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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]

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a devastating brain cancer for which new effective therapies are urgently needed. GBM, after an initial response to current treatment regimens, develops therapeutic resistance, leading to rapid patient demise. Cancer cells exhibit an inherent elevation of endoplasmic reticulum (ER) stress due to uncontrolled growth and an unfavorable microenvironment, including hypoxia and nutrient deprivation. Cancer cells utilize the unfolded protein response (UPR) to maintain ER homeostasis, and failure of this response promotes cell death. In this study, as integrins are upregulated in cancer, we have evaluated the therapeutic potential of individually targeting all αβ1 integrin subunits using RNA interference. We found that GBM cells are uniquely susceptible to silencing of integrin α3. Knockdown of α3-induced proapoptotic markers such as PARP cleavage and caspase 3 and 8 activation. Remarkably, we discovered a non-canonical function for α3 in mediating the maturation of integrin β1. In its absence, generation of full length β1 was reduced, immature β1 accumulated, and the cells underwent elevated ER stress with upregulation of death receptor 5 (DR5) expression. Targeting α3 sensitized TRAIL-resistant GBM cancer cells to TRAIL-mediated apoptosis and led to growth inhibition. Our findings offer key new insights into integrin α3's role in GBM survival via the regulation of ER homeostasis and its value as a therapeutic target. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is accompanied by activated neuro-immune pathways, increased physiosomatic and chronic fatigue-fibromyalgia (FF) symptoms. The most severe MDD phenotype, namely major dysmood disorder (MDMD), is associated with adverse childhood experiences (ACEs) and negative life events (NLEs) which induce cytokines/chemokines/growth factors. To delineate the impact of ACE + NLEs on physiosomatic and FF symptoms in first episode (FE)-MDMD, and examine whether these effects are mediated by immune profiles. ACEs, NLEs, physiosomatic and FF symptoms, and 48 cytokines/chemokines/growth factors were measured in 64 FE-MDMD patients and 32 normal controls. Physiosomatic, FF and gastro-intestinal symptoms belong to the same factor as depression, anxiety, melancholia, and insomnia. The first factor extracted from these seven domains is labeled the physio-affective phenome of depression. A part (59.0%) of the variance in physiosomatic symptoms is explained by the independent effects of interleukin (IL)-16 and IL-8 (positively), CCL3 and IL-1 receptor antagonist (inversely correlated). A part (46.5%) of the variance in physiosomatic (59.0%) symptoms is explained by the independent effects of interleukin (IL)-16, TNF-related apoptosis-inducing ligand (TRAIL) (positively) and combined activities of negative immunoregulatory cytokines (inversely associated). Partial least squares analysis shows that ACE + NLEs exert a substantial influence on the physio-affective phenome which are partly mediated by an immune network composed of interleukin-16, CCL27, TRAIL, macrophage-colony stimulating factor, and stem cell growth factor. The physiosomatic and FF symptoms of FE-MDMD are partly caused by immune-associated neurotoxicity due to T helper (Th)-1 polarization and M1 macrophage activation and relative lowered compensatory immunoregulatory protection. [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]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising agent for treatment of AML due to its specific apoptosis-inducing effect on tumor cells but not normal cells. However, emergence of resistance to TRAIL in the AML cells limits its potential as an antileukemic agent. Previously, we revealed increase in the resistance of the human AML THP-1 cells to the TRAIL-induced death during their LPS-dependent proinflammatory activation and in the in vitro model of LPS-independent proinflammatory activation – in a long-term high-density cell culture. In this study, we investigated mechanisms of this phenomenon using Western blot analysis, caspase 3 enzymatic activity analysis, quantitative reverse transcription-PCR, and flow cytometry. The results showed that the increased resistance to the TRAIL-induced cell death of AML THP-1 cells during their pro-inflammatory activation is associated with the decrease in the surface expression of the proapoptotic receptors TRAIL-R1/DR4 and TRAIL-R2/DR5, as well as with the increased content of members of the IAPs family – Livin and cIAP2. The results of this article open up new insights into the role of inflammation in formation of the resistance of AML cells to the action of mediators of antitumor immunity, in particular TRAIL. [ABSTRACT FROM AUTHOR]

The article provides updated information on a study that aims to detect and differentiate between pancreatic neuroendocrine tumors (PanNET) and small intestinal neuroendocrine tumors (SI-NET). The correction addresses errors in the previous publication and provides more accurate information on the study's findings. The article includes tables that present the performance metrics of two models, which use various plasma biomarkers and chromogranin A (CgA) to predict the type of tumor. The top biomarkers used in the models are listed. [Extracted from the article]

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]

Objective: To explore the impact of inflammatory factors on the incidence of cerebral small vessel disease (CSVD), we performed a mendelian randomization (MR) study to analyze the causal relationship between multiple inflammatory factors and CSVD imaging markers and utilized summary‐data‐based mendelian randomization (SMR) analysis to infer whether the impact of instrumental variables (IVs) on disease is mediated by gene expression or DNA methylation. Methods: Using public databases such as UKB and IEU, and original genome‐wide association studies, we obtained IVs related to exposure (inflammatory factors) and outcome (CSVD imaging markers). We performed the inverse variance weighted, weighted median, and MR‐Egger methods to assess causal effects between exposure and outcome in univariate MR analysis. To evaluate their heterogeneity, a series of sensitivity analyses were conducted, including the Cochrane Q test, MR‐Egger intercept test, MR‐Presso, and leave‐one‐out analysis. We also applied mediation and multivariate MR analysis to explore the interactions between positive exposures on the same outcome. Additionally, we conducted the SMR, which utilizes instruments within or near relevant genes in blood or brain tissues, to elucidate the causal associations with CSVD markers. Results: ABO Univariate MR of multiple cohorts revealed that the risk of small vessel stroke (SVS) increases with elevated levels of TNF‐related apoptosis‐inducing ligand (TRAIL, OR, 1.23, 95% CI, 1.08–1.39) and interleukin‐1 receptor‐like 2, (IL‐1RL2, OR, 1.29, 95% CI, 1.04–1.61). IL‐18 was a potential risk factor for extensive basal ganglia perivascular space burden (BGPVS, OR, 1.02, 95% CI, 1.00–1.05). Moreover, the risk of extensive white matter perivascular space burden (WMPVS) decreased with rising levels of E‐selectin (OR,.98, 95% CI,.97–1.00), IL‐1RL2 (OR,.97, 95% CI,.95–1.00), IL‐3 receptor subunit alpha (IL‐3Ra, OR,.98, 95% CI,.97–1.00), and IL‐5 receptor subunit alpha (IL‐5Ra, OR,.98, 95% CI,.97–1.00). Mediation and multivariate MR analysis indicated that E‐selectin and IL‐3Ra might interact during the pathogenesis of WMPVS. SMR estimates showed that TRAIL‐related IVs rs5030044 and rs2304456 increased the risk of SVS by increasing the expression of gene Kininogen‐1 (KNG1) in the cerebral cortex, particularly in the frontal cortex (βsmr =.10, Psmr =.003, FDR =.04). Instruments (rs507666 and rs2519093) related to E‐selectin and IL‐3Ra could increase the risk of WMPVS by enhancing DNA methylation of the gene ABO in blood tissue (βsmr =.01–.02, Psmr =.001, FDR =.01–.03). Conclusion: According to MR and SMR analysis, higher levels of TRAIL increased the risk of SVS by upregulating gene expression of KNG1 in brain cortex tissues. In addition, protective effects of E‐selectin and IL‐3a levels on WMPVS were regulated by increased DNA methylation of gene ABO in blood tissue. [ABSTRACT FROM AUTHOR]

TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report, we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity (KD = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL, and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy. [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]

Oncology patients presenting to EDs with acute respiratory illnesses (ARI) require a broad workup and early treatment due to risk of underlying infection and immunocompromised status. Early antibiotic administration is often required as determining a nonbacterial source is time consuming. A novel host bio-array developed to rapidly differentiate bacterial from viral sources could improve ED resource utilization, reduce unnecessary antibiotics, and increase healthcare quality. An IRB approved subject on multiple immunosuppressants presents with ARI and positive SIRS criteria. The MeMed BV® (BV) is an FDA approved rapid immunoassay that reports a computationally integrated score (0-100) of three host proteins (TNF-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein 10 (IP-10), and C-reactive protein (CRP). The BV score and ED standard of care tests were obtained in a modified ED sepsis protocol (mEDSP). Scores above 65 are associated with bacterial infections, while scores below 10 are associated with viral infections. Cost of laboratory, radiology, professional and facilities fees (room charges, nursing, and ancillaries) were summed for the admission. Investigators received three surveys to: (1) establish pretest probability of disease, (2) determine posttest probability after receiving BV results, (3) query what resources might be withheld or changed if presented with the BV test results early. The BV reported a '0' value (viral source) within 20 minutes. Further testing confirmed no bacterial source of infection. An adjudicated cost and resource review of the mEDSP and admission revealed a potential reduction of unnecessary antibiotics by 59%, lab testing by 24.2%, and overall costs by 23.2%. Admission time could have been reduced by 24 hours (43%). Furthermore, the ED physician was amenable to changing care based on this test. Significant improvement in resource utilization and greater quality was identified with early identification of nonbacterial sources in ARI in the ED. Adjunct biomarkers differentiating viral from other sources can improve quality and resource utilization when deployed early in the ED. Further trials in the Emergency Oncology realm are necessary. [ABSTRACT FROM AUTHOR]

Although recombinant human TNF-related apoptosis-inducing ligand (TRAIL) protein exhibits antitumor activity in a number of lung and liver cancer cells and tumor-bearing animals, TRAIL resistance has substantially restricted its clinical application. Pyrroline-5-carboxylate reductase 1 (PYCR1) is a key enzyme in the regulation of proline synthesis. PYCR1 is highly expressed in various types of malignant tumor, in which it has been implicated in 5-fluorouracil resistance. However, the possible relationship between PYCR1 and TRAIL resistance remains unclear. In the present study, both reverse transcription-quantitative PCR and western blotting were performed. The results indicated that H1299 cells had higher PYCR1 expression levels and were less sensitive to TRAIL compared with the TRAIL-sensitive cell line, H460. PYCR1 knockdown in H1299 cells increased TRAIL sensitivity, increased the localization of death receptors (DRs) on the cell surface and activated Caspase-3/8. By contrast, overexpression of PYCR1 in H1299 cells decreased TRAIL sensitivity, reduced the distribution of DRs on the cell surface and suppressed the activation of Caspase-3/8. Taken together, these results suggested that PYCR1 promoted TRAIL resistance in the non-small cell lung cancer cell line, H1299, by preventing redistribution of DRs to the plasma membrane. This in turn inhibited TRAIL-mediated cell apoptosis by reducing the activation of Caspase-3/8. [ABSTRACT FROM AUTHOR]

Novel strategies in intratumoral injection and emerging immunotherapies have heralded a new era of precise cancer treatments. The affinity of SARS-CoV-2 to ACE2 receptors, a feature which facilitates virulent human infection, is leveraged in this research. Colon cancer cells, with their high ACE2 expression, provide a potentially strategic target for using this SARS-CoV-2 feature. While the highly expression of ACE2 is observed in several cancer types, the idea of using the viral spike protein for targeting colon cancer cells offers a novel approach in cancer treatment. Intratumoral delivery of nucleic acid-based drugs is a promising alternative to overcoming the limitations of existing therapies. The increasing importance of nucleic acids in this realm, and the use of Lipid Nanoparticles (LNPs) for local delivery of nucleic acid therapeutics, are important breakthroughs. LNPs protect nucleic acid drugs from degradation and enhance cellular uptake, making them a rapidly evolving nano delivery system with high precision and adaptability. Our study leveraged a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combined with a receptor-binding domain from the SARS-CoV-2 spike protein, encapsulated in LNPs, to target colon cancer cells. Our results indicated that the TRAIL fusion-mRNA induced apoptosis in vitro and in vivo. Collectively, our findings highlight LNP-encapsulated TRAIL fusion-mRNA as a potential colon cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

ERCC2 plays a pivotal role in DNA damage repair, however, its specific function in cancer remains elusive. In this study, we made a significant breakthrough by discovering a substantial upregulation of ERCC2 expression in glioblastoma (GBM) tumor tissue. Moreover, elevated levels of ERCC2 expression were closely associated with poor prognosis. Further investigation into the effects of ERCC2 on GBM revealed that suppressing its expression significantly inhibited malignant growth and migration of GBM cells, while overexpression of ERCC2 promoted tumor cell growth. Through mechanistic studies, we elucidated that inhibiting ERCC2 led to cell cycle arrest in the G0/G1 phase by blocking the CDK2/CDK4/CDK6/Cyclin D1/Cyclin D3 pathway. Notably, we also discovered a direct link between ERCC2 and CDK4, a critical protein in cell cycle regulation. Additionally, we explored the potential of TRAIL, a low-toxicity death ligand cytokine with anticancer properties. Despite the typical resistance of GBM cells to TRAIL, tumor cells undergoing cell cycle arrest exhibited significantly enhanced sensitivity to TRAIL. Therefore, we devised a combination strategy, employing TRAIL with the nanoparticle DMC-siERCC2, which effectively suppressed the GBM cell proliferation and induced apoptosis. In summary, our study suggests that targeting ERCC2 holds promise as a therapeutic approach to GBM treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Programmed cell death, in particular apoptosis, is essential during development and tissue homeostasis, and also is the primary strategy to induce cancer cell death by cytotoxic therapies. Precision therapeutics targeting TRAIL death receptors are being evaluated as novel anti-cancer agents, while in parallel highly specific proteasome inhibitors have gained approval as drugs. TRAIL-dependent signalling and proteasomal control of cellular proteostasis are intricate processes, and their interplay can be exploited to enhance therapeutic killing of cancer cells in combination therapies. This review provides detailed insights into the complex signalling of TRAIL-induced pathways and the activities of the proteasome. It explores their core mechanisms of action, pharmaceutical druggability, and describes how their interplay can be strategically leveraged to enhance cell death responses in cancer cells. Offering this comprehensive and timely overview will allow to navigate the complexity of the processes governing cell death mechanisms in TRAIL- and proteasome inhibitor-based treatment conditions. • TRAIL therapeutics and proteasome inhibitors are clinically tested or approved. • Proteasome inhibition can sensitize to TRAIL-based therapeutics. • We mechanistically describe and review the complex signalling interplay. [ABSTRACT FROM AUTHOR]

A novel host-protein score (called MMBV) helps to distinguish bacterial from viral infection by combining the blood concentrations of three biomarkers: tumour necrosis factor related apoptosis inducing ligand (TRAIL), interferon gamma induced protein 10 (IP-10), and C-reactive protein (CRP). These host biomarkers are differentially expressed in response to bacterial versus viral acute infection. We conducted a prospective study, with a time series design, in healthy adult volunteers in the Netherlands. The aim was to determine the variability of TRAIL, IP-10, and CRP and the MMBV score in healthy adults across time. Up to six blood samples were taken from each healthy volunteer over a period of up to four weeks. In 77 healthy participants without recent or current symptoms, MMBV scores (maximal) were bacterial in 1.3 % and viral (or other non-infectious etiology) in 93.5 % of participants. There was little variation in the mean concentrations of TRAIL (74.5 pg/ml), IP-10 (113.6 pg/ml), and CRP (1.90 mg/L) as well as the MMBV score. The variability of biomarker measurement was comparable to the precision of the measurement platform for TRAIL, IP-10, and CRP. Our findings establish the mean values of these biomarkers and MMBV in healthy individuals and indicate little variability between and within individuals over time, supporting the potential utility of this novel diagnostic to detect infection-induced changes. [ABSTRACT FROM AUTHOR]

• MMBV is a host signature based on TRAIL, IP10, and CRP for infection diagnosis. • This is the first evaluation of MMBV in the ICU cohort. • MMBV is not useful in ICU patients, neither in diagnosing nor monitoring infection. • MMBV may be a negative prognostic factor. Infection complications are common in intensive care unit patients, and early detection remains a diagnostic challenge. Procalcitonin (PCT) and C-reactive protein (CRP) are commonly used biomarkers. A novel diagnostic approach focuses on the host immune response. One of the approaches, the MMBV index, is based on measuring in a blood sample three parameters: (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), (ii) interferon-γ-induced protein-10 (IP10), and (iii) CRP. This study aimed to evaluate the usefulness of MMBV as an infection biomarker in an ICU cohort. Forty-six patients treated in the University Clinical Center in Gdansk ICU were enrolled in the study, and their clinical data were retrospectively analyzed. In total, 91 MMBV results were analyzed. Most of the patients had high MMBV values, suggesting bacterial etiology. A weak correlation between PCT and MMBV was observed, and no correlation between parameter changes was noted. There was a correlation between CRP/MMBV and between changes in CRP / changes in MMBV. It seems that MMBV is not valuable for ICU patients neither in diagnosing nor monitoring infection. Higher MMBV values may predict unfavorable treatment outcomes. [ABSTRACT FROM AUTHOR]