The objective of this study was to identify key transcription factors involved in lipid metabolism and immune response related to the differentially expressed genes (DEG) from the liver samples of 35 pig model for metabolic diseases fed diets containing either 1.5 or 3.0% soybean oil (SOY1.5 or SOY3.0). A total of 281 DEG between SOY1.5 and SOY3.0 diets (log2fold-change ≥ 1 or ≤ −1; FDR-corrected p-value < 0.1) were identified, in which 129 were down-regulated and 152 were up-regulated in SOY1.5 group. The functional annotation analysis detected transcription factors linked to lipid homeostasis and immune response, such as RXRA, EGFR, and SREBP2 precursor. These findings demonstrated that key transcription factors related to lipid metabolism could be modulated by dietary inclusion of soybean oil. It could contribute to nutrigenomics research field that aims to elucidate dietary interventions in animal and human health, as well as to drive the food technology and science.

This study aims to systematically review and meta-analyze the nitro-oxidative stress (O&NS)/antioxidant (ANTIOX) ratio in the peripheral blood of people with mild cognitive impairment (MCI). We searched PubMed, Scopus, Google Scholar, and Web of Science for articles published from inception until July 31, 2021. Forty-six studies on 3.798 MCI individuals and 6.063 healthy controls were included. The O&NS/ANTIOX ratio was significantly higher in MCI than in controls with a Standardized Mean Difference (SMD)=0.378 (95% CI: 0.250; 0.506). MCI individuals showed increased lipid peroxidation (SMD=0.774, 95%CI: 4.416; 1.132) and O&NS-associated toxicity (SMD=0.621, CI: 0.377; 0.865) and reduced glutathione (GSH) defenses (SMD=0.725, 95%CI: 0.269; 1.182) as compared with controls. MCI was also accompanied by significantly increased homocysteine (SMD=0.320, CI: 0.059; 0.581), but not protein oxidation, and lowered non-vitamin (SMD=0.347, CI: 0.168; 0.527) and vitamin (SMD=0.564, CI: 0.129; 0.999) antioxidant defenses. The results show that MCI is at least in part due to increased neuro-oxidative toxicity and suggest that treatments targeting lipid peroxidation and the GSH system may be used to treat or prevent MCI.

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To contain the virus, numerous preventive measures have been taken including isolation of patients, careful infection control, social distancing, and taking vaccine. So far, new confirmed and death cases are still increasing. SARS-CoV-2 invades cells by using the angiotensin converting enzyme 2 (ACE2). ACE2 is an essential enzyme of the renin-angiotensin system (RAS) which converts angiotensin II (Ang II) to angiotensin (1-7). ACE2 is expressed in different organs, including lung, heart, and kidney. A high number of COVID-19 patients developed kidney injury has been reported. Renal impairment and acute injury are associated with mortality of COVID-19, which is 14-16 times higher than other general patients. Acute Kidney Injury has been occured in 2.9 up to 43% of intensive care unit patients. The increasing evidence show that the components of RAS can activate the complement cascade, and cytokines production. Kidney injury caused by SARS-CoV-2 is related mainly to systemic and local inflammation. Moreover, the uncontrolled immune responses mediated by SARS-CoV-2 including hypercytokinaemia, secondary hemophagocytic lymphohistiocytosis, antibody dependent enhancement, complement system, and phagocytic cells activation can contribute in the virus pathogenesis leading to associated renal dysfunction. However, the role and crosstalk between of RAS components and immune response in mediating kidney injury remain undefined. In this review, we focus on the recent studies to provide the pathogenesis of SARS-CoV-2 interacting with RAS and immune responses to mediate kidney injury.

Cell-penetrating peptides (CPPs) have been evaluated as enhancers in drug delivery, their addition in medical formulations favors absorption allowing obtaining the pharmacological effect with lower drug doses. In vaccine formulations their inclusion has been also explored with interesting results. Currently mucosal vaccination constitutes a promising alternative with the main advantage of inducing both systemic and mucosal immune responses, which are crucial for control tumors and infections at mucosal tissues. The known CPP Penetratin was recently evaluated in vaccine formulations designed for nasal administration. The authors demonstrated that this non-covalent linked CPP could improve the antigen-specific systemic and mucosal antibody responses. In the present work we evaluate in Balb/C mice the nasal immune-enhancing effect of four CPPs. Animals were intranasally immunized with CPP and the recombinant hepatitis B surface protein (HBsAg) as model antigen. The IgG antibody response in sera and the mucosal IgA response were measured by ELISA. The IFN-g secretion response at spleen was also evaluated by ELISPOT and ELISA. Among the CPPs studied one novel peptide stand out by its ability to potentiate the humoral and cellular immune response against the co-administered antigen. Considering that the use of mucosal routes is a promising strategy in vaccination against infectious diseases and cancer, which are gaining special relevance nowadays in the development of novel candidates against SARS-CoV-2 and other potential emerging respiratory virus, the searching and development of safe mucosal adjuvants constitute a current need.

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spirals down to immune cell activation and chronic state of low‐level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback-loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.

An immune-inflammatory response is accompanied by increased nitro-oxidative stress. The aims of this mechanistic review are to review: a) the role of redox sensitive transcription factors and enzymes, ROS/RNS production and the activity of cellular antioxidants on the activation and performance of macrophages, dendritic cells, neutrophils, T cells, B cells and natural killer cells; b) the involvement of high-density lipoprotein (HDL), apolipoprotein (Apo)A1, paraoxonase (PON)-1, and oxidized phospholipids in the regulation of the immune response; and c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor (NF)-κB, HIF1alpha, the mechanistic target of rapamycin (mTor), the phosphatidylinositol 3‑kinase (PI3K) / protein kinase B (AKT) signalling pathway, mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR). The performance and survival of individual immune cells is under redox control and sensitive to intracellular and extracellular levels of ROS/RNS and is heavily influenced by cellular anti-oxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2 (Nrf-2), and the HDL complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, those redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although very limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which is able to stabilize the effector cells becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allows a great improvement in the management of asthma.

The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

Background. The aim of this study is to examine whether biomarkers of the immune-inflammatory response (IRS) and endogenous opioid (EOS) systems are associated with affective symptoms in schizophrenia. Methods. We recruited 115 schizophrenia patients and 43 healthy controls and assessed the Hamilton Depression (HDRS) and Anxiety (HAM-A) rating Scale scores as well as serum levels of interleukin (IL)-6, IL-10, eotaxin (CCL11), high mobility group box 1 (HMGB1), Dickkopf-related protein 1 (DKK1), and mu (MOR) and kappa (KOR) opioid receptors.Results. The HDRS and HAM-A scores are significantly and positively correlated with a) psychosis, hostility, excitation, mannerism, negative symptoms, psychomotor retardation, and formal thought disorders; and b) lowered scores on semantic and episodic memory, executive functions, and attention tests as measured with the Brief Assessment of Cognition in Psychiatry. Both HDRS and HAM-A are significantly increased in non-responders to treatment as compared with partial responders. Both affective scores are strongly associated with latent vectors extracted from all symptoms, reflecting overall severity of psychosis (OSOS), and neurocognitive test scores, reflecting a generalized cognitive decline (G-CoDe). The HDRS score was strongly and positively associated with IL-6, HMGB1, KOR, and MOR levels, and the HAM-A score with IL-6, IL-10, CCL11, HMGB1, KOR, and MOR levels. A single latent trait may be extracted from OSOS, G-CoDe, and the HDRS and HAMA scores, and this latent vector score is strongly predicted by HMGB1, MOR, and DKK1.Conclusion. Immune-inflammatory and EOS pathways contribute to the phenome of schizophrenia, which comprises OSOS, affective, and physiosomatic symptoms, and G-CoDe.

Covid-19 disease is caused by SARS Cov-2 virus. Despite its high transmissibility, the CFR (Case Fatality Rate) of COVID-19 seems to be lower than the SARS (9,5%) and MERS (34,4%) ones⁹³ , but higher than the influenza one (0-1%)^94,95 . The disease is asymptomatic or paucisymptomatic in most of the patients, although in few cases it can be characterized by serious complications. The main causes of hospitalization in intensive care are represented by ALI (Acute Lung Injury), ARDS (Acute Respiratory Distress Syndrome), cardiovascular problems and coagulopathies (diffuse thrombosis, microthrombosis, embolisms, myocarditis, arrhytmias, heart failure, stroke)^96-98, acute nephropathy^99,100 and encephalopathies¹⁰¹. The virus presence in the vascular wall can cause endotheliitis, which triggers the process of diffuse coagulation that can lead to a worsening of the systemic inflammation. The exaggerated inflammatory response seems to be connected with the development of ARDS, MOF (Multiple Organ Failure) and coagulopathies^102-107.

Objective: The purpose of this study was to determine if Porphyra tenera extract (PTE) has immune-enhancing effects and is safe in healthy adults. Methods: Subjects (3x10³ ≤ peripheral blood leukocyte levels < 8x10³ cells/μl) who met the inclusion criteria were recruited for this study. Enrolled subjects (n=120) were randomly assigned to either the PTE group (n=60) who were given 2.5 g/day of PTE (as Porphyra tenera extract) in capsule form or the placebo group (n=60) who were given crystal cellulose capsules with the identical appearance, weight, and flavor as the PTE capsules for 8 weeks. Outcomes were assessed by measuring natural killer cell (NK-cell) activity, cytokines, and upper respiratory infection (URI), and safety parameters were assessed at baseline and 8 weeks. Results: Compared to baseline, NK cell activity (%) increased for all effector cell to target cell ratios in the PTE group after 8 weeks, but there were no changes in the placebo group (p<0.1). Subgroup analysis of 101 subjects without an URI revealed that NK-cell activity in the PTE group tended to be increased for all E:T ratios (E:T=12.5:1 p=0.068; E:T=25:1 p=0.036; E:T=50:1 p=0.081) compared to the placebo group. There was a significant difference between these two groups for the E:T=25:1 ratio, which increased from 20.3±12.0% at baseline to 23.2±12.4% after 8 weeks in the PTE group (p=0.036). There was no significant difference in levels of cytokines between these two groups. Conclusions: PTE supplementation appears to enhance immune function by improving NK-cell activity without adverse effects in healthy adults.

Neutrophils play an important role as the first line of innate immune defense. One function of neutrophils, called neutrophil extracellular traps (NETs), has been discovered recently. NETs are extensive fibrous structures released extracellularly from activated neutrophils in response to infection. They are composed of cytosolic protein assembled on a scaffold of released chromatin. These structures suppress the dissemination of micro-organisms in blood by trapping them mechanically, and by exploiting coagulant function to segregate them within the circulation. In addition, NET components (DNA, histone, and granule proteins) also contribute to the triggering of an inflammatory process. NET function, however, can be regarded as a double-edged sword. On one hand, NET formation is an efficient strategy for neutralizing invading micro-organisms. On the other hand, NET can be harmful to the host, as its exposed by-products that are toxic to endothelial cells and parenchymal tissue. We present here the analogous biological and physiological features of the harmful positive amplification loop between inflammation and tissue damage induced by NETosis dysregulation and Coronavirus Disease-2019 (COVID-19) pathogenesis. Considering the rapid evolution of this disease symptoms and its lethality, we hypothesize that COVID-19 progresses under an amplifier loop, leading to an massive, uncontrolled inflammation process. We also describe the correlations of COVID-19 symptoms and biological features with those consecutive to uncontrolled NET formation causing various sterile or infectious diseases. General clinical conditions, and numerous pathological and biological features, are analogous with NETs deleterious effects. We postulate that Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2) induces a disproportionate virus-induced NET release, and that this plays a key role in COVID-19 pathogenesis. While neutrophils are the principal starting point for extracellular and circulating DNA release, targeting NETs rather than neutrophils themselves may stand for an effective strategy. This paper offers an in-depth review of NET formation, function and pathogenic dysregulation, as well as of current and future therapies to control NET unbalance. As such, it enables us also to suggest new therapeutic strategies to fight COVID-19. In combination with or independent of the latest tested approaches, we propose that, in the short term, deoxyribonuclease I (DNase-1) treatment should be evaluated; we also advocate a significant increase in research on the development of toll-like receptors (TLR) and C-type Lectin like receptors (CLEC) inhibitors, and on anti-IL26 therapies.

The coronavirus COVID-19 epidemic has wreaked havoc on inhabitants of earth killing thousands of humans from more than 150 countries. The epidemic has put a number of countries under complete lockdown and the deadly situation is still prevailing around the globe. Vaccines have been long known as the most effective means of preventing viral infections. However, the lack of vaccines against COVID-19 has further worsened the situation. In this time of health crisis, it is the duty of scientific research community to provide alternative, effective and affordable strategies to vaccinate human bodies against viral infections-COVID-19 based on focused experimental approaches. Growing evidence suggests that certain natural foods and lifestyle changes have potential to optimize immune functions against viral infections including improving defense function, resistance towards invading pathogens, while maintaining self-tolerance. Boosting immune system gives an edge in fending off viruses and staying healthy. This review presents the six smart steps to add to your to-do list which let the inner work of immunity take place against viral infections-COVID-19 by dissolving the powers of disease and illness. Many of these factors are associated in their functions to improve or properly maintain the immune function such as promoting anti-inflammatory functions, inhibiting pro-inflammatory mediators, modulating cell-mediated immunity, altering the antigen-presenting cellular functions as well as promoting communication between the innate and adaptive immune responses. Thus, a scientific illustration of boosting the immune system by proper sleep, moderate exercise, avoiding stress, utilizing vitamins enriched foods, intake of more water and use of fruits and vegetables will hopefully help the community to deal with the coronavirus by vaccinating the human systems naturally.

The outbreak of the 2019 Novel Coronavirus (2019-nCoV) has rapidly spread from Wuhan, China to multiple countries, causing staggering number of infections and deaths. A systematic profiling of the immune vulnerability landscape of 2019-nCoV is lacking, which can bring critical insights into the immune clearance mechanism, peptide vaccine development, and antiviral antibody development. In this study, we predicted the potential of all the 2019-nCoV viral proteins to induce class I and II MHC presentation and form linear antibody epitopes. We showed that the enrichment for T cell and B cell epitopes is not uniform on the viral genome, with several focused regions that generate abundant epitopes and may be more targetable. We showed that genetic variations in 2019-nCoV, though fewer for the moment, already follow the pattern of mutations in related coronaviruses, and could alter the immune vulnerability landscape of this virus, which should be considered in the development of therapies. We create an online database to broadly share our research outcome. Overall, we present an immunological resource for 2019-nCoV that could significantly promote both therapeutic development and mechanistic research.

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in schizophrenia patients with (n=40) and without (n=40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial Least Squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

In Schizophrenia, pathway-genotypes may be constructed by combining interrelated immune biomarkers with changes in specific neurocognitive functions that represent aberrations in brain neuronal circuits. These constructs provide insight on the phenome of schizophrenia and show how pathway-phenotypes mediate the effects of genome X environmentome interactions on the symptomatology/phenomenology of schizophrenia. Nevertheless, there is a lack of knowledge how to construct pathway-phenotypes using Partial Least Squares (PLS) path modeling and Soft Independent Modeling of Class Analogy (SIMCA). This paper aims to provide a step-by-step utilization guide for the construction of pathway-phenotypes that reflect aberrations in the neuroimmune - brain circuit axis (NIBCA) in deficit schizophrenia. This NIBCA index is constructed using immune biomarkers (CCL-2, CCL-11, IL-1β, sIL-1RA, TNF-α, sTNFR1, sTNFR2) and neurocognitive tests (Brief Assessment of Cognition in Schizophrenia) predicting overall severity of schizophrenia (OSOS) in 120 deficit SCZ and 54 healthy participants. Using SmartPLS path analysis, a latent vector is extracted from those biomarkers and cognitive tests, which shows a good construct reliability (Cronbach alpha and composite reliability) and replicability and which is reflectively measured through its NIBCA manifestations. This NIBCA pathway-phenotype explains 75.0% of the variance in PHEMN (psychotic, hostility, excitation, mannerism and negative) symptoms. Using SIMCA, we constructed a NIBCA pathway-class that defines deficit schizophrenia as a qualitatively distinct nosological entity and which allows patients with deficit schizophrenia to be authenticated as belonging to the deficit schizophrenia class. In conclusion, our nomothetic approach to develop a nomological network combining neuro-immune and neurocognitive phenome markers to predict OSOS and cross-validate a diagnostic class generated replicable models reflecting the key phenome of the illness, which may mediate the effects of genome X environmentome interactions on the final outcome phenome features, namely symptomatology and phenomenology.

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity.Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia (“OSOS”); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in the OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

This study analyzes oral supplement of molecular iodine (I2) alone and in combination with the neoadjuvant therapy 5-fluorouracil/epirubicin/cyclophosphamide or taxotere/epirubicin (FEC/TE) in women with Early (stage II) and Advanced (stage III) breast cancer. In the Early group, 30 women were treated with I2 (5 mg/day) or placebo (colored water) for 7–35 days before surgery. For the Advanced group, 30 patients received I2 or placebo along with FEC/TE treatment. After surgery, all patients received FEC/TE + I2 for 170 days. I2 supplementation showed a significant attenuation of the side effects and absence of tumor chemoresistance. Control, I2, FEC/TE, and FEC/TE+I2 groups exhibit response rate of 0, 33%, 73%, and 100%, respectively, and a pathologic complete response of 18%, and 36% in the last two groups. Five-year disease-free survival rate was significantly higher in patients with I2 supplement before and after surgery compared to those receiving the supplement only after surgery (82% vs. 46%). I2-treated tumors exhibit less invasive potential, and significant increases in apoptosis, estrogen receptor expression, and immune cell infiltration. Transcriptomic analysis indicated activation of the antitumoral immune response. The results led us to register a phase III clinical trial analyzing chemotherapy + I2 treatment for advanced breast cancer.

Schizophrenia comprises various symptom domains, including positive and negative symptoms. Machine learning showed that a) negative symptoms are significantly interrelated with PHEM (psychosis, hostility, excitation, and mannerism) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR); and b) stable phase schizophrenia comprises two distinct classes, namely Major Neuro-Cognitive Psychosis (MNP, largely overlapping with deficit schizophrenia) and Simple NP (SNP). In this study, we recruited 120 MNP patients and 54 healthy subjects and measured the above-mentioned symptom domains. In MNP, there were significant associations between negative and PHEM symptoms, FTD and PMR. A single latent trait, which is essentially unidimensional, underlies these key domains of schizophrenia and MNP and additionally shows excellent internal consistency reliability, convergent validity, and predictive relevance. Confirmatory Tedrad Analysis indicates that this latent vector fits a reflective model. The lack of discriminant validity shows that PHEM and negative symptoms greatly overlap and probably measure the same construct. Soft Independent Modeling of Class Analogy (SIMCA) shows that MNP (diagnosis based on negative symptoms) is better modeled using PHEM symptoms, FTD, and PMR than negative symptoms. In conclusion, in stable phase MNP, a restricted sample of the schizophrenia population, negative and PHEM symptoms, FTD and PMR belong to one underlying latent vector reflecting overall severity of schizophrenia (OSOS). The bi-dimensional concept of “positive” and “negative” symptoms cannot be validated and, therefore, future research in stable phase schizophrenia should consider that the latent phenomenon OSOS as well as its 8 reflective manifestations are the key factors of schizophrenia phenomenology.

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They are invisible to antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation, and “educate” (i.e., reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies, targeting not only tumor cells but also the tumor microenvironment, are being developed. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become protective or immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

Rationale: Major depressive disorder (MDD) is characterized by signaling aberrations in interleukin (IL)-6, IL-10, beta-endorphins as well as mu (MOR) and kappa (KOR) opioid receptors. Here we examined whether these biomarkers may aid in the classification of unknown subjects into the target class MDD.Methods: The aforementioned biomarkers were assayed in 60 first-episode, drug-naïve depressed patients and 30 controls. We analyzed the data using joint principal component analysis (PCA) performed on all subjects to check whether subjects cluster by classes; support vector machine (SVM) with 10-fold validation; and linear discriminant analysis (LDA) and SIMCA performed on calibration and validation sets and we computed the figures of merit and learnt from the data. Results: PCA shows that both groups were well separated using the first three PCs, while correlation loadings show that all 5 biomarkers have discriminatory value. SVM and LDA yielded an accuracy of 100% in validation samples. Using SIMCA there was a highly significant discrimination of both groups (model-to-model distance=87.5); all biomarkers showed a significant discrimination and modeling power, while 10% of the patients were identified as outsiders and no aliens could be identified.Discussion: We have delineated that MDD is a distinct class with respect to neuro-immune and opioid biomarkers and that future unknown subjects can be authenticated as having MDD using this SIMCA fingerprint. Precision psychiatry should employ SIMCA a) to authenticate patients as belonging to the claimed target class and identify other subjects as outsiders, members of another class or aliens; and b) to acquire knowledge through learning from the data by constructing a biomarker fingerprint of the target class.

Deficit schizophrenia is characterized by leaky tight and adherens junctions and bacterial translocation. Here we examine whether (deficit) schizophrenia is accompanied by leaky paracellular, transcellular and vascular barriers in the gut and blood brain barriers. We measured IgA responses to occludin, claudin-5, E-cadherin and β-catenin (paracellular pathway, PARA), talin, actin, vinculin and epithelial intermediate filament (transcellular pathway, TRANS) and plasmalemma vesicle-associated protein (PLVAP, vascular pathway) in 78 schizophrenia patients and 40 controls. IgA responses to claudin-5, E-cadherin and β-catenin, the sum of the four PARA proteins and the ratio PARA/TRANS were significantly higher in deficit schizophrenia than in non-deficit schizophrenia and controls. A large part of the variance in PHEMN (psychosis, hostility, excitation, mannerism and negative) symptoms, psychomotor retardation, formal thought disorders, verbal fluency, word list memory, word list recall and executive functions was explained by the PARA/TRANS ratio coupled with plasma IgA responses to Gram-negative bacteria, IgM to malondialdehyde, CCL-11 (eotaxin), IgA levels of the ratio of noxious to more protective tryptophan catabolites (NOX/PRO TRYCATs) and a plasma immune activation index. Moreover, IgA levels to Gram-negative bacteria were significantly associated with IgA to E-cadherin, β-catenin and PLVAP, while IgA levels to claudin-5 were significantly predicted by IgA to E-cadherin, NOX/PRO TRYCAT ratio, Gram-negative bacteria and CCL11. The phenomenology of the deficit syndrome is to a large extent explained by the cumulative effects of lowered natural IgM, breakdown of the paracellular and vascular pathways, increased bacterial translocation, peripheral immune-inflammatory responses and indices of BBB breakdown.

A new mathematical model is presented to study the effects of macrophages on the bone fracture healing process. The model consists of a system of nonlinear ordinary differential equations that represents the interactions among classically and alternatively activated macrophages, mesenchymal stem cells, osteoblasts, and pro- and anti-inflammatory cytokines. A qualitative analysis of the model is performed to determine the equilibria and their corresponding stability properties. Numerical simulations are also presented to support the theoretical results and to monitor the evolution of a broken bone for different types of fractures under various medical interventions. The model can be used to guide clinical experiments and to explore possible medical treatments that accelerate the bone fracture healing process either by surgical interventions or drug administrations.

Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety.A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sex-related differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men and therefore females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through production of anxiogenic TRYCATs.

In plants and animals, endogenous biological molecules, termed damage-associated molecular patterns (DAMPs) or alarmins, are released by damaged, stressed or dying cells following abiotic stress such as radiation and drought stress. In turn, a cascade of downstream signaling events is initiated leading to the up-regulation of defense-related genes. In the present study, in an effort to investigate the conservation status of the molecular mechanisms implicated in the danger signaling, thorough in silico phylogenetic and structural analyses of the effector biomolecules were performed in taxonomically diverse plant species. On the basis of our results, the defense mechanisms appear to be largely conserved within the plant kingdom. Of note is our finding that the sequence and/or function of several components of these mechanisms were found to be conserved in animals, as well.

It has recently been discovered that mere cell contact by human cytomegalovirus (CMV) particles leads to profound modulation of cellular gene expression. Reduced monocyte human leukocyte antigen (HLA-DR) expression is a novel biomarker of severity and outcome in many diseases. Modulation of CD14 protein by CMV was shown in vitro, but little is known about the phenomenon in vivo (during active cytomegalovirus disease). Therefore, we investigated monocyte CD14 and HLA-DR expression in CMV infected patients in relation to logarithmic phase of infectious process. Samples from patients with active CMV replication (exponential growth of CMV viremia) were tested. After CD45/SSC gating monocyte CD14 and HLA-DR expression were determined by double-color flow-cytometry. Significant monocytosis and poor correlation between CMV replication and CD14+HLA-DR(-) cells prompted CD14 investigation. During logarithmic phase of CMV infection increased count and percentage of CD14low monocytes were observed which correlated with viral replication in several clinical situations except when there was a rapid recovery without relapse. Furthermore, most of CD14low monocytes are HLA-DR+. The increase of CD14low monocytes is also observed under the influence of high dose of glucocorticoids (20 mg of dexamethasone). The reduction in CD14 induced by CMV and dexamethasone indicates that the monocyte balance is disturbed between the classical and non-classical phenotype. A high percentage of CD14lowHLA-DR+ probably gives rise to adaptive and a decrease of innate immune response. In light of the logarithmic increase of viral load (with exponent between 3,23 and 5,77), high monocytosis above 1200 / µl is a hallmark of CMV replication.

Gastric cancer is among the prevalent types of cancer that cause high mortality rates globally, due to which worrisome new therapeutic approaches cannot be ruled out. The present review aims at providing an extensive overview of the recent development in the field of immunotherapy for gastric cancer, with a special reference to exosomes and their potential for regulating tumor progression. In this review, we provide a stepwise approach towards understanding of the status of knowledge of exosomes in intercellular communication comprehensively discussing biochemical contents, immune modulation, drug resistance and disease progression. Inclusive in our search strategy are the articles published in the last 15 years, and using keywords such as “exosomes,” “immunotherapy,” and “gastric cancer.” For this systematic review, two rounds of article filtering were conducted before reviewing of the articles and their findings thoroughly. This field’s specific areas of focus embrace the functionalities attached to the exosome-associated microRNAs, processes on which the exosome signalling depends on, and the utilization of non-tumor cell-derived exosomes in the tumor microenvironments. Combining these findings, this review seeks to systematically identify and discuss the roles of exosomes in biomarkers and novel targets for GC treatment. In conclusion, our current study supports further exploration of the application of exosomal biology to enhance immunotherapeutic approaches in gastric cancer treatment.’

Objectives: This study focused on the presence or absence of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma (HCC) and examined their impact on systemic treatment outcomes. Methods: We retrospectively analyzed 362 patients with unresectable HCC who received first-line systemic therapy. The prognostic evaluation was based on the presence of vascular invasion and extrahepatic metastasis at the time of treatment initiation. Results: Patients with vascular invasion or extrahepatic metastasis (advanced group) had significantly worse outcomes than those without these features (intermediate group), with median survival times of 434 and 658 days, respectively. Further subdivision of the advanced group into three categories—patients with only extrahepatic metastasis (m group, n = 77), patients with only vascular invasion (v group, n = 78), and patients with both vascular invasion and extrahepatic metastasis (vm group, n = 52)—revealed that the m group had significantly better outcomes than those in the other two groups, with median survival times of 649, 323, and 187 days, respectively. A comparison of the clinical backgrounds among the three groups demonstrated that the m group had significantly better liver function at the time of treatment initiation than that in the other two groups. Multivariate analysis, including performance status, Child–Pugh score, and the use of immune checkpoint inhibitors as first-line therapy, identified the m group as an independent and significant prognostic factor (hazard ratio, 0.50). Conclusions: Unresectable HCC with extrahepatic metastasis and no vascular invasion represents a novel staging category for systemic treatment.

Endocrine-disrupting chemicals (EDCs) significantly damage biological systems related to reproductive, neurological, and metabolic functions. Approximately 1,000 chemicals are known to possess endocrine-acting properties, including bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP). This study primarily focuses on the potential effects of EDCs on the transcriptional levels of innate immune prophenoloxidase (proPO) system-related genes to oxidative stress in the gonad and stomach of the mud crab Macrophthalmus japonicus, an indicator species for assessing coastal benthic environments, when exposed to BPA or DEHP. After EDC exposure, the expression of lipopolysaccharide and β-1,3-glucan-binding protein (LGBP), a pattern recognition protein that activates the proPO system, was upregulated in the stomach of M. japonicus, whereas LGBP gene expression was downregulated in the gonad. In the gonad, which is a reproductive organ, EDC exposure mainly induced the transcriptional upregulation of trypsin-like serine protease (Tryp) at relatively low concentrations. In the stomach, which is a digestive organ, LGBP expression was upregulated at relatively low concentrations of EDCs over 7 days, whereas all proPO system-related genes (LGBP, Tryp, serine protease inhibitor (Serpin), and peroxinectin (PE)) responded to all concentrations of EDCs. These results suggest that the antioxidant and immune defense responses of the proPO system to EDC toxicity may vary, causing different degrees of damage depending on the tissue type in the mud crab.

The interplay between the human gut microbiota and the peripheral immune system significantly affects the efficacy of immune checkpoint inhibitors (ICIs) in cancer therapy. Despite this profound connection, the practical implications of microbiota dysbiosis in cancer immunotherapy ICIs & and CAR-T remain intricate and poorly understood in practical terms. This paper offers a comprehensive review of current literature on the role of gut microbiota dysbiosis in tumor development, and emerging microbiota modulation interventions, with a focus on fecal microbiota transplantation (FMT). FMT is a cost-effective therapeutic avenue, particularly in addressing diseases rooted in antibiotic-resistant bacteria, such as Clostridium difficile. Here we provided insights into the applications of FMT and other gut microbiota therapies in the landscape of cancer treatment, emphasizing their influence on the tumor microenvironment and the efficacy of ICIs with suggestions for future research directions and their implications for clinical practice.

This study simulated the effects of direct predatory pressure, indirect predatory pressure, and conspecific injury signals on the sea cucumber (Apostichopus japonicus) to determine changes in the activity of immune defense enzymes (lysozyme, acid phosphatase, alkaline phosphatase) and antioxidant stress enzymes (catalase, superoxide dismutase, malondialdehyde). Samples of sea cucumber juveniles were collected at 3 hours, 12 hours, 72 hours, and 96 hours post-predatory stress, and six enzymes related to immune defense and antioxidant stress were selected for activity assays, namely lysozyme (LZM), acid phosphatase (ACP), alkaline phosphatase (AKP), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). The results indicated that under direct predatory pressure, the activity of catalase in sea cucumbers was significantly higher than that of the control group at 3 hours (P < 0.05), while the activities of acid phosphatase, alkaline phosphatase, and catalase were significantly lower at 72 hours (P < 0.05). Under indirect predatory pressure, the activity of malondialdehyde in sea cucumbers was significantly higher than that of the control group at 12 hours (P < 0.05), the activity of alkaline phosphatase was significantly higher at 72 and 96 hours (P < 0.05), catalase was significantly lower at 72 hours, and the activity of superoxide dismutase was significantly higher at 72 hours (P < 0.05). Under the influence of conspecific injury signals, the activity of malondialdehyde in sea cucumbers was significantly higher than that of the control group at 12 hours (P < 0.05), and the activity of superoxide dismutase was significantly higher at 96 hours (P < 0.05). The sea cucumber enhanced its antioxidant capacity 3 hours after facing the predator, while its immune defense mechanism was suppressed at 72 hours. When facing indirect predatory pressure, the sea cucumber may have made immune and antioxidant preparations for the arrival of unknown risks. The experimental results show that predatory pressure has a significant impact on the immune and antioxidant functions of sea cucumbers, which may be related to the physiological state and environmental adaptability of the sea cucumber. This study provides a new perspective for understanding how sea cucumbers cope with predatory pressure in the natural environment and offers theoretical support for the cultivation management of sea cucumbers.

Systemic inflammation and immunodeficiency are the key components of Cirrhosis Associated Immune Dysfunction (CAID); its severity is dynamic and progressive and is associated with the greater deterioration of the liver function. There are two different immune phenotypes: the low-grade systemic inflammation phenotype and the high-grade systemic inflammation phenotype. Each of these phenotypes is related with the function of liver cirrhosis; thus, the presence of high-grade inflammation is correlated with the severity of the hepatic insufficiency, the bacterial translocation, and the organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation plays a relevant role in the persistent systemic inflammation in patients with cirrhosis; the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.

Neonatal hypoxic ischemic encephalopathy (HIE) occurs in 1.5 per 1000 live births, leaving affected children with long-term motor and cognitive deficits. Few animal models of HIE incorporate maternal immune activation (MIA) despite the significant risk MIA poses to HIE incidence and diagnosis. Our non-invasive model of HIE pairs late gestation MIA with postnatal hypoxia. HIE pups exhibited a trend toward smaller overall brain size and delays in the ontogeny of several developmental milestones. In adulthood, HIE animals had reduced strength and gait deficits, but no difference in speed. Surprisingly, HIE animals performed better on the rotarod, an assessment of motor coordination. There was significant upregulation of inflammatory genes in microglia 24 hours after hypoxia. Single cell RNAseq revealed two microglia subclusters of interest following HIE. Pseudobulk analysis revealed increased microglia motility gene expression and upregulation of epigenetic machinery and neurodevelopmental genes in macrophages following HIE. No sex differences were found in any measures. These results support a two-hit noninvasive model pairing MIA and hypoxia as a model for HIE in humans. This model results in a milder phenotype compared to established HIE models; however, HIE is a clinically heterogeneous injury resulting in a variety of outcomes in humans. The pathways identified in our model of HIE may reveal novel targets for therapy for neonates with HIE.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) shows that inflammation starts early and progresses with age. B cells play a central role in this process, contributing to cytokine production, defective regulatory functions, and abnormal immunoglobulin production, even in the central nervous system. Anti-CD20 (aCD20) therapies, which deplete CD20+ B cells, are effective for both relapsing-remitting (RR) and progressive-relapsing (PR) MS. While effective against MS symptoms and lesions detectable by magnetic resonance imaging, aCD20 therapies can reduce the immune response to COVID-19 vaccination. By using high-parameter flow cytometry, we examined the antigen-specific (Ag+) immune response six months post-third COVID-19 mRNA-vaccination in MS patients with RR and PR forms on aCD20 therapy. Despite lower Ag+ B cell responses and lower levels of anti-SARS-CoV2, both total and neutralizing antibodies, RR and PR patients developed strong Ag+ T cell responses. We observed similar percentages and numbers of Ag+ CD4+ T cells and high proportion of Ag+ CD8+ T cells, with slight differences in T cell phenotype and functionality, that however suggested the presence of differences in immune responses driven by age and disease severity.

The role of the microbiome in cancer and its crosstalk with the tumor microenvironment (TME) has been extensively studied and characterized. An emerging field in the cancer microbiome research is the concept of the intratumoral microbiome, which refers to the microbiome residing within the tumor. This microbiome primarily originates from the local microbiome of the tu-mor-bearing tissue or from translocating microbiome from distant sites, such as the gut. Despite the increasing number of studies on intratumoral microbiome, it remains unclear whether it is a driver or a bystander of oncogenesis and tumor progression. This review aims to elucidate the intricate role of the intratumoral microbiome in tumor development by exploring its effects on reshaping the multi-leveled ecosystem in which tumors thrive, the TME. To dissect the complexity and the multitude of layers within the TME, we distinguish six specialized tumor microenvironments, namely the immune, metabolic, hypoxic, acidic, mechanical and innervated microenvironments. Accordingly, we attempt to decipher the effects of the intratumoral microbiome on each specialized microenvironment and ultimately decode its tumor-promoting or tumor-suppressive impact. Additionally, we portray the intratumoral microbiome as an orchestrator in the tumor milieu, fine-tuning the responses in distinct, specialized microenvironments and remodeling the TME in a multi-leveled and multi-faceted manner.

Skeletal muscle (SKM), despite comprising ~40% of body mass, is rare. This review explores the mechanisms that help to explain this rarity, including unique SKM architecture and function, which prohibits development of new cancer as well as negates potential metastasis to SKM. SKM also presents a unique immune environment that may magnify the anti-tumorigenic effect. Moreover, the SKM microenvironment manifests characteristics such as decreased extracellular matrix stiffness and altered lactic acid, pH, and oxygen levels that may interfere with tumor development. SKM also secretes anti-tumorigenic myokines and other molecules. Collectively, these mechanisms help account for the rarity of SKM cancer.

In this article, we consider the relationship between the brain and the immune system in the context of the Orch OR (Orchestrated Objective Reduction) theory of consciousness. Orch OR is a theory that postulates that consciousness arises from quantum computations occurring inside microtubules. The immune system is capable of acquiring, learning, and remembering information, thus showing all the attributes of natural intelligence. We argue that the immune system also has the attribute of consciousness and can gain access to an amount of information greater than what is accessible to the brain since it is not constrained by brain's reducing valve that is responsible for cognitive bottlenecks. We also describe the role of meditation and religious chanting in affecting the brain and immune system. We speculate that some effects of religious chanting on the immune system may not be mediated by the brain. Finally, we examine the role of the immune system in connecting with the consciousness embedded in the universe.

A number of studies suggested that influenza vaccination can provide protection against COVID-19 but the underlying mechanisms that could explain this association is still unclear. In this study, the effect of the 2021/2022 seasonal influenza vaccination on the immune response to the booster dose of anti-SARS-CoV-2 vaccination was evaluated in a cohort of healthy individuals. One hundred and thirteen participants were enrolled, and 74 of them with no prior COVID-19 diagnosis or significant co-morbidities were considered for the analysis. Participants received the anti-influenza tetravalent vaccine and the booster dose of the anti-SARS-CoV-2 vaccine or the anti-SARS-CoV-2 vaccine alone. Blood was collected before and 4 weeks after each vaccination and 12 weeks after SARSCoV2 vaccination and analyzed for anti-flu and anti-spike-specific antibody titers and for in vitro influenza and SARS-CoV-2 neutralization capacity. Results indicated an increased reactivity in subjects who received both influenza and SARSCoV2 vaccinations, as compared to those who received only the SARS-CoV-2 vaccine, with sustained anti-spike antibody titers up to 12 weeks post-vaccination. Immune response to influenza vaccine was evaluated and individuals were stratified as high or low responders. High responders showed increased antibody titers against SARSCoV2 vaccine both after 4- and 12-weeks post-vaccination. On the contrary, the individuals classified as low responders were less responsive to the SARS-CoV-2 vaccine. These data indicate that both external stimuli, such as influenza vaccination, and the host's intrinsic ability to respond to stimuli play a role in the response to vaccine.

Atherosclerosis, a complex metabolic-immune disease characterized by a chronic inflammation driven by the buildup of lipid-rich plaques within arterial walls, has emerged as a pivotal factor in the intricate interplay between cancer and cardiovascular disease. This bidirectional relationship, marked by shared risk factors and pathophysiological mechanisms, underscores the need for a comprehensive understanding of how these two formidable health challenges intersect and influence each other. Cancer and its treatments can contribute to the progression of atherosclerosis while atherosclerosis with its inflammatory microenvironment can exert profound effects on cancer development and outcomes. Both cancer and cardiovascular disease involve intricate interactions between general and personal exposomes. In this review we want to summarize the state-of-the-art of translational data and try to show how oncologic studies on cardiotoxicity can broaden our knowledge of crucial pathways in cardiovascular biology with a positive impact on precision cardiology and cardioncology.

In this study, we investigated the role of Giardia EVs in cellular communication and their potential as vaccine candidates. Our findings revealed that Giardia EVs activate pro-inflammatory signalling cascades, including SAPK/JNK and ERK1/ERK2, as well as the NF-kB pathway, resulting in IκB-α degradation and p65 translocation to the nucleus, in mouse macrophages. Moreover, Giardia EVs increased the expression of genes encoding pro-inflammatory molecules, such as Il1β, Il6, Il4, Ptgs2, Nos2, and Tnf. Interestingly, Giardia EVs enhanced the maturation status of human Mo-DCs and significantly increased T-cell proliferation with a Th1 profile. Immunization studies demonstrated that Giardia EVs elicited antigen-specific antibodies, with IgG subclasses indicating a balance Th1/ Th2 response. Mass spectrometry analysis identified EV proteins (22 KDa and 50 KDa) that bind to serum antibodies of immunized mice including elongation factor 1-alpha, Alpha-7.3 giardin, tubulin, and Variant Surface Proteins (VSP), known antigenic proteins in Giardia infections. Overall, our results indicated that Giardia EVs modulate innate immune cells in vitro, induce antibody-based immune response in vivo, and contain conserved immunogenic proteins. Consequently, Giardia EVs hold promise as a cell-free vaccine candidate for giardiasis.

Opossums, native to the Americas, are unique marsupials with over 100 species. The Common Opossum and Virginia Opossum are notable species. They are nocturnal, omnivorous, and adapt to various habitats. Their reproduction involves a short gestation and marsupial pouch development. Despite their ecological benefits like seed dispersal and insect control, their proximity to human habitats exposes them to pathogens, posing public health risks. These include protozoa, helminths, and arthropods that can spread zoonotic parasites and vector-borne diseases. The marsupial immune system, including opossums, is complex, rivaling eutherian mammals. Key immune genes were identified in the grey short-tailed opossum genome. CD1 protein and VpreB surrogate light chain were also found. Marsupials are proposed as ideal models for studying developmental immunology. A West Indian opossum (Didelphis marsupialis) was found and examined. Blood tests revealed abnormalities, including a low white blood cell count and signs of anemia. The results contribute to understanding the species’ health and adaptability in the wild.

Porcine epidemic diarrhea virus (PEDV) has affected the pork industry worldwide and during outbreaks the mortality of piglets has reached 100%. Lipid nanocarriers are commonly used in the development of immunostimulatory particles due to their biocompatibility and slow-release delivery properties. In this study, we developed a lipid nanoparticle (LNP) complex based on glycyrrhizinic acid (GA) and tested its efficacy as an adjuvant in mice immunized with the recombinant N-terminal domain (NTD) of porcine epidemic diarrhea virus (PEDV) spike (S) protein (rNTD-S). The dispersion stability analysis (Z-potential–27.6 mV) confirmed the size and charge stability of the LNP-GA, demonstrating that the particles were homogeneously dispersed and strongly anionic, that favors nanoparticles binding with the rNTD-S protein, which showed a slightly positive charge (2.11 mV) by in silico analysis. TEM image of LNP-GA revealed nanostructures with a spherical-bilayer lipid vesicle (⁓100 nm). The immunogenicity of the LNP-GA-rNTD-S complex induced an efficient humoral response 14 days after the first immunization (P &lt; 0.05) as well as an influence on the cellular immune response by decreasing serum TNF-α and IL-1β concentrations, which was associated with an anti-inflammatory effect.

Coronaviruses are a large family of diverse enveloped RNA viruses found in numerous animal species. They are well-known for their ability to cross species barriers and have been transmitted from bats or intermediate hosts to humans on several occasions. Four of the seven human coronaviruses (hCoVs) are responsible for approximately 20% of common colds (hCoV-229E, -NL63, -OC43, -HKU1). Two others (SARS-CoV-1 and MERS-CoV) cause severe and frequently lethal respiratory syndromes but have only spread to very limited extents in human populations. In contrast, SARS-CoV-2, while exhibiting intermediate pathogenicity, has a profound impact on public health due to its enormous spread. In this review, we discuss which initial features of the SARS-CoV-2 Spike protein and subsequent adaptations to the new human host may have helped this pathogen to cause the COVID-19 pandemic. Our focus is on host forces driving changes in the Spike protein and their consequences for virus infectivity, pathogenicity, immune evasion and resistance to preventive or therapeutic agents. In addition, we discuss the significance and perspectives of broad-spectrum therapeutics and vaccines.

Immune-mediated necrotizing myopathy (IMNM) is a rare and severe disease that corresponds to a specific entity of idiopathic inflammatory myopathy. Patients with IMNM suffer from proximal muscle weakness, and present high levels of creatine kinase and necrotic myofibers. Anti-Signal Recognition Particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies (HMGCR) have recently been identified in two thirds of patients with IMNM and are used as a hallmark of the disease. In this review, we provide a detailed description of these antibodies and the tests used to detect them in the serum of patients. Based on in vitro studies and mouse models of IMNM, we will discuss the role of autoantibodies in the pathogenesis of the disease. Finally, in the light of the latest knowledge, we will conclude with a review of recent therapeutic approaches.

Alternaria alternata is a saprophyte and is also known to cause many opportunistic infections in humans. Alternaria infections are important factors of morbidity and mortality in im-mune-compromised and solid organ transplant (SOT). Sensitivity to the airborne fungus Alter-naria alternata is also believed to be a common cause of allergic asthma. Therapies are limited by the lack of knowledge about the role of individual fungal gene products and symptoms in im-mune-compromised and transplant patients. This review summarizes the published case studies on Alternaria alternata infections in transplant patients.

Thirty-six healthy 21-day-old weaned ternary piglets (Duroc × Landrace × Yorkshire) were randomly divided into 2 treatments with 18 replicates per treatment and 1 pig per replicate. The control group was fed with basal diet and the test group was fed with diets supplemented with 1 kg/t tea residue. The test period was 28 days. The results are as follows: The addition of tea residue in the diet has no significant effect on the growth performance of weaned piglets (P > 0.05), but it could significantly reduce the diarrhea rate of piglets from 1 to 7 days and 1 to 28 days (P < 0.05). Compared with the control group, the dietary supplementation of tea residue had no significant effect on nutrient apparent digestibility, plasma biochemical indexes and plasma immune indexes (P > 0.05), but increased the content of glutathione in plasma (P < 0.05). Tea residue had no significant effect on the morphology of jejunum and ileum of piglets (P > 0.05), but it could significantly reduce the content of chloride ion in feces (P < 0.05). Compared with the basal diet group, there was no significant difference in the relative expression of TMEM16A and CFTR mRNA in the colon of weaned piglets (P > 0.05). The whole-cell patch clamp recording showed that the TMEM16A and CFTR ion channels could be activated by ionomycin and forskolin, respectively. However, when the HT-29 cells transfected with TMEM16A and CFTR channels were treated with tea residue extract, it could significantly inhibit the chloride current of the TMEM16A and CFTR ion channels (P < 0.05).

The first 1000 days of life is a critical period that contributes significantly to the programming of an individual's future health. Among the many changes that occur during this period, there is growing evidence that the establishment of a healthy gut microbiota early in life plays an important role in the prevention of both short- and long-term health problems. Numerous publications suggest that the quality of gut microbiota colonization depends on several dietary factors, including breastfeeding. In this respect, a relationship between breastfeeding and the risk of inflammatory bowel disease (IBD) has been suggested. IBD are chronic intestinal diseases in which perinatal factors may be partly responsible for its onset. We propose to review the existence of links between breastfeeding and IBD, based on experimental and clinical studies. Overall, despite encouraging experimental data in rodents, the association between breastfeeding and the development of IBD remains controversial in humans, partly due to considerable heterogeneity between clinical studies. The duration of exclusive breastfeeding is probably decisive for its lasting effect on IBD. Thus, specific improvements in our knowledge could support dietary interventions targeting the gut microbiome, such as the early use of prebiotics, probiotics or postbiotics in order to prevent the disease.

Background：Increasingly, epidemiological surveys and experimental research findings indicate the involvement of immune cells in the onset and progression of prostate cancer. However, it remains unclear whether the relationship between specific immune cell types and prostate cancer is causal or influenced by bias. Through a two-sample Mendelian randomization design, our study aims to uncover the association between different immune cells and the risk of prostate cancer.Methods：A comprehensive study was conducted to investigate the association between immunophenotypes and prostate cancer risk. The study included a total of 731 immunophenotypes as potential exposure factors and analyzed data from 182,625 individuals of European ancestry from the UK Biobank. A screening of 12,097,504 single nucleotide polymorphisms (SNPs) was performed. The main analysis utilized the two-sample Mendelian randomization method with inverse variance weighting (IVW). Additionally, multiple analysis methods were combined, and various tests were conducted to assess heterogeneity and pleiotropy.Results：The resulting study showed a causal relationship between a total of 34 immune phenotypes and prostate cancer. Among them, the four immune phenotypes of CD62L- DC AC, CD19 on sw mem, FSC-A on plasmacytoid DC and HLA DR on monocyte simultaneously meet three or more statistical methods, suggesting a significant causal relationship with prostate cancer. Additionally, among the 34 immunophenotypes, CD28-CD8dim AC was shown to be positive in reverse Mendelian randomization. Most of these cell phenotypes have been reported to be potentially associated with prostate cancer.Conclusions：Our study demonstrates a causal link between immune cells and prostate cancer risk. Filled in the possible roles of all current immune cell pathways in the development and progression of prostate cancer. The next step is to verify the content and influencing mechanism of these immune phenotypes in cancer cells and adjacent cells through experiments, so as to provide new ideas and methods for the prevention and treatment of prostate cancer.

In the present study, bivalent nanovaccines of S. iniae and F. covae were administered by immersion vaccination at 30 and 40 days after hatching (DAH), and the third vaccination was orally administered by feeding at 50 DAH. Five different groups were designed: group 1 was set as the control group, and groups 2-4 were vaccinated using the same protocols. ELISA revealed that the levels of total IgM and specific IgM to S. iniae, and F. covae were significantly elevated in groups 2-4 at 10, 20, and 30 days after vaccination (DAV). A qRT‒PCR analysis of immune-related genes revealed significantly higher IgT expression in the vaccinated groups compared with the control group, as revealed by 44-100-fold changes in the vaccinated groups compared with the control (p &lt; 0.001) at every tested time point after vaccination. All vaccinated groups expressed IgM, MHCIIα and TCRα at significantly higher levels than the control group at 10 and/or 20 DAV (p &lt; 0.05). In the S. iniae challenge tests, the survival of vaccinated groups 2-4 ranged from 62.15 ± 2.11 to 75.70 ± 3.36%, which significantly differed from that of the control group (44.44 ± 1.92%). Similarly, all vaccinated groups showed higher survival rates of 68.89 ± 3.85 to 77.78 ± 5.09% during F. covae challenge than the control groups (50.00 ± 3.33%) (p &lt; 0.05).

Abatacept (CTLA4-Ig) – a monoclonal antibody which restricts T cell activation – is an effective treatment for rheumatoid arthritis (RA). Herein, we aimed to investigate for biomarkers of response to abatacept. We performed a detailed immunological profiling of CTLA4-treated RA patients’ peripheral blood (PB) cells and sera using flow cytometry and proteomics analysis, respectively. At 6 months of treatment, 34.5% of patients attained clinical response. Notably, baseline levels of Th1 and myeloid cell populations were significantly elevated in PB of responders compared to non-responders (P-value<0.05). Additionally, proteomics analysis revealed 10 amongst 303 molecules which were associated with clinical responses. Should the present data be confirmed in a larger cohort could be of clinical value.

Commercial formulates of beneficial microbes have been used to enrich the rhizosphere microbiome of tomato plants grown in pots located in a glasshouse. These plants have been subjected to attacks by soil-borne parasites, such as root-knot nematodes (RKNs), and herbivores, such as the miner insect Tuta absoluta. The development of both parasites and the symptoms of their parasitism were restricted in these plants with respect to plants left untreated. A mixture, named in the text as Myco, containing plant growth promoting rhizobacteria (PGPR), opportunistic biocontrol fungi (BCF), and arbuscular mycorrhizal fungi (AMF) was more effective in limiting pest damages than a formulate containing the sole AMF (Ozor). Therefore, Myco-treated plants inoculated with RKNs were taken as a model to further study which biocontrol agent (BCA) was specifically responsible of plant immunization and the molecular pathways exploited to achieve such an immunization. The PGPR contained in Myco were not able to reduce nematode infection, rather, they worsened symptoms on plants, compared with those observed on untreated plants. When plants were treated with suspensions of Bacillus subtilis at concentrations similar to those provided with Myco and then inoculated with RKNs, infection was actually more severe than that on untreated plants. Therefore, it was argued that both BCF and AMFwere the microorganisms that, colonizing roots, synergistically stimulate plant immune system against RKNs. Beneficial fungi lowered the activities of the defense supporting enzymes endochitinases and β-1,3-glucanase to be able to colonize the roots. However, as early as three days after nematode inoculation, these enzyme activities, and the expression of the encoding pathogenesis related genes (PR-2, PR-3) were found to be enhanced in roots with respect to not inoculated plants, thus indicating that plants had been primed against RKNs. Addition of paclobutrazol, which reduced salicylic acid (SA) levels in cells, and of diphenyliodonium chloride, which inhibits superoxides generation, completely abolished the repressive effect of Myco on nematode infection and presumably plant immune reaction. Inhibitors of copper enzymes and of the alternative cyanide-resistant respiration did not significantly alter resistance induction by Myco. When Myco-treated plants were subjected to a moderate water stress and inoculated with nematodes, they retained numbers of developed individuals in the roots similar to those present in regularly watered plants, in contrast to what occurred in roots of untreated stressed plants that hosted very few individuals because of poor nutrient availability.

Anthocyanins (ACNs) have attracted considerable attention for their potential to modulate the immune system. Research has revealed their antioxidant and anti-inflammatory properties, which play a crucial role in immune regulation by influencing key immune cells such as lymphocytes, macrophages, and dendritic cells. Moreover, ACNs contribute to maintaining a balance between proinflammatory and anti-inflammatory cytokines, thus promoting immune health. Beyond their direct effects on immune cells, ACNs significantly impact gut health and the microbiota, essential factors in immune regulation. Emerging evidence suggests that they positively influence the composition of the gut microbiome that enhance the immunomodulatory effects of ACNs. Furthermore, these compounds synergize with other bioactive substances, such as vitamins and minerals, further enhancing their potential as immune-supporting dietary supplements. However, detailed clinical studies must fully validate these findings and determine safe dosages for different populations. Incorporating these natural compounds into functional foods or supplements can revolutionize the management of immune-related conditions. Personalized nutrition and healthcare strategies can be developed to enhance overall well-being and immune resilience by fully understanding the mechanisms underlying their actions. Recent advancements in delivery methods have focused on improving the bioavailability and effectiveness of ACNs, providing promising avenues for future applications.

The Receptor Binding Domain (RBD) of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is the functional region of the viral Spike protein (S), which is involved in cell attachment to target cells. The virus has accumulated progressively mutations in its genome, particularly in the RBD region, many of them associated with immune evasion to the host neutralizing antibodies. Some of the viral lineages derived from this evolution, have been classified as Variant of Interest (VOI) or Concern (VOC). The neutralizing capacity of a F(ab’)2 preparation from sera of horses immunized with viral RBD was evaluated, by lytic plaque reduction assay, against different SARS-CoV-2 variants. A F(ab’)2 preparation of an hyperimmune serum with 15 immunizations with RBD, exhibited a high titer of neutralizing antibodies against the ancestral-like strain (1/18,528). A reduction in the title of the F(ab’)2 preparation was observed against the different variants tested. The highest reduction was observed for the Omicron VOC (4.7 fold), followed by the Mu VOI (2.6), Delta VOC (1.8 fold) and Gamma VOC (1.5). Even if a progressive reduction in the neutralizing antibodies titer against the different variants evaluated was observed, the serum still exhibited a significant neutralizing titer, against the Mu VOI and the Omicron VOC (1/7113 and 1/3918 respectively), the strains evaluated most resistant to neutralization.

The newly emerged variants of SARS-CoV-2 created a potential threat among societies and highlighted one of the significant concerns in facing the pandemic. SARS-CoV-2 variants harboring mutations in the structural protein, especially in the RBD domain of spike protein, have raised concern about potential immune escape. The spike protein of SARS-CoV-2 play a vital role in infection and is an important target for neutralizing antibodies. The mutations that occur in the structural proteins, especially in the spike protein, lead to changes in the virus attributes of transmissibility, an increase in disease severity, a notable reduction in neutralizing antibodies generated, and thus a decreased response to vaccines and therapy. The immune response against SARS-CoV-2 has been reported mainly through innate immune responses rather than adaptive immune responses. SARS-CoV-2 invades the host's innate immunity, possibly through inducing cytokine storm, impairing type I IFN responses, and suppressing antigens presentation to T cells. Therefore, the adaptive immune response is required to combat SARS-CoV-2 infection. The SARS-CoV-2 infections activated both arms of adaptive immunity; humoral and cell-mediated immunity. The observed multiple mutations in the RBD domain of the spike protein compromised the adaptive immune response and showed immune escape because it increases the affinity of spike protein binding with the ACE-2 receptor of host cells and increases resistance to neutralizing antibodies. Cytotoxic T-cell responses are crucial in controlling SARS-CoV-2 infections from the infected tissues and clearing them from circulation. CD8+cytotoxic T cells identify and directly kill the infected cells by releasing soluble mediators perforin and granzymes. The functional exhaustion of cytotoxic T cells may increase the severity of the disease. The expression of activation markers of T cells could indicate hyperactivation or functional exhaustion; the exact implication is not yet understood in SARS-CoV-2 infections. These mutations at critical residues influence the antigenic profile of SARS-CoV-2, which may evade the immune responses and thus reduce the immunogenicity and efficacy of vaccines. Therefore, the spike protein may be recognized as a primary target for vaccines and drugs. This review article summarizes the impact of mutations in the spike protein of SARS-CoV-2, especially mutations of RBD, on immunogenicity, immune escape, and vaccine-induced immunity, which could potentially contribute to future studies focusing on vaccine design and immunotherapy.

This study proposes a nonlinear mathematical model of virus transmission based on the SEIR model. In this study, the interaction between viruses and immune cells is investigated using phase-space analysis of a mathematical model. Specifically, it is focused on the dynamics and stability behavior of the mathematical model of a virus spread in a population and its interaction with human immune systems cells. The endemic equilibrium points are found and local stability analysis of all equilibria points of the related model is obtained. Further, the global stability analysis either, at disease-free equilibria, or in endemic equilibria is discussed by constructing the Lyapunov function which shows the validity of the concern model exists. Finally, a simulated solution is achieved and the relationship between viruses and immune cells is highlighted.

This study investigates the expression and prognostic value of TRIM6 in gliomas, the most prevalent primary brain and spinal cord tumors. Our results show that TRIM6 is predominantly overexpressed in glioma tissues and is associated with reduced overall survival, disease-specific survival, and progression-free interval. Furthermore, TRIM6 expression is correlated with WHO grade and primary treatment outcomes. Functional analysis indicates that interactions between cytokines and their receptors play a critical role in the prognosis of glioma patients. A protein-protein interaction network reveals 10 hub genes closely linked to cytokine-cytokine receptor interaction. In vitro experiments demonstrate that silencing TRIM6 impairs the proliferation, invasion, and migration of glioma cells, while overexpressing TRIM6 enhances these abilities. Additionally, TRIM6 expression is positively associated with the abundance of innate immune cells and negatively associated with the abundance of adaptive immune cells. In summary, TRIM6 is significantly upregulated in gliomas and linked to poor prognosis, making it a potential diagnostic and prognostic biomarker. TRIM6 plays a crucial role in promoting cell viability, clonogenic potential, migration, and invasion in glioma cells. It may regulate glioma progression by modulating cytokine-cytokine receptor interaction, leading to an inflammatory response and an imbalance in immunomodulation, thereby representing a potential therapeutic target.

Toxocara canis is a helminth parasite with importance in public and veterinary health. Although different studies have evaluated the immune response, to date there are no studies where it is analyzed from the point of view of sexual dimorphism. At 7 days of infection, female rats had a higher number of larvae in the liver, while male rats had them in the lungs. The percentages of immune cells were evaluated, and in most cases, no significant differences were observed. Regarding the cytokines production, infection can generate a decrease in Th1 such as IL-1β in both sexes and IL-6 only in females. In the case of Th2, IL-4 increases only in infected males and IL-5 increases in males and decreases in females due to the effect of infection. IL-10 also decreases in both sexes as a consequence of the infection and TGF-β only in females. Finally, the infection generates the production of antibody against the parasite, however, their quantity is lower in females. Thus, this study demonstrates that Toxocara canis infection is dimorphic and affects females more than males. This is due to a polarization of the inadequate immune response, which is reflected as a higher parasite load in this sex.

Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and class 2 UM having a high metastatic risk. Class 2 UM have a distinctive genomic, transcriptomic, histopathologic, and clinical phenotype characterized by biallelic inactivation of the BAP1 tumor suppressor gene, an immune suppressive microenvironment enriched for M2-polarized macrophages, and poor response to checkpoint inhibitor immunotherapy. To identify potential mechanistic links between BAP1 loss and immune suppression in class 2 UM, we performed an integrated analysis of UM samples, as well as genetically engineered UM cell lines and uveal melanocytes (UMC). Using RNA sequencing (RNA-seq), we found that the most highly up-regulated gene associated with BAP1 loss across these datasets was PROS1, which encodes a ligand that triggers phosphorylation and activation of the immunosuppressive macrophage receptor MERTK. The inverse association between BAP1 and PROS1 in class 2 UM was confirmed by single-cell RNA-seq, which also revealed that MERTK was up-regulated in CD163+ macrophages in class 2 UM. Using ChIP-seq, BAP1 knockdown in UM cells resulted in an accumulation of H3K27ac at the PROS1 locus, suggesting epigenetic regulation of PROS1 by BAP1. Phosphorylation of MERTK in RAW 264.7 monocyte-macrophage cells was increased upon co-culture with BAP1-/- UMCs, and this phosphorylation was blocked by depletion of PROS1 in the UMCs. These findings were corroborated by multi-color immunohistochemistry, where class 2/BAP1-mutant UMs demonstrated increased PROS1 expression in tumor cells and increased MERTK phosphorylation in CD163+ macrophages compared to class 1/BAP1-wildtype UMs. Taken together, these findings provide a mechanistic link between BAP1 loss and suppression of the tumor immune microenvironment in class 2 UMs, and they implicate the PROS1-MERTK pathway as a potential target for immunotherapy in UM.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Sustained hepatic inflammation is a key driver of the transition from simple fatty liver to nonalcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. Hepatic inflammation is orchestrated by chemokines, a family of chemoattractant cytokines, which are produced by hepatocytes, Kupffer cells (liver resident macrophages), hepatic stellate cells, endothelial cells, and vascular smooth muscle cells. Over the last three decades, accumulating evidence from both clinical and experimental investigations demonstrated that chemokines and their receptors are increased in the livers of NAFLD patients and that CC chemokine ligand (CCL) 2 and CCL5, in particular, play a pivotal role in inducing insulin resistance, steatosis, inflammation, and fibrosis in the liver disease. Cenicriviroc (CVC), a dual antagonist of these chemokine’s receptor, CCR2 and CCR5, has been tested in clinical trials in patients with NASH-associated liver fibrosis. Additionally, recent studies revealed that other chemokines, such as CCL3, CCL25, CX3C chemokine ligand 1 (CX3CL1), CXC chemokine ligand 1 (CXCL1), and CXCL16 can also contribute to the pathogenesis of NAFLD. Here, we review recent updates on the roles of chemokines in the development of NAFLD and their blockade as potential therapeutic approaches.

Carboxypeptidase A4 (CPA4) has shown the potential possibility as a biomarker in the early diagnosis for certain cancers. However, no previous research has linked CPA4 to therapeutic or prognostic significance in bladder cancer. Using data from The Cancer Genome Atlas (TCGA) database, we set out to determine the full extent of the link between CPA4 and BLCA. We further analyzed the interacting proteins of CPA4 and infiltrated immune cells via TIMER2，STRING and GEPIA2 databases. The expression of CPA4 in tumor and normal tissues was compared using the TCGA+GETx database. The connection between CPA44 expression and clinicopathologic characteristics and overall survival (OS) was investigated using multivariate methods and Kaplan-Meier survival curves. The potential functions and pathways were investigated via gene set enrichment analysis. Furthermore, we analyze the associations between CPA4 expression and infiltrated immune cells with their respective gene marker sets using the ssGSEA, TIMER2, and GEPIA2 databases. Compared to matching normal tissues, human CPA4 was found to be substantially expressed. We confirmed that overexpression of CPA4 is linked with shorter OS, DSF, PFI, and increased diagnostic potential using Kaplan-Meier and ROC analysis. The expression of CPA4 is related to T-bet, IL12RB2, CTLA4, and LAG3, among which T-bet and IL12RB2 are Th1 marker genes, while CTLA4 and LAG3 are related to T cell exhaustion, which may be used to guide the application of checkpoint blockade and the adoption of T cell transfer therapy.

This study used established biomarkers of death due to ischemic stroke (IS) and performed network, enrichment, and annotation analysis. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell surface interactions, and the proteoglycan-integrin-extra cellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, VEGFA, proteoglycan-integrin-ECM complex, NFKB/RELA and SP1.

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory (CIRS) systems and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AF-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of the disease. However, the interactome of FEP/FES is not well delineated. The aim of the current study was to delineate the characteristics of the protein-protein interaction (PPI) network of AN-FEP and its transition to FES and the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. PPI network analysis shows that FEP and FEP/FES are strongly associated with a response to a bacterium, TNF, NFκB, RELA, SP1, JAK-STAT, death receptor and TLR4 signaling, and tyrosine phosphorylation of STAT proteins. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin/Trk, RTK and Wnt/catenin signaling and adherens junction organization. Lowered neuroprotection due to reduced neurotrophin/Trk and Wnt/catenin signaling, and DISC1 expression and multiple interactions between lowered BDNF, CDH1, CTNNB, and DISC1 expression, increase the vulnerability to the neurotoxic effects of immune products including cytokines and complement factors. All pathways or molecular patterns enriched in the interactome of FEP/FES are directly or indirectly affected by LPS. In summary: FEP appears to be triggered by a biotic stimulus (e.g. Gram-negative bacteria) which may induce neuro-immune toxicity cascades especially when anti-inflammatory and neurotrophic protections are deficient.

The control of Porcine Reproductive and Respiratory Syndrome (PRRS) is still a major issue worldwide in the pig farming sector. Despite extensive research efforts and the practical experience gained so far, the syndrome still heavily affects farmed pigs worldwide and challenges established beliefs in veterinary virology and immunology. The clinical and economic repercussions of PRRS are based on concomitant, additive features of virus pathogenicity, host susceptibility and influence of environmental, microbial and non-microbial stressors. This makes a case for integrated, multi-disciplinary research efforts in which the three types of contributing factors are critically evaluated toward the development of successful disease control strategies. These could be definitely eased by the definition of reliable markers of disease risk and virus pathogenicity. As for the host’s susceptibility to PRRSV infection and disease onset, the roles of both innate and adaptive immune responses are still ill-defined. In particular, the overt discrepancy between passive and active immunity and the uncertain role of adaptive immunity vis-à-vis an established PRRSV infection should prompt the scientific community to the development of novel research schemes, in which apparently diverging and contradictory findings could be reconciled, and eventually brought to a satisfactory conceptual framework.

In the first year of its appearance, the 2019 coronavirus disease (COVID-19) has affected more than 150 million individuals and killed 3 million people worldwide. The pandemic has also triggered numerous global initiatives to tackle the newly emerging disease, including the development of SARS-CoV-2 vaccines and the attempt to discover potential pharmacological therapies. Nonetheless, despite the success of SARS-CoV-2 vaccines development, COVID-19 therapy remains challenging. Several repurposed drugs that were documented to be useful in small clinical trials have been shown to be ineffective in larger studies. Additionally, the pathophysiology of SARS-CoV-2 infection displayed the predominance of hyperinflammation and immune dysregulation in inducing multiorgan damage. Therefore, the potential benefits of both immune modulation and suppression in COVID-19 have been extensively discussed. Here, we reviewed the roles of immunomodulation as potential COVID-19 pharmacological modalities based on the existing data and proposed several new immunologic targets to be tested in the foreseeable future.

Background: COVID-19 is associated with neuropsychiatric symptoms including increased depressive, anxiety and chronic fatigue-syndrome (CFS)-like physiosomatic (previously known as psychosomatic) symptoms.Aims: To delineate the associations between affective and CFS-like symptoms in COVID-19 and chest CT-scan anomalies (CCTAs), oxygen saturation (SpO₂), interleukin (IL)-6, IL-10, C-Reactive Protein (CRP), albumin, calcium, magnesium, soluble angiotensin converting enzyme (ACE2) and soluble advanced glycation products (sRAGEs).Method: The above biomarkers were assessed in 60 COVID-19 patients and 30 heathy controls who had measurements of the Hamilton Depression (HDRS) and Anxiety (HAM-A) and the Fibromyalgia and Chronic Fatigue (FF) Rating Scales. Results: Partial Least Squares-SEM analysis showed that reliable latent vectors could be extracted from a) key depressive and anxiety and physiosomatic symptoms (the physio-affective or PA-core), b) IL-6, IL-10, CRP, albumin, calcium, and sRAGEs (the immune response core); and c) different CCTAs (including ground glass opacities, consolidation, and crazy paving) and lowered SpO2% (lung lesions). PLS showed that 70.0% of the variance in the PA-core was explained by the regression on the immune response and lung lesions latent vectors. Moreover, one common “infection-immune-inflammatory (III) core” underpins pneumonia-associated CCTAs, lowered SpO2 and immune activation, and this III core explains 70% of the variance in the PA core, and a relevant part of the variance in melancholia, insomnia, and neurocognitive symptoms.Discussion: Acute SARS-CoV-2 infection is accompanied by lung lesions and lowered SpO2 which both may cause activated immune-inflammatory pathways, which mediate the effects of the former on the PA-core and other neuropsychiatric symptoms due to SARS-CoV-2 infection.

Use of antibiotics and other chemicals to combat disease outbreaks have been a bottleneck for the sustainable growth of shrimp industry. Among various replacement proposed, organic acid (OA) and their salts (OS) are commonly used by farmers and feed millers. However, in free forms, their requirement is very high (2-3 kg/MT) as they tend to disassociate before reaching the hindgut. The dosage can be reduced by microencapsulation of the ingredients. In this study, a 63-day trial was conducted to assess the effects of OA and OS (COMP) microencapsulated (ENCAP) with fat (HF), fat + alginate (HA), wax esters – (WE), and HA and WE (HAWE) on performance, digestive enzyme, immune, and resistance to Vibrio parahaemolyticus. A positive control (PC, 200 g/kg fishmeal - FM) and a negative control (NC, 130 g/kg FM) diet were formulated. Eight other diets were formulated supplementing NC diet with microencapsulated OA (OAHF, OAHA, OAWE, OAHAWE) and OS (OSHF, OSHA, OSWE, OSHAWE). Among the ENCAPs, significant difference was observed in serum malondialdehyde (P = 0.026) where HF showed the lowest level (6.4 ±0.3 mmol/L). Significant interactions between COMP and ENCAP were observed in lipid deposition (P = 0.047), serum alkaline phosphatase and acid phosphatase (P < 0.0001), and hepatopancreatic and serum phenol oxidase (P < 0.0001). Despite no differences, 96-h mortality during pathogenic Vibrio parahaemolyticus challenge in all treatment diets (45% - 56%) was lower compared to the NC diets (63%). In conclusion, use of HF microencapsulated OA diets could provide improved performance and disease resistance that could contribute to the reduction of antibiotic use by the shrimp industry.

We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1,010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis including also age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870 – 0.995, P = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724 – 0.983, P = 0.029), but not in luminal (HR 0.957, 95% CI 0.867 – 1.056, P = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826 – 1.055, P = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (Pinteraction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC.

Bovine respiratory disease is still a major concern in feedlots and has major economic impact. Another consequence of respiratory infections is the use of antimicrobial molecules to control bacterial pathogens. This can participate to the emergence and shedding of antimicrobial re-sistance that can threaten animal as well as human health. Appeasing pheromones with their capacity to reduce stress and thus their ability to preserve the functions of the immune system have been proposed to reduce the use of antimicrobial substances. In the current report we as-sessed the effect of appeasing pheromone administration on bovine health and performance during the fattening period. Zootechnical and health parameters as well as whole blood immune transcript expressions were measured over weeks in young bulls to determine the effect of the pheromone. We observed a reduction of clinical signs at day 30 in young bulls who received the pheromone and a higher expression of interleukin 8 transcripts in this group than in the control group. Our results are in line with previous reports in bovine and other mammals and ask for further studies to shed more light on the beneficial impact of appeasing pheromones and to de-cipher their exact mechanisms of action.

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabelled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.

Aquaculture is one of the fastest-growing animal food-producing agricultural industries in the world and proper performance of fish in morphological, physiological and immunological aspects is important for fish production and sustainable expansion of aquaculture. But several inhibitors like disease, pathogen, and adverse environment can overpower these performances. At present, antibiotics in preventing these inhibitors have been seen as becoming favorable to those inhibitors. So, Bacillus, an important group of probiotic bacteria can be an alternative to these antibiotics in aquaculture. Bacillus has been seen used in different experiments, mainly as a supplement in feed at various concentrations. Bacillus showed effective results like improved growth with minimum cost, improvement in reproduction, hematology, improved immune response and disease, and stress resistance as well as better proximate composition in different fish species. Application of Bacillus strains has proven efficient in improving water quality by reducing ammonia and nitrite toxicity, harmful algal blooms and utilization of H⁺ ion. Larger application of probiotic Bacillus instead of the hazardous synthetic chemicals would promote eco-friendly low-input sustainable aquaculture for food and nutritional security of the increasing world population. So many more experiments should be conducted in commercially important fishes for better growth and health of fishes which will certainly increase fish

Respiratory Syncytial Virus (RSV) causes severe inflammation and airway pathology in children and the elderly by infecting the epithelial cells of the upper and lower respiratory tract. RSV replication is sensed by intracellular pattern recognition receptors upstream of the IRF and NF-B transcription factors. These proteins coordinate an innate inflammatory response via Bromodomain containing protein 4 (BRD4), a protein that functions as a scaffold for unknown transcriptional regulators. To better understand the pleiotropic regulatory function of BRD4, we examine the BRD4 interactome and identify how RSV infection dynamically alters it. To accomplish these goals, we leverage native immunoprecipitation and Parallel Accumulation – Serial Fragmentation (PASEF) mass spectrometry to examine BRD4 complexes isolated from human alveolar epithelial cells in the absence or presence of RSV infection. In addition, we explore the role of BRD4’s acetyl-lysine binding bromodomains in mediating these interactions by using a highly selective competitive bromodomain inhibitor. We identify 101 proteins that are significantly enriched in the BRD4 complex and are responsive to both RSV-infection and BRD4 inhibition. These proteins are highly enriched in transcription factors and transcriptional coactivators. Among them, we identify members of the AP1 transcription factor complex, a complex important in innate signaling and cell stress responses. We independently confirm the BRD4/AP1 interaction in primary human small airway epithelial cells. We conclude that BRD4 recruits multiple transcription factors during RSV infection in a manner dependent on acetyl-lysine binding domain interactions. This data suggests that BRD4 recruits transcription factors to target its RNA processing complex to regulate gene expression in innate immunity and inflammation.

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding have been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens.

Cisplatin-based chemotherapy has long been viewed as the first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC have been classified as “cisplatin-ineligible patient”, which requires alternative chemotherapy due to their poor responses. In fact, vast majority of those who initially responded to cisplatin-based chemotherapy eventually progressed. Understanding of UC tumor immunology provided an immunopathogenic bases for immune checkpoint inhibitors, targeting PD-1 and CTLA-4, to treat cisplatin ineligible metastatic UC and patients with platinum-refractory metastatic UC. In 2020, data from the trail further showed that PD-L1 inhibitors benefit prolonged survival and progression-free survival as maintenance therapy. Besides immune-targeting therapies, manipulation of tumor microenvironment via metabolic pathways alternation, such as inhibiting tumor glycolysis, lactate accumulation and exogenous glutamine uptake, has been investigated in the past few years. In this comprehensive review, we started by introducing traditional chemotherapy of UC, and summarized current evidences supporting the use of immune checkpoint inhibitors and highlighted ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting metabolic pathways.

Purpose: Myelodysplastic syndromes (MDS) are caused by a stem cell failure, but the relationship between immune dysregulation and the course of disease has not yet been analyzed in detail. Experimental design: To get insights into the pathophysiologic and clinical relevance of the histotopography of immune cell subpopulations in this process, the immune cell infiltrate with focus on its spatial distribution was determined by multispectral imaging (MSI) in 147 bone marrow biopsies from MDS or secondary acute myeloid leukemia (sAML) patients and healthy controls (HC). In addition, the data were correlated to genetic alterations and clinical features of these patients including therapy response. Results: A high inter-tumoral heterogeneity in the frequency and spatial distribution of CD3⁺CD8⁺, CD3⁺CD8^-, CD3⁺FOXP3⁺ T cell subsets, MUM1p⁺CD3^- post-germinal B/plasma cells and CD34⁺ blasts was found in MDS and sAML samples. In HC only few B cells/plasma cells, but no T cell subpopulations were detected in the proximity to CD34⁺ blasts. In contrast, the frequency of these lymphocytes was increased in proximity to CD34⁺ blasts in both MDS and sAML independent of the karyotype, genetic alterations frequently detected in MDS, clinical risk stratification systems or treatment response to hypomethylating agents. Furthermore, an increased frequency of CD3⁺CD8⁺ T cells and MUM1p⁺ CD3^- B cells was found in responders to epigenetic drugs. Conclusions: Thus, we conclude that (i) T cell subsets do not belong to the normal stem cell niche, (ii) the presence of T and B cell subpopulations not directly affect the course of MDS, (iii) lymphocytes in the proximity to CD34⁺ blasts might indicate defective stem cell properties and (iv) the number of lymphocytes is a predictor of therapy response to hypomethylating agents.

Background: Cutaneous Melanoma (SKCM) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of SKCM (n=328) was utilized. The immune microenvironment was characterized using CIBERSORTX to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Samples were separated into those obtained from the primary tumor site and regional skin or soft tissue (locoregional), or distant metastasis and regional lymph node (metastatic). Analysis of overall survival (OS) was performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by lymphocyte:monocyte (L:M) ratio, monocyte-enrichment, and M0-macrophage-enrichment (L:MLow, MonocyteHigh, M0High; L:MLow, MonocyteMid, M0Low; L:MMid, MonocyteLow, M0Low; L:MHigh, MonocyteLow, M0Low). The L:MLow, MonocyteHigh, M0High cluster demonstrated significantly worse OS than clusters 2-4 in the locoregional group (HR 2.804, 95% CI 1.262–6.234, p=0.0114). Membership in the L:MLow, MonocyteHigh, M0High cluster was an independently poor prognostic factor for survival (HR 3.03, 95% CI 1.12–8.20, p=0.029). The L:MLow, MonocyteHigh, M0High cluster correlated with higher rates of metastasis and decreased predicted response to immune checkpoint blockade compared to the other clusters as determined by the Tumor Immune Dysfunction and Exclusion tool (TIDE). Conclusion: Distinct tumor immune clusters with a M0-macrophage-enriched, L:M ratio low phenotype in the primary melanoma tumor site independently characterize an aggressive phenotype that may differentially respond to treatment.

Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data of 40 healthy controls and 80 patients with schizophrenia. Using partial least Squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAaase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.

As a major infectious disease in chickens, Newcastle disease causes considerable economic losses in the poultry industry, especially in developing countries where there is limited access to effective vaccination. Therefore, enhancing resistance to the virus in commercial chickens through breeding is a promising way to promote poultry production. In this study, we investigated gene expression changes at 2 and 6 dpi after infection at day21 with a lentogenic Newcastle disease virus in a commercial egg-laying chicken hybrid using RNA sequencing analysis. By comparing NDV challenged and nonchallenged groups, 526 differentially expressed genes (DEGs) (FDR &lt; 0.05) were identified at 2 dpi, and only 36 at 6 dpi. For the DEGs at 2 dpi, IPA analysis predicted inhibition of multiple signaling pathways in response to NDV that regulate immune cell development and activity, neurogenesis and angiogenesis. Upregulation of Interferon Induced Protein with Tetratricopeptide Repeats 5 (IFIT5) in response to NDV was consistent between the current and most previous studies. Sprouty RTK Signaling Antagonist 1 (SPRY1), a DEG in the current study is located in a significant QTL associated with virus load at 6 dpi in the same population. These identified pathways and DEGs provide potential targets to further study breeding strategy to enhance NDV resistance in chickens.

Transfusion dependent thalassemia (TDT) patients are treated with continued blood transfusions and show a higher prevalence of depression. TDT with consequent iron overload and inflammation is associated with increased severity of depressive symptoms in TDT children.Aim of the study: To construct a pathway-phenotype which combines iron overload and neuro-immune biomarkers with depressive symptom subdomains in TDT children.Methods: We measured iron status parameters (iron, ferritin, transferrin saturation percentage) and inflammatory (interleukin-1β and tumour necrosis factor-α) biomarkers in TDT (n=111) and healthy (n=53) children and analyzed the results using machine learning.Results: Cluster analysis separated TDT children with depression from those without depression and revealed two depressive subgroups one with low self-esteem and another with increased social-irritability scores. Exploratory factor analysis validated four depressive symptom dimensions as reliable constructs, namely key depressive, physiosomatic, lowered self-esteem and social-irritability dimensions. Partial Least Squares showed that 73.0% of the variance in a latent vector extracted from those four clinical subdomains, immune-inflammatory and iron overload biomarkers was explained by exposure variables including the number of blood transfusions and hospitalizations and use of deferoxamine. The exposure data, iron and immune biomarkers, and symptom subdomains are reflective manifestations of a single latent trait, which shows internal consistency reliability and predictive relevance.Conclusions: The nomological network combining exposure, pathways and behavioral phenome manifestations provides an index of overall severity and disease risk and, therefore, constitutes a new drug target, indicating that iron overload and immune activation should be targeted to treat depression due to TDT.

The role of innate immunity in neutralization of viral infections (including COVID-19) and forming long-lasting and specific immune memory is considered. It is assumed that antiviral protection is generated by the mechanism of RNA interference (RNAi) and is based on the presence of specific viral patterns in the DNA library of the host cells.

Purpose: At a time of a pandemic SARS-CoV2 infection, and in the context of the multiorgan crosstalk widely accepted as a mechanism participating in the pathophysiology of all organs and systems, a correlation between adipose tissue, muscle and the immune system has been investigated. Physical Activity (PA) represents the first line of defence against metabolic diseases and infections, like SARS-CoV2, modulating several crucial functions such as inflammation and immune response. Conversely, obesity, type 2 diabetes and cardiovascular disorders – all correlated with PA - negatively impact on general health status, including susceptibility to infections. Here we review the complex interplay between type 2 diabetes, obesity, immune response, inflammation and viral infections, such as the current SARS-CoV2, focusing on the molecular mechanisms modulated by exercise. Methods: A comprehensive literature search was completed to identify joint biomarkers previously used to investigate acute and chronic exercise training. Results: we show that PA may counteract/mitigate viral adverse effects. We also describe data suggesting that vitamin D supplementation, frequently observed in practitioners of sport and regular exercise, could represent an additional positive factor in supporting COVID-19 with fighting against the virus. Conclusion: Altogether this evidence confirms that an active lifestyle and PA not only counteract dysmetabolic diseases but could also be effective for counteracting SARS-CoV2 infection. It is therefore essential to persuade people to keep active.

Background: There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: To compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. Methods: We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (-SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n=40) and non-deficit (n=40) schizophrenia and healthy controls (n=40). Results: Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered -SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (Odds ratio=3.15, p<0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas -SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. Discussion: Our findings indicate that with increasing overall severity of schizophrenia, neuro-immune and neuro-oxidative (especially protein oxidation indicating chlorinative stress) toxicities become more prominent and together with lowered antioxidant defenses and impairments in innate immunity-associated resilience against neurotoxic processes shape a distinct nosological entity, namely deficit schizophrenia.

Objective: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is > 0.666 percentile. We assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. Results: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in women with MCAS. The total DRSP score was predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. Conclusion: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC-associated symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

A subset of patients with schizophrenia experience physio-somatic symptoms reminiscent of chronic fatigue and fibromyalgia. In schizophrenia, these symptoms contribute to impaired quality of life, and are strongly related to neuro-cognitive deficits, and increased IgA responses to tryptophan catabolites. Negative and PHEM (psychosis, hostility, excitation, mannerism) symptoms, psychomotor retardation (PMR) and formal thought disorders, appear to be manifestations of a single trait reflecting overall severity of schizophrenia (OSOS). In this study, 120 patients with deficit schizophrenia (DEFSCZ) and 54 healthy subjects were assessed with the FibroFatigue (FF) rating scale, and the above-mentioned symptom domains as well as neuro-cognitive tests and biomarkers were measured. In DEFSCZ, there were robust associations between the FF score and all above-mentioned symptom domains, and impairments in semantic and episodic memory and executive functions. Furthermore, the FF score loaded highly on an OSOS latent vector (LV), which showed adequate convergent validity, internal consistency reliability and predictive relevance and fitted a reflective model. Soft Independent Modelling of Class Analogy (SIMCA) showed that the FF items discriminated DEFSCZ from controls with an overall accuracy of 100%. Interleukin IL-1β, IL-1 receptor antagonist (sIL-1RA), tumour necrosis factor (TNF)-α and CCL-11 (eotaxin) explained 66.8% of the variance in the FF score and 59.4% of the variance in OSOS. In conclusion, these data show that physio-somatic symptoms are a core component of the phenomenology of DEFSCZ and are largely mediated by neurotoxic effects of activated immune pathways, including aberrations in CCL-11, IL-1β and TNF-α signalling.

In 2001, the first author of this paper reported that schizophrenia is associated with an increased frequency of the haptoglobin (Hp)-2 gene. The precursor of Hp-2 is zonulin, a molecule that affects intercellular tight junction integrity. Recently, we reported increased plasma IgA/IgM responses to Gram-negative bacteria in deficit schizophrenia indicating leaky gut and gut dysbiosis. The current study was performed to examine the integrity of the paracellular (tight and adherens junctions) and transcellular (cytoskeletal proteins) pathways in deficit versus non-deficit schizophrenia. We measured IgM responses to zonulin, occludin, E-cadherin, talin, actin and vinculin in association with IgA responses to Gram-negative bacteria, CCL-11, IgA responses to tryptophan catabolites (TRYCATs), immune activation and IgM to malondialdehyde (MDA) and NO-cysteinyl in 78 schizophrenia patients and 40 controls. We found that the ratio of IgM to zonulin + occudin / talin + actin + viculin (PARA/TRANS) was significantly greater in deficit than in non-deficit schizophrenia and higher in schizophrenia than controls and was significantly associated with increased IgA responses to Gram-negative bacteria. IgM responses to zonulin were positively associated with schizophrenia (versus controls), while IgM to occludin was significantly associated with deficit schizophrenia (versus non-deficit schizophrenia and controls). A large part of the variance (90.8%) in negative and PHEM (psychosis, hostility, excitation and mannerism) symptoms was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, IgM to E-cadherin and malondialdehyde (MDA) and memory dysfunctions, while 53.3% of the variance in the latter was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, CCL-11, TRYCATs and immune activation. The results show an upregulated paracellular pathway with breakdown of the tight and ahherens junctions and increased bacterial translocation in deficit schizophrenia. These dysfunctions in the intestinal paracellular route together with lowered natural IgM, immune activation and production of CCL-11 and TRYCATs contribute to the phenomenology of deficit schizophrenia.

Although, staging models gained momentum to stage define affective disorders, no attempts were made to construct mathematical staging models using clinical and biomarker data in patients with major depression and bipolar disorder.The aims of this study were to use clinical and biomarker data to construct statistically-derived staging models, which are associated with early lifetime traumata (ELTs), affective phenomenology and biomarkers.In the current study, 172 subjects participated, 105 with affective disorders (both bipolar and unipolar) and 67 controls. Staging scores were computed by extracting latent vectors (LVs) from clinical data including ELTs, recurring flare ups and suicidal behaviors, outcome data such as disabilities and health-related quality of life (HR-QoL), and paraoxonase (PON)1 actvities and nitro-oxidative stress biomarkers.Recurrence of episodes and suicidal behaviors could reliably be combined into a LV with adequate composite reliability (the “recurrence LV”), which was associated with female sex, the combined effects of multiple ELTs, disabilities, HR-QoL and impairments in cognitive tests. All those factors could be combined into a reliable “ELT-staging LV” which was significantly associated with nitro-oxidative stress biomarkers. A reliable LV could be extracted from serum PON1 activities, recurrent flare ups, disabilities and HR-QoL.Our ELT-staging index scores the severity of a relevant affective dimension, shared by both major depression and bipolar disorder, namely the trajectory from ELTs, a relapsing course and suicidal behaviors to progressive disabilities. Patients were classified into three stages, namely an early stage; a relapse-regression stage; and a suicidal-regression stage. Lowered lipid-associated antioxidant defenses may be a drug target to prevent the transition from the early to the later regression stages.

Bacterial pathogens have been attributed to poultry housing structure, financial strength, and incessant use of antibiotics, variable seasons and management systems practiced. Variant forms of bacterial pathogens can be detected by recognizing the molecular pattern of the pathogens through an innate immune mechanism such as mannose-binding lectin. Mannose-binding lectin (MBL) possesses an innate pattern recognition molecule that easily sequestered to region of infections and inflammations. This works by attaching itself to antigen surface thus hinders proliferation and disease activity in the host organism. Baker’s method, nephelometric assays technique, Enzyme-Linked Immunosurbent Assay technique, Polymerase Chain Reaction, Deoxyribonucleic Acid typing and other biotechnology related methods are techniques used in detecting and quantifying MBL. Mannose-binding lectin levels in serum can be influenced by age, management systems, feed formulation strategies and seasons. Therefore, knowledge of MBL should be encouraged in all aspect of poultry production, in order to discourage incessant use of drugs at a slight exposure to prevailing bacterial which can help in maximizing cost.

Schizophrenia is characterized by an interrelated activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in natural regulatory autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative specific epitopes (OSEs), nitroso (NO) and nitro (NO₂) adducts in schizophrenia remain unknown.This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl and NO₂-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls.Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO₂-tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2 – 42.2 %) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO₂-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall.These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in lowered IgM responses to MDA and azelaic acid (part of the CIRS) attenuate the negative immune-regulatory feedback on the primary immune response and that this process may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia.

The voluminous daily output of autism research has become increasingly disconnected, existing largely within highly specific subspecialty areas, and lacking cross-disciplinary linkages of context, theory, and findings to inform a unified body of knowledge. Robust syntheses of published research across the fields of psychiatry, cellular and molecular biology, neurology, endocrinology, immunology, behavioral and social sciences, and pedagogy may help clarify and extend current knowledge by guiding more efficient future research efforts investigating underlying causes, developmental divergences, novel treatments, and specific, sensitive biological markers in autism. This synthesis of interdisciplinary research indicates the hypothalamic-pituitary-adrenal (HPA) stress axis may be at the center of an interaction among sex steroids, immune function, signaling protein transcriptions, neurogenesis, and dysregulation of brain structures sending or receiving projections from the HPA stress axis. These interaction manifest observably as a range of sexually dimorphic behaviors and functional limitations often falling within the current diagnostic features of Autism Spectrum Disorder (ASD). The pathogenicity of endocrine dysregulation may serve as a valuable model for developing a cohesive theory of ASD by explaining how the HPA and connected brain areas respond to extreme conditions of dysregulated endocrine signaling to cause symptoms associated with autism.

Biological control provides a safer alternative to reduce the population of agricultural pest. Mirabilis jalapa is one of biopesticides containing chemical substances that have a feeding deterrent property against Spodoptera litura as folifagus insect pest. This study aimed to analyze the humoral and cellular immunes responses of S. litura after exposure to biopesticide extracted from M. jalapa. The measured indicator immune responses were activity of hemocyte, lectin, phenoloxidase (PO), and phagocytic activity. The results showed that the average total hemocyte was different significantly depending on the treatment. Exposure to 0.1% and 0.2% (w/v) of M. jalapa extract increased the total number of hemocytes as much as 38.08% and 64.15%, respectively. Lectin was quickly formed at 0.1% and 0.2% (w/v) concentrations. The amount of PO enzymes was significantly different at sublethal concentrations compared with control samples (P < 0.05). The highest increase in PO activity occurred at 2 h post-treatment and at M. jalapa extract concentrations of 0.2% (592.33 IU/mg) and 0.1% (521.33 IU/mg), whereas the highest concentration of the extract (0.8% w/v) caused a decrease in lectin and PO activities. In terms of phagocytic activity, the proportion of phagocytosis cells were 47.62% in control group, and decreased significanlty in both concentrations exposure.

Noni juice is a globally popular health beverage that originates from the tropics. Traditional Tahitian healers believe the noni plant to be useful for a wide range of maladies, and noni juice consumers throughout the world have similar perceptions. Nevertheless, human clinical trials are necessary for an understanding of what the health benefits of noni juice truly are. A review of published human intervention studies suggest that noni juice may provide protection against tobacco smoke-induced DNA damage, blood lipid and homocysteine elevation, and systemic inflammation. Human interventions studies also suggest that noni juice may improve joint health, increase physical endurance, increase immune activity, inhibit glycation of proteins, aid weight management, help maintain bone health in women, help maintain normal blood pressure, and improve gum health. Further, these studies point to noni juice possessing notable antioxidant activity, more so than the other fruit juices that served as placebos. It is this antioxidant effect, and its interaction with the immune system and inflammation pathways, that may account for many of the observed health benefits of noni juice. However, the existing evidence does have some limitations in its application to noni juice products in general as all the peer-reviewed human interventions studies to-date have involved only one source of French Polynesian noni juice. Geographical factors and variations in processing methods are known to produce commercial noni juice products with divergent phytochemical and nutrient compositions. Therefore, other sources of noni products may have different toxicological and pharmacological profiles.

After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex anti-tumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these fields of research for more efficient development and effective treatments.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases including oral cancer. Cancer cells usually escape from immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα in the tumor microenvironment of oral squamous cell carcinoma (OSCC), and performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating seven immune-related factors and several clinicopathological statuses. However, the immune-checkpoint related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference of the tumor immunity in the originating-epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC might be different in the originating-epithelium, keratinized or non-keratinized.

VEXAS syndrome, a monogenic X-linked disorder resulting from mutations in the UBA1 gene, has emerged as a key model for unraveling the links between systemic inflammatory or autoimmune diseases (SIAD) and myelodysplastic syndromes (MDS). This syndrome is characterized by the presence of vacuoles, X-linked inheritance, autoinflammation and somatic mutation patterns, highlighting a unique intersection between genetic and immunological dysregulation. Apart from VEXAS, 10% to 30% of individuals diagnosed with MDS exhibit SIAD phenotypes, a significant increase compared to the 5% incidence in the general population. In this comprehensive review, we aim to elucidate the molecular mechanisms driving the pro-inflammatory environment in MDS, focusing on the contribution of VEXAS syndrome to this complex interplay. We examine how UBA1 mutations disrupt cellular homeostasis, triggering inflammatory pathways. Furthermore, we explore the broader implications of these findings for the pathogenesis of MDS, proposing that the inflammatory dysregulation of VEXAS may shed light on mechanisms of disease progression and identify potential therapeutic targets in MDS. Through an integrated analysis of genetic, immunological and clinical data, this review seeks to deepen our understanding of the complex relationship between systemic inflammation and hematological malignancies, paving the way for new diagnostic and therapeutic strategies.

The failure of immunotherapies in cancer patients is being widely studied due to the complexities present in the tumor microenvironment (TME), where regulatory T cells (Treg) appear to actively participate in providing an immune escape mechanism for tumors. Therefore, therapies to specifically inhibit tumor-infiltrating Treg represent a challenge because Treg are distributed throughout the body and provide physiological immune homeostasis to prevent autoimmune diseases. Characterization of immunological and functional profiles could help to identify the mechanisms that need to be inhibited or activated to ensure Treg modulation in the tumor. To address this, quantitative in-silico approaches based on mechanistic mathematical models integrating multi-scale information from immune and tumor cells and the effect of different therapies have allowed the building of computational frameworks to simulate different hypotheses, some of which have subsequently been experimentally validated. Therefore, this review presents a list of diverse computational mathematical models that examine the role of Treg as a crucial immune resistance mechanism contributing to the failure of immunotherapy. In addition, this review highlights the relevance of certain molecules expressed in Treg that are associated with the TME immunosuppression, which could be incorporated into the mathematical model for a better understanding of the contribution of Treg modulation. Finally, different pre-clinical and clinical combinations of molecules are also included to show the trend of new therapies targeting Treg.

The objective of this study was to investigate the transcriptomic profiling of differentially ex-pressed genes between a commercial layer breed and an indigenous Indian breed. RNA was ex-tracted from NDV-infected and uninfected embryo lung tissue samples of Aseel, Kadaknath, and White Leghorn chickens. RNA-Seq was performed, and reads were aligned to the chicken refer-ence genome (Galgal7). A total of 594 genes were significantly differentially expressed, with 264 upregulated and 330 downregulated in infected embryos. Highly overexpressed genes in infect-ed conditions included C8A, FGG, PIT54, FETUB, APOC3, FGA, SPIA1, AvBD13, APOH, AMBP, TTR, PLA2G12B. Additionally, 29 novel transcripts and 20 lncRNAs were upregulated. White Leghorn embryos showed distinct expression patterns for CAV1 and GATA3, while Kadaknath healthy embryos had higher levels of CYTB, HBBA, ND4, ND4L, and ND5, indicating breed uniqueness. The analysis revealed significant gene involvement through Gene Ontology and KEGG pathways, highlighting alterations in gene expression related to immune function, me-tabolism, cell cycle, nucleic acid processes, and mitochondrial activity due to NDV infection. ALDOB, PRPS2, XDH, DCK2, and TK1 genes, which were involved in several metabolic path-ways, clearly displayed an altered expression pattern in the infected embryo. Additionally, ALB, TLR4, TLR2, TLR21, IL1R2, IL22RA2, HSP90AA, HSPB9(p60), and HSPB8 were significantly up-regulated in infected lung samples, while CXCR4, CXCL14, GATA3, IL17REL, and IL22RA1 were downregulated. Notably, higher expression of HSPs in Kadaknath suggests heat tolerance. This research provides insights into the genetic differences between commercial and local breeds and reveals the impact of NDV infection on metabolic processes, potentially identifying candidate genes for breed improvement.

We were tasked by Canada’s COVID-19 Immunity Task Force to describe severe adverse events (SAE) associated with emergency department (ED) visits and/or hospitalizations in immune-mediated inflammatory diseases (IMID). At 8 Canadian centres, data were collected from adults with rheumatoid arthritis (RA), axial spondyloarthritis (AxS), systemic lupus (SLE), psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). We administered questionnaires, analyzing SAEs experienced within 31 days following SARS-CoV-2 vaccination. About two-thirds (63%) of 1556 participants were female; mean age was 52.5 years. BNT162b2 (Pfizer) vaccine was the most common, with mRNA-1273 (Moderna) being second. Forty-nine percent of participants had IBD, 27.4% RA, 14.3% PsA, 5.3% SpA, and 4% SLE. Twelve SAEs leading to ED visit or hospitalization were self-reported, occurring in 11 participants. SAEs included 6 ED visits (including one Bell’s Palsy 31 days after first vaccination) and 6 hospitalizations (including one Guillain-Barré syndrome 15 days after the first vaccination). Two SAEs involved pericarditis, one in SLE (considered a serious disease flare) and one in RA. Thus, in the 31 days after SARS-CoV-2 vaccination in IMID, though several serious AEs occurred, these were relatively few. As SARS-CoV2 continues to be a common cause of death, our findings may help optimize vaccination acceptance.

Ever since the discovery of dendritic cells by Ralph Steinman and Zanvil Cohn in 1973, it is increasingly evident that dendritic cells are integral for adaptive immune responses, and there is an undeniable focus on them for vaccines development. Fungal infections, often thought in-nocuous, are becoming significant threats due to increased immunocompromised or im-mune-suppressed population and climate change. Further, the recent COVID-19 pandemic unraveled the wrath of fungal infections and devastating outcomes. Invasive fungal infections cause significant case fatality rates ranging from 20% to 90%. Regrettably, no licensed fungal vaccines exist, and there is an urgent need for preventive and therapeutic purposes. In this re-view, we discuss the ontogeny, subsets, tissue distribution, and functions of lung dendritic cells. In the latter part, we summarize and discuss the studies on the DC-based vaccines against pulmonary fungal infections. Finally, we highlight some emerging potential avenues that can be incorporated for DC-based vaccines against fungal infections.

Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population [1]. Current treatment strategies, the combination of BRAF and MEK inhibitors (BRAF/MEKi) in BRAFV600 mutant melanoma, and immune checkpoint inhibitors (ICI), have changed the clinical evolution of this disease [2]. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphoid populations, could contribute to the identification of ICI responders. The aim of this review is to thoroughly examine significant published data on this topic in melanoma patients and to evaluate the potential role of lymphoid subsets as prognostic and predictive response biomarkers.

Immunosuppressed individuals, such as people living with HIV (PLWH), remain vulnerable to severe COVID-19. We analyzed the persistence of specific SARS-CoV-2 humoral and cellular immune responses in a retrospective, cross-sectional study in PLWH on antiretroviral therapy. Among 104 participants, 70.2% had anti-S IgG antibodies and 55.8% had significant neutralizing activity against the Omicron variant in a surrogate virus neutralization test. Only 38.5% were vaccinated (8.76 ± 4.1 months prior), all displaying anti-S IgG, 75% with neutralizing antibodies and anti-S IgA. 29.8% had no SARS-CoV-2 serologic markers and displayed significantly lower CD4 counts and HIV viral load. Severe immunosuppression (present in 12.5% of participants) was linked to lower levels of detectable anti-S IgG (0.0003), anti-S IgA (p &lt; 0.0001) and lack of neutralizing activity against Omicron variant (p &lt; 0.0001). T-cell responses were present in 86.7% of tested participants, even in those lacking serological markers. In PLWH without severe immunosuppression, neutralizing antibodies and T-cell responses persisted for up to 9 months post-infection or vaccination. Advanced immunosuppression led to diminished humoral immunity, but retained cellular immune.