Predictors of medications-free and long-term remission in anti-neutrophil cytoplasmic antibody-associated vasculitis: Real-world evidence.

BACKGROUND AND AIM: In this study, we report the outcomes of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in daily practice based on Connective Tissue Diseases Research Center-Vasculitis Registry (CTDRC-VR) data. METHODS: Patients were included if they were 18 years or older, had a diagnosis of the groups of AAV based on 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis, and were followed for a period longer than 2 years or were died. Complete clinical remission was defined as granulomatosis with polyangiitis (BVAS/GPA) of 0. Sustained remission was defined as a complete clinical remission for at least six months and tapering prednisolone dose to ≤ 7.5 mg/d. Long-term remission was defined as complete clinical remission for ≥ 5 years and tapering prednisolone dose to ≤ 7.5 mg/d. Medications-free remission was defined as complete clinical remission and discontinuation of glucocorticoids, cytotoxic medications and biologics. RESULTS: Sixty patients with AAV were enrolled in this study. Sustained and long-term remission were developed in 91.7 and 72.1 percent of patients, respectively. Relapse was developed in 27 (45%) patients. Medications-free remission was developed in 23 (33.3%) patients. Vasculitis induced damage was developed in 40 (66.7%) patients. Patients with damage had significantly lower age and higher BVAS at the baseline. Upper airway and renal involvement, and non-adherence in patients with damage was significantly more common. CONCLUSIONS: Induction therapy leads to long-term and medications-free remission in 72% and 38% of patients with AAV, respectively.

Cigarette smoking and risk of adult-onset Still disease: a propensity score matching analysis.

BACKGROUND: Environmental factors play an important role in the pathogenesis of rheumatic diseases. Smoking is thought to be a risk factor for autoimmune rheumatic diseases. AIMS: The purpose of the present study was to assess the association between smoking and adult-onset Still disease (AOSD) and the effect of smoking on outcomes of this disease. METHODS: In this case-control study, patients with AOSD who met the Yamaguchi criteria, were older than 16 years at the disease onset and were in follow-up for at least 12 months were consecutively enrolled in the study. The outcome of AOSD was assessed by acquiring remission on treatment, remission off treatment, time to remission and rate of flare. The smoking status of participants was defined by direct or phone interviews. Individuals who had smoked daily for at least 6 months were defined as a smoker. We performed propensity score matching analyses by using four parameters, including age, sex, educational status and marital status. RESULTS: Propensity score matching resulted in 72 patients with AOSD and 216 matched controls. The number of ever smokers in the AOSD and control groups were 11 (15.3%) and 25 (11.6%) respectively. There was no significant increase in the risk of AOSD in multivariate analysis after adjustment for age, sex, marital status and educational level. There were no significant differences in the outcomes of AOSD between ever and never smokers. CONCLUSIONS: Smoking probably is not a risk factor for AOSD and did not affect the response to treatment.

Evaluation of hsa-let-7d-5p, hsa-let-7g-5p and hsa-miR-15b-5p plasma levels in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder MicroRNAs (miRNAs) may be promising diagnostic biomarkers for AD. Previous evidence shows that miR-15b-5p, hsa-let7g-5p and hsa-let7d-5p might confer potential blood biomarkers for timely diagnosis of AD. Therefore, in this replication study, we aimed to investigate the serum transcript level of these miRNAs to assess for their potential as diagnostic or prognostic biomarker in AD patients. METHODS: Blood samples were obtained from 50 AD patients and 50 age- and sex-matched healthy individuals. Then, total RNA was extracted from serum samples, cDNA was synthesized, and the expression level of miRNAs was measured by the real-time PCR method. RESULTS: The expression level of hsa-let7d-5p (fold change = 2.14, P = 0.007) and hsa-let7g-5p (fold change = 1.94; P = 0.013) was significantly increased in the AD patients compared to control individuals. However, the difference in the transcription of miR-15b-5p between the two groups was not statistically significant (fold change = 1.08; P = 0.76). The AROC for transcript levels of hsa-let-7d-5p was 0.68 (P = 0.014; 95% CI, 0.39-0.88) and it was 0.64 for hsa-let-7g-5p (P = 0.028; 95% CI, 0.27-0.89). The cut-off value for let-7d-5p had 0.82 sensitivity and 0.34 specificity. Moreover, the cut-off value for hsa-let-7g-5p indicated a 0.79 sensitivity and 0.28 specificity. CONCLUSION: Our findings suggest the potential of measuring the transcript levels of hsa-let7d-5p and hsa-let7g-5p miRNAs as a diagnostic biomarker for AD.

Cigarette smoking and risk of palindromic rheumatism: A propensity score matching analysis.

Present study was conducted to investigate smoking status in palindromic rheumatism (PR) patients compared to healthy individuals as well as to assess the effect of smoking on clinical features and outcomes of PR. One hundred and forty-six patients with diagnosis of PR and 346 healthy controls were included in this study. Demographic, clinical, and laboratory characteristics and the smoking history of PR patients at the cohort entry were obtained from patients' records. Demographic and smoking history of the control group were obtained by direct interview. In order to reduce heterogeneity between the studied groups, propensity score matching (PSM) analyses was performed. Matching was achieved by considering age, gender, educational status, and marital status. After PSM, we carried out a multivariate analysis with PR as the main outcome variable, ever smoking as the main predictor variable and age, gender, educational status, and marital status as covariates. PSM resulted in 123 PR patients and 246 matched controls. Multivariate analysis did not show a significant increase in the risk of PR in ever smokers. Seventy-six patients were anti-citrullinated protein/peptide antibody positive (ACPA-positive). Multivariate logistic regression showed a significant increase in the risk of PR in ACPA-positive ever smokers. Except lower sustained remission rate in ever smokers, no significant differences were observed in clinical manifestations and outcomes of PR between ever and never smokers. In conclusion, smoking is a risk factor for ACPA-positive PR.

Cancer immunotherapy: Challenges and limitations.

Although cancer immunotherapy has taken center stage in mainstream oncology inducing complete and long-lasting tumor regression, only a subset of patients receiving treatment respond and others relapse after an initial response. Different tumor types respond differently, and even in cancer types that respond (hot tumors), we still observe tumors that are unresponsive (cold tumors), suggesting the presence of resistance. Hence, the development of intrinsic or acquired resistance is a big challenge for the cancer immunotherapy field. Resistance to immunotherapy, including checkpoint inhibitors, CAR-T cell therapy, oncolytic viruses, and recombinant cytokines arises due to cancer cells employing several mechanisms to evade immunosurveillance.

Integrative analysis of DNA methylation and gene expression profiles to identify biomarkers of glioblastoma.

Glioblastoma multiforme (GBM) is the most common, most invasive, and malignant type of primary brain tumor with poor prognosis and poor survival rate. Using GSE22891 the expression and methylation status of same GBM patients was evaluated to identify key epigenetic genes in GBM. Using |log2FC| > 1 and FDR 〈 0.05 as the threshold, DEGs including 4910 downregulated and 2478 upregulated were screened and by |log2FC| 〉 0.2 and p-value < 0.05, 3223 DMCs were detected. By merging the results of DEGs and DMCs, 643 genes were selected for network analysis by WGCNA, and based on expression values three modules and by methylation values, one module was selected. Using STRING and Cytoscape databases, PPI network of genes of all modules were constructed separately. According to the PPI network, core genes were picked out. The expression status of core genes was evaluated using GSE77043, GSE42656, GSE30563, GSE22891, GSE15824, and GSE122498, and 50 genes were validated. The methylation status of 50 genes was explored using GSE50923, GSE22891, and GSE36245, and finally, 12 hub genes including ARHGEF7, RAB11FIP4, PPP1R16B, OLFM1, CLDN10, BCAT1, C1QB, C1QC, IFI16, NUP37, PARP9, and PCLAF were selected. Using GEPIA database, the expression and by cBioportal the survival plot and also scatterplot of methylation versus expression of 12 hub genes were extracted based on TCGA. To determine the diagnostic values of the hub genes, the receiver operating characteristic (ROC) curve and the area under the curve (AUC) were extracted based on GSE22891 and GSE122498. Finally, we evaluated the expression level of the genes in tissue of 83 GBM patients and also non-tumoral adjacent (as control) tissues.

Investigation the Cytotoxicity of 5-AZA on Acute Lymphoblastic Leukemia Cell Line In Vitro and Characterization the Underlying Molecular Mechanisms of Cell Death and Motility.

DNA methylation is a reversible biochemical process determinant of gene expression that is frequently observed in acute lymphoblastic leukemia (ALL). This is believed to arise from aberrant DNA methyltransferase activity establishing abnormal levels of DNA methylation in tumor cells. DNA methyltransferase inhibitor, 5-azacytidine (5-AZA), is a clinically used epigenetic drug which induces promoter demethylation and gene re-expression in human cancers. In this study, we investigated the cytotoxicity of on MOLT4 and Jurkat leukemic cell line in vitro and characterized the underlying molecular mechanisms of cell death and motility. MOLT4 and Jurkat cells were treated with 5-AZA for 12, 24 and 48 hours. The effect of the 5-AZA treatment on cell viability (MTT assay), apoptosis (annexin V/PI staining), microRNA (miRNA) and mRNA expression (real-time PCR) was measured. The results showed that 5-AZA could induce MOLT4 and Jurkat apoptotic cell death in vitro in a time-dependent manner and probably via apoptotic mechanisms. We found that treatment with 5-AZA could increase the expression of epigenetically silenced miRNAs, miR-34a, miR-34b and miR-124-1 in treated cells. In addition, mRNA analyses demonstrated that MOLT4 and jurkat cells, expressed p53 gene more than 10-fold higher compared with untreated cells in three independent experiments while the cells suppressed the expression of a subset of functionally related genes including MYC, BCL2, APEX, SIRT1, SNAIL1 and vimentin to some extent, following 5-AZA treatment. We found that a miRNAs expression level in treated cell lines was closely correlated to the expression of their target genes. Together, these findings suggest that 5-AZA may affect the viability of MOLT4 and jurkat cells, at least in part, by regulating the transcription of genes that are associated with cellular apoptotic response.

Stress Granules Involved in Formation, Progression and Metastasis of Cancer: A Scoping Review.

The assembly of stress granules (SGs) is a well-known cellular strategy for reducing stress-related damage and promoting cell survival. SGs have become important players in human health, in addition to their fundamental role in the stress response. The critical role of SGs in cancer cells in formation, progression, and metastasis makes sense. Recent researchers have found that several SG components play a role in tumorigenesis and cancer metastasis via tumor-associated signaling pathways and other mechanisms. Gene-ontology analysis revealed the role of these protein components in the structure of SGs. Involvement in the translation process, regulation of mRNA stability, and action in both the cytoplasm and nucleus are among the main features of SG proteins. The present scoping review aimed to consider all studies on the effect of SGs on cancer formation, proliferation, and metastasis and performed based on a six-stage methodology structure and the PRISMA guideline. A systematic search of seven databases for qualified articles was conducted before July 2021. Publications were screened, and quantitative and qualitative analysis was performed on the extracted data. Go analysis was performed on seventy-one SGs protein components. Remarkably G3BP1, TIA1, TIAR, and YB1 have the largest share among the proteins considered in the studies. Altogether, this scoping review tries to demonstrate and provide a comprehensive summary of the role of SGs in the formation, progression, and metastasis of cancer by reviewing all studies.

Neurological manifestations of COVID-19 infection: an umbrella review.

BACKGROUND: Neurological involvements of COVID-19 are one of the most reported manifestations of this infection. This study aims to systematically review the previous systematic reviews which addressed the neurological manifestations of the COVID-19 infection. METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, a comprehensive search was conducted in PubMed, Embase, Scopus, Web of Science databases and Google Scholar from December 2019 to December 2020. Articles were critically screened by two independent reviewers and if met the inclusion criteria, entered the study. Assessment of methodological quality was conducted by Assessment of Multiple Systematic Reviews-2 (AMSTAR-2) tool. Statistical analysis was not applicable. From a total of 1302 studies, 308 studies were removed due to their irrelevant title and abstract. After screening the full texts, a total of 66 found to be eligible. Twenty-one studies reported general manifestations of the COVID-19, 13 studies reported cerebrovascular events, 19 olfactory and oral dysfunctions, 5 systematic reviews on Guillen-Barré syndrome (GBS) and 8 articles on the sporadic manifestations like ocular signs and symptoms. The majority of the studies were classified as critically low or low in terms of quality. CONCLUSION: Despite great heterogeneity in the current literature, neurological involvements are an important extra-pulmonary aspect of the COVID-19; most commonly in the form of general manifestations like headache and olfactory disturbances. Long-term effects of this virus on the nervous system must be a research priority for future references. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41983-021-00366-5.

CircRNAs as potent biomarkers in ovarian cancer: a systematic scoping review.

More powerful prognostic and diagnostic tools are urgently needed for identifying and treating ovarian cancer (OC), which is the most fatal malignancy in women in developed countries. Circular RNAs (circRNAs) are conservative and stable looped molecules that can regulate gene expression by competing with other endogenous microRNA sponges. This discovery provided new insight into novel methods for regulating genes that are involved in many disorders and cancers. This review focuses on the dysregulated expression of circRNAs as well as their diagnostic and prognostic values in OC. We found that studies have identified twenty-one downregulated circRNAs and fifty-seven upregulated ones. The results of these studies confirm that circRNAs might be potent biomarkers with diagnostic, prognostic and therapeutic target value for OC. We also consider the connection between circRNAs and OC cell proliferation, apoptosis, metastasis, and chemotherapy resistance and sensitivity.

The serum levels of testosterone in coronary artery disease patients; relation to NO, eNOS, endothelin-1, and disease severity.

OBJECTIVES: The changes in testosterone level and its correlation with the endothelial nitric oxide systems balance in patients with coronary artery disease (CAD) remains uncertain. Therefore, in our study, we aimed to evaluate the levels of testosterone, endothelin-1 (ET-1), nitric oxide (NO), and endothelial NOS (eNOS) in CAD patients, and control group to find the relationship between these parameters and disease severity. METHODS: Forty-four patients as CAD group with significant (≥50%) stenosis confirmed by angiography was included in the study, and 40 healthy men were included as the control group. According to the number of vessels obstruction, CAD severity was determined. The serum indicated parameters were assessed to discriminate between patients and controls. RESULTS: It was found that testosterone levels in the CDA group were significantly lower than those of the control group (p<0.05). In addition, the level of ET-1 in the CAD group was higher than that in the control group, but levels of NO and eNOS in observation were significantly lower than those in the control group (p<0.05). The correlation analysis revealed that testosterone was passivity correlated with serum NO levels (r=0.550, p=0.001). CONCLUSIONS: The current study reports that serum levels of testosterone are closely related to endothelial NO levels and might be of relevance to the pathogenesis of endothelial dysfunction and disease severity in CAD patients.

The related miRNAs involved in doxorubicin resistance or sensitivity of various cancers: an update.

Doxorubicin (DOX) is an effective chemotherapy agent against a wide variety of tumors. However, intrinsic or acquired resistance diminishes the sensitivity of cancer cells to DOX, which leads to a cancer relapse and treatment failure. Resolutions to this challenge includes identification of the molecular pathways underlying DOX sensitivity/resistance and the development of innovative techniques to boost DOX sensitivity. DOX is classified as a Topoisomerase II poison, which is cytotoxic to rapidly dividing tumor cells. Molecular mechanisms responsible for DOX resistance include effective DNA repair and resumption of cell proliferation, deregulated development of cancer stem cell and epithelial to mesenchymal transition, and modulation of programmed cell death. MicroRNAs (miRNAs) have been shown to potentiate the reversal of DOX resistance as they have gene-specific regulatory functions in DOX-responsive molecular pathways. Identifying the dysregulation patterns of miRNAs for specific tumors following treatment with DOX facilitates the development of novel combination therapies, such as nanoparticles harboring miRNA or miRNA inhibitors to eventually prevent DOX-induced chemoresistance. In this article, we summarize recent findings on the role of miRNAs underlying DOX sensitivity/resistance molecular pathways. Also, we provide latest strategies for utilizing deregulated miRNA patterns as biomarkers or miRNAs as tools to overcome chemoresistance and enhance patient's response to DOX treatment.