Systematic Pan-Cancer Analysis Reveals the Prognostic Value and Immunological Role of EPHX2

Background Accumulating evidence indicates the essential role of EPHX2 in tumorigenesis. However, to date, no studies have performed a systematic evaluation of EPHX2 gene in human cancers and the predictive role of EPHX2 in cancer immunotherapy response has still not been explored. Methods In the present study, Oncomine, TIMER2, UALCAN, GEPIA2, PrognoScan, HPA and Kaplan-Meier Plotter database were utilized to comprehensively analyze the expression landscape and prognostic clinical value of EPHX2 across 33 human cancers. To gain a better understanding of the role of EPHX2 in cancer immunotherapy, the correlations between EPHX2 and tumor immune microenvironment (TME) such as immune cell infiltrations, immune modulators, and the major histocompatibility complex were demonstrated. The underlying EPHX2-associated signaling pathways in cancer were also analysed. Moreover, the correlation between EPHX2 and immunotherapeutic biomarkers such as tumor mutational burden (TMB) and microsatellite instability (MSI) was explored. At last, the potential immune checkpoint blockers (ICB) response was predicted using tumor immune dysfunction and exclusion (TIDE) algorithm. Results Overall, the mRNA expression of EPHX2 was significantly downregulated in the majority of tumors compared with normal tissues. Despite the significant prognostic value of EPHX2 expression across cancers, EPHX2 played a protective or detrimental role in different kinds of cancers. Generally speaking, immune cell infiltrations, immune modulators and immunotherapeutic biomarkers were all strongly related to the expression of EPHX2. Besides, EPHX2 expression was significantly related to immune-relevant pathways, especially in PAAD, THYM and UVM. Furthermore, our study demonstrated diverse response patterns of ICB in response to EPHX2 expression in different tumor types. Conclusion Our findings here suggest that EPHX2 could be a prognostic factor in multiple cancers and play an important role in tumor immunity by affecting infiltrating immune cells, TMB and MSI. This study provides further insight into the role of EPHX2 in tumor immunotherapy.

The Study of Traditional Medicine for the Treatment of COVID-19

SARS-CoV-2 is a novel virus communicable disease affected by serious acute respiratory condition coronavirus 2 (SARS-CoV-2) which goes to the family of coronavirus. December 2019, in Wuhan, China, the first case of novel coronavirus was reported, and this widespread virus globally became a pandemic. Various studies show that drug applicants are used as antivirals or immune modulators. Yet, the outcome of this examination reported the drug applicants were not ominously operative in contrast to the infection. In the interim, it's believed that taking herbal immune-modulators can avoid and/or resist COVID-19. Unluckily, definite clinical and preclinical trials to assess the special herbal immune regulators' effects have not been directed. Specific natural elements might be actual for treating COVID-19 built on universal thoughts from former tests. Though there are no exact anti-COVID-19 medicines as well as a drugs until now, the use of traditional medicine and epidemiology of novel coronavirus disease will be discussed for COVID-19 treatment.

Role of Plasma Membrane Redox Activities in Immune Response Mechanisms

The plasma membrane redox system (PMRS) is an important component of the cell's ability to defend itself against oxidative stress. Many immune signaling pathways are regulated through redox reactions. Biological systems utilize oxidationreduction reactions to modulate their responses to environmental cues. The role of redox molecules such as NO and ROS as key mediators of immunity has recently gathered a lot of interest and attention. Beyond the chemical interactions of NO and ROS that combine to eradicate pathogens, these redox small molecules are effective immune-modulators that regulate cellular metabolism as well as multiple pro-inflammatory and repair/tissue-restoration pathways. Redox molecules such as peroxide, superoxide, NO, and RNS, once thought to be only toxic, are essential in tissue repair. These species are generated, converted and metabolized during host microbe interaction involving the innate immune system. Cytochrome b558 is the flavin binding component of the NADPH oxidase. NADPH oxidases are key producers of ROS. A variety of RNS and ROS is produced in the acidic mileu of phagosomes, which provide an environment conducive to the redox chemistry, which is the first line in fighting infection. Bacterial cell immune response also involves NO. Thus understanding the plasma membrane redox activities can help unravel the mechanisms of immune response. Keywords: Plasma membrane, Redox activities, oxidative stress, NO, ROS, RNS. Nitrous Oxide, Reactive Oxygen Species, Reactive Nitrogen species.

Cellular Functions of ER Chaperones in Regulating Protein Misfolding and Aggregation: An Emerging Therapeutic Approach for Preeclampsia

Proteinuria is one of the hallmarks of preeclampsia (PE) that differentiates other hypertensive disorders of pregnancy. Protein misfolding and aggregation is an emerging pathological condition underlying many chronic metabolic diseases and neurodegenerative diseases. Recent studies indicate protein aggregation as an emerging biomarker of preeclampsia, wherein several proteins are aggregated and dysregulated in the body fluids of preeclamptic women, provoking the multi-systemic clinical manifestations of the disease. At the cellular level, these misfolded and aggregated proteins are potentially toxic interfering with the normal physiological process, eliciting the unfolded protein response (UPR) pathway activators in the endoplasmic reticulum (ER) that subsequently augments the ER quality control systems to remove these aberrant proteins. ER resident chaperones, folding enzymes and other proteins serve as part of the ER quality control machinery in restoring nascent protein folding. These ER chaperones are crucial for ER function aiding in native protein folding, maintaining calcium homeostasis, as sensors of ER stress and also as immune modulators. Consequently, ER chaperones seems to be involved in many cellular processes, yet the association is expanding to be explored. Understanding the role and mechanism of ER chaperones in regulating protein misfolding and aggregation would provide new avenues for therapeutic intervention as well as for the development of new diagnostic approaches.

Recent Advances in Aptasensor for Cytokine Detection: A Review

Cytokines are proteins secreted by immune cells. They promote cell signal transduction and are involved in cell replication, death, and recovery. Cytokines are immune modulators, but their excessive secretion causes uncontrolled inflammation that attacks normal cells. Considering the properties of cytokines, monitoring the secretion of cytokines in vivo is of great value for medical and biological research. In this review, we offer a report on recent studies for cytokine detection, especially studies on aptasensors using aptamers. Aptamers are single strand nucleic acids that form a stable three-dimensional structure and have been receiving attention due to various characteristics such as simple production methods, low molecular weight, and ease of modification while performing a physiological role similar to antibodies.

FunHoMic: A Marie Skłodowska-Curie Innovative Training Network for the study of the Fungus-Host-Microbiota interplay

Introduction The FunHoMic project is a Marie Skłodowska-Curie Innovative Training Network comprising 13 PhD students, 8 academic partners and 3 industry partnersaimingto understand the interplay between fungi, hostsand microbiota to improve prevention and treatment of fungal infections. Importance About 2 billion people suffer fungal infections, which have a mortality rate close to that of malaria or breast cancer. Candida albicans has a high clinical and economic burden, making it of particular interest to the FunHoMic project. 70% of women experience at least one episode of vulvovaginal candidiasis (“thrush”) during their lifetime; 8% suffer recurring infections. C. albicans may live as a commensal but can cause symptoms when the fungus-host-microbiota equilibrium is disrupted. Infections by C. albicans have a significant clinical impact, with fatalities in severe cases. Many factors are associated with C. albicans infections; intensive care, neutropenic and diabetic patients are most at risk of systemic infection. Rising antifungal drug resistance has led to certain C. albicans infections having no treatment option. Aim The FunHoMic consortium combines projectson fungal pathogenesis, immunology, microbial ecology and’omics technologies to understand and exploit interactions between fungus, host and microbiota. Identification of novel bio markers on the fungal side such as genetic polymorphisms or on the host side such asmicrobiota profiles, metabolites and/or immune markers can lead to patient classification based on relative risk of infection. This could be the beginning of personalised management for fungal infections using preventive or therapeutic interventions like new antifungals, immune modulators or Live Biotherapeutic Products (LBPs). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the MarieSklodowska-Curie grant agreement No 812969.

Immunomodulatory Properties of Polysaccharides from the Coral Pseudopterogorgia americana in Macrophages

Polysaccharides from marine organisms produce an important regulatory effect on the mammalian immune system. In this study, the immunomodulatory properties of a polysaccharide that was isolated from the coral Pseudopterogorgia americana (PPA) were investigated. PPA increased the expression levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), but not inducible nitric oxide synthase and nitric oxide, in macrophages. A mechanistic study revealed that PPA activated macrophages through the toll-like receptor-4 and induced the generation of reactive oxygen species (ROS), increased the phosphorylation levels of protein kinase C (PKC)-α, PKC-δ and mitogen-activated protein kinases (MAPK), and activated NF-κB. The inhibition of ROS and knockdown of PKC-α reduced PPA-mediated TNF-α and IL-6 expression; however, the knockdown of PKC-δ significantly increased PPA-mediated TNF-α expression. In addition, the inhibition of c-Jun N-terminal kinase-1/2 and NF-κB reduced PPA-mediated TNF-α, IL-6 and COX-2 expression. Furthermore, the inhibition of ROS, MAPK and PKC-α/δ reduced PPA-mediated NF-κB activation, indicating that ROS, MAPK and PKC-α/δ function as upstream signals of NF-κB. Finally, PPA treatment decreased the phagocytosis activity of macrophages and reduced cytokine expression in bacteria-infected macrophages. Taken together, our current findings suggest that PPA can potentially play a role in the development of immune modulators in the future.

PP180 Optimal Treatment Sequence For Targeted Immune Modulators For The Treatment Of Moderate To Severe Ulcerative Colitis

IntroductionSeveral targeted immune modulators (TIMs) have demonstrated effectiveness in moderate-to-severe ulcerative colitis, including adalimumab, golimumab, infliximab, infliximab biosimilars, tofacitinib, ustekinumab, and vedolizumab. In addition to assessing individual TIMs, evaluating TIM sequences can inform clinical care as well as coverage and reimbursement policies. Our objective was to identify optimal treatment sequences based on maximum net health benefit (NHB), lowest total cost (cost minimizing), quality-adjusted life-year (QALY) maximization, or convenience (avoidance of intravenous treatments), and to evaluate their cost effectiveness compared with conventional treatment from the health sector perspective.MethodsWe developed a Markov model with eight-week cycles and a lifetime time horizon. The health states were active, clinical response without remission, remission, and death. TIM efficacy was informed by a network meta-analysis conducted by the Institute for Clinical and Economic Review. Sequences were generated by ranking TIMs and then conventional treatment according to NHB, cost minimization, QALY maximization, or convenience and combining top ranked TIMs in the biologic naïve and biologic experienced populations. NHB was calculated at USD 150,000 per QALY. Probabilistic sensitivity analysis (PSA) was undertaken to estimate the probability of each sequence having the highest NHB rank, QALY maximizing rank, and cost-minimizing rank.ResultsTwenty-one sequences were evaluated. The sequence with the highest NHB was infliximab followed by tofacitinib (-0.12 QALYs), which also had the lowest incremental costs (USD37,266). For orally and subcutaneously administered TIMs, the sequence of golimumab-tofacitinib had the highest NHB (-0.34 QALYs). Ustekinumab-vedolizumab was not only the top ranked sequence as measured by QALY maximization (0.172 incremental QALYs), but it also had the highest total incremental cost (USD166,094). Results of the PSA were consistent with deterministic rankings for the top-ranking sequences and showed that the top two or three regimens were close in magnitude.ConclusionsThe optimal sequence with regard to NHB and cost minimization was infliximab or biosimilars, followed by tofacitinib, adalimumab, or vedolizumab. Sequences that generated the most QALYs began with ustekinumab, followed by vedolizumab, tofacitinib, and adalimumab.

Dual Targeting of Cancer Cells and MMPs with Self-Assembly Hybrid Nanoparticles for Combination Therapy in Combating Cancer

The co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor. The released PTX@TF entered cancer cells via transferrin-receptor-mediated endocytosis and inhibited the survival of tumor cells. MMST was intelligently employed as an immunomodulator to improve immunotherapy by inhibiting matrix metalloproteinases to reduce chemokine degradation and recruit T cells. The TMNPs promoted the tumor infiltration of CD3+ T cells by 2-fold, including memory/effector CD8+ T cells (4.2-fold) and CD4+ (1.7-fold), but not regulatory T cells. Our in vivo anti-tumor experiment suggested that TMNPs possessed the highest tumor growth inhibitory rate (80.86%) compared with the control group. We demonstrated that the nanoplatform could effectively inhibit the growth of tumors and enhance T cell recruitment through the co-delivery of paclitaxel and marimastat, which could be a promising strategy for the combination of chemotherapy and immunotherapy for cancer treatment.

Systematic Pan-Cancer Analysis Reveals the Prognostic Value and Immunological Role of EPHX2

Background: Accumulating evidence indicates the essential role of EPHX2 in tumorigenesis. However, to date, no studies have performed a systematic evaluation of EPHX2 gene in human cancers and the predictive role of EPHX2 in cancer immunotherapy response has still not been explored. Methods: In the present study, Oncomine, TIMER2, UALCAN, GEPIA2, PrognoScan, HPA and Kaplan-Meier Plotter database were utilized to comprehensively analyze the expression landscape and prognostic clinical value of EPHX2 across 33 human cancers. To gain a better understanding of the role of EPHX2 in cancer immunotherapy, the correlations between EPHX2 and tumor immune microenvironment (TME) such as immune cell infiltrations, immune modulators, and the major histocompatibility complex were demonstrated. The underlying EPHX2-associated signaling pathways in cancer were also analysed. Moreover, the correlation between EPHX2 and immunotherapeutic biomarkers such as tumor mutational burden (TMB) and microsatellite instability (MSI) was explored. At last, the potential immune checkpoint blockers (ICB) response was predicted using tumor immune dysfunction and exclusion (TIDE) algorithm. Results: Overall, the mRNA expression of EPHX2 was significantly downregulated in the majority of tumors compared with normal tissues. Despite the significant prognostic value of EPHX2 expression across cancers, EPHX2 played a protective or detrimental role in different kinds of cancers. Generally speaking, immune cell infiltrations, immune modulators and immunotherapeutic biomarkers were all strongly related to the expression of EPHX2. Besides, EPHX2 expression was significantly related to immune-relevant pathways, especially in PAAD, THYM and UVM. Furthermore, our study demonstrated diverse response patterns of ICB in response to EPHX2 expression in different tumor types. Conclusion: Our findings here suggest that EPHX2 could be a prognostic factor in multiple cancers and play an important role in tumor immunity by affecting infiltrating immune cells, TMB and MSI. This study provides further insight into the role of EPHX2 in tumor immunotherapy.