Fas Receptor Research Articles

Different methods of detaching adherent cells and their effects on the cell surface expression of Fas receptor and Fas ligand

In cell culture environment, some cells adhere firmly to the culture plates and may be vulnerable to cell detachment during passage. Therefore, it is important to harvest cells with a proper detaching method to maintain the viability of cells after detachment. Trypsinization is frequently used for cellular dissociation and detachment. However, most surface proteins and the extracellular matrix are degraded by enzymatic digestion. A mild cell detachment buffer, accutase, is recommended for the replacement of trypsin to dissociate adherent cells and thereby avoid cellular damage. In this study, we demonstrated that use of accutase for cellular detachment may compromise some surface proteins. Compared with ethylenediaminetetraacetic acid (EDTA)-based nonenzymatic cell dissociation buffers, accutase was associated with significant decreases in the surface Fas ligands and Fas receptors. Moreover, we found that accutase may be able to cleave surface Fas ligands into pieces. Our results also illustrated that surface proteins required 20 h to recover after accutase treatment. We demonstrated that using accutase to dissociate adherent cells compromised the expression of Fas ligands and Fas receptors on the cell surface. These findings indicate that it is important to choose suitable cell detachment buffers and allow cells to recover after detachment before experiments.

Role of interleukin-4 and their antagonistic effect in asthma

Asthma is a chronic inflammatory disease of the lower airways, characterize by wheezing cough, chest tightness along with inflammation of airway and shortness of breath. Allergens like environmental substance are predispose asthmatics patients to allergy. Mast cells produced interleukin (IL)- 4 which either activate signal transducer and activator of transcription 6 (STAT-6) pathway that involved in differentiation of na ve T-cells to TH2 or activation of TH2 cells indirectly. The aim of the current context is to present role of IL-4 in asthma and effect as antagonist. IL-4 results in increased mucus production and involve in IgE synthesis from B cells. IL4 facilitate chemotaxis and aid in displaying of VCAM-1 which attract eosinophil basophils monocytes T-lymphocytes to blood vessel. IL4 inhibit apoptosis either by preventing decrease in BCL-2 level or binding of FasL to Fas (cd32) receptor which result in acute allergic response. Elevated level of IL-4 has greatly adverse impact on asthmatic patients so by decreasing the level of IL-4 will greatly reduce asthma phenotype.

Breed dependent regulatory mechanisms of beneficial and non-beneficial fatty acid profiles in subcutaneous adipose tissue in cattle with divergent feed efficiency

The current study aimed to determine whether breed and feed efficiency affect the molecular mechanisms regulating beneficial and non-beneficial fatty acid profiles in subcutaneous adipose tissue of beef steers. Fatty acid profiling and RNA-Seq based transcriptome analysis were performed on subcutaneous adipose tissues collected from beef steers with three divergent breeds (Angus, ANG, n = 47; Charolais, CHAR, n = 48; Kinsella Composite, KC, n = 48) and different residual feed intake (RFI, a measure of feed efficiency). The comparison of fatty acid profiles showed that KC had higher beneficial FAs compared to the other two breeds. Distinct FA profiles between H-RFIfat and L-RFIfat steers was more obvious for KC steers, where H-RFIfat steers tended to have higher proportion of healthy FAs and lower proportion of the unhealthy FAs. A higher number of differentially expressed (DE) genes were observed for KC steers, whereas ANG and CHAR steers had a lower number of DE genes between H- and L-RFIfat steers. The association analyses of the gene expressions and FA profiles showed that 10 FA metabolism-associated genes together with the one upstream regulator (SREBF1) were associated with the proportion of C18:2n-6, total n-6, PUFA and PUFA/SFA for KC steers but not the other two breeds. Subcutaneous adipose tissue FA profiles and healthy FA index differed in cattle with divergent feed efficiency and such variation was unique for the three examined cattle breeds. Key FA metabolism-associated genes together with SREBF1 which is the upstream regulator of a set of genes involved in lipid metabolism may be of importance for genetic selection of meat with higher healthy FA index in beef cattle.

Genetic basis of the lobedness degree in tomato fruit morphology

Fruit shape is a key trait in tomato (Solanum lycopersicum L.). Since most studies focused on proximo-distal fruit morphology, we hypothesized that unknown QTLs for medio-lateral direction ones could be found analysing segregating populations where major shape genes are fixed. We examined the diversity of fruit morphology in medio-lateral direction; defined divergent traits in cultivars carrying identical genetic constitution at LC and FAS genes; and identified QTLs for lobedness degree (LD) by a QTL-seq approach. We found that LC and FAS genes were not enough to explain LD variability in a large tomato collection. Then, we derived F2 populations crossing cultivars divergent for LD where LC and FAS were fixed (Yellow Stuffer x Heinz 1439 [F2YSxH] and Voyage x Old Brooks [F2VxOB]). By QTL-seq we identified a QTL for LD on chromosome 8 in both F2, which was validated in F2YSxH by interval mapping accounting for ~ 17% of the variability. Other two QTLs located on chromosomes 6 and 11 with epistasis explained ~ 61% of the variability in the F2VxOB. In conclusion, three novel QTLs with major effect for LD (ld6, ld8, and ld11) were identified through the study of diversity and genetic segregation in intraspecific tomato crosses.

Identifying HSV-1 Inhibitors from Natural Compounds via Virtual Screening Targeting Surface Glycoprotein D.

Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could interact synergistically with first-line antiherpetic agents to accelerate the resolution of HSV-1-associated lesions. For this study, we applied a structure-based molecular docking approach targeting the nectin-1 and herpesvirus entry mediator (HVEM) binding interfaces of the viral glycoprotein D (gD). More than 527,000 natural compounds were virtually screened using Autodock Vina and then filtered for favorable ADMET profiles. Eight top hits were evaluated experimentally in African green monkey kidney cell line (VERO) cells, which yielded two compounds with potential antiherpetic activity. One active compound (1-(1-benzofuran-2-yl)-2-[(5Z)-2H,6H,7H,8H-[1,3] dioxolo[4,5-g]isoquinoline-5-ylidene]ethenone) showed weak but significant antiviral activity. Although less potent than antiherpetic agents, such as acyclovir, it acted at the viral inactivation stage in a dose-dependent manner, suggesting a novel mode of action. These results highlight the feasibility of in silico approaches for identifying new antiviral compounds, which may be further optimized by medicinal chemistry approaches.

FAS receptor regulates NOTCH activity through ERK-JAG1 axis activation and controls oral cancer stemness ability and pulmonary metastasis

Pulmonary metastasis occurring via the colonization of circulating cancer stem cells is a major cause of oral squamous cell carcinoma (OSCC)-related death. Thus, understanding the mechanism of OSCC pulmonary metastasis may provide a new opportunity for OSCC treatment. FAS, a well-known apoptosis-inducing death receptor, has multiple nonapoptotic, protumorigenic functions. Previously, we found that SAS OSCC cells with FAS receptor knockout did not affect orthotopic tumor growth or cervical lymph node metastasis. However, FAS knockout cells could not colonize in distant organs to form metastases upon intravenous injection, which hinted at the cancer stemness function of the FAS receptor. Immunohistochemistry staining indicated that the FAS receptor serves as a poor prognosis marker in OSCC patients. FAS knockout inhibited in vitro cancer spheroid formation, migration and invasion, and prevented mesenchymal transition in OSCC cells and inhibited OSCC pulmonary metastasis in vivo. To determine the regulatory mechanism by which the FAS receptor exerts its oncogenic function, we utilized cDNA microarrays and phosphoprotein arrays to discover key candidate genes and signaling pathway regulators. JAG1 expression and NOTCH pathway activation were controlled by the FAS receptor through ERK phosphorylation. Both JAG1 and NOTCH1 silencing decreased in vitro cancer spheroid formation. In OSCC cells, FAS ligand or JAG1 protein treatment increased NOTCH pathway activity, which could be abolished by FAS receptor knockout. In FAS knockout cells, restoring the NOTCH1 intracellular domain stimulated cancer spheroid formation. Both JAG1 and NOTCH1 silencing decreased in vivo OSCC growth. In conclusion, we found a novel FAS-ERK-JAG1-NOTCH1 axis that may contribute to OSCC stemness and pulmonary metastasis.

16P Checkpoint modification of BTLA-HVEM-LIGHT signaling by HSV-1 glycoprotein D (gD) improves vaccine-induced CD8+ T cell responses in pre-clinical cancer models

Signaling through the immunoinhibitory B and T lymphocyte attenuator (BTLA), upon binding to the herpes virus entry mediator (HVEM), on dendritic cells, regulates early steps of CD8+ T cell activation. HSV-1 glycoprotein D (gD) attaches to HVEM and blocks BTLA-HVEM inhibitory signaling and allows for co-stimulation through LIGHT, which binds to a different domain on HVEM. Here we present preclinical studies exploring CD8+ T cell responses induced by chimpanzee adenovirus (AdC) vector-based vaccines expressing tumor antigens genetically fused into gD.

Cytokine and Chemokine Receptor Patterns of Human Malignant Melanoma Cell Lines.

Cytokine and chemokine receptors can promote tumor progression, invasion, and metastasis development by inducing different intracellular signaling pathways. The aim of this study was to determine the cytokine and chemokine receptor gene expression patterns in human melanoma cell lines. We found a large set of cytokine and chemokine receptor genes that were significantly differentially expressed between melanoma cell lines that originated from different subtypes of primary melanomas as well as cell lines that originated from melanoma metastases. The relative expressions of two receptor genes (CCR2 and TNFRSF11B) were positively correlated with the invasive potential of the cell lines, whereas a negative correlation was observed for the TNFRSF14 gene expression. We also found a small set of receptor genes that exhibited a significantly decreased expression in association with a BRAFV600E mutation. Based on our results, we assume that the analyzed cytokine and chemokine receptor collection may provide potential to distinguish the different subtypes of melanomas, helping us to understand the biological behavior of BRAFV600E-mutated melanoma cells.

Clinical Significance of BTLA and HVEM Expression on Circulating CD4+ T and CD8+ T Cells in Chronic Hepatitis B Virus Infection.

In this study, B and T lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) expression on the surface of circulating CD4+ T and CD8+ T cells of patients with chronic hepatitis B (CHB) was investigated to explore their relationship with hepatitis B virus (HBV) clinical parameters. Both BTLA and HVEM were significantly upregulated on CD4+ T and CD8+ T cells of CHB patients compared with healthy controls (p < 0.01). Intriguingly, in CHB patients, the percentage of BTLA expression was positively correlated with that of HVEM (CD4+ T cells: r = 0.5461, p < 0.001 and CD8+ T cells: r = 0.4206, p < 0.01). Moreover, the percentage of BTLA expression was positively correlated with the levels of aspartate aminotransferase (AST) (CD4+ T cells: r = 0.3136, p < 0.05 and CD8+ T cells: r = 0.3159, p < 0.05) and alanine aminotransaminase (ALT) (CD4+ T cells: r = 0.3177, p < 0.05 and CD8+ T cells: r = 0.3311, p < 0.05). At the same time, the percentage of HVEM expression was also positively correlated with AST levels (CD4+ T cells: r = 0.3721, p < 0.05 and CD8+ T cells: r = 0.3325, p < 0.05) and ALT (CD4+ T cells: r = 0.3689, p < 0.05 and CD8+ T cells: r = 0.3476, p < 0.05). However, the percentage of BTLA and HVEM expression did not show significant relevance to HBV viral load. Further study demonstrated that BTLA inhibitory signaling could significantly inhibit T cell proliferation, activation, and cytokine production under optimal T cell receptor signaling (p < 0.05). Thereby, our findings indicate that the increased BTLA and HVEM expression on the surface of CD4+ and CD8+ T cells might represent a certain clinical significance and be involved in CHB progression during T cell exhaustion.

Investigation of Fas (APO-1)-Related Apoptosis in Piglets Intradermally or Intramuscularly Vaccinated with a Commercial PRRSV MLV.

Porcine reproductive and respiratory syndrome virus (PRRSV) induces apoptosis through the activation of death receptors, including cell-surface Fas receptor. The aim of this study was to investigate the impact of intradermal (ID) and intramuscular (IM) vaccination with a commercial PRRSV-modified live vaccine in piglets on Fas-related apoptosis. The study included 104 suckling piglets from a commercial farrow-to-finish pig farm, suffering from positive unstable PRRSV status. Animals were assigned in four groups: group A-Porcilis PRRS ID-vaccinated pigs, group B-Porcilis PRRS IM-vaccinated pigs, group C-Diluvac ID adjuvant-administered pigs, and group D-Diluvac IM adjuvant-administered pigs. Vaccines were administered at 2 weeks of age. Blood samples were collected from the same pigs at 4, 7, and 10 weeks of age. Sera were examined by quantitative real-time reverse transcription-PCR (qRT-PCR) for PRRSV and by ELISA for soluble Fas (sFas). At 4 weeks of age, all groups were negative qRT-PCR for PRRSV; at 7 weeks only group A was negative; and at 10 weeks all groups were positive. sFas was significantly increased in groups C (4 vs. 7, 4 vs. 10, and 7 vs. 10 weeks) and D (7 vs. 10 weeks). Significant differences among groups were noticed only at 10 weeks (A vs. C, A vs. D, B vs. C, B vs. D). A significant positive and moderate correlation between PRRSV viral load and Fas level was observed. In unvaccinated piglets, increased serum sFas levels reveal apoptotic suppression compared with vaccinated piglets. In the latter, vaccine-derived antibodies limit the infection and may attribute to the reduced Fas expression, suggesting a weak induction of lymphocyte-mediated cytotoxicity.

Effects of N-Acetylcysteine on FAS Gene Expression Level in Testicular Tissue of Acrylamide-Treated Adult Rats

Background &amp; Objectives: Acrylamide (ACR) is a chemical with toxic effects on various body tissues. The present study was conducted to investigate the antioxidant effect of N-acetylcysteine (NAC) on the level of testicular apoptosis in acrylamide-treated adult rats. Material &amp; Methods: Thirty-six adult male Wistar rats were randomly divided into 6 equal groups. The intact control group was without treatment, the positive control group (PC) received 50 mg/kg ACR by oral gavage, the negative control group (NC) received 40 mg/kg NAC intraperitoneally, the animals in experimental groups of 1 (EXP1), 2 (EXP2) and 3 (EXP3) received 10, 20 and 40 mg/kg NAC intraperitoneally, respectively, and then all groups received 50 mg/kg acrylamide by oral gavage. The treatment period in all groups was 28 days. At the end of the study, FAS mRNA expression level was measured by real-time PCR and testicular tissue was evaluated histopathologically. Results: The PC group showed a significant increase in FAS gene expression level (p&lt;0.05) and spermatogenic degradation compared to the intact control and NC groups. The EXP1 and EXP2 groups showed decrease in FAS gene expression level (p˃0.05) and spermatogenesis improvement in a dose-dependent manner while the EXP3 group exhibited a significant decrease in FAS gene expression level (p˂0.05) and complete spermatogenesis recovery compared to the PC group. Conclusion: The findings indicate that ACR increases apoptosis and destroys spermatogenesis by increasing FAS gene expression levels. In contrast, at the maximum dose (40 mg/kg), NAC could inhibit ACR-induced apoptosis by reducing FAS gene expression and improves spermatogenesis in rats.

The HVEM-BTLA Immune Checkpoint Restrains Murine Chronic Cholestatic Liver Injury by Regulating the Gut Microbiota.

The herpes virus entry mediator (HVEM) is an immune checkpoint molecule regulating immune response, but its role in tissue repair remains unclear. Here, we reported that HVEM deficiency aggravated hepatobiliary damage and compromised liver repair after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury. A similar phenotype was observed in B and T lymphocyte attenuator (BTLA)-deficient mice. These were correlated with impairment of neutrophil accumulation in the liver after injury. The hepatic neutrophil accumulation was regulated by microbial-derived secondary bile acids. HVEM-deficient mice had reduced ability to deconjugate bile acids during DDC-feeding, suggesting a gut microbiota defect. Consistently, both HVEM and BTLA deficiency had dysregulated intestinal IgA responses targeting the gut microbes. These results suggest that the HVEM-BTLA signaling may restrain liver injury by regulating the gut microbiota.

Zinc Finger Protein LipR Represses Docosahexaenoic Acid and Lipid Biosynthesis in Schizochytrium sp.

The heterotrophic marine microalgae Schizochytrium sp. is an important industrial producer of docosahexaenoic acid (DHA). Increased production of DHA and lipids in Schizochytrium sp. has been achieved by standard fermentation optimization and metabolic engineering methods; however, regulatory mechanisms for DHA and lipid biosynthesis remain unknown. In this study, the C2H2 zinc finger protein LipR was identified in Schizochytrium sp. ATCC 20888 by transcriptional analysis. Deletion of the lipR gene significantly (P < 0.001) increased production of total lipids and DHA by 33% and 48%, respectively. LipR repressed DHA and lipid production by directly inhibiting transcription of polyunsaturated fatty acid (PUFA) and fatty acid synthase (FAS) genes (pfa1, pfa2, pfa3, and fas). Specific binding of LipR to 9-bp recognition sequence 5'-(C/A)(A/G)CCATCTT-3' in upstream regions of target genes was demonstrated by electrophoretic mobility shift assays (EMSAs) and DNase I footprinting assays. Expression of several key genes (acc, acl, ampD, fabD, mae, zwf, and dga1) related to levels of precursors and NADPH, and to triacylglycerol storage rate, were also directly repressed by LipR. Our findings, taken together, indicate that the evolutionarily unique regulator LipR is an essential repressor of DHA and saturated fatty acid biosynthesis in Schizochytrium sp. IMPORTANCE Regulatory mechanisms for DHA and saturated fatty acid biosynthesis in the heterotrophic marine microalgae Schizochytrium sp. are unclear. We demonstrate here that deletion of the gene (lipR) encoding the C2H2 zinc finger protein LipR promotes DHA and saturated fatty acid production in this genus. LipR acts as a key repressor of such production by binding to 9-bp consensus sequence 5'-(C/A)(A/G)CCATCTT-3' in the upstream regions of polyunsaturated fatty acid and fatty acid synthase genes (pfa1, pfa2, pfa3, and fas), and genes related to levels of precursors and NADPH (acc, acl, ampD, fabD, mae, and zwf), and to triacylglycerol storage rate (dga1). This is the first demonstration that a regulator inhibits synthesis of DHA and lipids in Schizochytrium sp. by directly controlling transcription of PUFA synthase and fas genes. Manipulation of the lipR gene provides a potential strategy for enhancing accumulation of polyunsaturated fatty acids and lipids in thraustochytrids.

Doxorubicin sensitizes breast cancer cells to natural killercells in connection with increased Fas receptors.

Breast cancer (BC) is the most common cancer in women. Although standard treatments are successful in patients with BC diagnosed at an early stage, an alternative treatment is required for patients with advanced-stage disease who do not respond to these treatments. The concept of using chemotherapy to sensitize cancer cells to become susceptible to immunotherapy was recently introduced and may be used as an alternative treatment for BC. The chemotherapeutic drug doxorubicin has been reported to sensitize cancer cells; however, the efficacy to sensitize the solid spheroids, in addition to its underlying mechanism regarding how doxorubicin sensitizes BC, has not previously been explored. In the present study, the effectiveness of a combined treatment of doxorubicin and natural killer-92 (NK-92) cells against BC in either 2D or 3D spheroid models, and its association with Fas receptor (FasR) expression, was demonstrated. The BC (MCF7) cell line expressing a higher level of FasR was more sensitive to NK-92 cell killing than the MDA-MB-231 cell line, which expressed a lower level of FasR. A sublethal dose of doxorubicin caused a significant improvement in NK cytotoxicity. Concordantly, a significant reduction in cell viability was observed in the doxorubicin-treated MCF7 spheroids. Notably, flow cytometric analysis revealed significantly increased FasR expression in the MCF7 cells, suggesting the underlying sensitization mechanism of doxorubicin in BC was related to the FasR upregulation. The present findings supported the use of combined doxorubicin and NK immunotherapy in BC treatment.

Cell Death in AMD: The Rationale for Targeting Fas.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the developed world. While great advances have been made in the treatment of the neovascular (“wet”) form of the disease, there is still a significant need for therapies that prevent the vision loss associated with the advanced forms of dry, atrophic AMD. In this atrophic form, retinal pigment epithelial (RPE) and photoreceptor cell death is the ultimate cause of vision loss. In this review, we summarize the cell death pathways and their relation to RPE and retinal cell death in AMD. We review the data that support targeting programmed cell death through inhibition of the Fas receptor as a novel approach to preserve these structures and that this effect results from inhibiting both canonical death pathway activation and reducing the associated inflammatory response. These data lay the groundwork for current clinical strategies targeting the Fas pathway in this devastating disease.

Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo.

Simple SummaryA key feature of human colorectal tumor is loss of FAS expression. FAS is the death receptor for FASL of activated T cells. Loss of FAS expression therefore may promote tumor cell immune escape. We aimed at determining whether restoring FAS expression is sufficient to suppress colorectal tumor growth. Mouse and human FAS cDNA was synthesized and encapsulated into cationic lipid nanoparticle DOTAP-Cholesterol to formulate DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Restoring FAS expression in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro and suppressed colon-tumor growth and progression in tumor-bearing mice in vivo. Restoring FAS expression induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells in vitro. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. Tumor-selective delivery of FAS DNA nanoparticle is potentially an effective therapy for human colorectal cancer.A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas. Analysis of single-cell RNA-Seq datasets revealed that FAS is highly expressed in epithelial cells and immune cells but down-regulated in colon-tumor cells in human colorectal-cancer patients. Codon usage-optimized mouse and human FAS cDNA was designed, synthesized, and encapsulated into cationic lipid to formulate nanoparticle DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Overexpression of codon usage-optimized FAS in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro, suppressed colon tumor growth, and increased the survival of tumor-bearing mice in vivo. Overexpression of codon-optimized FAS-induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. DOTAP-Chol-mFAS therapy exhibited no significant liver toxicity. Our data determined that tumor-selective delivery of FAS DNA nanoparticles is sufficient for suppression of human colon tumor growth in vivo.

Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

Can we consider soluble herpes virus entry mediator (sHVEM) as a tumor marker?

Immune checkpoint molecules have critical roles in directing immune responses into co-inhibitory and co-stimulatory signals. Herpes virus entry mediator (HVEM) is a receptor of tumor necrosis factor receptor superfamily with unique features due to its interaction with both inhibitory and stimulatory ligands. The aim of this study was to measure the serum level of the soluble form of HVEM in patients with gastric, colorectal and breast cancers and evaluating its diagnostic and prognostic value. The concentration of the soluble HVEM (sHVEM) was determined in the serum of 36 patients with breast cancer, 50 patients with colorectal cancer and 59 patients with gastric cancer using ELISA method. Moreover, 50 healthy donors (HD) as well as 31 patients with non-ulcer dyspepsia (NUD) were used as control groups. The patients' samples were obtained from the Biobank of Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran. The level of sHVEM was significantly higher in patients with gastric (P=0.001) and breast cancer (P=0.01) than in control groups (HD). The higher level of sHVEM was observed in colorectal cancer patients in comparison with HD group, although it was not significant. Moreover, the elevated level of sHVEM was shown to be higher significantly in stage III and IV compared to stage I and II in breast cancer (P=0.03). Similar finding was detected in gastric and colorectal cancers, but not to be statistically significant. The results of the present study suggest that the serum level of sHVEM may be considered as a promising indicator for diagnosis as well as evaluating the progression of cancers such as gastric, breast and colorectal cancers.

Fas cell surface death receptor/Fas ligand genetic variants in gastric cancer patients: A case-control study.

Various studies have suggested a correlation between Fas cell surface death receptor/Fas ligand (FAS/FASL) variants and multiple types of cancers. The present study aimed to investigate the association between FAS-670A/G and FASL-844C/T and the synergistic effects of both variants on the risk of gastric cancer (GC) in the Kurdish population of west of Iran. This study was conducted by polymerase chain reaction-restriction fragment length polymorphism technique using MvaI and BsrDI restriction enzymes in 98 GC patients and 103 healthy control individuals. According to the obtained results, a significant association (P=0.008) of FASL polymorphism among GC patients and the control group was detected. Furthermore, no significant differences were found in the FAS polymorphism frequencies between GC patients and the control group. Codominant and dominant models in FASL polymorphism showed significant protective effects against GC [odds ratio (OR)=0.307, 95% confidence interval (CI) (0.134-0.705), P=0.005; OR=0.205, 95% CI (0.058-0.718), P=0.013 and OR=0.295, 95% CI (0.129-0.673), P=0.004 for models of codominant CC vs. CT, codominant CC vs. TT and dominant, respectively]. Furthermore, the presence of both FAS-670G and FASL-844T alleles represented a significant protective effect against GC occurrence [OR=0.420, 95% CI (0.181-0.975), P=0.043]. So far, we believe this is the first study, the results of which suggest that FASL gene variation and its synergistic effects with FAS gene could be associated with the risk of GC in the Kurdish population in the west of Iran.

Soluble Fas ligand, soluble Fas receptor, and decoy receptor 3 as disease biomarkers for clinical applications: A review

&lt;abstract&gt; &lt;p&gt;Soluble Fas ligand (sFasL, sCD95L) and its specific soluble binders, soluble Fas receptor (sFas, sCD95) and decoy receptor 3 (DcR3), have been investigated as possible clinical biomarkers in many serious diseases. The present review aimed to provide an overview of the current state of this medically promising research by extensively examining the relevant literature. The summarized results of the survey are presented after classification into six categories according to the type of targeted disease. To date, the studies have been mainly devoted to the diagnosis of disease severity states and prognosis of treatments about various types of cancers and autoimmune diseases represented by autoimmune lymphoproliferative syndrome and systemic lupus erythematosus, because these important life-threatening or intractable diseases were suggested to be most relevant to the impairment of apoptotic cell death-inducing systems, including the Fas receptor-mediated signaling system, and the mechanisms responsible for their onset. However, various more general inflammation-related diseases, including, but not limited to, other autoimmune and allergic diseases (e.g., rheumatoid arthritis and atopic asthma), infectious diseases (e.g., sepsis and chronic hepatitis), cardiovascular system-specific disorders (e.g., acute coronary syndromes and heart failure) as well as other diseases specific to the renal, hepatic, and respiratory systems, etc., have also been targeted as important fields of research. The data obtained so far demonstrated that sFas, sFasL, and DcR3 possess significant potential in the assessment of various disease states, which can contribute to the development of therapeutic interventions. Although further studies in various relevant fields are essential, it is expected that clinical translation of sFas, sFasL, and DcR3 into practical biomarkers will contribute to effective treatments of a wide variety of diseases.&lt;/p&gt; &lt;/abstract&gt;