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Aim Methods Results Conclusion This prospective pilot study evaluated urinary interferon‐γ‐induced protein‐10 (IP‐10)/creatinine and tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL)/creatinine ratios as non‐invasive biomarkers for distinguishing bacterial from viral infections and assessing disease severity in febrile children.The study involved 85 febrile children and 29 healthy controls, measuring urinary IP‐10/creatinine and TRAIL/creatinine ratios to determine their diagnostic utility.Both ratios were significantly elevated in infected patients compared to controls. The IP‐10/creatinine ratio effectively assessed disease severity in the overall cohort and subgroups (AUC: 0.7324, 0.7192, 0.7277; p < 0.05). Serum C‐reactive protein showed limited discriminatory ability in viral infections (AUC = 0.5385, p = 0.7257). Differentiation between bacterial and viral infections using IP‐10/creatinine approached significance (p = 0.082). No significant differences in biomarker levels were observed across pathogens.The urinary IP‐10/creatinine ratio shows promise as a biomarker for assessing paediatric infection severity, particularly when traditional markers are less effective. Larger studies are needed to validate these results and improve its discriminatory accuracy in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Cisplatin (DDP) is an efficacious and widely applied chemotherapeutic drug for cervical cancer patients who are diagnosed as metastatic and inoperable, or desiring fertility preservation. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) selectively triggers cancer cells apoptosis by binding to cognate death receptors (DR4 and DR5). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been regarded as ideal drug carriers on account of their nanoscale, low toxicity, low immunogenicity, high stability, biodegradability, and abundant sources. Methods: Human chorion-derived mesenchymal stem cells (hCD-MSCs) were isolated by adherent culture method. TRAIL-engineered hCD-MSCs (hCD-MSCsTRAIL) were constructed by lentivirus transfection, and its secreted Exo (hCD-MSCs-ExoTRAIL) were acquired by differential centrifugation and confirmed to overexpress TRAIL by western blotting. Next, nanoscale drug delivery systems (DDP & hCD-MSCs-ExoTRAIL) were fabricated by loading DDP into hCD-MSCs-ExoTRAIL via electroporation. The CCK-8 assay and flow cytometry were conducted to explore the proliferation and apoptosis of cervical cancer cells (SiHa and HeLa), respectively. Cervical cancer-bearing nude mice were constructed to examine the antitumor activity and biosafety of DDP & hCD-MSCs-ExoTRAIL in vivo. Results: Compared with hCD-MSCs-Exo, hCD-MSCs-ExoTRAIL weakened proliferation and enhanced apoptosis of cervical cancer cells. DDP & hCD-MSCs-ExoTRAIL were proved to retard cervical cancer cell proliferation and propel cell apoptosis more effectively than DDP or hCD-MSCs-ExoTRAIL alone in vitro. In cervical cancer-bearing mice, DDP & hCD-MSCs-ExoTRAIL evidently hampered tumor growth, and its role in inducing apoptosis was mechanistically associated with JNK/p-c-Jun activation and survivin suppression. Moreover, DDP & hCD-MSCs-ExoTRAIL showed favorable biosafety in vivo. Conclusions: DDP & hCD-MSCs-ExoTRAIL nanoparticles exhibited great promise for cervical cancer treatment as an Exo-based chemo-gene combinational therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Glutamine plays an important role in tumor metabolism. It is known that the core region of solid tumors is deprived of glutamine, which affects tumor growth and spread. Here we investigated the effect of glutamine deprivation on cellular metabolism and sensitivity of human glioblastoma cells U87MG and T98G to drugs of various origin: alkylating cytostatic agent temozolomide; cytokine TRAIL DR5-B – agonist of the DR5 receptor; and GMX1778 – a targeted inhibitor of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), limiting NAD biosynthesis. Bioinformatics analysis of the cell transcriptomes showed that U87MG cells have a more differentiated phenotype than T98G, and also differ in the expression profile of the genes associated with glutamine metabolism. Upon glutamine deprivation, growth rate of the U87MG and T98G cells decreased. Analysis of cellular metabolism by FLIM microscopy of NADH as well as assessment of lactate content in the medium showed that glutamine deprivation shifted metabolic status of the U87MG cells towards glycolysis. This was accompanied by the increase in expression of the stemness marker CD133, which collectively could indicate de-differentiation of these cells. At the same time, we observed increase in both expression of the DR5 receptor and sensitivity of the U87MG cells to DR5-B. On the contrary, glutamine deprivation of T98G cells induced metabolic shift towards oxidative phosphorylation, decrease in the DR5 expression and resistance to DR5-B. The effects of NAMPT inhibition also differed between the two cell lines and were opposite to the effects of DR5-B: upon glutamine deprivation, U87MG cells acquired resistance, while T98G cells were sensitized to GMX1778. Thus, phenotypic and metabolic differences between the two human glioblastoma cell lines caused divergent metabolic changes and contrasting responses to different targeted drugs during glutamine deprivation. These data should be considered when developing treatment strategies for glioblastoma via drug-mediated deprivation of amino acids, as well as when exploring novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D. [ABSTRACT FROM AUTHOR]

Obesity is an important healthcare issue caused by abnormally increased adipose tissue because of energy-intake overcoming energy expenditure. Disturbances in the physiological function of adipose tissue mediate the development of diabetes. It is a metabolic disease that results from decreased insulin-levels and/or changes in the insulin action mechanism. Tumor Necrosis Factor-Associated Apoptosis-Inducing Ligand(TRAIL), which is a member of the Tumor Necrosis Factor(TNF)-family with an important role in adipose tissue biology, is included in many studies with its ability to induce apoptosis in cancer cells, but the number of human-studies conducted on the gene related to its protective-role against diabetes and obesity at this level is insufficient. Our study was carried out as a case and control and included three groups (80 diabetic obese, 80 non-diabetic obese, and 80 healthy individuals as the control group). The Real-Time-PZR(RT-qPZR), and DNA Sanger-Sequencing Methods were used for gene expression and gene squences. As a result of the analyses, TRAIL gene expression level was found to be higher in the controls than in the diabetic-obese and non-diabetic-obese group. This change in TRAIL gene expression suggests that TRAIL maybe a protective factor against diabetes. The presence of rs781673405, rs143353036, rs1244378045, rs767450259, rs759369504, rs750556128, and rs369143448 mutations, which was determined with the Sequencing-Method, was shown for the first time in the present study. In addition, it is the first study in which human TRAIL gene-expression and sequencing were performed together. We believe that these data will make an important contribution to the literature. [ABSTRACT FROM AUTHOR]

Background: This study evaluates tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and interferon-g-induced protein-10 (IP-10) in pregnant women with COVID-19 and their newborns, exploring the effects of antiviral treatments and vaccine-induced neutralizing antibody (Nab) inhibition on these key viral infection biomarkers. Methods: We studied 61 pregnant women with past COVID-19 and either three (n=56) or four (n=5) doses of vaccination, and 46 without COVID-19 but vaccinated. We analyzed them and their newborns' blood for TRAIL, IP-10, and Nab levels using enzyme-linked immunosorbent assays (ELISA), correlating these with other clinical factors. Results: Our study found lower TRAIL but higher IP-10 levels in maternal blood than neonatal cord blood, irrespective of past COVID-19 diagnosis. Cases diagnosed with COVID-19 < 4 weeks previously had higher maternal blood TRAIL levels (16.49 vs. 40.81 pg/mL, p=0.0064) and IP-10 (154.68 vs. 225.81 pg/mL, p=0.0170) than those never diagnosed. Antiviral medication lowered TRAIL and IP-10 in maternal blood without affecting Nab inhibition (TRAIL: 19.24 vs. 54.53 pg/mL, p=0.028; IP-10: 158.36 vs. 255.47 pg/mL, p=0.0089). TRAIL and IP-10 levels were similar with three or four vaccine doses, but four doses increased Nab inhibition (p=0.0363). Previously COVID-19 exposed pregnant women had higher Nab inhibition (p < 0.0001). No obvious correlation was found among TRAIL, IP-10, and Nab inhibition level. Conclusions: Our study suggests that lower maternal TRAIL and higher IP-10 levels compared to neonatal cord blood coupled with a rise in both markers following COVID-19 diagnosis that could be reduced by antivirals indicates a correlation to infection severity. Higher vaccine doses enhance Nab inhibition, irrespective of antiviral medication use and independent of TRAIL or IP-10 levels, highlighting the significance and safety of adequate vaccination and antiviral use post-diagnosis in pregnant women. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD. Methods: Hippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1−42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aβ-treated HEBSCs. Results: Neurotoxicity induced by soluble Aβ1−42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention. Conclusion: Microglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Increasing public health awareness has stressed the significance of the mental and physical benefits of outdoor activities. Government involvement and support for urban redevelopment projects in Korea, such as Seoul Dulle-gil, connected previously disconnected green spaces. Despite the ecological and cultural importance of urban spaces, their impact on residents and tourists and their role in exploring the city's dynamic remains limited. This study aims to evaluate how green space activities engage in sustainable land management and offer insights into surrounding communities. A quantitative big data research method was employed, analyzing 3995 online blog post reviews using Python code, and sentiment analysis conducted with pandas and KoNLPy's Okt library. The results indicated that sentiment scores were generally higher in sections located south of the Han River. Among the eight trail courses, courses 6, 3, 4, and 5, located south of the Han River, exhibited higher sentiment scores compared to courses 7, 8, 2, and 1, located north of the Han River, which showed lower satisfaction levels. Among the 16 characteristics influencing visitor satisfaction, the study emphasized the importance of potential space maintenance to enhance trail user safety and community well-being, contributing to sustainable land management. [ABSTRACT FROM AUTHOR]

Abstract Background Cisplatin (DDP) is an efficacious and widely applied chemotherapeutic drug for cervical cancer patients who are diagnosed as metastatic and inoperable, or desiring fertility preservation. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) selectively triggers cancer cells apoptosis by binding to cognate death receptors (DR4 and DR5). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been regarded as ideal drug carriers on account of their nanoscale, low toxicity, low immunogenicity, high stability, biodegradability, and abundant sources. Methods Human chorion-derived mesenchymal stem cells (hCD-MSCs) were isolated by adherent culture method. TRAIL-engineered hCD-MSCs (hCD-MSCsTRAIL) were constructed by lentivirus transfection, and its secreted Exo (hCD-MSCs-ExoTRAIL) were acquired by differential centrifugation and confirmed to overexpress TRAIL by western blotting. Next, nanoscale drug delivery systems (DDP & hCD-MSCs-ExoTRAIL) were fabricated by loading DDP into hCD-MSCs-ExoTRAIL via electroporation. The CCK-8 assay and flow cytometry were conducted to explore the proliferation and apoptosis of cervical cancer cells (SiHa and HeLa), respectively. Cervical cancer-bearing nude mice were constructed to examine the antitumor activity and biosafety of DDP & hCD-MSCs-ExoTRAIL in vivo. Results Compared with hCD-MSCs-Exo, hCD-MSCs-ExoTRAIL weakened proliferation and enhanced apoptosis of cervical cancer cells. DDP & hCD-MSCs-ExoTRAIL were proved to retard cervical cancer cell proliferation and propel cell apoptosis more effectively than DDP or hCD-MSCs-ExoTRAIL alone in vitro. In cervical cancer-bearing mice, DDP & hCD-MSCs-ExoTRAIL evidently hampered tumor growth, and its role in inducing apoptosis was mechanistically associated with JNK/p-c-Jun activation and survivin suppression. Moreover, DDP & hCD-MSCs-ExoTRAIL showed favorable biosafety in vivo. Conclusions DDP & hCD-MSCs-ExoTRAIL nanoparticles exhibited great promise for cervical cancer treatment as an Exo-based chemo-gene combinational therapy in clinical practice. Graphical abstract

Abstract Background Alzheimer’s disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD. Methods Hippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1−42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aβ-treated HEBSCs. Results Neurotoxicity induced by soluble Aβ1−42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention. Conclusion Microglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity.

Natural killer cells (NK cells) exert cytotoxicity towards target cells in several ways, including the expression of apoptosis-mediating ligands (TRAIL, FasL). In addition, NK cells themselves may be susceptible to apoptosis due to the expression of TRAIL receptors. These receptors include TRAIL-R1 (DR4), TRAIL-R2 (DR5), capable of inducing apoptosis, and TRAIL-R3 (DcR1), TRAIL-R4 (DcR2), the so-called “decoy receptors”, which lack an intracellular domain initiating activation of caspases. Of particular interest is the interaction of uterine NK cells with cells of fetal origin, trophoblasts, which are potential targets for natural killer cells to carry out cytotoxicity. The aim of this work was to evaluate the expression of proapoptotic receptors and their ligands as well as CD107a expression by NK cells in a model of interaction with trophoblast cells. To evaluate NK cells, we used cells of the NK-92 line; cells of the JEG-3 line were used as target cells. The cytokines IL-1β, IL-15, IL-18, TNFα, IL-10, TGFβ and conditioned media (CM) of the first and third trimester chorionic villi explants were used as inducers. We established that cytokines changed the expression of apoptotic receptors by NK cells: in the presence of TNFα, the amount and intensity of Fas expression increased, while in the presence of TGFβ, the amount and intensity of expression of the DR5 receptor decreased. Soluble chorionic villi factors alter the expression of TRAIL and FasL by NK-92 cells, which can reflect the suppression of the TRAIL-dependent mechanism of apoptosis in the first trimester and stimulating the Fas-dependent mechanism in the third trimester. In the presence of trophoblast cells, the expression of TRAIL and DcR1 by NK cells was reduced compared to intact cells, indicating an inhibitory effect of trophoblast cells on NK cell cytotoxicity. In the presence of chorionic villi CM and trophoblast cells, a reduced number of NK-92 cells expressing DR4 and DR5 was found. Therefore, soluble factors secreted by chorionic villi cells regulate the resistance of NK cells to death by binding TRAIL, likely maintaining their activity at a certain level in case of contact with trophoblast cells.

Abstract Multiple Myeloma (MM) prognosis has recently improved thanks to the incorporation of new therapies to the clinic. Nonetheless, it is still a non-curable malignancy. Targeting cancer cells with agents inducing cell death has been an appealing alternative investigated over the years, as is the case of TRAIL, an agonist of DR4 and DR5 death receptors. This pathway, involved in apoptosis triggering, has demonstrated efficacy on MM cells. In this research, we have investigated the sensitivity of a panel of MM cells to this agent and generated TRAIL-resistant models by continuous culture of sensitive cells with this peptide. Using genomic and biochemical approaches, the mechanisms underlying resistance were investigated. In TRAIL-resistant cells, a strong reduction in cell-surface receptor levels was detected and impaired the apoptotic machinery to respond to the treatment, enabling cells to efficiently form the Death Inducing Signalling Complex. In addition, an upregulation of the inhibitory protein c-FLIP was detected. Even though the manipulation of these proteins was able to modify cellular responses to TRAIL, it was not complete, pointing to other mechanisms involved in TRAIL resistance.

Abstract Background Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. Methods First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. Results AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. Conclusion Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

Background Host-response biomarkers to differentiate bacterial from viral etiology in children with respiratory infections have shown high accuracies, but are understudied in Mycoplasma pneumoniae (Mp) infections. Methods We compared BV scores (0–34 indicating viral etiology, and 66–100 indicating bacterial etiology), tumor necrosis factor–related apoptosis-inducing ligand (TRAIL; pg/mL), interferon-γ inducible protein 10 (IP-10; pg/mL), and C-reactive protein (CRP; mg/L) serum levels between Mp -positive (Mp +) and Mp -negative (Mp −) community-acquired pneumonia (CAP) patients. We performed receiver operating characteristic (ROC) curve analyses for clinical features and biomarkers. Results Of 80 CAP patients (median age, 6.3 years; 57.5% male), 26 had Mp +CAP. In Mp +CAP patients, compared to Mp −CAP patients, BV scores were lower (14.0 [3.0–27.8] vs 54.0 [12.0–84.8]; P =.0008), TRAIL levels were higher (86.5 [67.4–123.0] vs 65.5 [42.5–103.9]; P =.025), CRP levels were lower (12.9 [4.0–22.3] vs 36.7 [13.0–132.8]; P =.0019), and IP-10 levels were comparable (366.0 [150.2–603.8] vs 331.0 [154.3–878.8]; P =.73) (all median [interquartile range]). ROC analyses yielded a comparable discriminatory accuracy for the combination of age, fever duration, and duration of respiratory symptoms, with either procalcitonin or BV score (area under the ROC curve, 0.87 vs 0.86; P =.94). Conclusions Children with Mp +CAP have atypically low, viral levels of the BV score, underscoring the complementary role of microbiological testing. [ABSTRACT FROM AUTHOR]

Multiple Myeloma (MM) prognosis has recently improved thanks to the incorporation of new therapies to the clinic. Nonetheless, it is still a non-curable malignancy. Targeting cancer cells with agents inducing cell death has been an appealing alternative investigated over the years, as is the case of TRAIL, an agonist of DR4 and DR5 death receptors. This pathway, involved in apoptosis triggering, has demonstrated efficacy on MM cells. In this research, we have investigated the sensitivity of a panel of MM cells to this agent and generated TRAIL-resistant models by continuous culture of sensitive cells with this peptide. Using genomic and biochemical approaches, the mechanisms underlying resistance were investigated. In TRAIL-resistant cells, a strong reduction in cell-surface receptor levels was detected and impaired the apoptotic machinery to respond to the treatment, enabling cells to efficiently form the Death Inducing Signalling Complex. In addition, an upregulation of the inhibitory protein c-FLIP was detected. Even though the manipulation of these proteins was able to modify cellular responses to TRAIL, it was not complete, pointing to other mechanisms involved in TRAIL resistance. [ABSTRACT FROM AUTHOR]

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate of their parental fibroblasts, and TRAIL produced by iNSCs was naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed that Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays demonstrated that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts by approximately 3000-fold compared to treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a novel, easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer. [Display omitted] • Induced neural stem cells can be engineered to secrete the therapeutic TRAIL. • Some TRAIL is secreted on the surface of exosomes released by iNSCs. • Exo-iNSC-TRAIL can be isolated and delivered as a cell-free therapy. • Exo-iNSC-TRAIL is more stable and more potently kills cancer cells than free TRAIL. [ABSTRACT FROM AUTHOR]

Daurisoline (DS) is an isoquinoline alkaloid that exerts anticancer activities in various cancer cells. However, the underlying mechanisms through which DS affects the survival of breast cancer cells remain poorly understood. Therefore, the present study was undertaken to investigate the potential anticancer effect of DS on breast cancer cells and reveal the mechanism underlying the enhanced tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐mediated apoptosis by DS. Cell counting kit‐8 (CCK‐8) and 5‐ethynyl‐2‐deoxyuridine (EdU) assay were used to evaluate the ability of cell proliferation. Flow cytometry was selected to examine the cell cycle distribution. TUNEL assay was used to detect the cell apoptosis. The protein expression was measured by Western blot analysis. DS was found to reduce the cell viability and suppress the proliferation of MCF‐7 and MDA‐MB‐231 cells by causing G1 phase cell cycle arrest. DS could trigger apoptosis by promoting the cleavage of caspase‐8 and PARP. The phosphorylation of ERK, JNK, and p38MAPK was upregulated clearly following DS treatment. Notably, SP600125 (JNK inhibitor) pretreatment significantly abrogated DS‐induced PARP cleavage. DS inactivated Akt/mTOR and Wnt/β‐catenin signaling pathway and upregulated the expression of ER stress‐related proteins. Additionally, DS amplified TRAIL‐caused viability reduction and apoptosis in breast cancer cells. Mechanismly, DS upregulated the protein level of DR4 and DR5, and knockdown of DR5 attenuated the cotreatment‐induced cleavage of PARP. Inhibition of JNK could block DS‐induced upregulation of DR5. This study provides valuable insights into the mechanisms of DS inhibiting cell proliferation, triggering apoptosis, and enhancing TRAIL sensitivity of breast cancer cells. [ABSTRACT FROM AUTHOR]

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Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. Methods: First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. Results: AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. Conclusion: Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients. [ABSTRACT FROM AUTHOR]

Checkpoint kinase 1 (Chk1) plays an important role in regulation of the cell cycle, DNA damage response and cell death, and represents an attractive target in anticancer therapy. Small-molecule inhibitors of Chk1 have been intensively investigated either as single agents or in combination with various chemotherapeutic drugs and they can enhance the chemosensitivity of numerous tumor types. Here we newly demonstrate that pharmacological inhibition of Chk1 using potent and selective inhibitor SCH900776, currently profiled in phase II clinical trials, significantly enhances cytotoxic effects of the combination of platinum-based drugs (cisplatin or LA-12) and TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in human prostate cancer cells. The specific role of Chk1 in the drug combination-induced cytotoxicity was confirmed by siRNA-mediated silencing of this kinase. Using RNAi-based methods we also showed the importance of Bak-dependent mitochondrial apoptotic pathway in the combined anticancer action of SCH900776, cisplatin and TRAIL. The triple drug combination-induced cytotoxicity was partially enhanced by siRNA-mediated Mcl-1 silencing. Our findings suggest that targeting Chk1 may be used as an efficient strategy for sensitization of prostate cancer cells to killing action of platinum-based chemotherapeutic drugs and TRAIL. [ABSTRACT FROM AUTHOR]

Tumor-homing neural stem cell (NSC) therapy is emerging as a promising treatment for aggressive cancers of the brain. Despite their success, developing tumor-homing NSC therapy therapies that maintain durable tumor suppression remains a challenge. Herein, we report a synergistic combination regimen where the novel small molecule TR-107 augments NSC-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy (hiNeuroS-TRAIL) in models of the incurable brain cancer glioblastoma (GBM) in vitro. We report that the combination of hiNeuroS-TRAIL and TR-107 synergistically upregulated caspase markers and restored sensitivity to the intrinsic apoptotic pathway by significantly downregulating inhibitory pathways associated with chemoresistance and radioresistance in the TRAIL-resistant LN229 cell line. This combination also showed robust tumor suppression and enhanced survival of mice bearing human xenografts of both solid and invasive GBMs. These findings elucidate a novel combination regimen and suggest that the combination of these clinically relevant agents may represent a new therapeutic option with increased efficacy for patients with GBM.

BackgroundDeath Receptor 5 (DR5) is expressed on the surface of primary bone and soft tissue sarcoma cells, and its activation induces cell death primarily through apoptosis. The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death. Currently, clinical trials are investigating the effectiveness of DR5 activation using new biological agents, such as bi-specific or tetravalent antibodies, in improving the survival of patients with relapsed or refractory cancers. Furthermore, investigations continue into the use of novel combination therapies to enhance DR5 response, for example, with inhibitor of apoptosis protein (IAP) antagonist agents [such as the second mitochondria-derived activator of caspase (SMAC) mimetics] and with immune checkpoint inhibitor anti-programmed death-ligand 1 (anti-PD-L1) or anti-programmed cell death-1 (anti-PD-1) antibodies. Other therapies include nanoparticle-mediated delivery of TRAIL plasmid DNA or TRAIL mRNA and stem cells as a vehicle for the targeted delivery of anti-cancer agents, such as TRAIL, to the tumor.MethodsScoping review of the literature from November 2017 to March 2024, utilizing PubMed and Google Scholar.ResultsNew agents under investigation include nanoTRAIL, anti-Kv10.1, multimeric IgM, and humanized tetravalent antibodies. Developments have been made to test novel agents, and imaging has been used to detect DR5 in preclinical models and patients. The models include 3D spheroids, genetically modified mouse models, a novel jaw osteosarcoma model, and patient-derived xenograft (PDX) animal models. There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies.ConclusionIn vitro, in vivo, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.

Abstract Background Prion diseases are transmissible and fatal neurodegenerative diseases characterized by accumulation of misfolded prion protein isoform (PrPSc), astrocytosis, microgliosis, spongiosis, and neurodegeneration. Elevated levels of cell membrane associated PrPSc protein and inflammatory cytokines hint towards the activation of death receptor (DR) pathway/s in prion diseases. Activation of DRs regulate, either cell survival or apoptosis, autophagy and necroptosis based on the adaptors they interact. Very little is known about the DR pathways activation in prion disease. DR3 and DR5 that are expressed in normal mouse brain were never studied in prion disease, so also their ligands and any DR adaptors. This research gap is notable and investigated in the present study. Methods C57BL/6J mice were infected with Rocky Mountain Laboratory scrapie mouse prion strain. The progression of prion disease was examined by observing morphological and behavioural abnormalities. The levels of PrP isoforms and GFAP were measured as the marker of PrPSc accumulation and astrocytosis respectively using antibody-based techniques that detect proteins on blot and brain section. The levels of DRs, their glycosylation and ectodomain shedding, and associated factors warrant their examination at protein level, hence western blot analysis was employed in this study. Results Prion-infected mice developed motor deficits and neuropathology like PrPSc accumulation and astrocytosis similar to other prion diseases. Results from this research show higher expression of all DR ligands, TNFR1, Fas and p75NTR but decreased levels DR3 and DR5. The levels of DR adaptor proteins like TRADD and TRAF2 (primarily regulate pro-survival pathways) are reduced. FADD, which primarily regulate cell death, its level remains unchanged. RIPK1, which regulate pro-survival, apoptosis and necroptosis, its expression and proteolysis (inhibits necroptosis but activates apoptosis) are increased. Conclusions The findings from the present study provide evidence towards the involvement of DR3, DR5, DR6, TL1A, TRAIL, TRADD, TRAF2, FADD and RIPK1 for the first time in prion diseases. The knowledge obtained from this research discuss the possible impacts of these 16 differentially expressed DR factors on our understanding towards the multifaceted neuropathology of prion diseases and towards future explorations into potential targeted therapeutic interventions for prion disease specific neuropathology.

Aim. To study the association of dynamics of the ejection fraction (EF) of the left ventricle (LV) with the development of adverse cardiovascular events within 12 months after revascularization in patients with chronic heart failure with preserved LV EF (HFpEF), and to determine the value of TNF-related apoptosis-inducing ligand (TRAIL) in predicting changes of LVEF. Materials and methods. 52 patients with HFpEF hospitalized for coronary artery bypass grafting (CABG) were included in the prospective study. The levels of plasma NTproBNP (before CABG) and TRAIL protein (before CABG and 10 days after CABG) were determined. Echocardiography was performed for these patients at the time of enrollment in the study and after 12 months of follow-up. The patients were divided into 2 groups: group 1 (n=23) included patients with increased LVEF, group 2 (n=29) – with unchanged or reduced LVEF. The development of a combined endpoint (cardiovascular death, decompensated of HF, repeat unplanned revascularization) was studied. Results. LVEF before CABG was comparable in the studied groups. The frequency of the combined endpoint was 0 in the first group and 17.2% in the second group (p=0.02). There was an inverse correlation between change of LVEF one year after revascularization and the dynamics of the TRAIL protein in the perioperative period (r=-0.45, p=0.049). The area under the ROC for perioperative TRAIL changes and changes in LVEF during a follow-up was 0.79 (95% confidence interval 0.6–0.985; p=0.018). Conclusion. The increase of LVEF 12 months after CABG in patients with HFpEF is associated with a rarer development of cardiovascular events. The changes of LVEF after CABG can be predicted based on the analysis of the perioperative changes of the TRAIL protein.

Walison Nunes da Silva,1 Pedro Augusto Carvalho Costa,1 Sérgio Ricardo Aluotto Scalzo Júnior,1 Heloísa AS Ferreira,1 Pedro Henrique Dias Moura Prazeres,2 Caroline Leonel Vasconcelos Campos,3 Marco Túllio Rodrigues Alves,1 Natália Jordana Alves da Silva,1 Ana Luiza de Castro Santos,1 Lays Cordeiro Guimarães,1 Maria Eduarda Chen Ferris,1 Ajay Thatte,4 Alex Hamilton,4 Kelly Alves Bicalho,5 Anderson Oliveira Lobo,6 Helton da Costa Santiago,3 Lucíola da Silva Barcelos,1 Maria Marta Figueiredo,7 Mauro Martins Teixeira,3 Vivian Vasconcelos Costa,8 Michael J Mitchell,4 Frédéric Frézard,1 Pedro Pires Goulart Guimaraes1 1Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; 2Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil; 3Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil; 4Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; 5Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil; 6Department of Materials Engineering, Federal University of Piauí, Teresina, PI, Brazil; 7State University of Minas Gerais, Divinopolis, MG, Brazil; 8Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, MG, BrazilCorrespondence: Pedro Pires Goulart Guimaraes, Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil, Email ppiresgo@reitoria.ufmg.brIntroduction: Immunotherapy has revolutionized cancer treatment by harnessing the immune system to enhance antitumor responses while minimizing off-target effects. Among the promising cancer-specific therapies, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted significant attention.Methods: Here, we developed an ionizable lipid nanoparticle (LNP) platform to deliver TRAIL mRNA (LNP-TRAIL) directly to the tumor microenvironment (TME) to induce tumor cell death. Our LNP-TRAIL was formulated via microfluidic mixing and the induction of tumor cell death was assessed in vitro. Next, we investigated the ability of LNP-TRAIL to inhibit colon cancer progression in vivo in combination with a TME normalization approach using Losartan (Los) or angiotensin 1– 7 (Ang(1– 7)) to reduce vascular compression and deposition of extracellular matrix in mice.Results: Our results demonstrated that LNP-TRAIL induced tumor cell death in vitro and effectively inhibited colon cancer progression in vivo, particularly when combined with TME normalization induced by treatment Los or Ang(1– 7). In addition, potent tumor cell death as well as enhanced apoptosis and necrosis was found in the tumor tissue of a group treated with LNP-TRAIL combined with TME normalization.Discussion: Together, our data demonstrate the potential of the LNP to deliver TRAIL mRNA to the TME and to induce tumor cell death, especially when combined with TME normalization. Therefore, these findings provide important insights for the development of novel therapeutic strategies for the immunotherapy of solid tumors.Keywords: immunotherapy, TRAIL, mRNA, lipid nanoparticle, losartan, angiotensin (1– 7)

This paper studies three edge-removing games on graphs. In each game, there are two players and a simple graph G at the beginning. The players take turns removing at least one edge of a certain type from the current graph. The one who cannot move loses the game, and the other one, who plays the last move, wins. This paper gives results for these games on some interesting classes of graphs by either computing their Grundy numbers or proposing winning strategies. [ABSTRACT FROM AUTHOR]

This article puts into dialogue the field of theatre and the European and North American geographic tradition of 'commodity trailing', including its Marxist underpinning. In recent years, a number of performances have emerged that engage with the process and provenance of commodities. Such performances often present their makers on the trail of commodity origins, consumer experiences, and historic routes of trade. This article introduces a framework in which performances that dramaturgically engage with commodities and their trails can be identified and analysed. It commences with an overview of the geographic principles of commodity trailing, and how this approach might be deployed in theatre scholarship. It applies the framework of commodity trailing to two case studies: Sh!t Theatre's DollyWould (2017) and Selina Thompson Production's salt. (2017). In analysing these performances against the principles of commodity trailing, this article supports an enhanced understanding of how dramaturgies attend to commodities and, in so doing, contribute to emergent discourses on performance and political economy. [ABSTRACT FROM AUTHOR]

Aim: Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) can selectively kill tumor cells but has no significant effect on normal cells. However, the use of TRAIL is limited for resistance by more than 50% of the tumor cell lines. It's very important to develop a more efficient form of TRAIL for cancer treatment. Methods: The N‐terminal in soluble fragments (114–281aa) of TRAIL was redesigned to construct a novel TRAIL mutant‐MuR5S4‐TR. The Cell Counting Kit‐8 method to explore the antitumor effects. The potential mechanisms were also explored. Results: Novel TRAIL mutant with cell‐penetrating peptides (CPP) like and Second mitochondria‐derived activator of caspases (Smac) like structure‐MuR5S4‐TR was successfully constructed. The prokaryotic expression system was successfully built, and the MuR5S4‐TR was purified and reconfirmed by western blot. MuR5S4‐TR could enhance the antitumor effects of TRAIL in most of the cancer cell lines significantly, NCI‐H460 lung cancer cell line, for instance. After MuR5S4‐TR treatment, the expressions of death receptor 4 (DR4), DR5, Caspase‐8, and cleaved Caspase‐3 were remarkably increased, however, there was no significant difference in X‐linked inhibitor of apoptosis expression. Conclusion: We constructed a novel TRAIL mutant with CPP‐like and Smac‐like structure‐MuR5S4‐TR. The MuR5S4‐TR showed significantly stronger antitumor effects than TRAIL in many tumor cell lines. The MuR5S4‐TR showed strong antitumor effects both in vitro and in vivo. This preliminary study implies that MuR5S4‐TR may be a more efficient form of TRAIL for cancer therapy. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study is to investigate changes in TNF-related apoptosis-inducing ligand (TRAIL) and gamma interferon-induced protein 10 (IP-10) after COVID-19 vaccination in pregnant women and to explore their association with neutralizing antibody (Nab) inhibition. Methods: The study evaluated 93 pregnant women who had previously received two (n=21), three (n=55) or four (n=17) doses of COVID-19 vaccine. Also we evaluated maternal blood samples that were collected during childbirth. The levels of TRAIL, IP-10 and Nab inhibition were measured using enzyme-linked immunosorbent assays (ELISA). Results and discussion: Our study revealed four-dose group resulted in lower TRAIL levels when compared to the two-dose and three-dose groups (4.78 vs. 16.07 vs. 21.61 pg/ml, p = 0.014). The two-dose group had reduced IP-10 levels than the three-dose cohort (111.49 vs. 147.89 pg/ml, p=0.013), with no significant variation compared to the four-dose group. In addition, the four-dose group showed stronger Nab inhibition against specific strains (BA.2 and BA.5) than the three-dose group. A positive correlation was observed between TRAIL and IP-10 in the two-dose group, while this relationship was not found in other dose groups or between TRAIL/IP-10 and Nab inhibition. As the doses of the COVID-19 vaccine increase, the levels of TRAIL and IP-10 generally increase, only by the fourth dose, the group previously vaccinated with AZD1222 showed lower TRAIL but higher IP-10. Despite these changes, more doses of the vaccine consistently reinforced Nab inhibition, apparently without any relation to TRAIL and IP-10 levels. The variation may indicate the induction of immunological memory in vaccinated mothers, which justifies further research in the future. [ABSTRACT FROM AUTHOR]

Background: Lupus pathogenesis is mainly ascribed to increased production and/or impaired clearance of dead cell debris. Although self-reactive T and B lymphocytes are critically linked to lupus development, neutrophils, monocytes, and natural killer (NK) cells have also been implicated. This study assessed apoptosis-related protein expressions in NK cells of patients with juvenileonset systemic lupus erythematosus (jSLE) and relations to disease activity parameters, nephritis, and neuropsychiatric involvement. Methods: Thirty-six patients with jSLE, 13 juvenile dermatomyositis (JDM) inflammatory controls, and nine healthy controls had Fas, FasL, TRAIL, TNFR1, Bcl-2, Bax, Bim, and caspase-3 expressions in NK cells (CD3-CD16+CD56+) simultaneously determined by flow cytometry. Disease activity parameters included Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, erythrocyte sedimentation rate, C-reactive protein level, anti-double strain DNA antibody level, complement fractions C3 and C4 levels. Results: Patients with jSLE had a profile of significantly reduced expression of TRAIL, Bcl-2, and TNFR1 proteins in NK cells when compared to healthy controls. Similar profile was observed in patients with jSLE with active disease, positive anti-dsDNA, nephritis, and without neuropsychiatric involvement. Patients with jSLE with positive anti-dsDNA also had reduced expression of Bax in NK cells when compared healthy controls and to those with negative anti-dsDNA. Yet, patients with jSLE with negative anti-dsDNA had reduced mean fluorescence intensity (MFI) of Bim in NK cells compared to healthy controls. Patients with jSLE with nephritis also had reduced MFI of Fas in NK cells when compared to those without nephritis. In addition, in patients with jSLE, the proportion of FasLexpressing NK cells directly correlated with the SLEDAI-2K score (rs = 0.6, p = 0.002) and inversely correlated with the C3 levels (rs = -0.5, p = 0.007). Moreover, patients with jSLE had increased NK cell percentage and caspase-3 protein expression in NK cells when compared to JDM controls. Conclusion: This study extends to NK cells an altered profile of TRAIL, Bcl-2, TNFR1, Fas, FasL, Bax, Bim, and caspase-3 proteins in patients with jSLE, particularly in those with active disease, positive anti-dsDNA, nephritis, and without neuropsychiatric involvement. This change in apoptosis-related protein expressions may contribute to the defective functions of NK cells and, consequently, to lupus development. The full clarification of the role of NK cells in jSLE pathogenesis may pave the way for new therapies like those of NK cell-based. [ABSTRACT FROM AUTHOR]

TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. Over the last three decades, this tumour selectivity has prompted many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives. Although most of these attempts have failed, so far, novel formulations are still being evaluated. However, emerging evidence indicates that TRAIL can also trigger a non-canonical signal transduction pathway that is likely to be detrimental for its use in oncology. Likewise, an increasing number of studies suggest that in some circumstances TRAIL can induce, via Death receptor 5 (DR5), tumour cell motility, potentially leading to and contributing to tumour metastasis. While the pro-apoptotic signal transduction machinery of TRAIL is well known from a mechanistic point of view, that of the non-canonical pathway is less understood. In this study, we the current state of knowledge of TRAIL non-canonical signalling. [ABSTRACT FROM AUTHOR]

Conservation units are strategic territories that have a high demand for public use, as they protect attractions of great scenic beauty, geodiversity sites, and numerous leisure areas. However, when carried out in an intensive and disorderly manner, tourist activity in these areas tends to catalyze environmental degradation, triggering, for example, water erosion processes caused by intensive soil trampling on the trails. In this sense, the aim of this study was to determine the soil's physicochemical characteristics, and to spatiotemporally monitor the microtopography of those areas degraded by erosion along two trails on Serra da Bocaina National Park coast of the Paraty Municipality. The findings verified that intensive trampling, the values of some soil physicochemical characteristics, and the specific meteorological conditions of the coastal region of this protected area were factors that contributed significantly to the evolution of erosion features monitored on these trails. Finally, strategies for appropriate management and recovery actions for these degraded areas are proposed in order to not only stop the erosive processes and re-establish the local ecosystem balance, but also avoid accidents involving the numerous tourists who visit the coastal region. [ABSTRACT FROM AUTHOR]

Increased inflammation in the liver during ethanol exposure is a major feature of alcoholic liver disease (ALD). An important contributing component to the development of ALD is the inflammatory response brought on by immunological response, however the connection between individual circulating cytokines and ALD is still unclear. To ascertain the causation, we conducted a two-sample bidirectional Mendelian randomization research. We extracted 41 cytokines and growth factors of 8293 Europeans and ALD cases of the same ethnicity (1416 cases and 217,376 controls) from the Genome-Wide Association Studies (GWAS) database for two-sample bidirectional MR analysis. Our analyses suggest that higher interleukin-7 (IL-7) levels are associated with an increased risk of ALD (p = 0.028, OR = 1.191,95% CI = 1.019–1.392), while tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a protective factor for ALD (p = 0.032, OR = 0.863, 95% CI = 0.754–0.988) which can reduce the risk of disease occurrence. In addition, genetically predicted ALD does not affect the expression of circulating cytokines regulators. Our study supports that cytokines play a pivotal role in the pathogenesis of ALD. To determine the mechanisms and pathways of action of these biomarkers, further basic research is required to ensure their clinical suitability for preventing and treating ALD. [ABSTRACT FROM AUTHOR]

Introduction: Dark under‐eye circles or periorbital hyperpigmentation constitute a prevalent and challenging cosmetic problem with diverse etiologies and types. While modifying exacerbating habits can provide partial relief for the pigmentary and vascular factors associated with this condition, and despite the abundance of available treatment options, there is currently a lack of gold‐standard evidence‐based treatments proposed for curing this disorder. Objectives: This study aimed to assess the safety and effectiveness of carboxytherapy in treating periorbital hyperpigmentation. Material and Methods: In this 4‐week single‐arm clinical trial, 20 eligible Iranian patients with symmetric periorbital hyperpigmentation received weekly intradermal carboxytherapy. The treatment involved administering 10–20 mL of CO2 at a rate of 20 mL/min and a temperature of 15°C for a duration ranging from a few seconds to 1 min. Follow‐up assessments were conducted 1 month after the final session. The primary outcome was defined as the changes in ΔE or the variations in pigmentation observed between the orbital and extra‐orbital skin before and after the trial. Results: The patients reported satisfaction with the statistically significant reduction in hyperpigmentation achieved through carboxytherapy in the lateral (p = 0.002), middle (p = 0.001), and medial (p = 0.001) regions of the periorbital area. The total response rate of the patients was estimated at 20%. Patient satisfaction exceeded ΔE changes, with no significant linear relationship (p = 0.084). Conclusion: Carboxytherapy can be proposed as an effective and safe treatment for periorbital hyperpigmentation. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as APO2L, has emerged as a highly potential anticancer agent because of its capacity to effectively trigger apoptosis in tumor cells by specifically binding to either of its death receptors (DR4 or DR5) while having no adverse effects on normal cells. Nevertheless, its practical use has been hindered by its inefficient pharmacokinetics characteristics, the challenges involved in its administration and delivery to targeted cells, and the resistance exhibited by most cancer cells towards TRAIL. Gene therapy, as a promising approach would be able to potentially circumvent TRAIL-based cancer therapy challenges mainly through localized TRAIL expression and generating a bystander impact. Among different strategies, using nanoparticles in TRAIL gene delivery allows for precise targeting, and overcoming TRAIL resistance by combination therapy. In this review, we go over potential mechanisms by which cancer cells achieve resistance to TRAIL and provide an overview of different carriers for delivering of the TRAIL gene to resistant cancer cells, focusing on different types of nanoparticles utilized in this context. We will also explore the challenges, and investigate future perspectives of this nanomedicine approach for cancer therapy.

Introduction: As a result of the recent professionalization of trail running, the epidemiology of injury and illness of professional athletes is still unknown. The aim of the study is to describe the epidemiology of musculoskeletal injuries and illnesses among professional trail runners of two national teams participating at the World Mountain and Trail Running Championships 2023. Material and Methods: The study included 77 professional trail running athletes from Spanish and French National Teams that competed in the Championships. Data of injuries and illnesses were recorded in “Daily Medical Report on Injuries and Illnesses” form, designed according to the recommendations of the International Olympic Committee consensus statement. Results: Thirty-eight percent of the athletes had an injury or illness; of them 22 % suffered an injury and 16 % an illness. Regarding sport performance, 24 % of the athletes suffered an injury and illness that affect their sport performance and 12 % had to withdraw due to a major injury or illness. By anatomical location foot is the most affected and hyperthermia and dehydration are the most frequent aetiology of illness. Conclusions: More than one third of professional trail running athletes suffered an injury or illness during the World Championship and around one in ten were unable to finish the competition due to a major injury or illness. The principal cause of withdrawal is dehydration, followed by overuse injuries and acute traumas.

Treatment resistance and immune escape are hallmarks of metastatic rhabdomyosarcoma (RMS), underscoring the urgent medical need for therapeutic agents against this disease entity as a key challenge in pediatric oncology. Chimeric antigen receptor (CAR)-based immunotherapies, such as the ErbB2 (Her2)-CAR-engineered natural killer (NK) cell line NK-92/5.28.z, provide antitumor cytotoxicity primarily through CAR-mediated cytotoxic granule release and thereafter—even in cases with low surface antigen expression or tumor escape—by triggering intrinsic NK cell-mediated apoptosis induction via additional ligand/receptors. In this study, we showed that bortezomib increased susceptibility toward apoptosis in clinically relevant RMS cell lines RH30 and RH41, and patient-derived RMS tumor organoid RMS335, by upregulation of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor DR5 in these metastatic, relapsed/refractory (r/r) RMS tumors. Subsequent administration of NK-92/5.28.z cells significantly enhanced antitumor activity in vitro. Applying recombinant TRAIL instead of NK-92/5.28.z cells confirmed that the synergistic antitumor effects of the combination treatment were mediated via TRAIL. Western blot analyses indicated that the combination treatment with bortezomib and NK-92/5.28.z cells increased apoptosis by interacting with the nuclear factor κB, JNK, and caspase pathways. Overall, bortezomib pretreatment can sensitize r/r RMS tumors to CAR- and, by upregulating DR5, TRAIL-mediated cytotoxicity of NK-92/5.28.z cells.

Chondrosarcoma (CS) is a malignant cartilage-forming bone tumor that is inherently resistant to chemotherapy and radiotherapy, leaving surgery as the only treatment option. We have designed a tumor-targeted bacteriophage (phage)-derived particle (PDP), for targeted systemic delivery of cytokine-encoding transgenes to solid tumors. Phage has no intrinsic tropism for mammalian cells; therefore, it was engineered to display a double cyclic RGD4C ligand on the capsid to target tumors. To induce cancer cell death, we constructed a transgene cassette expressing a secreted form of the cytokine tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). We detected high expression of αvβ3 and αvβ5 integrin receptors of the RGD4C ligand, and of the TRAIL receptor-2 in human CS cells (SW1353), but not in primary normal chondrocytes. The RGD4C.PDP-Luc particle carrying a luciferase reporter gene, Luc, effectively and selectively mediated gene delivery to SW1353 cells, but not primary chondrocytes. Transduction of SW1353 cells with RGD4C.PDP-sTRAIL encoding a human sTRAIL, resulted in the expression of TRAIL and subsequent cell death without harming the normal chondrocytes. Intravenous administration of RGD4C.PDP-sTRAIL to mice with established human CS resulted in a decrease in tumor size and tumor viability. Altogether, RGD4C.PDP-sTRAIL can be used to target systemic treatment of CS with the sTRAIL.

Abstract Objectives To determine the diagnostic accuracy of a rapid host‐protein test for differentiating bacterial from viral infections in patients who presented to the emergency department (ED) or urgent care center (UCC). Methods This was a prospective multicenter, blinded study. MeMed BV (MMBV), a test based on tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), interferon gamma‐inducible protein‐10 (IP‐10), and C‐reactive protein (CRP), was measured using a rapid measurement platform. Patients were enrolled from 9 EDs and 3 UCCs in the United States and Israel. Patients >3 months of age presenting with fever and clinical suspicion of acute infection were considered eligible. MMBV results were not provided to the treating clinician. MMBV results (bacterial/viral/equivocal) were compared against a reference standard method for classification of infection etiology determined by expert panel adjudication. Experts were blinded to MMBV results. They were provided with comprehensive patient data, including laboratory, microbiological, radiological and follow‐up. Results Of 563 adults and children enrolled, 476 comprised the study population (314 adults, 162 children). The predominant clinical syndrome was respiratory tract infection (60.5% upper, 11.3% lower). MMBV demonstrated sensitivity of 90.0% (95% confidence interval [CI]: 80.3–99.7), specificity of 92.8% (90.0%–95.5%), and negative predictive value of 98.8% (96.8%–99.6%) for bacterial infections. Only 7.2% of cases yielded equivocal MMBV scores. Area under the curve for MMBV was 0.95 (0.90–0.99). Conclusions MMBV had a high sensitivity and specificity relative to reference standard for differentiating bacterial from viral infections. Future implementation of MMBV for patients with suspected acute infections could potentially aid with appropriate antibiotic decision‐making.

Abstract Objective Our current study aimed to assess the relationship between TNF-related apoptosis-inducing ligand (TRAIL) and ferroptosis in non-small cell lung cancer (NSCLC) development. Methods The expression of TRAIL was detected by western blot, RT-qRCR and immunohistochemistry. The viability of NSCLC cells was analyzed by CCK-8 kit. The migration and invasion of NSCLC cells were detected by wound healing assay and transwell assay, respectively. Labile iron pool (LIP) was detected based on the calcein-acetoxymethyl ester method. Ferrous iron (Fe2+) and iron levels were assessed by detection kits. The levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured using corresponding detection kits. Mice tumor xenograft models were used for the in vivo research. Results The expression of TRAIL was reduced in H1299, NCL-H1395, and A549 cells compared with BEAS-2B cells. The up-regulation of TRAIL expression significantly reduced cell viability, invasion, and migration of H1299 and A549 cells. TRAIL reduced the expression of ferroptosis-related genes (FTH1, GPX4, and SLC7A11), increased the levels of LIP, iron, and Fe2+, and promoted lipid peroxidation, thereby predisposing NSCLC cells to ferroptosis. TRAIL up-regulated the expression of phosphate modification of ASK-1 and JNK. ASKI-1 inhibitor GS-4977 attenuated the effects of TRAIL on the viability, migration, invasion, and ferroptosis of H1299 cells. Furthermore, TRAIL further suppressed tumor growth and ferroptosis in mice tumor xenograft models. Conclusion We indicated that overexpression of TRAIL induced ferroptosis in NSCLC cells and exerted anti-tumor effects. Mechanistically, TRAIL promoted ferroptosis by the activation of the ASK-1/JNK1 pathway. Our results may provide new therapeutic strategies for NSCLC.

The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following death receptors’ (DRs) activation via the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. The inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These molecules selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these nine molecules using the human lung cancer cell line H1703, overexpressing c-FLIP. Our results showed that six of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC immunoprecipitation assay. The overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis; however, a combination of TRAIL with these selected molecules significantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical molecules efficiently prevent c-FLIP recruitment into the DISC complex, thus restoring the caspase-8-dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory molecules that may serve as anticancer agents in tumors overexpressing c-FLIP.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D.

Objective: Our current study aimed to assess the relationship between TNF-related apoptosis-inducing ligand (TRAIL) and ferroptosis in non-small cell lung cancer (NSCLC) development. Methods: The expression of TRAIL was detected by western blot, RT-qRCR and immunohistochemistry. The viability of NSCLC cells was analyzed by CCK-8 kit. The migration and invasion of NSCLC cells were detected by wound healing assay and transwell assay, respectively. Labile iron pool (LIP) was detected based on the calcein-acetoxymethyl ester method. Ferrous iron (Fe2+) and iron levels were assessed by detection kits. The levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured using corresponding detection kits. Mice tumor xenograft models were used for the in vivo research. Results: The expression of TRAIL was reduced in H1299, NCL-H1395, and A549 cells compared with BEAS-2B cells. The up-regulation of TRAIL expression significantly reduced cell viability, invasion, and migration of H1299 and A549 cells. TRAIL reduced the expression of ferroptosis-related genes (FTH1, GPX4, and SLC7A11), increased the levels of LIP, iron, and Fe2+, and promoted lipid peroxidation, thereby predisposing NSCLC cells to ferroptosis. TRAIL up-regulated the expression of phosphate modification of ASK-1 and JNK. ASKI-1 inhibitor GS-4977 attenuated the effects of TRAIL on the viability, migration, invasion, and ferroptosis of H1299 cells. Furthermore, TRAIL further suppressed tumor growth and ferroptosis in mice tumor xenograft models. Conclusion: We indicated that overexpression of TRAIL induced ferroptosis in NSCLC cells and exerted anti-tumor effects. Mechanistically, TRAIL promoted ferroptosis by the activation of the ASK-1/JNK1 pathway. Our results may provide new therapeutic strategies for NSCLC. [ABSTRACT FROM AUTHOR]

To investigate the correlation between serum interleukin-16 (IL-16), CC chemokine ligand 27 (CCL27) and TNF-related apoptosis-inducing ligand (TRAIL) and the severity of multiple sclerosis and its predictive value, and to provide theoretical basis for the diagnosis of MS. A total of 72 patients with multiple sclerosis admitted to our hospital from January 2018 to October 2022 were selected as the study objects. According to the severity of symptoms, they were divided into acute attack period (n=40) and remission period (n=32), and 65 healthy volunteers who underwent physical examination in our hospital during the same period were selected as the control group. Serum levels of IL-16, CCL27 and TRAIL were determined by enzyme-linked immunosorbent assay(ELISA). Spearman correlation was used to analyze the correlation between serum IL-16, CCL27 and TRAIL levels and the severity of multiple sclerosis, and receiver characteristic curve (ROC) was drawn to analyze the predictive value of serum IL-16, CCL27 and TRAIL levels on the severity of multiple sclerosis. The levels of IL-16, CCL27 and TRAIL in the study group were higher than those in the control group (P<0.05). The levels of IL-16, CCL27 and TRAIL in patients with acute attack period were higher than those in remission period (P<0.05). Spearman correlation analysis showed that serum IL-16, CCL27 and TRAIL levels were positively correlated with the severity of multiple sclerosis (r=0.436, 0.461, 0.447, P<0.05). ROC curve analysis showed that the area under the curve (AUC) of serum IL-16, CCL27 and TRAIL combined to predict the severity of multiple sclerosis was 0.939, which was significantly better than that evaluated by each indicator alone. Serum IL-16, CCL27 and TRAIL levels are closely related to the occurrence and development of multiple sclerosis. Early detection of serum IL-16, CCL27 and TRAIL levels has a certain predictive value for multiple sclerosis, and the combined prediction value is higher. [ABSTRACT FROM AUTHOR]

Objectives: Colorectal cancer is one of the most common cancers worldwide. However, surgical intervention and chemotherapy provide only limited benefits for the recovery and survival of patients. The anticarcinogenic effect of genistein has attracted attention because epidemiological studies have shown that soybean consumption is associated with a decrease in the incidence of cancer. There are limited studies on the effects of genistein in colorectal carcinoma cells. We aimed to investigate the cytotoxic, genotoxic, and apoptotic effects of genistein in SW480 and SW620 colon adenocarcinoma cells treated with 5-fluorouracil, the basis of chemotherapy, and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) ligand, the mediator of apoptosis, both alone and in combination. Materials and Methods: Cytotoxicity and genotoxicity were determined by MTT and comet assays, respectively. The apoptotic effects were evaluated by reverse transcription-polymerase chain reaction assay, with the additional use of Annexin V FITC, mitochondrial membrane potential (MMP), caspase 3, 8, and 9 activity, and reactive oxygen species (ROS) assay kits. Results: According to our findings, genistein, 5-fluorouracil, and TRAIL had synergistic apoptotic effects because of DR5 upregulation, ROS production, and DNA damage, which were mediated by increased caspase-8, and -9 activity and decreased MMP. Conclusion: The applied combinations of these compounds may contribute to the resistance problem that may occur in treating colorectal cancer, with a decrease in DcR1 and XIAP genes. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has impacted non-motorized mobility in the U.S. since March 2020. Many trail facilities have served as a venue for both recreational and commuting options for pedestrians and bicyclists. With social distancing, as well as the promotion of physical health and wellness during the pandemic, trail facilities serve as alternatives for travel for pedestrians and cyclists. Since 2011, Phase 1 of the Buffalo Valley Rail Trail has been open to users as a pedestrian and cycling connection in central Pennsylvania. In 2015, Phase 2 was developed in order to provide direct connection into downtown Lewisburg. This study evaluates trail usage at four counters over a period of 10 years using a six-step process. The results show that the 2 years with the highest trips over the entire 10-year period were in 2020 and 2021 (the 2 years during the COVID-19 pandemic). In addition, the highest recorded daily count for one of the counters over the entire 10-year period occurred on one of the days during the week of Pennsylvania's stay-at-home order period (in March 2020). By developing and implementing the six-step method on the BVRT, this study serves as a foundation for exploring trail demand on facilities throughout the United States and applications with regard to evaluating pandemic impacts. [ABSTRACT FROM AUTHOR]

Liver tumor organoids derived from liver tumor tissues and pluripotent stem cells are used for liver tumor research but have several challenges in primary cell isolation and stem cell differentiation. Here, we investigated the potential of HepG2-based liver tumor organoids for screening anticancer drugs by evaluating their responsiveness to IFN-β produced by mesenchymal stem cells (MSCs). Liver tumor organoids were prepared in three days on Matrigel using HepG2, primary liver sinusoidal epithelial cells (LSECs), LX-2 human hepatic stellate cells, and THP-1-derived macrophages at a ratio of 4:4:1:1, with 105 total cells. Hepatocyte-related and M2 macrophage-associated genes increased in liver tumor organoids. IFN-β treatment decreased the viability of liver tumor organoids and increased M1 macrophage marker expression (i.e., TNF-α and iNOS) and TRAIL. TRAIL expression was increased in all four cell types exposed to IFN-β, but cell death was only observed in HepG2 cells and macrophages. Further, MSCs overexpressing IFN-β (ASC-IFN-β) also expressed TRAIL, contributing to the reduced viability of liver tumor organoids. In summary, IFN-β or ASC-IFN-β can induce TRAIL-dependent HepG2 and macrophage cell death in HepG2-based liver tumor organoids, highlighting these liver tumor organoids as suitable for anticancer drug screening and mechanistic studies. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the seventh most frequently diagnosed cancer among women worldwide. Most patients experience recurrence and succumb eventually to resistant disease, underscoring the need for an alternative treatment option. In the presented manuscript, we investigated the effect of the TRAIL‐gene, transfected by an innovative bioinspired lipid vector BSV163/DOPE in the presence or absence of cisplatin, to fight against sensitive and resistant ovarian cancer. We showed that BSV163/DOPE can transfect ovarian cancer cell lines (Caov3, OVCAR3, and our new cisplatin‐resistant, CR‐Caov3) safely and efficiently. In addition, TRAIL‐gene transfection in association with cisplatin inhibited cellular growth more efficiently (nearly 50% in Caov3 cells after the combined treatment, and 15% or 25% by each treatment alone, respectively) owing to an increase in apoptosis rate, caspases activity and TRAIL's death receptors expression. Most importantly, such synergistic effect was also observed in CR‐Caov3 cells demonstrated by an apoptosis rate of 35% following the combined treatment in comparison with 17% after TRAIL‐gene transfection or 6% after cisplatin exposition. These results suggest this combination may have potential application for sensitive as well as refractory ovarian cancer patients. [ABSTRACT FROM AUTHOR]