Background: Celiac disease (CeD) is an autoimmune enteropathy triggered by dietary gluten. Almost 90% of CeD patients have HLA-DQ2 or -DQ8 haplotypes. As a high proportion of first-degree relatives (FDRs) of CeD patients have the same haplotype, it is assumed that they are at a higher risk of disease development than the general population. Nevertheless, the prevalence of CeD among FDRs is considerably low (7.5%). Methods: In order to figure out this discrepancy, a microarray dataset of intestinal mucosal biopsies from CeD, FDR, and control groups was reanalyzed, and gene co-expression network using WGCNA was constructed. The differentially expressed genes in the opposite modules from the consensus analysis were applied for functional enrichment analysis. Results: WGCNA analysis identified 10 consensus modules in both CeD and FDR groups, including 5 modules with opposite correlation. Among the genes of opposing modules, 159 of them were identified as commonly differentially expressed genes with an adjusted p-value< 0.05 between FDR and CeD groups. Functional enrichment analysis revealed the significant contributions of these genes in host energy metabolism, programmed cell death, antigen cross presentation, and actin folding. In a deep view to the relation of actin folding to celiac disease occurrence, it was found that misfolding of actin and presentation of anti-actin antibodies occur in CeD patients. The current study reports that this pathway is oppositely regulated in FDR group and this might be a trigger for celiac manifestation. Conclusions: The consensus signaling pathways with opposing expression patterns identified in this study give us a clue about the gene circuits that are dysregulated in celiac patients. Considering the prominent relation of actin folding to disease occurrence and its opposite manner in celiac patients and healthy individuals, it is proposed that targeting CCT/TriC chaperonin family might result in a reduction of misfolded actin and the production of autoantibodies.
Background and purpose: Despite the widespread utilization of cancer vaccines with specified antigens, the use of whole tumor cell lysates in tumor immunotherapy would be a very promising approach that can overcome several significant obstacles in vaccine production. Whole tumor cells provide a broad source of tumor-associated antigens and can activate cytotoxic T lymphocytes and CD4+ T helper cells concurrently. On the other hand, as an effective immunotherapy strategy, recent investigations have shown that the multi-targeting of tumor cells with polyclonal antibodies, which are also more effective than monoclonal antibodies at mediating effector functions for target elimination, might minimize the escape variants. Experimental approach: We prepared polyclonal antibodies by immunizing rabbits with the highly invasive 4T1 breast cancer cell line. Findings/Results: In vitro investigation indicated that the immunized rabbit serum inhibited cell proliferation and induced apoptosis in target tumor cells. Moreover, in vivo analysis showed enhanced anti-tumor efficacy of whole tumor cell lysate in combination with tumor cell-immunized serum. This combination therapy proved beneficial in significant inhibition of the tumor growth and the established tumor was entirely eradicated in treated mice. Conclusion and implications: Serial intravenous injections of tumor cell immunized rabbit serum significantly inhibited tumor cell proliferation and induced apoptosis in vitro and in vivo in combination with whole tumor lysate. This platform could be a promising method for developing clinical-grade vaccines and open up the possibility of addressing the effectiveness and safety of cancer vaccines.
Background: Celiac disease is an autoimmune enteropathy triggered by dietary gluten. Almost 90% of celiac disease patients have HLA-DQ2 or -DQ8 haplotypes. As a high proportion of first-degree relatives of celiac disease patients have the same haplotype, it is assumed that they are at a higher risk of disease development than the general population. Nevertheless, the prevalence of celiac disease among first-degree relatives is considerably low (7.5%). Results: In order to figure out this discrepancy, a microarray dataset of intestinal mucosal biopsies of celiac disease patients, first-degree relatives, and control groups was reanalyzed, and protein-protein interaction network was constructed. Principle component analysis showed that celiac disease and first-degree relative groups are far away in terms of gene expression. Comparing differentially expressed genes of both networks demonstrated inverse expression of some genes mainly related to cell cycle mechanisms. Moreover, analysis of the modular structures of up and downregulated gene networks determined activation of protein degradation mechanisms and inhibition of ribosome-related protein synthesis in celiac patients with an upside-down pattern in first-degree relatives.Conclusions: The top-down systems biology approach determined some regulatory pathways with inverse function in celiac disease and first-degree relative groups. These genes and molecular mechanisms could be a matter of investigation as potential druggable targets or prognostic markers in celiac disease.
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