Transcriptional repression and apoptosis influence the effect of APOBEC3A/3B functional polymorphisms on biliary tract cancer risk.

APOBEC3-related somatic mutations are predominant in biliary tract cancers (BTCs). We aimed to elucidate the roles of APOBEC3A/3B functional polymorphisms and their influencing factors on the development of cholangiocarcinoma (CCA) and gallbladder cancer (GBC). Polymorphisms at the promoter regions of APOBEC3A and APOBEC3B were genotyped in 3231 participants using quantitative PCR. Dual-luciferase reporter assay was applied to investigate the promoter activity. The difference in gene accessibility between CCA cells and GBC cells was analyzed through single-cell transposase accessible chromatin sequencing. The effect of APOBEC3A on apoptosis was examined by cytometry. It is found that rs2267401-G at the APOBEC3B promoter decreases CCA risk (age-, gender-adjusted odds ratio [AOR], 0.69; 95% confidence interval [CI], 0.51-0.94) but increases GBC risk (AOR, 2.04; 95% CI, 1.35-3.10). rs2267401-G confers a decreased APOBEC3B promoter activity in CCA cells but an increased activity in GBC cells, possibly because the transcriptional repressor TFAP2A is over-expressed in CCA. Tumor necrosis factor-α (TNF-α) increases the level of APOBEC3B via inhibiting TFAP2A expression rather than directly increasing the accessibility of APOBEC3B promoter. APOBEC3A promoter rs12157810-C decreased the risks of CCA and GBC, with an AOR (95% CI) of 0.80 (0.66-0.97) and 0.75 (0.59-0.95), respectively. rs12157810-C upregulated the promoter activity in both CCA and GBC cells. TNF-α upregulated the activity of the APOBEC3A promoter with rs12157810-C via increasing the accessibility of Ets-1 p68. APOBEC3A overexpression attenuates cancer evolution by causing apoptosis, in contrast to APOBEC3B. The heterogeneity in the transcriptional regulation of APOBEC3B affects the evolutionary potential of cancer cells in the inflammatory microenvironment.

Silica nanoparticles as an enhancer in the IL-1ß-induced inflammation cycle of A549 cells.

Objective: The industrial production and combustion of coal can produce silica nanoparticles (nano-SiO2). It enters the human body mainly through the respiratory tract and exerts a toxic effect. However, whether nano-SiO2 can increase the IL-1ß-induced inflammatory expression in A549 cells has not been tested. Therefore, the synergistic toxicity of nano-SiO2 and IL-1ß to A549 was observed in our study. Materials and methods: We exposed A549 cells to nano-SiO2 (0, 100, 500, and 1000 µg/ml) for 12 and 24 h. The effect of nano-SiO2 on the viability of A549 cells was observed by the CCK-8 method. The A549 cells were exposed to nano-SiO2 (1 mg/mL) and cytokine IL-1ß (10 ng/mL) for 4 h, and we detected the expression of IL-1ß and IL-6 cytokines by real time quantitative polymerase chain (RT-qPCR) and enzyme linked immunosorbent assay (ELISA). The expression of ß-Actin, I-κB, phospho-ERK1/2 (P-ERK1/2), total-ERK1/2 (T-ERK1/2), phospho-JNK (P-JNK), total-JNK (T-JNK), phospho-P38 (P-P38), and total-P38 (T-P38) in A549 cells was detected by the Western Blot method. Results: The nano-SiO2 treatment resulted in a time-dependent decrease in the viability of A549 cells. The synergistic effect of nano-SiO2 and IL-1ß was observed on the new production of IL-1ß and IL-6 in A549 cells. The Western blot results showed that nano-SiO2 can increase the expression of IL-1ß and IL-6 by promoting the phosphorylation of ERK1/2 and elevating the phosphorylation of I-κB by IL-1ß. IL-1ß and IL-6 were induced by nano-SiO2, and the IL-1ß treatment with 20 µM of I-κBα phosphorylation inhibitor (PD98059) and 20 µM of ERK1/2 inhibitor (BAY11-7082) for 1 h was significantly lower than that of the control group in A549 cells. Discussion and conclusion: These results indicated that nano-SiO2 had a toxic effect on A549 cells, and this effect could increase IL-1ß on the A549 cell-induced inflammatory response. The results suggested that the release of IL-1ß and IL-6 in A549 was enhanced by the synergistic IL-1ß-induced phosphorylation of ERK1/2 and I-κB. This process is similar to a snowball, and it is possible that IL-1ß is continuously produced and repeatedly superimposed in A549 cells to produce an inflammatory effect; then, a vicious circle occurs, and an inflammatory storm is accelerated.

LncRNA expression profiling in exosomes derived from synovial fluid of patients with rheumatoid arthritis.

OBJECTIVE: To identify the long non-coding RNA (lncRNA) expression profiling in exosomes derived from synovial fluid of rheumatoid arthritis (RA) patients, and carry out bioinformatics analysis on target genes of differentially expressed lncRNAs. METHODS: Exosomes were isolated from synovial fluid via ultracentrifugation. RNAs were extracted from exosomes by using HiPure Liquid RNA/miRNA kits, followed by lncRNA sequencing. Differentially expressed lncRNAs in RA were screened, and bioinformatics analysis of their target genes was carried out. qRT-PCR was used to verify the lncRNA expression levels. RESULTS: Compared with osteoarthritis (OA), 347 lncRNAs were found differentially expressed in RA. Compared with gout, 805 lncRNAs were found differentially expressed in RA. Compared with both OA and gout, 85 lncRNAs were found specially expressed in RA (65 were upregulated (including ENST00000433825.1)). Functional analysis of target genes of the specially expressed lncRNAs revealed significant enrichment of "autophagy" and "mTOR signaling pathway". The qRT-PCR results indicated that ENST00000433825.1 was highly expressed in RA, compared with both OA and gout (P < 0.05), which matched the lncRNA sequencing results. Correlation analysis showed that the level of ENST00000433825.1 in RA patients was significantly and positively correlated with the level of C-reactive protein (CRP) (P < 0.001). CONCLUSIONS: The lncRNA expression profiling in exosomes derived from synovial fluid of RA was significantly different from OA and gout. ENST00000433825.1 was highly and uniquely expressed in RA and significantly and positively correlated with CRP, which might provide a diagnostic and therapeutic biomarker for RA.

Proteomics profiling of CD4 + T-cell-derived exosomes from patients with rheumatoid arthritis.

OBJECTIVES: Our study profiled the CD4 + T-cell-derived exosomes from patients with rheumatoid arthritis (RA) using proteomics. METHODS: Proteomic analysis of CD4 + T-cell-derived exosomes was performed by tandem mass tags (TMT) combined with LC-MS/MS. We validated the most significantly upregulated and downregulated proteins using ELISA and WB. RESULTS: The proteomic results showed that there were 3 upregulated differentially expressed proteins and 31 downregulated differentially expressed proteins in the RA group. The results indicated that dihydropyrimidinase-related protein 3 (DPYSL3) was significantly upregulated in CD4 + T-cell-derived exosomes, whereas proteasome activator complex subunit 1 (PSME1) was significantly downregulated in the RA group. Bioinformatics analysis showed that proteins were enriched in "positive regulation of gene expression", "antigen processing and presentation", "acute-phase response" and "PI3K-AKT signaling" pathways. ELISA verified that compared to the control group, the RA group showed significant upregulation of DPYSL3, and downregulation of PSME1 in CD4 + T-cell-derived exosomes. CONCLUSIONS: The proteomic analysis results of CD4 + T-cell-derived exosomes from patients with RA suggest that these differentially expressed proteins may be involved in RA pathogenesis. DPYSL3 and PSME1 may become useful biomarkers for RA.

Cordyceps sinensis extracts attenuate aortic transplant arteriosclerosis in rats.

BACKGROUND: Transplant arteriosclerosis is a hallmark of chronic rejection and is still the major limiting factor affecting the success of long-term organ transplants. Development of transplant arteriosclerosis is refractory to conventional immunosuppressive drugs, and adequate therapy is not yet available. The aim of this study was to determine the role of Cordyceps sinensis extracts in reducing the formation of transplant arteriosclerosis in a rat aortic transplant model. METHODS: Lewis rat aortic allografts were transplanted into Brown-Norway recipient rats. Recipients received 0.5, 1, 2, and 5 mg/kg of Cordyceps sinensis extracts (or control saline) daily via intragastric injection for 60 d. Grafts were harvested 60 d post-transplantation and intimal thickness determined microscopically following hematoxylin and eosin (H and E) staining and abdominal aorta protein profiles determined by Western blot analysis. Cellular localization was assessed by histology and immunohistochemistry and the serum analyzed for tumor necrosis factor alpha (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) by enzyme-linked immunosorbent assay (ELISA). RESULTS: C. sinensis administration resulted in a significant reduction in neointimal formation (neointimal thickness 8.27 ± 1.95 µm [0.5 mg/kg], 3.69 ± 1.43 µm [1 mg/kg], 3.69 ± 1.43 µm [1 mg/kg], 3.69 ± 1.43 µm [1 mg/kg] versus 11.42 ± 2.67 µm [control]) and in the proliferative activity of vascular smooth muscle cells. In addition, localized expression of TNF-α and ICAM-1 in transplant aortas was characterized by immunohistochemistry and immunoblot analyses demonstrating that C. sinensis treatment significantly reduced TNF-α and ICAM-1 levels compared with levels observed in controls (P < 0.05). Serum TNF-α and ICAM-1 levels were significantly reduced in C. sinensis-treated animals compared with controls (P < 0.05). CONCLUSION: C. sinensis treatment effectively reduced the formation of transplant arteriosclerosis in a rat aortic transplant model.

Case Report: Baricitinib as an Alternative in the Maintenance Therapy for Macrophage Activation Syndrome Secondary to Nodular Panniculitis.

Background: Macrophage activation syndrome (MAS) is a severe complication of autoimmune diseases with high mortality. We report the effectiveness of baricitinib as an option for the maintenance therapy in MAS secondary to nodular panniculitis. Case summary: A 24-year-old female came to our hospital with repeated fever and a skin nodule on right tibial tuberosity. Results were notable for raised serum ferritin (SF), triglycerides (TG), elevated liver function enzymes, interleukin-6 (IL-6), interferon-γ (IFN-γ), soluble interleukin-2 receptor (sIL-2R) and decreased activity of NK cells. The pathological biopsy of the subcutaneous nodules indicated nodular panniculitis. Hemophagocytic cells were found in bone marrow aspiration. She was diagnosed as MAS secondary to nodular panniculitis. With the treatment of methylprednisolone (MP) and immunoglobulin, her symptoms and laboratory data gradually improved. Nevertheless, her disease relapsed when the MP dose was tapered. Regarding the usage of JAK inhibitors in MAS, we used baricitinib (JAK1/2 inhibitor) to treat MAS and her symptom and abnormal laboratory findings returned to normal. During follow-up, though the MP dose was tapered, she was stable without a MAS recurrence. Conclusion: The case report suggested baricitinib is an option for MAS in the maintenance therapy phase and is potentially beneficial to prevent recurrence.

Serum metabolic profiling analysis of gout patients based on UPLC-Q-TOF/MS.

BACKGROUND: Gout is a common kind of inflammatory arthritis with metabolic disorders. However, the detailed pathogenesis of gout is complex and not fully clear. We investigated the serum metabolic profiling of gout patients by ultra-performance liquid chromatograph quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). METHODS: Serum metabolites were extracted from 31 gout patients and 31 healthy controls. Metabolite extracts were analyzed in negative mode by UPLC-Q-TOF/MS for global metabolomics. Principal components analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) and hierarchical clustering analysis were performed to detect different compounds between the two groups. Receiver operating characteristic (ROC) curve analysis and pathway analysis of the different metabolites were conducted. RESULTS: A total of 9192 compounds were detected, of which 138 significantly different compounds were selected, according to the criteria of (Variable importance in projection (VIP) > 3). Hierarchical clustering analysis showed that the relative levels of the differential compounds were different between the 2 groups. Ninety-one reliable metabolites matching the human metabolome database (HMDB) were confirmed. ROC curve results revealed that 4-hydroxytriazolam, urate and bilirubin exerted higher AUC values. Pathway analysis indicated that the significantly different metabolites were mainly involved in primary bile acid biosynthesis, purine metabolism and glycerophospholipid metabolism. CONCLUSIONS: The serum metabolic profiling of gout patients was significantly different from healthy subjects based on UPLC-Q-TOF/MS. Bilirubin was the potential biomarker. Primary bile acid biosynthesis may be a novel metabolic pathway of gout.

Correlation between C-Reactive Protein to Albumin Ratio and Disease Activity in Patients with Axial Spondyloarthritis.

BACKGROUND: The C-reactive protein (CRP) to albumin (ALB) ratio (CAR) has emerged as a novel inflammatory biomarker. This study was designed to investigate the role of CAR in the disease activity of axial spondyloarthritis (axSpA). METHODS: A total of 241 patients and 61 healthy controls were retrospectively enrolled in this study. AxSpA patients were further divided into the inactive group (n = 176) and active group (n = 65) according to Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) cutoff value of 4. Laboratory data and clinical assessment indices were recorded. Spearman's correlation analysis, receiver operation characteristic (ROC) curve analysis, and binary logistic regression analysis were performed. RESULTS: In axSpA patients, CAR was significantly higher than the healthy group (P < 0.001). Similarly, axSpA patients in the active group had higher CAR than the inactive group (P < 0.001). Besides, CAR was positively correlated with erythrocyte sedimentation rate (ESR) (r = 0.704, P < 0.001), CRP (r = 0.996, P < 0.001), BASDAI (r = 0.329, P < 0.001), and Bath Ankylosing Spondylitis Functional Index (BASFI) (r = 0.330, P < 0.001). ROC curve analysis suggested that the area under the curve (AUC) of CAR for axSpA of the active group was 0.701, which was higher than that of CRP and ESR. The optimal cutoff point of CAR for axSpA of the active group was 0.3644, with a sensitivity and specificity of 58.5% and 79.0%. Binary logistic analysis results revealed that CAR was an independent predictive factor for axSpA disease activity (odds ratio = 4.673, 95% CI: 1.423-15.348, P = 0.011). CONCLUSIONS: CAR was increased in axSpA and axSpA of the active group. CAR may be a novel and reliable indicator for axSpA disease activity.

Effect of APOBEC3A functional polymorphism on renal cell carcinoma is influenced by tumor necrosis factor-α and transcriptional repressor ETS1.

Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) 3 cytidine deaminases are the prominent drivers of somatic mutations in cancers. However, the effect of APOBEC3s functional polymorphisms on the development of renal cell carcinoma (RCC) remains unknown. Five genetic polymorphisms affecting the expression of APOBEC3A (A3A), APOBEC3B, and APOBEC4 and uracil DNA glycosylase (UNG) were genotyped in 728 RCC patients and 1500 healthy controls. The effects of tumor necrosis factor-α (TNFα) and interleukin-6 on the activity of the A3A promoter with rs12157810-A or -C in four RCC cell lines (786-O, A498, Caki2, ACHN) and two colorectal cancer cell lines (HCT116, SW620) were evaluated using dual-luciferase assays. Transcriptional repressors to the A3A promoter were identified by chromatin immunoprecipitation-quantitative PCR. The proapoptotic effect of A3A on RCC cells was evaluated using cytometry. The prognostic values of A3A and ETS1 were evaluated by the Cox regression analysis. The expressions of A3A and ETS1 were evaluated in clear cell RCC (ccRCC) specimens with different polymorphic genotypes using quantitative RT-PCR and immunohistochemistry. Of those functional polymorphisms, CC genotype at rs12157810 in the A3A promoter was significantly associated with a decreased risk of ccRCC, compared to the AA genotype (odds ratio adjusted for age and gender, 0.41, 95% confidence interval [CI], 0.28-0.57). Other polymorphic genotypes were not associated with the risk of RCC. The activity of the A3A promoter with rs12157810-C was significantly higher than that with rs12157810-A in the four RCC cell lines and two colorectal cancer cell lines. The activity of the A3A promoter with rs12157810-C was greatly up-regulated by TNFα and predominantly inhibited by a transcriptional repressor ETS1. The binding of ETS1 to the A3A promoter with rs12157810-C was looser than that with rs12157810-A. Ectopic expression of A3A significantly promoted apoptosis in ccRCC cells, rather than in colorectal cancer cells. Higher ETS1 expression predicted a favorable prognosis in ccRCC, with a hazard ratio of 0.58 (95% CI, 0.43-0.78). Rs121567810-C up-regulates the A3A promoter activity, possibly due to higher response to TNFα and looser transcriptional repression by ETS1. Up-regulation of A3A increases apoptosis, thus decreasing ccRCC risk in those carrying rs121567810-C.

C-peptide and islet transplantation improve glomerular filtration barrier in diabetic nephropathy rats.

OBJECTIVES: Islet transplantation has been proved to be effective in delaying early stage of DN. This study was established to observe the mechanism of islet transplantation on early diabetic nephropathy (DN). METHOD: The diabetes mellitus (DM) rat model was established by an injection of a single-dose streptozotocin. According to the treatment, the rats were randomly divided into 4 groups: the untreated DN rats (DN group); the C-peptide treated rats (CP group); the islet transplanted rats (IT group); the normal control rats (NC group). Renal function and structure of glomerular filtration barrier (GFB) were evaluated by urinalysis and histopathological examination, respectively. The renal fibrotic factors, TGF- ß1 and CTGF, as well as the anti-renal fibrosis factor HGF were assessed by immunohistochemical staining and western blotting methods. RESULTS: After C-peptide treatment and islet transplantation, the GFB structure was obviously improved. The blood glucose significantly decreased in the IT group. The 24h urine protein and glomerular basement membrane thickness decreased, the pathological changes of podocytes improved, TGF- ß1 and CTGF decreased and HGF increased in the CP group and the IT group compared with that in the DN group (P < 0.05), especially in the IT group. CONCLUSION: Islet transplantation could ameliorate the structure of GFB of early DN in a rat model, and the treatment effect was partly attributed to the restoration of C-peptide concentration. Suppressing the fibrosis system can be the potential mechanism of islet transplantation, which is independent of blood glucose control.

Role of plasma fibrinogen in assessing disease activity of patients with gout.

BACKGROUND: Gout is an inflammatory disease characterized by the deposition of monosodium urate (MSU) in synovial fluid and other tissues. Many studies have shown that the activation of coagulation system had been proposed correlated with systemic inflammation. The concentrations of plasma fibrinogen and D-dimer are increased in abnormal coagulation, emerging as available indicators to predict systemic inflammation. The aim of this study is to reveal the predictive value of plasma fibrinogen, D-dimer in the disease activity of gout patients. METHODS: This retrospective study included 334 gout patients and 101 age- and gender- matched healthy controls. The gout patients were divided into two groups according to the gout activity score (GAS = 0.09 × last 12 month attacks + 1.01 × sUA + 0.34 × VAS patient + 0.53 × ln(1 + tophi number). The remission group included 46 patients with GAS of lower than 2.5 and the active group included 288 patients with GAS of 2.5 or higher. Clinical and laboratory data were recorded. The correlations between plasma fibrinogen, D-dimer and GAS were analyzed by Spearman's correlation analysis and Partial correlation analysis. Receiver operating characteristic (ROC) was used to evaluate the diagnostic value for the active group compared with remission group. The predictive value of fibrinogen, D-dimer to the disease activity of gout patients was tested by Binary logistic regression analysis. RESULTS: Plasma fibrinogen and D-dimer in gout patients (3.66 (2.88, 5.20), 0.29 (0.22, 0.80)) were increased as compared with the control group (2.88 (2.51, 3.24), 0.22 (0.22, 0.32), both P < 0.001). Fibrinogen and D-dimer in active group (3.91 (3.00, 5.53), 0.34 (0.22, 0.86)) were higher than those in remission group (2.88 (2.34, 3.22), 0.22 (0.22, 0.26), both P < 0.001)). Plasma fibrinogen, D-dimer, ESR and CRP were positively correlated with GAS (r = 0.606, r = 0.419, r = 0.570, r = 0.440, all P < 0.001). ROC curve showed fibrinogen yielded a highest AUC than D-dimer, ESR, CRP. In addition, the optimal cutoff value of fibrinogen for active group was 3.60, with a specificity of 89.1% and sensitivity of 58.3%. Binary logistic regression analysis showed fibrinogen (odds ratio = 2.71, 95% confidence interval: 1.28-5.74, p = 0.011) was a predictor for gout disease activity. CONCLUSION: Fibrinogen was increased in active gout group. Fibrinogen can serve as a reliable inflammatory marker for monitoring inflammatory response and disease activity in gout patients.

Proteomic analysis of serum-derived extracellular vesicles in ankylosing spondylitis patients.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease, whose pathogenesis is still unclear. Many studies show the proteins in extracellular vesicle (EVs) would change regularly in many diseases. The study aims to explore the proteins contents of serum-derived EVs in AS patients. METHODS: EVs were separated by ExoQuickTM kit. The protein profiles of AS patients and healthy subjects were analyzed by Label-free-liquid chromatography mass spectrometry (LC-MS/MS) technology. Enzyme-linked immunosorbent assay (ELISA) was used to verify the levels of the differently expressed proteins. Receiver operation characteristic (ROC) curves and bioinformatic analysis were conducted. RESULTS: Six hundred and ten serum-derived EVs proteins from AS patients were detected. Seventy-three diferentially expressed proteins were found in AS group, compared with healthy subjects. Of these, 31 proteins were up-regulated in AS group, while 42 proteins were down-regulated. ELISA result showed that EVs-derived serum amyloid A-1 (SAA1) was higher in AS group, which was consistent with the Label-free-LC-MS/MS data. ROC curves result revealed that the area under curve (AUC) value of EVs-derived SAA1 for AS was 0.768 (0.652-0.885). Bioinformatic analysis revealed that the differently expressed proteins in AS group were significantly involved in "complement and coagulation cascades", "staphylococcus aureus infection", "systemic lupus erythematosus" and "PI3K-Akt signaling pathway". CONCLUSIONS: The protein profiles of serum-derived EVs in AS patients and healthy subjects were different. EVs-derived SAA1 may be a potential biomarkes of AS. The function analysis indicated that the differentially expressed proteins may potentially participate in immune response.

Interstitial Lung Disease and Psoriasis in a Child With Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome (AGS) is characterized by progressive neurologic decline, cerebral calcification, and variable manifestations of autoimmunity. Seven subtypes of AGS have been defined and aberrant activation of the type I interferon system is a common theme among these conditions. We describe a 13-year-old boy who presented with an unusual constellation of psoriasis, interstitial lung disease (ILD), and pulmonary hypertension in addition to cerebral calcifications and glomerulonephritis. He was found to have late-onset AGS due to a gain-of-function mutation in IFIH1 and over-activation of the type I interferon pathway was confirmed by RNA sequencing. The majority of his clinical manifestations, including ILD, psoriasis and renal disease improved markedly after treatment with the combination of corticosteroids, cyclophosphamide, and the Janus-kinase inhibitor tofacitinib. This case extends the clinical spectrum of AGS and suggests the need for lung disease screening in patients with AGS.

Association between triclocarban and triclosan exposures and the risks of type 2 diabetes mellitus and impaired glucose tolerance in the National Health and Nutrition Examination Survey (NHANES 2013-2014).

BACKGROUND: There has been increasing interest in the concept that exposure to environmental chemicals may be contributing factors to epidemics of diabetes mellitus (DM). Triclocarban and triclosan (TCs) are synthetic antibacterial chemicals that are widely used in personal care products. Studies have shown that TCs are endocrine disruptors that alter metabolic conditions. However, it remains unclear whether exposure to TCs is a risk factor for impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). OBJECTIVE: We explored the hypothesis that TCs exposure is associated with an increased risk of IGT and T2DM. METHOD: To test our hypothesis, we analyzed the U.S. National Health and Nutrition Examination Survey (NHANES) cross-sectional data from 2013 to 2014. IGT and T2DM were diagnosed based on an oral glucose tolerance test (OGTT) and the WHO standards. The levels of urinary TCs were measured using an HPLC-MS/MS method that NHANES investigators developed. The association between urinary TCs status and IGT and T2DM was examined separately in men and women using multivariable logistic regression models adjusted for age, race, BMI, education, ratio of family income to poverty, smoking, exercise and hypertension. RESULTS: Nine hundred US participants (429 men and 471 women) were included in the analysis, of whom 242 (26.89%) were diagnosed with T2DM and 117 (13.00%) had IGT. Among women, there was a significant positive association between triclocarban, but not triclosan exposure and T2DM (OR: 1.79, 95% CI: 1.05, 2.05) after adjusting for potential confounding factors. Among men, no significant association between TCs exposure and IGT or T2DM was observed. CONCLUSIONS: Triclocarban exposure may increase the risk of T2DM in the women, although additional studies are needed to confirm the results of this study and to investigate the underlying mechanisms.

Serum miR-638 Combined with Squamous Cell Carcinoma-Related Antigen as Potential Screening Biomarkers for Cervical Squamous Cell Carcinoma.

Aims: Cervical cancer is the second most common cause of cancer-related deaths in developing nations. Human papillomavirus prophylactic vaccines are not widely available, and there are shortages of gynecologists and cytologists in the already overburdened health care systems. The aim of this study was to identify circulating microRNAs (miRNAs) that could be used as feasible screening tests for cervical cancer in low-resource regions. Materials and Methods: Serum expression levels of five miRNAs were measured and validated by quantitative real-time polymerase chain reaction in cervical squamous cell carcinoma (CSCC) patients, cervical intraepithelial neoplasia patients, and healthy individuals. Squamous cell carcinoma-related antigen (SCC-Ag) was also measured in the serum. Results: Serum miR-638, miR-203a-3p, miR-1914-5p, and miR-521 levels were downregulated in the CSCC group (p < 0.05). Receiver operating characteristic (ROC) curve analysis indicated that the area under the ROC curve (AUC) values for miR-638 and miR-521 were 0.734 and 0.742, respectively, for discriminating CSCC patients from healthy controls. Furthermore, the combined use of miR-638 and SCC-Ag yielded the best screening performance and increased the AUC value, sensitivity, and specificity to 0.956, 94.87%, and 80.00%, respectively. Conclusion: This study suggested that miR-638 and miR-521 have independent screening value and that the combined measurement of miR-638 and SCC-Ag resulted in a better ability to discriminate patients with CSCC from healthy individuals.

PM2.5 promotes replication of VSV by ubiquitination degradation of phospho-IRF3 in A549 cells.

Both PM2.5 and respiratory viruses are part of the atmospheric constituents. Respiratory viruses are often associated with PM2.5 exposure, but the mechanism of toxicity remains to be explored. The vitro models that adequately reproduce healthy cells or diseased cells exposing to PM2.5 and infecting VSV can provide a useful tool for studying innate immune mechanisms and investigating new therapeutic focus. In the environment of PM2.5, an infection model in which VSV infected A549 cells was established, that mimics the state in which the antiviral innate immune pathways are activated after the respiratory system is infected with RNA viruses. Subsequently, the model was exposed to PM2.5 for 24 h. PM2.5 could be ingested by A549 cells and synergize with VSV to inhibit cell viability and promote apoptosis. The expression of VSV-G were more abundant after VSV-infected A549 cells were exposed to PM2.5. Furthermore, PM2.5 inhibits VSV-induced IFN-ß expression in A549 cells. ISG15, CCL-5, and CXCL-10 had the same expression tendency with IFN-ß mRNA, consistently. Interestingly, when MG132 was applied, the expression of p-IRF-3 and IFN-ß proteins reduced by PM2.5 were refreshed. Conversely, the expression of VSV-G proteins were decreased. PM2.5 could degrade p-IRF-3 proteins by ubiquitination pathway to inhibit VSV-induced IFN-ß expression in A549 cells. Therefore, replication of the VSV viruses was promoted.

A fast SSP-PCR method for genotyping the ATP-binding cassette subfamily B member 1 gene C3435T and G2677T polymorphisms in Chinese transplant recipients.

AIM: P-glycoprotein, the product of the ATP-binding cassette subfamily B member 1 (ABCB1) gene (or the so-called multidrug resistance 1 gene), is an ATP-driven efflux pump contributing to the pharmacokinetics as well as the pharmacokinetics of drugs that are P-glycoprotein substrates, such as tacrolimus. This paper describes the development of a new method for detection of the 3435C/T and 2677G/T/A single nucleotide polymorphisms of the ABCB1 gene. The method is a simple sequence-specific primer polymerase chain reaction (SSP-PCR). METHODS: 158 Chinese health checkup examinees and 214 transplant recipients were included in the study. Genomic DNA was extracted from peripheral blood and amplified with SSP-PCR to detect the 3435C/T and 2677G/T/A mutations in ABCB1. The SSP-PCR condition was optimized, and the PCR results were compared with those of DNA sequencing. RESULTS: In the optimized condition, the two polymorphisms could be clearly distinguished after one-step PCR and electrophoresis. The ABCB1 3435C/T and 2677G/T/A genotypes of the subjects were scanned, and allele-specific bands were successfully amplified by SSP-PCR, which were in full accordance with the results of sequencing. CONCLUSION: As a fast, simple and inexpensive genotyping tool, the method would be practicable in large clinical studies on interindividual pharmacokinetics.

Tofacitinib Treatment of Refractory Systemic Juvenile Idiopathic Arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is an aggressive form of childhood arthritis accompanied by persistent systemic inflammation. Patients with sJIA often exhibit poor response to conventional disease-modifying antirheumatic drugs, and chronic glucocorticoid use is associated with significant adverse effects. Although biologics used to target interleukin 1 and interleukin 6 are efficacious, the long-term commitment to frequent injections or infusions remains a challenge in young children. Janus-activated kinase (JAK) inhibitors block the signaling of numerous proinflammatory cytokines and are now used clinically for the treatment of rheumatoid arthritis in adults. Whether this new class of medication is effective for sJIA has not been reported. Here, we describe the case of a 13-year-old girl with recalcitrant sJIA characterized by polyarticular arthritis, fever, lymphadenopathy, and serological features of inflammation. She showed minimal response to nonsteroidal antiinflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs, and etanercept. She also developed osteoporosis and vertebral compression fracture as the result of chronic glucocorticoid therapy. Oral therapy with the JAK inhibitor tofacitinib was initiated, and the patient experienced steady improvement of both arthritis and systemic features. Complete remission was achieved after 3 months, and no evidence of disease activity or adverse effects was seen through 6 months of follow-up. Our experience reveals the effectiveness of JAK inhibition in a case of refractory sJIA. Tofacitinib is an intriguing oral alternative to the available biologics for children with sJIA, and its efficacy and safety should be further assessed by clinical trial.

Giant Cell Tumor of Tendon Sheath and Tendinopathy as Early Features of Early Onset Sarcoidosis.

Giant cell tumor of tendon sheath (GCTTS) is characterized by diffuse proliferation of synovial-like cells and multinucleated giant cells along tendon sheaths. This benign tumor typically presents in the third to fourth decade of life and is exceeding rare in children. Here we describe a case of a 10-years-old girl with a history of soft tissue swelling involving the third digit of left hand, bilateral wrists and ankles. Pathology of the finger mass revealed abundant multinucleated giant cells consistent with GCTTS. Resection of the tendinous masses from the ankles also showed multinucleated giant cells along with chronic bursitis. She began to show features of polyarticular arthritis by age 7. Due to progression of arthritis, whole exome sequencing was performed and found a de novo heterozygous mutation in NOD2 (p. R334Q). This variant is the most common mutation responsible for early onset sarcoidosis (EOS)/Blau syndrome, an autoinflammatory disease characterized by granulomatous inflammation of joints, skin and eyes. The early onset of symptoms and presence of multinucleated giant cells and granuloma in this case are in keeping with a diagnosis of EOS/Blau syndrome. The patient responded well to treatment with methotrexate and etanercept. This case extends the clinical spectrum of EOS/Blau syndrome, which should be considered for GCTTS and other unusual presentations of tendon inflammation in children, even in the absence of the characteristic triad of arthritis, dermatitis and uveitis.