Search

The FAS antigen (Apo-1/CD95) is a key molecule of apoptosis in most cell types, including activated immune cells and fibroblasts. The FAS gene promoter region contains a single-nucleotide polymorphism (-670A/G) associated with a substitution of the nucleotide arginine for guanine, which is associated with the predisposition to systemic lupus erythematosus, multiple sclerosis, sarcoidosis, and autoimmune hepatitis.Objective: to test the hypothesis that the FAS -670А/G polymorphism may predispose to systemic sclerosis (SS), its clinical and autoimmune phenotypes in a Russian patient sample.Subjects and methods. The instigation enrolled 90 SS patients who were classified according to clinical and autoimmune phenotypes. A control group consisted of 152 apparently healthy unrelated individuals matched for sex and age. The FAS -670А/G polymorphism was studied by polymerase chain reaction, followed by restriction fragment length polymorphism analysis.Results and discussion. A relatively small sample of Russian patients showed no statistically significant association of the studied FAS -670 A/G polymorphism with the predisposition to SS as a whole and the majority of its clinical and immunological phenotypes. There was a statistically significant positive association of the G allele (the FAS -670 GG+GA genotype) with the presence of digital ulcers and the chronic course of the disease. The G allele (the FAS -670 GG+ GA) was detected less frequently in patients with interstitial lung disease (ILD) than in those without ILD.Conclusion. The findings show that the FAS -670A>G polymorphism plays a role in the predisposition to some clinical phenotypes of SS in Russian patients.

Human T-lymphotropic virus 1 (HTLV-1) infection has been associated with ATL and inflammatory diseases but remains a neglected health problem. HTLV-1 associated diseases were originally described as sporadic entities, but family aggregations have been reported. Viral, genetic, immunological and behavioral factors were used to explain family clusters, but until now a clear explanation remains uncertain. In the present study we report, for the first time, a family cluster of diseased persons presenting the infection across three generations associated with FAS -670A/G polymorphism.

The present study aimed to investigate the therapeutic effect and safety of targeted use of Fas-expressing adenoviruses combined with γδ T cell-mediated killing to treat human ovarian cancer xenografts in BALB/c mice. Shuttle plasmids containing control elements of human telomerase reverse transcriptase promoter and two-step transcriptional amplification system were constructed and packaged into adenovirus-5 vectors to generate expression of an exogenous Fas gene. A mouse xenograft model of human ovarian carcinoma was constructed. A total of 35 BALB/c mice were randomly divided into five groups, which were injected with PBS, γδ T cells, Fas-expressing adenoviruses, taxol, or Fas-expressing adenovirus and γδ T cells. The weight and volume of tumors in mice in each group was monitored. Tissue sections of the various tissues of mice in the Fas-expressing adenovirus and γδ T cells group was compared with those in the PBS group to evaluate the safety of Fas-expressing adenovirus and γδ T cells in the treatment of human ovarian cancer xenograft tumors. The results of the present study indicated that mice in all treatment groups were alive at the end of the treatment course. Tumor weight and volume was the highest in the PBS group, followed successively by the adenovirus group, the γδ T cell group, the adenovirus and γδ T cell group, and the taxol group. The weight and volume inhibition rate in adenovirus and γδ T cell group were significantly higher compared with in the PBS group (P<0.05). Pathological observation of tissue samples revealed that none of vital organs in the adenovirus and γδ T cell group developed any evident morphological changes during treatment, when compared with healthy controls. In conclusion, the combined therapy with Fas-expressing adenoviruses and γδ T cells is efficient and safe for the treatment of mouse human ovarian carcinoma xenografts. [ABSTRACT FROM AUTHOR]

Human T-lymphotropic virus 1 (HTLV-1) infection has been associated with ATL and inflammatory diseases but remains a neglected health problem. HTLV-1 associated diseases were originally described as sporadic entities, but family aggregations have been reported. Viral, genetic, immunological and behavioral factors were used to explain family clusters, but until now a clear explanation remains uncertain. In the present study we report, for the first time, a family cluster of diseased persons presenting the infection across three generations associated with FAS -670A/G polymorphism. [ABSTRACT FROM AUTHOR]

Low tissue specificity and efficiency of exogenous gene expression are the two major obstacles in tumor‑targeted gene therapy. The Fas cell surface death receptor (Fas)/Fas ligand pathway is one of the primary pathways responsible for the regulation of cell apoptosis. The aim of the present study was to explore whether the regulation of tumor specific promoters and a two‑step transcriptional amplification system (TSTA) assured efficient, targeted expression of their downstream Fas gene in human ovarian cancer cells, and to assess the killing effect of γδT cells on these cells with high Fas expression. Three shuttle plasmids containing different control elements of the human telomerase reverse transcriptase (hTERT) promoter and/or TSTA were constructed and packaged into adenovirus 5 (Ad5) vectors for the expression of exogenous Fas gene. The human ovarian cancer cell line SKOV3 and a control human embryonic lung fibroblast cell line were transfected with Ad5‑hTERT‑Fas or Ad5‑hTERT‑TSTA‑Fas. Fas mRNA and protein expression were examined by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. γδT lymphocytes were isolated, cultured and mixed at different ratios with SKOV3 cells with Fas expression in order to assess the killing effect of γδT cells. hTERT promoter induced the specific expression of FAS gene in SKOV3 cells, and the TSTA strategy increased FAS expression by 14.2‑fold. The killing effect of γδT cells increased with the expression level of Fas and the effector‑target cell ratio. The killing rate for SKOV3 cells with high FAS expression was 72.5% at an effector‑target cell ratio of 40:1. The regulators of hTERT promoter and TSTA assure the efficient and targeted expression of their downstream Fas gene in SKOV3 cells. The killing effect of γδT cells for ovarian cancer cells with relatively high Fas expression was improved. [ABSTRACT FROM AUTHOR]

Objectives Fas is the prototypic representative of the death receptor subgroup of the tumor necrosis factor (TNF) receptor family. Recently, single nucleotide polymorphisms (SNPs) of the Fas or Fas ligand (FasL) genes have been shown to be associated with an increased risk of several cancers and with the prognosis of several cancers. The objective of this study was to evaluate the association between the SNPs of the Fas and FasL genes and papillary thyroid cancer (PTC) and to assess the relationship between these SNPs and the clinicopathological characteristics of PTC. Methods Five SNPs located within the two genes of Fas and FasL were genotyped using direct sequencing in 94 patients with PTC and 364 healthy controls. Genetic data were analyzed using commercially available software. And, the statistical analyses were performed according to clinicopathologic characteristics of PTC. Results Genotyping analysis demonstrated that the intron SNP (rs1571013), promoter SNP (rs1800682) and 3′-UTR SNP (rs1468063) of Fas were significantly associated with the development of PTC. We also detected a significant difference between patients with PTC and healthy controls with respect to Fas gene allele frequencies. Furthermore, we found that the 3′-UTR SNP (rs1468063) of Fas was associated with the multifocality of cancer [dominant model, OR 0.28, p = 0.028; log-additive model, OR 0.43, p = 0.033]. Conclusion We observed a significant association between SNPs of the Fas gene and the development of PTC. In addition, there was a significant association between a Fas SNP and the multifocality of PTC. [ABSTRACT FROM AUTHOR]

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disease caused germline mutation of FAS gene, gene encoding Fas ligand or Caspase 10 gene. However, in 20% of all ALPS patients, genetic defect is unknown. We presented a case of a 20-year-old male with a history of autoimmune lymphoproliferative syndrome (ALPS; confirmed by genetic study) who came to our medical center with a concern for malignancy. Although no malignancy was detected, his lack of IgA, very low level of IgG (requiring therapy with intravenous IgG) and highly elevated polyclonal IgM (hyperimmunoglobulin M syndrome) were unusual findings because ALPS patients with hypergammaglobulinemia usually demonstrate elevated IgA or IgG., (Copyright © 2022 by the Association of Clinical Scientists, Inc.)

Abstract: FAS (TNF receptor superfamily member 6, also known as CD95) plays a major role in T-cell apoptosis and is often dysregulated in CTCL. We searched for structural alterations of the FAS gene with the potential to affect its function. Although several heterozygous FAS promoter single nucleotide polymorphisms (SNPs) were detected, the only homozygous one was the −671 GG SNP present in 24/80 CTCL cases (30%). This SNP maps to an interferon response element activated by STAT-1. EMSA and supershift EMSA showed decreased CTCL nuclear protein/STAT-1 binding to oligonucleotides bearing this SNP. Luciferase reporters showed significantly less interferon-alfa responsive expression by FAS promoter constructs containing this SNP in multiple CTCL lines. Finally, FAS was upregulated by interferon-alfa in wildtype CTCL cells but not those bearing the −671 GG SNP. These findings indicate that many CTCL patients harbor the homozygous FAS promoter −671 GG SNP capable of blunting its response to interferon. This may have implications for CTCL pathogenesis, racial incidence and the response of patients to interferon-alfa therapy. In contrast, functionally significant mutations in FAS coding sequences were detected uncommonly. Among CTCL lines with the potential to serve as models of FAS regulation, FAS-high MyLa had both FAS alleles, FAS-low HH was FAS-hemizygous and FAS-negative SeAx was FAS-null. [Copyright &y& Elsevier]

Abstract: Alzheimer''s disease (AD) is a progressive neurodegenerative disorder characterized by excessive neuronal loss, intracellular neurofibrillary tangles and extracellular deposition of amyloid β-peptide (Aβ). The Fas antigen is a cell surface receptor-mediating cell apoptosis. Several lines of evidence have made Fas/Fas ligand induced apoptosis play an important role in the pathogenesis of AD. Moreover, the Fas gene is located on chromosome 10q24.1, a region of linkage to late-onset AD. Several reports have investigated the association between a single nucleotide polymorphism (SNP) that is located at position −670 of Fas gene and AD, but yielded ambiguous results. To figure out the association of this SNP with sporadic AD in Chinese Han population, we have analyzed 509 patients with AD and 561 controls for the genetic association studies. Our results indicate that the distribution of the Fas genotypes (χ 2 = 0.66, P = 0.72) and alleles (χ 2 = 0.70, P = 0.40) did not differ significantly. The similar results were observed when AD and control groups were stratified by age/age at onset and sex (P > 0.10). The present data revealed no significant effect of the genotypes on the age of onset for developing AD, and no significant association between the genotypes and the severity of the disease. [Copyright &y& Elsevier]

Pneumocystis pneumonia or PCP is caused by Pneumocystis jirovecii, an obligate parasite of the human lung. In this study P. jirovecii genomic sequence encoding FAS, a trifunctional protein including dihydroneopterin aldolase (DHNA), hydroxymethyldihydropterin pyrophosphokinase (PPPK) and dihydropteroate synthase (DHPS) were identified by PCR amplification from fixed broncheolar lavage samples from patients having Pneumocystis pneumonia. The P. jirovecii trifunctional DHNA–PPPK–DHPS genes (PjFAS) showed a high degree of conservation with the rat Pneumocystis carinii and P. carinii f. sp. macaca sequences. To test the functionality of the PjFAS sequences introns were removed followed by cloning and expression of PjFAS sequences in a DHPS-disrupted Escherichia coli strain. Complementation depended on the presence of N-terminal FAS sequences in addition to a glutathione S- transferase tag to the N-terminus of PjFAS. Functional complementation allowed evaluation of DHPS mutations implicated with sulfa drug resistance. [Copyright &y& Elsevier]

Fas (APO-1/CD95) is a transmembrane protein which mediates programmed cell death (apoptosis). Cells with a mutated Fas gene are resistant to apoptosis and thus accumulate in lesional tissues. This might provide a basis for the development of neoplasias. Genomic DNA selectively obtained from Pautrier’s microabscesses in 16 cases of mycosis fungoides (MF) using a laser capture microdissection method was analyzed. Fas gene mutations were detected in 3 of 16 cases of MF (18.8%); 1 was silent and 2 were missense mutations located in exon 9. One of the 2 missense mutations involved the death domain of the Fas gene, which is essential for apoptotic signal transduction. The missense mutations resulted in the substitution of Ala with Asp at codon 220 and Ile with Thr at codon 314. Mouse T cell lymphoma cells transfected with mutant genes were resistant to apoptosis induced by the anti-Fas antibody, indicating that the missense mutations found in MF were loss-of-function mutations, thus causing the accumulation of cells in the cutaneous lesions. These findings suggest that the accumulation of lymphoid cells with Fas mutations provides, in part, a basis for the development or maintenance of MF. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The inhibitory effects of purified fractions isolated from guava seed polysaccharides (GSPS) including guava seed polysaccharide fraction 1 (GSF1), GSF2, and GSF3 on prostate cancer cells remain unclear. To clarify the anti-prostate cancer potential, GSPS, GSF1, GSF2, and GSF3 were isolated using Sepharose 6B gel filtration chromatography to assay their inhibitory effects on prostate PC-3 cell growth with direct action or indirect immunotherapy using either splenocyte conditioned media (SCM) or macrophage conditioned media (MCM). Correlations between cytokine profiles in the conditioned media and pro-apoptotic gene expression levels in the corresponding treated PC-3 cells were analyzed. Results showed that GSPS, GSF1, GSF2, and GSF3, particularly GSF3, through either direct action or indirect treatments using SCM or MCM, significantly (p < 0.05) inhibited PC-3 cell growth. GSF3 direct treatments increased pro-apoptotic Bax/anti-apoptotic Bcl-2 mRNA expression ratios in corresponding treated PC-3 cells. Either SCM or MCM cultured with GSF3 increased Fas mRNA expression levels in corresponding treated PC-3 cells. Both Th2-polarized and anti-inflammatory cytokine IL-10 either secreted in SCM or MCM were positively correlated with Fas mRNA expression levels in corresponding treated PC-3 cells. Our results suggest that GSF3 is a potent biological response modifier to decrease PC-3 cell growth through inducing apoptosis. [ABSTRACT FROM AUTHOR]

Fulminant hepatic failure is a life-threatening disease which occurs in patients without preexisting liver disease. Nowadays, there is no ideal therapeutic tool in the treatment of fulminant hepatic failure. Recent studies suggested that a novel technology termed CRISPR/Cas9 may be a promising approach for the treatment of fulminant hepatic failure. In this project, we have designed single chimeric guide RNAs specifically targeting the genomic regions of mouse Fas gene. The in vitro and in vivo effects of sgRNAs on the production of Fas protein were examined in cultured mouse cells and in a hydrodynamic injection-based mouse model, respectively. The in vivo delivery of CRISPR/Cas9 could maintain liver homeostasis and protect hepatocytes from Fas-mediated cell apoptosis in the fulminant hepatic failure model. Our study indicates the clinical potential of developing the CRISPR/Cas9 system as a novel therapeutic strategy to rescue Concanavalin-A-induced fulminant hepatic failure in the mouse model. J. Cell. Biochem. 118: 530-536, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aim: To evaluate the Immunomodulatory effects of CagA expression; pepsinogen I, II & gastrin-17 on PMNs and lymphocytes Fas expression in inflammatory and gastric cells; demographic distribution of Fas molecule in gastric tissue and inflammatory cells., Methods: Gastroduodenal biopsies were taken from 80 patients for histopathology and H. pylori diagnosis. Serum samples were used for evaluation of pepsinogen I (PGI); (PGII); gastrin-17 (G-17)., Results: Significant difference (p < 0.001) in lymphocytes & PMNs Fas expression; epithelial & lamina propria Fas localization among H. pylori associated gastric disorders. No correlation between grade of lymphocytes & PMNs Fas expression in gastric epithelia; lamina propria and types of gastric disorder. Significant difference (p < 0.001) in total gastric Fas expression, epithelial Fas; lamina propria and gastric gland Fas expression according to CagA , PGI; PGII; PGI/PGII; Gastrin-17. Total gastric Fas expression has significant correlation with CagA , PGII levels. Gastric epithelial and gastric lamina propria Fas expression have significant correlation with CagA , PGI; PGII levels. Significant difference (p < 0.001) was found in lymphocytes & PMNs Fas expression; epithelial & lamina propria localization of lymphocytes & PMNs Fas expression according to CagA , PGI; PGII; PGI/PGII; Gastrin-17. Lymphocytes Fas expression have correlation with PGI, PGII, PGI/PGII. PMNs Fas expression have correlation with PGI, PGII., Conclusion: Fas gene expression and localization on gastric and inflammatory cells affected directly by H. pylori CagA and indirectly by gastric hormones. This contributes to progression of various gastric disorders according to severity of CagA induced gastric pathology and gastric hormones disturbance throughout the course of infection and disease.

A young patient with undefined autoimmune lymphoproliferative syndrome (ALPS-U) and low back pain underwent a CT and MRI study that showed enhancing vertebral lesions, some pulmonary nodules and diffuse latero-cervical lymphadenopathy. A (18)F-FDG-PET/CT scan showed many areas of intense (18)F-FDG uptake in multiple vertebrae, in some ribs, in the sacrum, in the liver, in both lungs, in multiple lymph nodes spread in the cervical, thoracic and abdominal chains. A bone marrow biopsy showed a "lymphomatoid granulomatosis", a rare variant of B-cell non-Hodgkin lymphoma (NHL). After the treatment, the (18)F-FDG-PET/CT scan showed a complete metabolic response., (Copyright © 2013 Elsevier España, S.L. and SEMNIM. All rights reserved.)