Evasion of the immune system is the tumor\'s key strategy for its maintenance and progression. Thus, targeting the tumor microenvironment (TME) is considered one of the most promising approaches for fighting cancer, where immune cells within the TME play a vital role in immune surveillance and cancer elimination.FasL is one of the most important death ligands expressed by tumor-infiltrating lymphocytes (TILs) and plays a vital role in eliminating Fas-expressing cancer cells via Fas/FasL pathway-induced apoptosis. However, tumor cells can express elevated levels of FasL inducing apoptosis to TILs. Fas/FasL expression is linked to the maintenance of cancer stem cells (CSCs) within the TME, contributing to tumor aggressiveness, metastasis, recurrence, and chemoresistance.This study is considered the first study designed to block the overexpressed FasL on the tumor cells within TME mimicking tissue culture system using rFas molecules and supplementing the Fas enriched tissue culture system with blocked Fas - peripheral blood mononuclear cells PBMCs (using anti-Fas mAb) to protect them from tumor counterattack and augment their ability to induce tumor cell apoptosis and stemness inhibition.A significantly increased level of apoptosis and decreased expression of CD 44 (CSCs marker) was observed within the east tumor tissue culture system enriched with Fas molecules and anti-Fas treated PBMCs and the one enriched with Fas molecules only compared to the breast tumor tissues cultured alone (p < 0.001). Accordingly, we can consider the current study as a promising proposed immunotherapeutic strategy for breast cancer.

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.

Severe burn injury activates shock, inflammation, and blood cell system, but inappropriate reactions may lead to adverse outcomes. Soluble Fas ligand (sFasL) participates in apoptosis and inflammatory response. The circulating sFasL levels we investigated in association with the burn severity, shock, inflammation, blood cells, and mortality in patients with severe burns.
A total of 56 patients with severe burns were recruited. The levels of sFasL and the biomarkers reflecting shock, organ damage, inflammation, and blood cells at 48 h postburn were analyzed. We compared the practical situation of patients that stratified by median sFasL levels and investigated the predictive value of sFasL for mortality.
High circulating sFasL levels were associated with the higher degrees of burn index, shock index, lactate, N-terminal probrain natriuretic peptide, total bilirubin, blood urea nitrogen, creatinine, tumor necrosis factor-α, interleukin-1β, interleukin-8, intercellular adhesion molecule 1, and complement 3, and the lower degrees of oxygenation index, lymphocytes, and platelets. Multiple linear regression analysis showed that the higher tumor necrosis factor-α (P < 0.001) and the lower oxygenation index (P = 0.031) and lymphocytes (P = 0.043) were associated with the higher sFasL. High sFasL (a unit is 50 ng/L) (odds ratio [OR] 5.50 [95% CI 1.04-29.20], P = 0.045) was an independent predictor of increased mortality by multivariate logistic regression analysis.
High circulating sFasL at 48 h postburn in patients with severe burns reflect shock, proinflammatory response, organ damage, and lymphocyte reductions and predict 30-day mortality.

The purpose of this study is to use Dicliptera chinensis (L.) Juss (Acanthaceae) polysaccharide (DCP) to act on the NF-κB inflammatory pathway and Fas/FasL ligand system, in order to find a new method to improve immune liver injury. Lipopolysaccharide (LPS) was used to establish an injury model in vivo (Kunming mice) and in vitro (LO2 cells). In this experiment, hematoxylin-eosin (H&E) staining and related biochemical indicators were used to observe the pathological changes of liver tissues, oxidative stress and inflammatory reactions. Immunohistochemistry, ELISA, RT-PCR and Western blot were used to detect protein or mRNA expressions associated with inflammation response and apoptosis. The experimental results show that the model group has obvious liver cell damage and inflammatory infiltration. After DCP intervention, it could significantly reduce the levels of ALT, AST, ALP, TBIL and MDA in serum, and increase the content of SOD and GSH-Px. In addition, DCP can reduce the expression level of NF-κB in the liver and reduce the release of downstream inflammatory factors TNF-α, IL-6 and IL-1β, thereby reducing the inflammation. At the same time, DCP can significantly inhibit the expression of Fas/FasL ligand system and apoptosis related-proteins and mRNA, which in turn can reduce cell apoptosis. In conclusion, DCP can alleviate liver injury by inhibiting liver inflammation and apoptosis, which provides a new strategy for clinical treatment of immune liver injury.

We have previously reported that a subset of cancers is defined by global transcriptional deregulations with widespread deficiencies in mRNA transcription elongation (TE)-we call such cancers as TEdeff. Notably, TEdeff cancers are characterized by spurious transcription and faulty mRNA processing in a large set of genes, such as interferon/JAK/STAT and TNF/NF-κB pathways, leading to their suppression. The TEdeff subtype of tumors in renal cell carcinoma and metastatic melanoma patients significantly correlate with poor response and outcome in immunotherapy. Given the importance of investigating TEdeff cancers-as it portends a significant roadblock against immunotherapy-the goal of this protocol is to establish an in vitro TEdeff mouse model to study these widespread, non-genetic transcriptional abnormalities in cancers and gain new insights, novel uses for existing drugs, or find new strategies against such cancers. We detail the use of chronic flavopiridol mediated CDK9 inhibition to abrogate phosphorylation of serine 2 residue on the C-terminal repeat domain (CTD) of RNA polymerase II (RNA Pol II), suppressing the release of RNA Pol II into productive transcription elongation. Given that TEdeff cancers are not classified under any specific somatic mutation, a pharmacological model is advantageous, and best mimics the widespread transcriptional and epigenetic defects observed in them. The use of an optimized sublethal dose of flavopiridol is the only efficacious strategy in creating a generalizable model of non-genetic widespread disruption in transcription elongation and mRNA processing defects, closely mimicking the clinically observed TEdeff characteristics. Therefore, this model of TEdeff can be leveraged to dissect, cell-autonomous factors enabling them in resisting immune-mediated cell attack.

We have previously identified the upregulation of the innate immune response, neutrophil activation, and apoptosis during anaphylaxis using a microarray approach. This study aimed to validate the differential gene expression and investigate protein concentrations of \"hub genes\" and upstream regulators during anaphylaxis.
Samples were collected from patients with anaphylaxis on their arrival at the emergency department, and after 1 and 3 h. mRNA levels of 11 genes (interleukin-6 [IL-6], IL-10, oncostatin M [OSM], S100A8, S100A9, matrix metalloproteinase 9 [MMP9], FASL, toll-like receptor 4 [TLR4], MYD88, triggering receptor expressed on myeloid cells 1 [TREM1], and cluster of differentiation 64 [CD64]) were measured in peripheral blood leucocytes using qPCR. Serum protein concentrations were measured by ELISA or cytometric bead array for 6 of these candidates.
Of 69 anaphylaxis patients enrolled, 36 (52%) had severe reactions, and 38 (55%) were female. Increases in both mRNA and protein of IL-10, S100A9, MMP9, and TREM1 were observed. OSM, S100A8, TLR4, and CD64 were upregulated and IL-6 protein concentrations were increased during anaphylaxis. Both FASL and soluble Fas ligand decreased during anaphylaxis.
These results provide evidence for the involvement of innate immune pathways and myeloid cells during human anaphylaxis, validating previous microarray findings. Elevated S100A8, S100A9, TLR4, and TREM1 expression, and increased S100A9 and soluble TREM1 protein concentrations strongly suggest that neutrophils are activated during acute anaphylaxis.

Triggering the extrinsic apoptotic pathway is an effective way to kill cutaneous T-cell lymphoma (CTCL) cells in vitro and ex vivo.
To compare small molecules that induce extrinsic apoptosis in CTCL to identify and analyze compounds that induce high levels of tumor cell death and block tumor cell growth.
From November 5, 2014, to January 30, 2018, this study performed high-throughput small molecule screening of 1710 compounds followed by detailed analysis of the ability of gentian violet (GV) to promote apoptosis and inhibit proliferation of CTCL cells.
In vitro and ex vivo analyses using enzyme-linked immunosorbent assays, flow cytometry, and immunoblotting.
Apoptosis, cleaved caspases, extrinsic apoptotic death receptors and ligands, cell proliferation, nuclear factor-κB expression, and other factors.
This study used high-throughput screening to detect cleaved caspase 8 induced in CTCL cells by 1710 unique compounds. The nonprescription, topical antimicrobial remedy GV induced more total apoptosis than did nitrogen mustard (mechlorethamine). Furthermore, GV induced 4 to 6 times greater apoptosis in CTCL lines than in normal keratinocytes, suggesting a favorable topical toxicity profile. In addition to increasing caspase 8, GV also upregulated death receptors 4 and 5, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, and Fas ligand but not the Fas receptor, TNF receptor, or TNF-α ligand. These results are consistent with induction of extrinsic apoptosis via the Fas and TNF-related apoptosis-inducing ligand pathways. Increased phosphorylation of phospholipase C-γ1, Ca2+ influx, and reactive oxygen species were also detected, indicating that the mechanism of Fas ligand upregulation involves key elements of the activation-induced cell death pathway. In ex vivo studies, 1-μmol/L GV induced up to 90% CTCL apoptosis in Sézary blood cells. In addition, GV reduced expression of antiapoptotic myeloid cell leukemia 1 and proproliferative nuclear factor-κB components and increased inhibitory κB levels. This finding was associated with cell cycle arrest and reduced CTCL tumor cell proliferation. Furthermore, the CTCL killing associated with GV was augmented when used in combination with methotrexate.
This study found that GV attacked tumor viability and growth in CTCL. Although purple at neutral pH, GV can be rendered colorless by altering its pH. These preclinical findings may help to broaden knowledge of the antineoplastic features of GV and provide a rationale for clinical studies of its use as a novel, inexpensive, topical therapy for CTCL that is available worldwide.

OBJECTIVE: We evaluated the association between the Fas-670A/G and the Fas ligand FasL IVS2nt 124 A/G polymorphisms and the risk of pre-eclampsia and its complications.
METHODS: A case-controlled study.
METHODS: University Hospitals in most areas of Tunisia.
METHODS: We recruited 300 pregnant women who developed pre-eclampsia and 300 age-matched healthy pregnant women from the same hospital.
METHODS: Genotyping of Fas-670A/G and the FasL IVS2nt 124A/G gene polymorphisms were conducted using polymerase chain reaction-restriction fragment length polymorphism among our cohort.
METHODS: Fisher\'s exact test was used to compare the statistical differences between groups for categorical variables and Student t tests were used for continuous variables.
RESULTS: The frequency of the Fas-670G gene variant was significantly increased in women with pre-eclampsia (42%) compared with control women (30%; P < 0.001). Also, a statistically significant difference was obtained in the distribution of the FasL IVS2nt 124G gene variant when comparing women with pre-eclampsia (43%) with controls (30%; P < 0.001). Interestingly, we found that the carriage of Fas-670G was associated with increased liver enzymes, suggesting an increased prevalence of the haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, a pre-eclampsia complication.
CONCLUSIONS: The Fas-670G and FasL IVS2nt 124G polymorphisms are associated with a higher risk of pre-eclampsia and its complications.
CONCLUSIONS: Polymorphisms in the Fas and FasL genes are associated with increased risk of pre-eclampsia and HELLP syndrome.

Neuroinflammation has been proposed as a major mechanism in schizophrenic disorder. Specifically, an increase in the inflammatory response in the central nervous system is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines and thus activating apoptotic signaling. An increase in apoptosis may underlie a potential role of immune neuropathology in the etiopathogenesis of schizophrenia and specifically, the onset of the disorder. We analyzed in whole blood, levels of S100B, the receptor for advanced glycation end products (RAGE) and the apoptotic marker Fas Ligand in a sample of 13 first episode of schizophrenia twice at baseline before the initiation of any antipsychotic medication (A) and 6 weeks later following an antipsychotic monotherapy with olanzapine (B) and in a sample of 10 healthy controls. The S100B, RAGE and Fas Ligand showed statistically significant differences before and after treatment; the S100B measurements yielded a p-value of 0.004 while the soluble RAGE and Fas Ligand measurements yielded a p=0.03, and p=0.04 respectively. The differences between cases and controls were not statistically significant for all measurements, with the only exception being the S100B values where both samples A and B showed significantly higher values than the controls with p=8.5x10-8 and p=2.9x10-10 respectively.
The levels of S100B, RAGE, and Fas Ligand of drug-naive first episode psychosis patients with schizophrenia were significantly higher than that of the same medicated first episode psychosis patients, indicating that an increase of apoptotic signaling is present at the onset of schizophrenia and is also associated with treatment progress.

Aberrant apoptosis at the trophoblast-maternal interface and abnormal expression of Fas and Fas ligand (FasL) have been reported in complicated pregnancies with recurrent pregnancy losses (RPL) and preeclampsia. We assessed the prevalence of Fas and FasL genetic polymorphisms in Korean women with RPL and in fertile controls. In total, 306 women with RPL and 298 fertile controls were enrolled. Genotype distributions of Fas and FasL in RPL patients versus fertile controls were examined under the Hardy-Weinberg equilibrium. Fas -670 A/G genotype (AA versus AG versus GG, p = 0.340) and allele frequencies (A versus G, p = 0.412) were not different between the RPL and control groups. There was no difference in each Fas -1377 G/A and FasL -844 C/T genotype, and their allele frequencies. In addition, the unions of two zygosities of each genotype and their combined genotypes did not differ between two groups. No difference in the prevalence of Fas and FasL single-nucleotide polymorphisms (SNPs) was observed between women with RPL and fertile controls among Korean women. To determine the possibility of genetic polymorphisms in Fas and its ligand as risk factors for RPL, further studies in various races and a large study population are needed.