohort were genotyped. Subsequently, the associations between CBZ plasma concentrations and target single-nucleotide polymorphisms (SNPs), as well as haplotypes, were analysed. Results In the CBZ monotherapy group, dose-adjusted CBZ concentrations were not associated with the eight SNPs and haplotypes. In the CBZ + PHT/PB group, rs776746, rs15524 and rs15524-rs776746 GT, AC haplotype were significantly associated with dose-adjusted CBZ plasma concentration ( P = 0.006, 0.006, 0.003, 0.003, respectively) and CBZ plus CBZ-E concentrations ( P = 0.006, 0.006, 0.006, 0.006, respectively); rs2032582, rs10234411 and rs2032582-rs10234411 AT, and CA haplotype were associated with the CBZ-E/CBZ ratio ( P = 0.007, 0.004, 0.004, 0.007, respectively). Conclusions rs776746 and rs15524 in the CYP3A5 gene tend to affect CBZ metabolism, and rs2032582, rs10234411 in the ABCB1 gene may contribute to inter-individual variation in CBZ and in CBZ-E transport among patients with epilepsy using CBZ in combination with PHT or PB. [ABSTRACT FROM AUTHOR]

What is known and objective: Administration of corticosteroids to immune checkpoint inhibitors (ICI)–treated patients has raised concerns due to doubts about ICIs' efficacy under those conditions. Hence, we reviewed studies comparing overall and progression‐free survival (OS and PFS) outcomes in patients with non–small‐cell lung carcinoma (NSCLC) treated with ICI and either with or without corticosteroids for any reason. Methods: We searched the PubMed Central, Cochrane library, EMBASE and MEDLINE databases from inception until February 2021 for relevant publications. We used the Newcastle‐Ottawa scale to assess the quality of the identified studies. We used the published data to carry out a meta‐analysis with a random‐effects model and report pooled odds ratios (ORs) with 95% confidence intervals (CIs). Results: We included data from 14 studies with 5461 participants in the meta‐analysis. Most studies were retrospective in nature and of low quality, and most of them were conducted in the USA and in European countries. Nivolumab is the most common ICI used in the included studies followed by pembrolizumab. We found that patients using corticosteroids had reduced OSs (pooled HR, 1.82; 95% CI, 1.51–2.18) and PFSs (pooled HR, 1.69; 95% CI, 1.41–2.04) than the patients not using corticosteroids. We identified significant heterogeneity and publication bias for both the outcomes. However, the sensitivity analysis revealed that the estimates were robust to the individual study effects. What is new and conclusion: Our findings suggest that corticosteroids significantly reduce the OS and PFS of patients with NSCLC under ICI therapy. Hence, clinicians and oncologists should consider this information when prescribing corticosteroids for this target population. [ABSTRACT FROM AUTHOR]

Lentiviral vectors offer well-recognized advantages as a gene delivery system both for the analysis of gene function and as a vehicle for gene therapy. In the present study optimized HIV-1-based vector systems that display efficient doxycycline (Dox)-dependent transgene expression in vitro and in vivo have been developed through the modification of factors that contribute to basal activity levels. Dissection of HIV-1 vectors harboring a tTA-dependent transgene expression cassette revealed several mechanisms that account for Dox-independent transgene expression, including those mediated by an internal CMV promoter, as well as a potential contribution from fusion proteins generated by translational readthrough. A precipitous reduction in basal activity levels was accomplished by separating the transactivator and the transgene cassettes into a binary vector system and by relocating the inducible promoter to the U3 region of the LTR. In addition, substituting the VP16 portion of tTA with the human p65 transactivating domain improved Dox-dependent transgene expression in a number of cell types. Optimizing HIV-1-based vectors culminated in a “toolbox” of vectors suitable for transgene delivery in vitro and in vivo, as conveyed by our ability to control the Dox-dependent differentiation of embryonic fibroblasts into muscle cells in vitro and transgene expression in rat brains. [Copyright &y& Elsevier]

• P2X7R is a direct target of miR-187-3p. • miR-187-3p mimics alleviate pain hypersensitivity in a mice spinal cord model. • miR-187-3 mimics prevent P2X7R upregulation and its induction in caspase-1 and IL-1β maturation. Ischemia-reperfusion (IR)-induced pain hypersensitivity shares features of neuroinflammation and neuropathic pain, accompanied by overproduction of interleukin (IL)-1β. Multiple microRNAs (miRs) are dysregulated during IR; among these miRs, miR-187-3p was recently reported to drive IL-1β release in retinal disease by activating members of the purinergic receptor family. However, the roles of miR-187-3p in the spinal cord are unclear. Thus, we investigated whether miR-187-3p is involved in the pathogenesis of IR-induced pain hypersensitivity by regulating the P2X7R signal and subsequent IL-1β release. A mouse model was established by 5-min occlusion of the aortic arch. Pain hypersensitivity was assessed by the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). MiR-187-3p, P2X7R, cleaved caspase-1 and mature IL-1β expression levels were measured by RT-PCR and Western blotting. The in vivo roles of miR-187-3p, P2X7R and IL-1β were explored by intrathecal treatment with synthetic miRs, selective agonists and antagonists in separate experiments. Double immunofluorescence staining was performed to delineate the cellular distribution of P2X7R and IL-1β. IR-induced progressively decreased PWT and PWL values were closely related to decreases in miR-187-3p and increases in P2X7R expression levels over time. The functional miR-187-3p/P2X7R pair was preliminarily predicted by a bioinformatic database and confirmed in vivo by quantitative analysis, as mimic-187 greatly increased miR-187-3p but decreased P2X7R expression levels, whereas inhibitor-187 reversed these changes. In contrast, downregulating P2X7R by mimic-187 or A-438079 treatment comparably increased PWT and PWL values in IR-injured mice, while upregulating P2X7R by inhibitor-187 or BzATP treatment decreased PWT and PWL values in sham-operated mice. Moreover, P2X7R and IL-1β immunoreactivities in each group were changed in the same patterns. This finding was further supported by results showing that downregulating IL-1β by A-438079 and IL-1β-neutralizing antibody similarly decreased P2X7R, cleaved caspase-1 and mature IL-1β expression levels, whereas BzATP treatment increased these levels. Expectedly, mimic-187 treatment preserved PWT and PWL values, with decreased cleaved caspase-1 and mature IL-1β expression levels, whereas inhibitor-187 reversed these effects. The spinal miR-187-3p/P2X7R pair functioned in a mouse IR model. Increasing miR-187-3p protected against pain hypersensitivity and mature IL-1β overproduction, partially through inhibiting P2X7R activation. [ABSTRACT FROM AUTHOR]

Triphala is a well-known prescription in Indian Ayurveda and TCM medicine for its great effect on gingivitis and hyperlipidemia. However, its solution is unstable for the containing of excessive polyphenol, leading to the production of sediment in the short term and the decrease of efficacy. Based on the analysis of sediment formation, a novel control strategy is proposed. To conduct the analysis, the sediment formation was recorded for a consecutive five days. The changes in the composition of the supernatant and the sediment were studied by the HPLC profile analysis. The main components of the sediment were identified as corilagin, ellagic acid and gallic acid, and the amount of ellagic acid sediment increased with the storage time. Then, with a series of pH status adjustments of the Triphala solution, the physical and chemical stabilities were acquired by Turbiscan and HPLC respectively. The results showed that as the pH value increased, so did the physical stability, but the particle size and TSI of the association decreased. While the fingerprint of chemical profile similarity decreased, so did the chemical stability. Combining physical and chemical stability parameters, an equilibrium point was found out. When the pH value was adjusted to 5.0, both the physical and chemical stabilities were better: the verification test showed that the sedimentation inhibition rates on the 3rd, 5th,10th and15th days were 41%, 55%, 41%, and 23%, respectively. This manuscript provided a new control strategy that will pique pharmaceutical and food development engineers’ interest and trigger research ideas controlling the quality of decoction. [ABSTRACT FROM AUTHOR]

Objective. To investigate the effects of electroacupuncture (EA) at “Zusanli” (ST36) and “Shangjuxu”(ST37) on reducing inflammatory reaction and improving intestinal dysfunction in patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi. Methods. A total of 71 patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi were randomly assigned to control group (n=36) and treatment group (n=35). Patients in control group were given conventional therapies including fluid resuscitation, anti-infection, vasoactive agents, mechanical ventilation, supply of enteral nutrition, and glutamine as soon as possible. In addition to conventional therapies, patients in treatment group underwent 20 minutes of EA at ST36-ST37 twice a day for five days. At baseline, day 1, day 3, and day 7 after treatment, the plasma levels of procalcitonin (PCT), tumor necrosis factor-α (TNF-α), intestinal fatty acid-binding proteins (I-FABP), D-lactate, citrulline, and TCM quantitative score of intestinal dysfunction were measured and recorded, respectively. And days on mechanical ventilation (MV), length of stay in intensive care unit (ICU), and 28d mortality were recorded. Results. During treatment, the plasma levels of PCT, TNF-α, I-FABP, D-lactate, and TCM quantitative score of intestinal dysfunction were declining in both groups, while the treatment group showed a significant decline (P<0.05). Plasma levels of citrulline were increasing in both groups, while the treatment group showed a significant increase (P<0.05). However, there were no significant differences in the days on MV, length of stay in ICU, and 28d mortality between two groups (P>0.05). Conclusions. EA at ST36-ST37 can reduce inflammatory reaction and has protective effects on intestinal function in patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi. Trial Registration. This trial was registered at http://www.chictr.org.cn/(ChiCTR-IOR-17010910). [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion (IR) affects microRNA (miR) expression and causes substantial inflammation. Multiple roles of the tumor suppressor miR-129-5p in cerebral IR have recently been reported, but its functions in the spinal cord are unclear. Here, we investigated the role of miR-129-5p after spinal cord IR, particularly in regulating high-mobility group box-1 (HMGB1) and the Toll-like receptor (TLR)-3 pathway.Methods: Ischemia was induced via 5-min occlusion of the aortic arch. The relationship between miR-129-5p and HMGB1 was elucidated via RT-PCR, western blotting, and luciferase assays. The cellular distribution of HMGB1 was determined via double immunofluorescence. The effect of miR-129-5p on the expression of HMGB1, TLR3, and downstream cytokines was evaluated using synthetic miRs, rHMGB1, and the TLR3 agonist Poly(I:C). Blood-spinal cord barrier (BSCB) permeability was examined by measuring Evans blue (EB) dye extravasation and the water content.Results: The temporal miR-129-5p and HMGB1 expression profiles and luciferase assay results indicated that miR-129-5p targeted HMGB1. Compared with the Sham group, the IR group had higher HMGB1 immunoreactivity, which was primarily distributed in neurons and microglia. Intrathecal injection of the miR-129-5p mimic significantly decreased the HMGB1, TLR3, interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels and the double-labeled cell count 48 h post-surgery, whereas rHMGB1 and Poly(I:C) reversed these effects. Injection of miR-129-5p mimic preserved motor function and prevented BSCB leakage based on increased Basso Mouse Scale scores and decreased EB extravasation and water content, whereas injection rHMGB1 and Poly(I:C) aggravated these injuries.Conclusions: Increasing miR-129-5p levels protect against IR by ameliorating inflammation-induced neuronal and BCSB damage by inhibiting HMGB1 and TLR3-associated cytokines. [ABSTRACT FROM AUTHOR]

The expression level of neutrophil elastase (NE) is closely related to the occurrence of inflammation. This enzyme has been identified as a research target for the development of anti-inflammatory drugs and for the early diagnosis and treatment of many diseases. This work developed the first near-infrared ratiometric fluorescence sensor (TMNF) for monitoring and imaging NE i n vivo and in vitro. Cell imaging results showed that NE was highly expressed in cells treated with pro-inflammatory factors, whereas NE activity was significantly reduced after pretreatment with the enzyme inhibitor. Relevant experiments have shown that inflammation can lead to increased expression of NE in vivo. The imaging of the probe in inflammation mouse shows excellent practicality, making the probe an effective tool for the early diagnosis and treatment of diseases related to inflammatory lesions. • One near-infrared sensor TMNF for Neutrophil elastase (NE) detection both in vivo and in vitro was designed. • TMNF shows highly sensitive (DL is 32 ng/mL), fast response time (18 min) and good biocompatibility. • Under stimulation, the imaging of TMNF in cells indicate that the high expression of NE is associated with inflammation. • This is the first time to confirm that NE expression in inflammatory mice is much higher than that in normal mice. [ABSTRACT FROM AUTHOR]

In this study, a bioactivity-guided isolation of antioxidant activity components of extracts from Sophora flavescens Ait. based on TLC bioautography and column chromatography was provided. The antioxidant activity of S. flavescens Ait. with different origins was evaluated by TLC bioautography, using 2,2-diphenyl-1-picrylhydrazyl radical as a detection reagent. The results showed that S. flavescens Ait. from different origins all expressed antioxidant activity. Then, based on a bioactivity-guided isolation principle, ten antioxidant activity ingredients including trifolirhizin(1), nor-anhydroicaritin(2), calycosin(3), isoxanthohumol(4), trifohrhizin-6′-monoacetate(5), 8-lavandulyl-5,7,4′-trihydroxyflavonol(6), kurarinone(7), sophoraflavanone G(8), maackiain(9) and formononetin(10) were yielded by the separation and purification of column chromatography. Their structures were elucidated by NMR data analysis. The results showed that the primary antioxidant constituents of S. flavescens Ait. were flavonoids, and significantly, prenylated flavonoids with phenolic hydroxyl in ring B had a stronger antioxidant effect than others. The study suggested that TLC bioautography-guided isolation of antioxidant components from S. flavescens Ait. was a kind of simple, rapid and effective means. [ABSTRACT FROM AUTHOR]

Background The rapid development of multi-drug resistance (MDR) process has hindered the effectiveness of advanced hepatocellular carcinoma (HCC) treatments. Notch-1 pathway, which mediates the stress-response, promotes cell survival, EMT (epithelial–mesenchymal transition) process and induces anti-apoptosis in cancer cells, would be a potential target for overcoming MDR process. This study investigated the potential application of rhamnetin, a specific inhibitor of Notch-1 pathway, in anti-tumor drug sensitization of HCC treatment. Methods The expression of miR-34a, proteins belonging to Notch-1 signaling pathway or MDR-related proteins was detected by quantitative polymerase chain reaction (qPCR) and western blot assay. To identify whether rhamnetin induces the chemotherapeutic sensitization in HCC cells, the MTT-assays, flow cytometry, soft agar, trans-well and nude mice assays were performed. Results The endogenous expression of miR-34a was significantly increased and the expression of Notch-1 and Survivin was downregulated after rhamnetin treatment. Treatment of rhamnetin also reduced the expression of MDR related proteins P-GP (P-glycoprotein) and BCRP (breast cancer resistance protein). Rhamnetin increased the susceptibility of HCC cells and especially HepG2/ADR, a MDR HCC cell line, to a small molecular kinase inhibitor sorafenib or chemotherapeutic drugs etoposide and paclitaxel. The IC 50 value of those drugs correspondingly decreased. Conclusions Together, our findings suggest that rhamnetin treatment may attenuate the MDR process in HCC cells. These findings may contribute to more effective strategies for HCC therapy. General significance Rhamnetin acts as a promising sensitizer to chemotherapy and may be a novel approach to overcome the MDR process of HCC. [ABSTRACT FROM AUTHOR]

A rapid expansion of HFMD with enterovirus 71 infection outbreaks has occurred and caused deaths in recent years in China, but no vaccine or antiviral drug is currently available for EV71 infection. This study aims to provide treatment programs for HFMD patients. We conducted a randomized, double-blind, controlled trial and evaluated clinical efficacy of therapy with rHuIFN-α1b in HFMD patients with EV71 infection. There were statistical differences in outcomes including the fever clearance time, healing time of typical skin or oral mucosa lesions, and EV71 viral load of the HFMD patients among ultrasonic aerosol inhalation group, intramuscular injection group and control group. rHuIFN-α1b therapy reduced the fever clearance time, healing time of typical skin or oral mucosa lesions, and EV71 viral load in children with HFMD. Trial Registration: Chinese Clinical Trial Registry [ABSTRACT FROM AUTHOR]

There is a significant unmet need in the treatment of primary biliary cirrhosis (PBC) despite significant data on the effector pathways that lead to biliary duct damage. We focused attention on a murine model of PBC, the dominant negative transforming growth factor β receptor II (Tg) mice. To further define the pathways that lead to biliary pathology in these mice, we developed Tg mice deleted of CD4 cells (CD4 −/− Tg). Interestingly, these mice developed more severe cholangitis than control Tg mice. These mice, which lack CD4 cells, manifested increased levels of IFN-γ produced by effector CD8 cells. It appears that increased cholangitis is due to the absence of CD4 Treg cells. Based on these data, we parabiosed CD4 −/− Tg mice with established disease at 8–9 weeks of age with C57BL/6 control mice. Such parabiotic “twins” had a significant reduction in autoimmune cholangitis, even though they had established pathology at the time of surgery. We prepared mixed bone marrow chimera mice constructed from CD4 −/− Tg and CD8 −/− mice and not only was cholangitis improved, but a decrease in terminally differentiated CD8 + T effector cells in the presence of wild type CD4 cells was noted. In conclusion, “correcting” the CD4 T cell subset, even in the presence of pathogenic CD8 T cells, is effective in treating autoimmune cholangitis. [ABSTRACT FROM AUTHOR]

Background: Bone marrow mesenchymal stem cells (MSCs) have been found to produce beneficial effects on ischemia-reperfusion injury. However, most of the MSCs died when transplanted into the ischemic tissue, which severely limit their therapeutic potential. Methods: Using an in vitro model of hypoxia and serum deprivation (H/SD), we investigated the hypothesis that sevoflurane preconditioning could protect MSCs against H/SD-induced apoptosis and improve their migration, proliferation, and therapeutic potential. The H/SD of MSCs and neuron-like PC12 cells were incubated in a serum-free medium and an oxygen concentration below 0.1% for 24 h. Sevoflurane preconditioning was performed through a 2-h incubation of MSCs in an airtight chamber filled with 2 vol% sevoflurane. Apoptosis of MSCs or neuron-like PC12 cells was assessed using Annexin V-FITC/propidium iodide (PI). Furthermore, the mitochondrial membrane potential was assessed using lipophilic cationic probe. The proliferation rate was evaluated through cell cycle analysis. Finally, HIF-1α, HIF-2α, VEGF and p-Akt/Akt levels were measured by western blot. Results: Sevoflurane preconditioning minimized the MSCs apoptosis and loss of mitochondrial membrane potential. Furthermore, it increased the migration and expression of HIF-1α, HIF-2α, VEGF, and p-Akt/Akt, reduced by H/SD. In addition, neuron-like PC12 cells were more resistant to H/SD-induced apoptosis when they were co-cultured with sevoflurane preconditioning MSCs. Conclusion: These findings suggest that sevoflurane preconditioning produces protective effects on survival and migration of MSCs against H/SD, as well as improving the therapeutic potential of MSCs. These beneficial effects might be mediated at least in part by upregulating HIF-1α, HIF-2α, VEGF, and p-Akt/Akt. [ABSTRACT FROM AUTHOR]

Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg's cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle-chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of ST zygotes (52%) showed abnormal fertilization as determined by an irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell isolation (38%) rates were comparable to controls. All embryonic stem cell lines derived from ST zygotes had normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing embryonic stem cells similar to controls. [ABSTRACT FROM AUTHOR]

1. Rosiglitazone is widely used in the treatment of Type 2 diabetes. However, in recent years it has become evident that the therapeutic effects of peroxisome proliferator-activated receptor γ ligands reach far beyond their use as insulin sensitizers. Recently, the ability of rosiglitazone pretreatment to induce cardioprotection following ischaemia–reperfusion (I/R) has been well documented; however, the protective mechanisms have not been elucidated. In the present study, examined the role of the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway in rosiglitazone cardioprotection following I/R injury. 2. Mice were pretreated with 3 mg/kg per day rosiglitazone for 14 days before hearts were subjected to ischaemia (30 min) and reperfusion (2 h). Wortmannin (1.4 mg/kg, i.p.), an inhibitor of PI3-K, was administered 10 min prior to myocardial I/R. Then, activation of the PI3-K/Akt/glycogen synthase kinase (GSK)-3α signalling pathway was examined. The effects of PI3-K inhibition on rosiglitazone-induced cardioprotection were also evaluated. 3. Compared with control rats, the ratio of infarct size to ischaemic area (area at risk) and the occurrence of sustained ventricular fibrillation in rosiglitazone-pretreated rats was significantly reduced ( P < 0.05). Rosiglitazone pretreatment attenuated cardiac apoptosis, as assessed by ELISA to determine cardiomyocyte DNA fragmentation. Rosiglitazone pretreatment significantly increased levels of phosphorylated (p-) Akt and p-GSK-3α in the rat myocardium. Pharmacological inhibition of PI3-K by wortmannin markedly abolished the cardioprotection induced by rosiglitazone. 4. These results indicate that rosiglitazone-induced cardioprotection in I/R injury is mediated via a PI3-K/Akt/GSK-3α-dependent pathway. The data also suggest that modulation of PI3-K/Akt/GSK-3α-dependent signalling pathways may be a viable strategy to reduce myocardial I/R injury. [ABSTRACT FROM AUTHOR]

Background: The concept of head and neck cancers (HNSCC) having unique molecular signatures is well accepted but relating this to clinical presentation and disease behaviour is essential for patient benefit. Currently the clinical significance of HNSCC molecular subtypes is uncertain therefore personalisation of HNSCC treatment is not yet possible.Methods: We performed meta-analysis on 8 microarray studies and identified six significantly up- (PLAU, FN1, CDCA5) and down-regulated (CRNN, CLEC3B and DUOX1) genes which were subsequently quantified by RT-qPCR in 100 HNSCC patient margin and core tumour samples.Results: Retrospective correlation with sociodemographic and clinicopathological patient details identified two subgroups of opposing molecular signature (+q6 and -q6) that correlated to two recognised high-risk HNSCC populations in the UK. The +q6 group were older, male, and excessive alcohol users whilst the -q6 group were younger, female, paan-chewers and predominantly Bangladeshi. Additionally, all patients with tumour recurrence were in the latter subgroup.Conclusions: We provide the first evidence linking distinct molecular signatures in HNSCC with clinical presentations. Prospective trials are required to determine the correlation between these distinct genotypes and disease progression or treatment response. This is an important step towards the ultimate goal of improving outcomes by utilising personalised molecular-signature-guided treatments for HNSCC patients. [ABSTRACT FROM AUTHOR]

Background: Although tolvaptan treatment improves hyponatremia, only few studies have investigated whether tolvaptan actually benefits the survival of cirrhotic patients. This study evaluated the impact of tolvaptan on six-month survival of decompensated cirrhotic patients with and without hyponatremia.Methods: Two hundred forty-nine decompensated cirrhotic patients with or without hyponatremia were enrolled in a multicenter cohort study. Patients were divided into two groups according to receiving either tolvaptan or placebo treatment for 7-day. Subsequently, the patients were followed up for 6 months.Results: Two hundred thirty patients, including 98 with hyponatremia (tolvaptan vs. placebo: 69 vs. 29) finished the study. Tolvaptan did not alter serum sodium levels and survival outcome of decompensated cirrhotic patients without hyponatremia. However, tolvaptan treatment remarkably improved serum sodium levels and six-month survival in patients with hyponatremia. Following tolvaptan treatment, serum sodium levels were restored to normal in 63.8% of patients, whereas in patients receiving placebo, only 36.2% showed the same effect (P < 0.05). Compared to a six-month survival rate of 68.97% in patients receiving placebo, the survival rate in tolvapatan-treated patients was 89.94% (P < 0.05). Furthermore, six-month survival rate in the tolvaptan-treated hyponatremia patients with resolved serum sodium was 81.32%, whereas the survival in those with unresolved serum sodium was only 24% (P < 0.05).Conclusions: Tolvaptan improves short term survival in most decompensated cirrhotic hyponatremia patients with resolved serum sodium.Trials Registration: Clinical trial one: ClinicalTrials.gov ID: NCT00664014 , Registered on April 14, 2008. Clinical trial two: ClinicalTrials.gov ID: NCT01349335 , Registered on March 5, 2010. Clinical trial three: ClinicalTrials.gov ID: NCT01349348 , Registered on May 4, 2011. [ABSTRACT FROM AUTHOR]

Objective: To study whether a combination of berberine and letrozole results in higher live births than letrozole alone in infertile women with polycystic ovary syndrome (PCOS).Design: A multicenter randomized double-blinded placebo-controlled trial.Setting: Reproductive and developmental network sites.Patient(s): Eligible women had PCOS as defined by the Rotterdam criteria. We enrolled 644 participants randomized 1:1:1 among letrozole, berberine, and combination groups.Interventions(s): Berberine or berberine placebo were administrated orally at a daily dose of 1.5 g for up to 6 months. Patients received an initial dose of 2.5 mg letrozole or placebo on days 3-7 of the first three treatment cycles. This dose was increased to 5 mg on the last three cycles if not pregnant.Main Outcomes Measure(s): Cumulative live births.Results: The cumulative live births were similar between the letrozole and combination groups after treatment (36% and 34%), and were superior to those in the berberine group (22%). Likely, conception, pregnancy, and ovulation rates were similar between the letrozole and combination groups, and these were significantly higher than in the berberine group. There was one twin birth in the letrozole group, three twin births in the combination group, and none in the berberine group.Conclusion(s): Berberine did not add fecundity in PCOS when used in combination with the new ovulation agent letrozole.Clinical Trial Registration Number: ChiCTR-TRC-09000376 (http://apps.who.int/trialsearch/). [ABSTRACT FROM AUTHOR]

Background: Hydrogen sulfide (H2S) is a newly discovered gas transmitter. It is synthesized by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MPST). Endogenous hydrogen sulfide has never been studied in bladder cancer.Purpose: We evaluated H2S production and its synthases expression levels in transitional cell carcinoma (urothelial cell carcinoma of bladder [UCB]) of human bladder tissue and cell lines.Materials and Methods: Immunostaining was performed in urothelial cell lines and bladder specimens from 94 patients with UCB of different stages/grades. The expression levels/activities of CBS, CSE, and MPST of specimens and cell lines were analyzed by image semiquantity assay, western blot, and a sulfur-sensitive electrode. We tried to find the correlation between hydrogen sulfide and its synthases with tumor stage in UCB. All experiments were repeated at least 3 times.Results: Immunoreactivity for CBS, CSE, and MPST was detected in malignant uroepithelium and muscular layer of all tissues examined and cultured cells. The expression levels of CBS, CSE, and MPST were associated with UCB stage/grade. Muscle-invasive bladder cancer samples showed the highest production of H2S (52.6±2.91 nmol/[mg·min]) among all tested samples and EJ cells (transitional cell carcinoma, grade IIIshowed the highest production of H2S among all tested cell lines (53.3±7.02nmol/[mg·min]).Conclusions: Protein levels and catalytic activities of CBS, CSE, and MPST increased with the increase of malignant degrees in human bladder tissues and human UCB cell lines. Our findings may promote the application of these novel enzymes to UCB diagnosis or treatment. [ABSTRACT FROM AUTHOR]