Mechanism underlying synergic activation of Tyrosinase promoter by MITF and IRF4

Background: The transcription factor interferon regulatory factor 4 (IRF4) was identified to be involved in human pigmentation by genome-wide association studies (GWASs). The rs12203592-[T/C], which is located in intron 4 of IRF4, shows the strongest link to these pigmentation phenotypes including freckling, sun sensitivity, eye and hair color. Previous studies indicated a functional cooperation of IRF4 with Microphthalmia-associated transcription factor (MITF), a causing gene of Waardenburg syndrome (WS), to synergistically trans-activate Tyrosinase (TYR). However, the underlying mechanism is still unknown. Methods: To investigate the importance of DNA binding in the synergic effect of IRF4. Reporter plasmids with mutant TYR promoters was generated to locate the IRF4 DNA binding sites in the Tyrosinase minimal promoter. By building MITF and IRF4 truncated mutations plasmids, the necessary regions of the synergy functions of these two proteins were also located. Results: The cooperative effect between MITF and IRF4 was specific for TYR promoter. The DNA-binding of IRF4 was critical for the synergic function. IRF4 DNA binding sites in TYR promoter were identified. The Trans-activation domains in IRF4 (aa134-207, aa300-420) were both important for the synergic function, whereas the auto-mask domain (aa207-300) appeared to mask the synergic effect. Mutational analysis in MITF indicated that both DNA-binding and transcriptional activation domains were both required for this synergic effect. Conclusions: Here we showed that IRF4 potently synergized with MITF to activate the TYR promoter, which was dependent on DNA binding of IRF4. The synergic domains in both IRF4 and MITF were identified by mutational analysis. This identification of IRF4 as a partner for MITF in regulation of TYR may provide an important molecular function for IRF4 in the genesis of melanocytes and the pathogenic mechanism in WS

Freezing of gait in Chinese patients with multiple system atrophy: prevalence and risk factors

ObjectiveFreezing of gait (FOG) is common in neurodegenerative forms of atypical parkinsonism, but few studies have examined FOG in multiple system atrophy (MSA). In this study, we examined the prevalence of freezing of gait and its relationship to clinical features in a large cohort of Chinese MSA patients.MethodsThis exploratory study included 202 Chinese patients with probable MSA. FOG was defined as a score ≥ 1 on item 14 of the Unified Parkinson’s Disease Rating Scale. Patients with or without FOG were compared in terms of the Unified MSA Rating Scale (UMSARS) as well as cognitive and neuropsychiatric assessments.ResultsThe frequency of FOG was 48.0, 52.1, and 38.7% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. FOG was associated with worse subscores on parts I, II and IV of the UMSARS as well as worse total UMSARS score; greater likelihood of speech difficulties, falls, gait impairment and balance disorder; more severe symptoms of anxiety and depression; and lower activities of daily living. The binary logistic regression model indicated that higher total UMSARS scores were associated with FOG in MSA, MSA-P, and MSA-C patients.ConclusionFreezing of gait may be common among Chinese MSA patients, FOG may correlate with severe motor symptoms, anxiety, depression and activities of daily living. Total UMSARS score may be an independent risk factor for FOG

The Sensor Proteins BcSho1 and BcSln1 Are Involved in, Though Not Essential to, Vegetative Differentiation, Pathogenicity and Osmotic Stress Tolerance in Botrytis cinerea

High-osmolarity glycerol (HOG) signaling pathway belongs to mitogen-activated protein kinase (MAPK) cascades that regulate responses of organism to diverse extracellular stimuli. The membrane spanning proteins Sho1 and Sln1 serve as biosensors of HOG pathway in Saccharomyces cerevisiae. In this study, we investigated the biological functions of BcSHO1 and BcSLN1 in the gray mold fungus Botrytis cinerea. Target gene deletion demonstrated that both BcSHO1 and BcSLN1 are important for mycelial growth, conidiation and sclerotial formation. The BcSHO1 and BcSLN1 double deletion mutant ΔBcSln1-Sho1 produced much more, but smaller sclerotia than ΔBcSho1 and the wild-type (WT) strain, while ΔBcSln1 failed to develop sclerotia on all tested media, instead, formed a large number of conidia. Infection tests revealed that the virulence of ΔBcSln1-Sho1 decreased significantly, however, ΔBcSho1 or ΔBcSln1 showed no difference with the WT strain. In addition, ΔBcSln1-Sho1 exhibited resistance to osmotic stress by negatively regulating the phosphorylation of BcSak1 (yeast Hog1). All the phenotypic defects of mutants were recovered by target gene complementation. These results suggest that BcSHO1 and BcSLN1 share some functional redundancy in the regulation of fungal development, pathogenesis and osmotic stress response in B. cinerea

Metformin downregulates PD-L1 expression in esophageal squamous cell catrcinoma by inhibiting IL-6 signaling pathway

Purpose: To characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response. Methods: The Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and prognosis and between IL-6 and PD-L1 gene expression in esophageal cancer. Reverse transcription-quantitative polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence were used to study the mechanism by which metformin affects PD-L1 expression. Additionally, T cell function was assessed in a coculture system containing ESCC cells and peripheral blood mononuclear cells (PBMCs) treated with metformin or IL-6. In an Results: The TCGA esophageal cancer data showed that IL-6 expression was positively correlated with PD-L1 expression and that patients with high IL-6 expression had a significantly lower overall survival rate than patients with low IL-6 expression. PD-L1 expression in ESCC cell lines was significantly inhibited by metformin Conclusions: Metformin downregulated PD-L1 expression by blocking the IL-6/JAK2/STAT3 signaling pathway in ESCC, which enhanced the antitumor immune response

Unraveling Enhanced Activity, Selectivity, and Coke Resistance of Pt–Ni Bimetallic Clusters in Dry Reforming

By introducing Pt atoms into the surface of reduced hydrotalcite (HT)-derived nickel (Ni/HT) catalysts by redox reaction, we synthesized an enhanced active and stable Ni-based catalyst for methane dry reforming reaction. The bimetallic Pt–Ni catalysts can simultaneously enhance the catalyst activity, increase the H2/CO ratio by suppressing reverse water–gas shift reaction, and enhance the stability by increasing the resistance to the carbon deposition during the reaction. Kinetic study showed that 1.0Pt–12Ni reduces the activation energy for CH4 dissociation and enhances the catalytic activity of the catalyst and lowers the energy barrier for CO2 activation and promotes the formation of surface O* by CO2 adsorptive dissociation. It is beneficial to enhance the resistance to the carbon deposition and prolong its service life in the reaction process. In addition, density-functional theory calculations rationalized the higher coke resistance of Pt–Ni catalysts where CH is more favorable to be oxidized instead of cracking into surface carbon on the Pt–Ni surface, compared with Ni(111) and Pt(111). Even if a small amount of carbon deposited on the Pt–Ni surface, its oxidation process requires a lower activation barrier. Thus, it demonstrates that the bimetallic Pt–Ni catalyst has the best ability to resist carbon deposition compared with monometallic samples.publishedVersio

Poly (lactic-co-glycolic acid)-encapsulated iodine-131 nanoparticles fabricated with rhTSH induce apoptosis and immobilization of thyroid cancer cells

BackgroundAggressive thyroid carcinoma (ATC) usually loses radioiodine avidity to iodine-131 (131I) due to the downregulation of sodium/iodide symporter (NIS). The expression of thyroid stimulating hormone receptor (TSHR) is more persistent than NIS and the administration of recombinant human thyroid stimulating hormone (rhTSH) promotes de novo NIS synthesis. Hence, exploring methods integrating 131I with rhTSH might be a feasible therapeutic strategy for selective delivery of 131I into thyroid cancer to fortify the effect of radioiodine ablation.MethodsThe 131I, poly (lactic-co-glycolic acid) (PLGA) and rhTSH were used to synthesize of the 131I-PLGA-rhTSH nanoparticles. The characteristics of the 131I-PLGA-rhTSH nanoparticles was determined using a light microscopy, scanning electron microscopy (SEM), autoradiography and immunofluorescence (IF) staining. The diameter of the 131I-PLGA-rhTSH nanoparticles was measured with a Mastersizer 3000, and the encapsulation efficiency (EF) of 131I in 131I-PLGA-rhTSH nanoparticles and the radioactivity of a single nanoparticle were determined. Then, the mouse tumor xenograft model was established, and the biodistribution and effect of 131I-PLGA-rhTSH nanoparticles on apoptosis of thyroid cance cells were investigated in vivo. Thereafter, the role of 131I-PLGA-rhTSH nanoparticles in cell viability using cell counting kit-8 and lactate dehydrogenase (LDH) release assays. Subsequently, the underlying mechanism of 131I-PLGA-rhTSH nanoparticles in reducing cell viability was assessed using immunostaining, boyden invasion assays and phalloidin staining.ResultsOur results showed that the method of developing nanoparticles-encapsulated 131I using poly (lactic-co-glycolic acid) (PLGA) and modified with rhTSH (131I-PLGA-rhTSH), was a feasible avenue for the integration of 131I and rhTSH. Meanwhile, the encapsulation efficiency (EF) of 131I-PLGA-rhTSH nanoparticles was approximately 60%, and the radioactivity of a single nanoparticle was about 1.1×10-2 Bq. Meanwhile, the 131I-PLGA-rhTSH nanoparticles were selectively delivered into, gradually enriched and slowly downregulated in xenograft tumor after the administration of 131I-PLGA-rhTSH nanoparticles through tail vein in mouse tumor xenograft model. Thereafter, the tumor weight was significantly reduced after the administration of 131I-PLGA-rhTSH nanoparticles. Subsequently, the application of 131I-PLGA-rhTSH nanoparticles facilitated apoptosis and attenuated immobilization via inhibiting F-actin assembling of FTC-133 cells.ConclusionThe present study develops a suitable approach integrating 131I and rhTSH, and this strategy is a feasible regimen enhancing the effect of radioiodine ablation for the treatment of thyroid cancer

DASES: a database of alternative splicing for esophageal squamous cell carcinoma

Esophageal carcinoma ranks as the sixth leading cause of cancer-related mortality globally, with esophageal squamous cell carcinoma (ESCC) being particularly prevalent among Asian populations. Alternative splicing (AS) plays a pivotal role in ESCC development and progression by generating diverse transcript isoforms. However, the current landscape lacks a specialized database focusing on alternative splicing events (ASEs) derived from a large number of ESCC cases. Additionally, most existing AS databases overlook the contribution of long non-coding RNAs (lncRNAs) in ESCC molecular mechanisms, predominantly focusing on mRNA-based ASE identification. To address these limitations, we deployed DASES (http://www.hxdsjzx.cn/DASES). Employing a combination of publicly available and in-house ESCC RNA-seq datasets, our extensive analysis of 346 samples, with 93% being paired tumor and adjacent non-tumor tissues, led to the identification of 257 novel lncRNAs in esophageal squamous cell carcinoma. Leveraging a paired comparison of tumor and adjacent normal tissues, DASES identified 59,094 ASEs that may be associated with ESCC. DASES fills a critical gap by providing comprehensive insights into ASEs in ESCC, encompassing lncRNAs and mRNA, thus facilitating a deeper understanding of ESCC molecular mechanisms and serving as a valuable resource for ESCC research communities

A case of malonyl coenzyme A decarboxylase deficiency with novel mutations and literature review

IntroductionMalonyl coenzyme A decarboxylase deficiency is caused by an abnormality in the MLYCD gene. The clinical manifestations of the disease involve multisystem and multiorgan.MethodsWe collected and analyzed a patient's clinical characteristics, genetic chain of evidence and RNA-seq. We use the search term “Malonyl-CoA Decarboxylase Deficiency” on Pubmed to collect cases reported.ResultsWe report a 3-year-old girl who is presented with developmental retardation, myocardial damage and elevated C3DC. High-throughput sequencing identified heterozygous mutation (c.798G>A, p.Q266?) in the patient inherited from her father. The other heterozygous mutation (c.641+5G>C) was found in the patient inherited from her mother. RNA-seq showed that there were 254 differential genes in this child, among which 153 genes were up-regulated and 101 genes were down-regulated. Exon jumping events occurred in exons encoding PRMT2 on the positive chain of chromosome 21, which led to abnormal splicing of PRMT2. (P<0.05, FDR<0.05). The result of SNP showed that there were multiple mutation sites on chromosome 1, which may affect the downstream gene variation at the DNA level. The literature review identified 54 cases described since 1984.DiscussionIt is the first report about the locus, adding a new item to the MLYCD mutation library. Developmental retardation and cardiomyopathy are the most common clinical manifestations, with commonly elevated malonate and malonyl carnitine levels in children

Cost-Effectiveness Analysis of Capecitabine Plus Oxaliplatin Versus Gemcitabine Plus Oxaliplatin as First-Line Therapy for Advanced Biliary Tract Cancers

Background: In the first-line treatment of biliary tract cancers (BTCs), XELOX (capecitabine plus oxaliplatin) showed comparable clinical efficacy and safety to gemcitabine and oxaliplatin (GEMOX), with fewer visits and better treatment management. Our study aims to investigate the cost-effectiveness of XELOX and GEMOX as the first-line therapy for BTCs from the perspective of the Chinese healthcare systems and to provide valuable suggestions for clinical decision-making.Methods: A Markov model was developed using the phase 3 randomized clinical trial (ClinicalTrials.gov number, NCT01470443) to evaluate the cost-effectiveness of XELOX and GEMOX. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were used as the primary outcomes of the model. Uncertainty was assessed using univariate and probabilistic sensitivity analysis.Results: The QALYs for the XELOX and GEMOX groups were 0.66 and 0.54, respectively. In China, the total cost of XELOX treatment is US $12,275.51, which is lower than that of the GEMOX regimen. In addition, XELOX is more effective than GEMOX, making it the preferred regimen. A sensitivity analysis determined that XELOX therapy has a stable economic advantage in China.Conclusion: Compared to GEMOX, XELOX is a more cost-effective treatment as a first-line treatment for advanced BTC from the perspective of the Chinese health service system

Reactivation of mutant p53 in esophageal squamous cell carcinoma by isothiocyanate inhibits tumor growth

p53 mutations are prevalent in human cancers; approximately half of patients with esophageal cancer present these mutations. Mutant p53 (mutp53) exerts oncogenic functions that promote malignant tumor progression, invasion, metastasis, and drug resistance, resulting in poor prognosis. Some small molecules have been shown to mitigate the oncogenic function of mutp53 by restoring its wild-type activity. Although these molecules have been evaluated in clinical trials, none have been successfully used in the clinic. Here, we investigated the antitumor effects of phenethyl isothiocyanate (PEITC) in p53-mutant esophageal squamous cell carcinoma (ESCC) and elucidated its mechanism to identify new therapeutic strategies. We observed that p53R248Q is a DNA contact mutation and a structural mutation and that PEITC can restore the activity of p53R248Qin vitro and in vivo, further clarifying the antitumor activity of PEITC in cancers with different types of p53 mutations. PEITC can inhibit ESCC growth, induce apoptosis, and arrest cell cycle progression and has a preferential selectivity for ESCC with p53 mutations. Mechanistic studies showed that PEITC induced apoptosis and arrested cells at G2/M transition in cells expressing the p53R248Q mutant by restoring the wild-type conformation and transactivation function of p53; these effects were concentration dependent. Furthermore, PEITC inhibited the growth of subcutaneous xenografts in vivo and restored p53 mutant activity in xenografts. According to these findings, PEITC has antitumor effects, with its ability to restore p53R248Q activity being a key molecular event responsible for these effects