Background: Migraine is the commonest complex neurological disorder affecting over a billion people worldwide. Neuroinflammation has long been considered to play an important role in the pathophysiology of migraine. The main aim of this single-centre, proof of concept, retrospective study was to determine the possible clinical utility of systemic immune-inflammatory response in migraine with and without aura in a hospitalized cohort. We measured the role of universally available serial white blood cell counts to calculate the serial systemic immune-inflammatory indices (SSIIi) and the potential association between aura and SSIIi changes in a cohort of migraine patients admitted to tertiary care center in Melbourne Australia.Main body: We retrospectively assessed patients' medical records presenting to Western Health with migraine over an 18 month period. Patients were classified as either having migraine with aura (MA) or without aura (MO) based on ICHD-3 criteria. Baseline demographics and brain imaging findings in each group were evaluated. Patients with two sets of white blood cell counts during the admission were included in the analysis. SSIIi were calculated as, neutrophil counts x platelet counts / lymphocyte counts. Correlation between SSIIi and MA and MO were assessed using SPSS27.Conclusion: SSIIi were elevated in MA and MO followed by a downward trend in both groups, with MA being statistically significant. This proof-of-concept study suggests the potential role of systemic inflammation in pathobiology of migraine. SSIIi appear to show clinical utility. Further comprehensive ,controlled , multicenter studies are required to clarify the exact role of systemic inflammatory response and the clinical utility of SSIIi in a subset of migraine in the Emergency department setting.

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.

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.

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.

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.

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.

Tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC), but high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with choles-tasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administra-tion. After a 7-months follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets suggesting their potential role in the pathophysiology of the disease.

Background: Suicide attempts (SA) frequently occur in patients with mood disorders and schizophrenia, which are both accompanied by activated immune-inflammatory and nitro-oxidative (IO&NS) pathways. Methods: We searched PubMed, Google Scholar, and Web of Science, for articles published from inception until February 1, 2021. We included studies that compared blood biomarkers in psychiatric patients with (SA+) and without SA (SA-) and heathy controls and we combined different IO&NS biomarkers into immune, inflammatory, and neurotoxic profiles and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence interval (CI).Findings: Our search included 51 studies comprising 4.945 SA+ patients and 24.148 controls. We stratified the control group into healthy controls and SA- patients. SA+ patients showed significantly (p<0.001) increased immune activation (SMD: 1.044; CI: 0.599-1.489), inflammation (SMD: 1.109; CI: 0.505, 1.714), neurotoxicity (SMD: 0.879; CI: 0.465, 1.293), and lowered neuroprotection (SMD: 0.648; CI: 0.354, 0.941) as compared with healthy controls. When compared with SA- patients, those with SA+ showed significant (p<0.001) immune activation (SMD: 0.290; CI: 0.183, 0.397), inflammation (SMD: 0.311; CI: 0.191, 0.432), and neurotoxicity (SMD: 0.315; CI: 0.198, 0.432), and lowered neuroprotection (SMD: 0.341; CI: 0.167, 0.515). Patients with current, but not lifetime, SA showed significant (p<0.001) levels of inflammation and neurotoxicity as compared with controls. Conclusions: Patients with immune activation are at a higher risk of SA which may be explained by increased neurotoxicity due to inflammation and nitro-oxidative stress. This meta-analysis discovered new biomarkers of SA and therapeutic targets to treat individuals with SA.

Multiple Sclerosis (MS) is a neurodegenerative disease that mainly affects young adults. The high prevalence of the disease and its impact on patients' quality of life led to priority being given to the etiopathogenesis of the disease to identify possible modifiable factors and consequent effective intervention strategies. Recent hypotheses suggest that the etiopathogenesis of MS is multifactorial and includes factors related to the immune system, neuroinflammation and neuro-degeneration. In this scenario, sleep has a close - although indirect - relationship with MS, through its relationship with each of those factors. In particular, the role of cytokines in immune system impairment and neuroinflammation, mitochondrial dysfunction and oxidative stress in neurodegeneration all are associated with sleep in different forms. Furthermore, melatonin in relation with vitamin D has a potential therapeutic effect in MS sleep-related problems. Given the growing interest of research in the mechanisms underlying MS and therapies able to alleviate MS-related symptoms at all stages of the disease, a more in-depth study of the role of sleep disturbances and the factors intrinsically related to sleep and MS could be useful both to investigate the etiopathogenetic factors of MS and to develop potential non-invasive intervention strategies for MS treatment.

Immunotherapy has been considered for years as a viable and attractive treatment option for patients with cancer. Among immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionized the treatment of several subtypes of tumours. These approaches aimed at restoring an effective anti-tumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells, and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because in these diseases the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and will build a projection of how the field may evolve in the near future. In particular, we will analyze the current strategies being evaluated both preclinically and clinically with the aim to foster the use of immune-checkpoint inhibitors in non-Hodgkin lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.

Major depression (MDD) is accompanied by higher serum IgM/IgA responses to LPS of Gram-negative bacteria, suggesting increased bacterial translocation and gut dysbiosis. Gut dysbiosis may occur in bipolar disorder (BD) and there are differences between MDD and BD type 1 (BP1) and -2 (BP2) in nitro-oxidative stress biomarkers associated with leaky gut. This study examines serum IgM/IgA responses directed to LPS of 6 Gram-negative bacteria in 29 BP1, 37 BP2, 44 MDD and 30 healthy individuals. MDD plus BD was best discriminated from controls by increased IgM/IgA responses to Pseudomonas aeruginosa. BP1 patients showed higher IgM responses to Morganella morganii as compared with MDD and BP2 patients. Patients with melancholia showed higher IgA responses to Citrobacter koseri as compared to controls and non-melancholic depression. The total score on the Hamilton Depression Rating Scale was significantly associated with IgA responses, especially C. koseri. IgG responses to oxidized low-density lipoprotein were significantly associated with signs of increased bacterial translocation. In conclusion, not only MDD but also BP1 and BP2 are accompanied by an immune response due to the increased load of plasma LPS of gut commensal bacteria while these aberrations in the gut-brain axis are most pronounced in BP1 and patients with melancholic features. Activated oxidative stress pathways and autoimmune responses to oxidative specific epitopes in mood disorders may be driven by a breakdown in gut paracellular, transcellular and/or vascular pathways. If replicated, drugs that protect the integrity of the gut barrier may offer novel therapeutic opportunities for BP1 and MDD.

The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system and their interplay and therefore potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

Introduction: Flow-cytometry (FC) is a powerful tool that can assist in lymphoma diagnosis in lymph node (LN) specimens. Although lymphoma diagnosis and classification are mainly based on tumor cell characteristics, surrounding cells are less employed in this process.Methods: We retrospectively investigated alterations in the ploidy status, proliferative cell fraction (PF) and the percentages of surrounding immune cells in 62 consecutive LN specimens with B-Cell Non-Hodgkin Lymphoma (B-NHL) that were submitted for FC evaluation between 2019-2022.Results: Compared with indolent B-NHLs, aggressive B-NHLs show increased DNA aneuploidy and PF, increased monocytes, immature-granulocytes, mature granulocytes, CD8⁺ T-cells, Double-Negative-T-cells and Double-Positive-T-cells, and decreased total CD45⁺ cells, total lymphocytes, CD4⁺ T-cells and CD4/CD8 ratio. Receiver operating characteristic analysis determined PF > 6.8% and immature-granulocytes > 0.9% as optimal cutoffs with highest specificity and sensitivity in differentiating aggressive and indolent B-NHLs.Conclusions: These findings further strength the diagnostic value of DNA content analysis by FC and suggest the utilization of tumor surrounding immune cells in NHL diagnosis and classification.

Intestinal commensal microbes, called the gut microbiota, play a critical role in host immune homeostasis through active microbial metabolites and innate and adaptive immune responses. Dysbiosis or imbalance of the gut microbiota composition is associated with inflammatory bowel disease (IBD) which includes Crohn’s disease and ulcerative colitis. The incidence and prevalence rates of IBD have been increasing worldwide. It is well recognized that butyrate, a microbial metabolite of diet fibers, is a major energy source for colonocytes and plays a crucial role in regulating immune function and maintaining epithelial barrier function and intestinal homeostasis. Emerging evidence suggests that butyrate might be a potential therapeutic agent to treat IBD. In this review, we discuss about gut microbial metabolites, particularly butyrate, the synthesis and metabolism of butyrate, mechanisms of butyrate in immune and epithelial barrier function. Furthermore, we review the current research on various therapeutic implications of butyrate in IBD.

Background. The characterization of new biomarkers of COVID-19 is extremely important. Few studies measured the soluble receptor for advanced glycation end product (sRAGE), angiotensin-converting enzyme 2 (ACE2), calcium and magnesium in COVID-19. Aims: To measure sRAGE, ACE2, interleukin (IL)-6, IL-10, CRP, calcium, magnesium, and albumin in COVID-19 patients in association with peripheral oxygen saturation (SpO2) and chest CT scan abnormalities (CCTA) including ground glass opacities. Methods. This study measured sRAGE, ACE2, IL-6, IL-10, CRP using ELISA techniques, and calcium, magnesium, and albumin using a spectrophotometric method in 60 COVID-19 patients and 30 healthy controls.Results. COVID-19 is characterized by significantly increased IL-6, CRP, IL-10, sRAGE, ACE2, and lowered levels of SpO2, albumin, magnesium and calcium. Neural networks showed that a combination of calcium, IL-6, CRP, and sRAGE yielded an accuracy of 100% in detecting COVID-19 patients with calcium being the most important predictor followed by IL-6, and CRP. COVID-19 patients with CCTAs showed lower SpO₂ and albumin levels than those without CCTAs. SpO2 was significantly and inversely correlated with IL-6, IL-10, CRP, sRAGE, and ACE2, and positively with albumin, magnesium and calcium. Patients with positive IgG results showed a significant elevation in the serum level of IL-6, sRAGE, and ACE2 compared to the negatively IgG patient subgroup.Conclusion. The results show that immune-inflammatory and RAGE pathway biomarkers may be used as external validating criterion for the diagnosis COVID-19. Those pathways coupled with lowered SpO2, calcium and magnesium are drug targets that may help to reduce the consequences of COVID-19.

End-stage renal disease (ESRD) is associated with fatigue and physio-somatic symptoms. The aims of this study are to delineate the associations between severity of fatigue and physio-somatic symptoms and glomerular filtration rate, inflammatory biomarkers, and Wnt/catenin-pathway proteins. The Wnt-pathway related proteins β-catenin, Dickkopf-related protein 1 (DKK1), R-spondin-1, and sclerostin were measured by ELISA technique in 60 ESRD patients and 30 controls. The Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to assess severity of FF symptoms. ESRD is characterized by a significant increase in the total FF score, muscle tension, fatigue, sadness, sleep disorders, GI symptoms, and a flu-like malaise. The total FF score was significantly correlated with serum levels of urea, creatinine, phosphate, and copper (positively), and β-catenin, eGFR, hemoglobin, albumin, and zinc (inversely). The total FF score was associated with the number of total dialysis and weekly dialysis sessions, and these dialysis characteristics were more important in predicting FF scores than eGFR measurements. Partial Least Squares analysis showed that the FF score comprised two factors which are differently associated with biomarkers: a) 43.0% of the variance in fatigue, GI symptoms, muscle tension, sadness, and insomnia is explained by hemoglobin, albumin, zinc, β-catenin, and R-spondin-1; and b) 22.3% of the variance in irritability, concentration and memory impairments by increased copper and cations/chloride ratio, and male sex. ESRD patients show high levels of fatigue and physio-somatic symptoms which are associated with hemodialysis and mediated by dialysis-induced changes in inflammatory pathways, the Wnt/catenin pathway, and copper.

The aim of this study was to identify the differentially expressed genes (DEG) from the skeletal muscle and liver samples of animal model for metabolic diseases in human. To perform the study, the fatty acid (FA) profile and RNA sequencing (RNA-Seq) data of 35 samples of liver tissue (SOY1.5, n=17 and SOY3.0, n=18) and 36 samples of skeletal muscle (SOY1.5, n=18 and SOY3.0, n=18) of Large White pigs were analyzed. The FA profile of the tissues was modified by the diet, mainly those related to monounsaturated (MUFA) and polyunsaturated (PUFA) FA. The skeletal muscle transcriptome analysis revealed 45 DEG (FDR 10%), and the functional enrichment analysis identified network maps related to inflammation, immune process, and pathways associated with the oxidative stress, type 2 diabetes and metabolic dysfunction. For the liver tissue, the transcriptome profile analysis revealed 281 DEG, which participate in network maps related to neurodegenerative diseases. With this nutrigenomics study, we verified that different levels of soybean oil in the pig diet, an animal model for metabolic diseases in humans, affected the transcriptome profile of skeletal muscle and liver tissue. These findings may help to better understand the biological mechanisms that can be modulated by the diet.

Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintained and reinforced their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.

Extracellular vesicles (EV) are a very heterogeneous group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular communication, both locally and systemically, since they induce signals and transfer their contents (proteins, lipids, RNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. How-ever, cell surface receptor-induced EV release is limited to cells from the immune system, includ-ing T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptor for antigen and several bioactive molecules, including proapoptotic proteins. These EV are thus specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we discuss the generation of EV by T lymphocytes and some potential therapeutic approaches of these EV.

Catalase, an antioxidant enzyme widely produced in mammalian cells and bacteria, is crucial in mitigating oxidative stress in a hostile environment. This function enhances the intracellular survivability of various intracellular growth pathogens, including Brucella abortus. In this study, to determine whether the inhibition of catalase can inhibit the intracellular growth of Brucella (B.) abortus, we employed 3-amino-1,2,4-triazole (3-AT), a catalase inhibitor, in both RAW 264.7 macrophage cells and an ICR mouse model during Brucella infection. The intracellular growth assay indicated that 3-AT exerts growth-inhibitory effects on B. abortus within macrophages. Aside from that, it contributes to the accumulation of reactive oxygen species and the formation of nitric oxide. Notably, 3-AT diminishes the activation of the nucleus transcription factor (NF-κB) and modulates cytokine secretion within infected cells. In our mouse model, the administration of 3-AT reduced B. abortus proliferation within the spleen and liver of infected mice. This reduction was accompanied by a diminished immune response to infection, as indicated by lowered levels of TNF-α, IL-6, IL-10, and altered CD4+/CD8+ T-cell ratio. These results suggest the protective and immunomodulatory effects of 3-AT treatment against Brucella infection.

Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Hypertension and atherosclerosis lead to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression. Methods: Patients with active TAK arteritis were compared with age- and sex-matched hypertensive and atherosclerotic patients. In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical evaluation of the vessel wall was performed to compare the in vivo results. Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. These data have been associated with uric acid levels. A significant increase in aortic stiffness was also noted and associated with peripheral T lymphocyte levels. CD3+CD4+ cell infiltrates were detected in the vessel wall samples of these patients. They had a lower mean percentage of Tregs at T0 than controls, but levels increased significantly at T18. Opposite results were found in Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Conclusion: Our data suggest that different pathogenic mechanisms of vessel damage, including atherosclerosis, underlie TAK patients compared with control subjects. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.

The crosstalk between gut microbiota, intestinal epithelial cells, and innate and adaptive immune system governs the maintenance of the intestinal homeostasis. Any interference in this tight dialogue and in the processes preserving cellular homeostasis (e.g., autophagy) may dysregulate the immune response and impair the clearance of harmful bacteria favoring the dysbiotic alteration of the microbic flora that leads to chronic inflammation. Gut dysbiosis is strongly associated with gastrointestinal inflammatory disorders, among them the inflammatory bowel disease (IBD). This review discusses the current knowledge on IBD, from the genetic background of high-risk patients to the molecular mechanisms underlying the disease, the contribution of the microbic flora, and the role of autophagy in intestinal epithelial cells and provides the state of art regarding the targeted-nutritional approaches aimed to restore the beneficial crosstalk between an “anti-inflammatory” microbiota and the host. Analysis of the molecular pathogenesis of IBD will help identify genetic and diet-associated risk factors and thus suggest personalized strategies to prevent and manage the disease to improve quality of life with long-term maintenance of the remission phase.

There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers. The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network. We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which we established in CFAS-D patients. PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks. MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA. The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease. Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

Gastric cancer is a challenging public health concern worldwide and remains a leading cause of cancer-related mortality. The primary risk factor implicated in gastric cancer development is infection with Helicobacter pylori. H. pylori induces chronic inflammation affecting the gastric epithelium, which can lead to DNA damage and promotion of precancerous lesions. Disease manifestations associated with H. pylori are attributed to virulence factors with multiple activities and its capacity to subvert host immunity. One of the most significant H. pylori virulence determinants is the cagPAI gene cluster, which encodes a type IV secretion system and the CagA toxin. This secretion system allows H. pylori to inject the CagA oncoprotein into host cells, causing multiple cellular perturbations. Despite the high prevalence of H. pylori infection, only a small percentage of affected individuals develop significant clinical outcomes, while most remain asymptomatic. Therefore, understanding how H. pylori triggers carcinogenesis and its immune evasion mechanisms is critical in preventing gastric cancer and miti-gating the burden of this life-threatening disease. This review aims to provide an overview of our current under-standing of H. pylori infection, its association with gastric cancer and other gastric diseases, and how it subverts the host immune system to establish persistent infection.

Omega-3 polyunsaturated fatty acids (PUFA) play a pivotal role in health, wellbeing, and inflammatory diseases in humans. Lack of omega-3 consumption is associated with diseases. Specialized Pro-resolving Mediators (SPM) are produced from Omega-3-PUFAs and accelerate resolution of inflammation. They are classified as resolvins, maresins, protectins, and lipoxins. SPMs actions in resolution consist in limiting neutrophilic infiltration, promote the clearance of apoptotic cell and cellular debris, enhancing efferocytosis and phagocytosis, counter regulate the production of pro-inflammatory mediators such as chemokines and cytokines, and promote pro-resolving macrophage phenotype. We identified temporal plasma and serum increases of SPMs after 6 g of oral supplementation of SPM-enriched emulsion in ten healthy subjects. We also described temporal increases of omega-3, as well as pharmacokinetics fundamentals in plasma and serum using LC-MS/MS lipid profiling. These results provide evidence of temporal increases of SPMs that together support the idea that given oral supplementation is a good source of essential bioactive SPMs.

During the coronavirus disease 2019 (COVID-19) pandemic, individuals with immune-mediated inflammatory diseases (IMIDs), such as systemic lupus erythematosus and rheumatoid arthritis, face a heightened risk of infection and severe outcomes due to immunological alterations resulting from their underlying conditions and immunosuppressive treatments. Even as the pandemic has transitioned to an endemic state, it remains crucial to recognize that these patients continue to be at risk. In this narrative review, we analyzed existing literature to explore the impact of IMIDs, clinical risk factors, and the influence of immunosuppressive therapies on COVID-19-related risks and outcomes. Notably, certain disease-modifying antirheumatic drugs (DMARDs), like rituximab, are associated with worse COVID-19 outcomes, and rituximab-treated patients show impaired immune responses to COVID-19 vaccination. Additionally, we outline the diverse effects of glucocorticoids on COVID-19 outcomes and management. To highlight real-life challenges faced by clinicians caring for patients with IMIDs, we present an illustrative scenario that underscores the importance of effective vaccination, timely boosting, and additional mitigation strategies against COVID-19. Given the clinical heterogeneity and diverse disease states within IMIDs, it is crucial to understand the ongoing implications and risks associated with COVID-19 in these patients, to guide the implementation of appropriate measures and optimize care and outcomes in the current endemic era.

Trace amines are a separate, independent group of biogenic amines, close in structure to classical monoamine neurotransmitters such as dopamine, serotonin and norepinephrine. G protein-coupled Trace Amine-Associated Receptors (TAAR) are mostly investigated for their involvement in the pathogenesis of neuropsychiatric disorders, but expression of TAAR family receptors is observed also in various populations of cells of the immune system. The review is focused on the basic information on the interaction of trace amines and their receptors with cells of the general immune system of humans and other mammals, as well as on data on TAARs role in the function of individual populations of myeloid and lymphoid cells. With further research on the regulatory role of the trace amine system in the pathogenesis of the immune response and determination of the biological mechanisms for their action it would be possible to develop new methods for treating diseases related to immune system dysfunctions.

The human innate immune response to the pore-forming toxin of Vibrio cholerae VCC, is currently under study. Here, in vitro studies on a human macrophage cell line (THP-1), helped explore the activated pathways involved on the onset the innate immune response towards the cytotoxin. The secreted monomeric 65 KDa form interacts with mature macrophages in pg/ml concentrations, determined by dose response experiments after treatments under 1 h. Non vacuolating concentrations (pg/ml) were applied to the cells; immunoblots revealed activation of MAPKs: early overexpression of p38 and ERK. Cell lysis by release of lactate dehydrogenase (LDH) was not apparent in the first hour, nonetheless it was positive after 24 h. Finally, to discern whether the VCC stimulates transcriptional activators via MAPKs pathway, NF-κB and AP-1 were studied by real time quantitation. Increased expression of p50 (NF-κB), cJun and cFos (AP-1) was observed. Given that NF-κB is the transcription factor initiating inflammation of innate immune response and in turn, AP-1 is responsible for cell surviving response, results from this study lead us to conclude that VCC in vitro treatments, induce a pro-inflammatory and a surviving response, in less than one hour on activated macrophages.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Background: The aim of this study has been to investigate if inflammatory biomarkers such as the systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have any correlation with the recurrence of pleomorphic adenomas (PA) in patients afflicted by this disease. Methods: A retrospective multicentre study involving two Italian centres, the Maxillofacial Sur-gery at the Policlinico Federico II in Naples and the ENT and Maxillofacial Surgery at the IRCCS G. Pascale National Cancer Institute in Naples, has been performed. The study, involving 608 pa-tients who had received a diagnosis of PA, was conducted between January 2000 and January 2020. A Receiver Operating Characteristic (ROC) curve was used to calculate the optimal cut-off values for the SII, PLR and NLR. A linear regression model (LRM) and a non-linear logistic re-gression model (NLRM) were realized with respect to the NLR, PLR and SII. Results: The highest performance was achieved by the NLR (cut-off 2.960) with the AUC = 0.91, with an accuracy of 96.1%, sensitivity of 78.4% and specificity of 97.2%, PPV = 64.4% and NPV = 98.6%. The LRM and NLRM including all the haematological parameters did not increase the per-formance in terms of recurrence detection. Conclusion: The NLR is an excellent support tool in predicting the recurrence of PA with a cut-off of 2.960. It can be a good reference point for surgical decision-making and follow-up in clinical practice.

Lynch syndrome (LS) is an inherited disorder in which affected individuals have a significantly higher-than-average risk of developing colorectal and non-colorectal cancers, often before the age of 50 years. In LS, mutations in DNA repair genes lead to a dysfunctional post-replication repair system. As a result, the unrepaired errors in coding regions of the genome produce novel proteins, called neoantigens. Neoantigens are recognised by the immune system as foreign and trigger an immune response. Due to the invasive nature of cancer screening tests, universal cancer screening guidelines unique for LS (including colonoscopy) are poorly adhered to by LS variant heterozygotes (LSVH). Currently, it is unclear whether immunogenomic components produced as a result of neoantigen formation can be used as novel biomarkers in LS. We hypothesize that: (i) LSVH produce measurable and dynamic immunogenomic components in blood, and (ii) these quantifiable immunogenomic components correlate with cancer onset and stage. Here, we discuss feasibility and propose the potential to: (a) identify personalised novel immunogenomic biomarkers, (b) reduce invasive cancer screening tests and thus increase non-invasive cancer surveillance, (c) improve compliance and adherence to recommended cancer screening guidelines in LSVH.

innate and adaptive immune responses lead to wound healing by regulating a complex series of events promoting cellular cross-talk. An inflammatory response is presented with its characteristic clinical symptoms: heat, pain, redness, and swelling. Some smart thermo-responsive polymers like chitosan can be used to create biocompatible and biodegradable scaffolds with 3D architectures similar to human structures, allowing their efficient and safe use as tissue engineering and drug delivery systems in chronic wounds. Locally heated tumors above polymer lower critical solution temperature can induce its conversion into a hydrophobic form, enhancing drug release until the thermal stimulus is gone, where a lower release is due to the swelling of the material. This paper integrates the relevant reported contributions of bioengineered scaffolds for thermo-responsive drug delivery in wound healing. Therefore, we present a comprehensive review that aims to demonstrate the capacity of these systems to provide spatially and temporally controlled release strategies for one or more drugs used in wound healing. In this sense, the novel manufacturing techniques of 3D-printing and electrospinning are explored for the tuning of their physicochemical properties to adjust therapies according to the patient’s convenience, as well as reduce drug toxicity and side effects.

Predictive biomarkers for immune checkpoint inhibitors (ICI), such as PD-L1 expression (TPS), remain limited in clinical applications. Improved novel ICI predictive biomarkers are urgently needed. We evaluated a live single-cell functional liquid biopsy cytokine profiling platform to track immunotherapy treatment response and outcomes. Peripheral blood mononuclear cell samples of healthy donors and NSCLC patients undergoing ICI-based therapies were collected longitudinally pre-/post-treatment under IRB-approved protocols. Samples were enriched for CD4+ and CD8+ T-lymphocytes and analyzed on the IsoLight platform. The single T-cells were captured in microchambers on IsoCode chips for cytokines profiling. Functional polyfunctionality data from 55,775 single cells were analyzed using the IsoSpeak software, kappa coefficient, and Kaplan-Meier survival plots. We found a significant difference between responders and non-responders in CD8+ T-cells’ changes in overall polyfunctionality and polyfunctional strength index (ΔPSI). ΔPSI score in CD8+ T-cells performed better than PD-L1 TPS and, when combined with PD-L1 TPS, strongly correlated with early ICI treatment response with a kappa coefficient of 1.0 (p=0.003). High CD4+ T-cells ΔPSI predicted a strong trend of improved PFS (3.9-fold) and OS (3-fold). In conclusion, single peripheral T-cell polyfunctionality dynamics analysis is a promising liquid biopsy profiling platform as NSCLC ICI predictive biomarker regardless of oncogene-addiction status.

The advent of immunotherapy has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), improving the prognosis of this disease and becoming a key part of the treatment, especially in the population without an oncogenic driver mutation. Two different groups of immune checkpoint inhibitors (ICIs) are used in lung cancer: Anti- Cytotoxic T-lymphocyte antigen-4 (Anti-CTLA 4) and Anti- T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti PD-L1). Here in, we review an uptodate on the use of immunotherapy for advanced NSCLC.

Bats are reservoirs of many pathogenic viruses including the lyssaviruses rabies virus (RABV) and Australian bat lyssavirus (ABLV). Lyssavirus strains are closely associated with particular host reservoir species, with evidence of specific adaptation. Associated phenotypic changes remain poorly understood but are likely to involve P protein, a key mediator of the intracellular virus-host interface. Here, we examine the phenotype of P protein of ABLV, which circulates as two defined lineages associated with frugivorous and insectivorous bats, providing the opportunity compare proteins of viruses adapted to divergent bat species. We report that key functions of P protein in interferon/STAT1 antagonism and the capacity of P protein to undergo nuclear trafficking differ between lineages. Molecular mapping indicates that these differences are functionally distinct, and appear to involve modulatory effects on regulatory regions or structural impact, rather than changes to defined interaction sequences. This results in partial but significant phenotypic divergence, consistent with ‘fine-tuning’ to host biology, and with potentially distinct properties in the virus-host interface between bat families that represent key zoonotic reservoirs.

In this experiment, the fermented pineapple residue (FPR) was replaced with 0% (CON), 25% (T25) and 50% (T50) in the diet based on silage royal grass roxb for 30 days in the fattened fatten bulls to evaluate the effect of FPR on growth performance, serum indicators and rumen characteristics.Thirty Simmental calves were selected and divided into three groups according to a completely random design.The temperature and humidity of the cowshed shall be measured every day.Rectal temperature and blood of cattle were measured, and blood and immune markers were measured.The results showed that the rectal temperature decreased significantly when adding 25% fermented pineapple residue (P&lt;0.05), and the rectal temperature decreased significantly when adding 50% fermented pineapple residue (P&lt;0.01).The content of T4 and TC in serum of cattle in T50 group was significantly lower than that in the control group (P&lt;0.01), and the content of T3 was significantly higher than that in the control group (P&lt;0.05), and the content of CR was significantly lower than that in the control group (P&lt;0.01). Fermented pineapple residue can indeed improve the oxidative (heat) stress resistance of finishing cattle. In the correlation experiment, bacterial genera such as Succinniclassicum, Melainabacteria, Lachnospiraceae, and Fibrobacteres all showed significant or extremely significant correlations with heat stress-related indicators.

Macrophages undergo different cellular states upon activation that can be hyporesponsive (tolerated) or hyperresponsive (primed or trained) to subsequent stimuli. Epigenetic modifications are known to play a key role in determining these cellular states. However, little is known about the role of signaling pathways that lead to these epigenetic modifications. Here, we examined the effects of various inhibitors targeting key signaling pathways induced by lipopolysaccharide (LPS) on tolerance and priming in the murine macrophages. We found that a prolonged inhibition (>18 h) of the MEK1/2-ERK signaling axis reversed tolerance and primed cells in expressing IL-1β and other inflammatory cytokines such as IL-6, TNFα, and CXCL10. Ectopic expression of catalytically active and inactive MEK1 mutants suppressed and enhanced IL-1β expression, respectively. Primed cells by the MEK1/2 inhibitor U0126 expressed higher levels of gene sets associated with immune responses and cytokine/chemokine production but lower levels of genes with cell cycle progression, chromosome organization, and heterochromatin formation than non-primed cells. Of interest, expression of the histone 3 lysine 9 (H3K9) methyltransferase Suv39h1 and the H3K9 methylation reader Cbx5 was substantially suppressed, whereas the H3K9 demethylase Kdm7a was enhanced, suggesting a role of the MEK1/2-ERK signaling axis in H3K9 demethylation. The H3K9 trimethylation levels in the genomic regions of IL-1β, TNFα, and CXCL10 were decreased by U0126. Also, the H3K9 methyltransferase inhibitor BIX01294 mimicked and overexpression of Cbx5 prevented the U0126 training effects in both RAW264.7 cells and bone marrow-derived macrophages. Collectively, these data suggest that prolonged inhibition of the MEK1/2-ERK signaling axis reverses tolerance and primed macrophages likely through decreasing H3K9 methylation levels.

Polycystic ovary syndrome (PCOS) is increasingly being characterized as an evolutionary mismatch disorder that presents with a complex mixture of metabolic and endocrine symptoms. The Evolutionary Model proposes that PCOS arises from a collection of inherited polymorphisms that have been consistently demonstrated in a variety of ethnic groups and races. In-utero developmental programming of susceptible genomic variants are thought to predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes and disturbance of the hallmarks of health. The resulting pathophysiological changes represent the consequences of poor-quality diet, sedentary behaviour, endocrine disrupting chemicals, stress, circadian disruption, and other lifestyle factors. Emerging evidence suggests that lifestyle-induced gastrointestinal dysbiosis plays a central role in the pathogenesis of PCOS. Lifestyle and environmental exposures initiate changes that result in disturbance of the gastrointestinal microbiome (dysbiosis), immune dysregulation (chronic inflammation), altered metabolism (insulin resistance), endocrine and reproductive imbalance (hyperandrogenism), and central nervous system dysfunction (neuroendocrine, autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type 2 diabetes, metabolic-associated fatty liver disease, metabolic syndrome, cardiovascular disease, and cancer. This review explores the mechanisms that underpin the evolutionary mismatch between ancient survival pathways and contemporary lifestyle factors involved in the pathogenesis and pathophysiology of PCOS.

Cancer-associated cachexia (CAC) is a debilitating condition marked by muscle and fat loss, unresponsive to nutritional support, and contributes significantly to morbidity and mortality in patients with cancer. Immune dysfunction, driven by cytokine imbalance, contributes to CAC progression. This review explores the potential relationship between CAC and anti-cancer immune response in pre-clinical and clinical studies. Pre-clinical studies showcase the involvement of cytokines like IL-1β, IL-6, IL-8, IFN-γ, TNF-α, and TGF-β, in CAC. IL-6 and TNF-α, interacting with muscle and adipose tissues, induce wasting through JAK/STAT and NF-κB pathways. Myeloid-derived suppressor cells (MDSCs) exacerbate CAC by promoting inflammation. Clinical studies confirm elevated pro-inflammatory cytokines (IL-6, IL-8, TNFα) and immune markers like neutrophil-to-lymphocyte ratio (NLR) in patients with CAC. Thus, immunomodulatory mechanisms involved in CAC may impact the anti-neoplastic immune response. Inhibiting CAC mechanisms could enhance anti-cancer therapies, notably immunotherapy. R-ketorolac, a new immunomodulator, reversed weight loss and increased survival in mice. Combining these agents with immunotherapy may benefit patients with cancer experiencing CAC. Further research is vital to understand the complex interplay between tumor-induced immune dysregulation and CAC during immunotherapy.

This article describes a novel topical composition constituted by gamma-amino butyric acid (GABA) and microbial chondroitin sulfate. This composition, formulated by the author and manufactured in a certified facility in the United States of America, exhibits potential for non-invasive intervention in anxiety management, sleep quality enhancement, and promotion of brain-related functions like meditation and nonlocal consciousness. The core component comprises GABA, a key inhibitory neurotransmitter within the central nervous system, complexed with a suitable carrier molecule, microbial chondroitin sulfate. This complexation aims to enhance transdermal absorption and optimize delivery of GABA to target tissues. The proposed mechanism of action involves modulation of GABAergic signal transduction pathways. Application of the topical composition allows GABA penetration into the skin and potentially deeper tissues, where it interacts with GABA receptors. This interaction leads to mental calmness and relaxation as assessed by electroencephalography. The influence of GABAergic signaling on brain circuits demonstrated in this article, when associated with meditation and nonlocal consciousness, suggests potential for the composition to support these practices. The advantage of such an approach consists in avoiding the potential systemic side effects associated with oral or injectable administration of GABA, anxiolytics or hypnotics. Furthermore, the combination of GABA and microbial chondroitin sulfate may offer synergistic benefits, potentially enhancing the overall biological effects. In conclusion, this article presents a novel topical approach for managing anxiety, enhancing sleep quality, and potentially facilitating meditation and nonlocal consciousness through modulation of GABAergic signaling pathways. While further research is necessary, the potential for a non-invasive and potentially side-effect-free intervention in these areas is promising.

Colorectal cancer is a high-incidence tumor that has a high mortality rate due to its frequent metastasis to the liver. The difference in genes, proteins, and immune microenvironment between the primary and metastatic sites causes them to show different responses to treatment. Colorectal cancer liver metastasis patients also tend to show poorer treatment response and prognosis. Therefore, in this paper, we summarize the heterogeneity exhibited after colorectal cancer liver metastasis from five aspects (gene, transcriptome, protein, metabolism, and immunity), and we found that except for the genetic heterogeneity, the other four aspects exhibite significant heterogeneity, which might serve as a new therapeutic direction and a prognostic marker for patients with liver metastasis. Finally, the therapeutic modalities regarding tumors are rapidly evolving, and we have also summarize the new clinical therapeutic modalities currently proposed based on these heterogeneities, aiming to provide new therapeutic ideas for the clinical treatment of patients with colorectal cancer liver metastases.

The liver is not only a digestive gland, but also an immune tissue that receives a double infusion from the hepatic artery and the hepatic portal vein. Receiving 80% of its blood supply from the intestine through the hepatic portal vein system, the liver is enriched with a large number of innate immune cells, which carry out the process of immune response by detecting pathogens entering the organism through the intestine. The intestine and liver communicate extensively through the bile ducts, portal vein and the somatic circulation, a bidirectional communication known as the intestinal-liver axis. The mammalian gut is considered an important microbial ecosystem. The interplay between the natural immune system and microbes coordinates the physiology of the whole organism, and in specific mammalian lineages, there is a dependency between the host and its associated microbes. To this end, we explored the regulatory mechanisms of natural immunity genes at the genome-wide level. Based on comparative genomics, 1473 bovine natural immunity genes were obtained by collecting the latest reports of human natural immunity genes and updated bovine genomic data for comparison, and a bovine natural immunity gene database was initially constructed to screen and match calf liver natural immunity differential genes mainly affected by the phylum Mimosoidea and the phylum Thick-walled Bacteria, and 16 differentially expressed natural immunity genes were obtained. In addition, the results of IPA analysis indicated that the upstream factor IL-2 initiated the PI3K/AKt/mTOR, mitogen-activated protein kinase (MAPK) pathway and JAK/STAT5 pathway, leading to the liver's involvement in gut microbial immune regulation.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia caused by both immune-mediated platelet destruction and impaired platelet production in the bone mar-row, in the absence of any other identifiable cause of low platelets count. ITP in adult patients is a disease that frequently relapses and/or becomes refractory to multiple treatments during its course, with only a small minority of adult patients attaining a sustained complete remission off-therapy. Treatment of refrac-tory ITP can be challenging, due to the unlikeliness of attaining complete response over time. On the other hand, isolated thrombocytopenia may be due to a misdiagnosed clonal myeloid disorder, such as myelodys-plastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), thus mimicking ITP. We here per-form a narrative review on the association between ITP and MDS/CMML and the possibility of overlap and misdiagnosis between these conditions, while we report also the case a patient treated for a severe re-fractory thrombocytopenia which bone marrow examination led to suspect an overlap of MDS and ITP. Our clinical case describes ITP which is refractory to glucocorticoids, high-dose immunoglobulins, Rituxi-mab, splenectomy, thrombopoietin receptor agonists and Fostamatinib, that ultimately attained a short-lived response to a hypometylating agent that was initiated due to bone marrow examination that aroused the suspect of MDS.

The potential of sericin, a protein derived from silkworms, is explored in bone graft applications. Sericin's biocompatibility, hydrophilic nature, and cost-effectiveness make it a promising candidate for enhancing traditional graft materials. Its antioxidant, anti-inflammatory, and UV-resistant properties contribute to a healthier bone-healing environment, and its incorporation into 3D-printed grafts could lead to personalized medical solutions. However, despite these promising attributes, there are still gaps in our understanding. The precise mechanism through which sericin influences bone cell growth and healing is not fully understood, and more comprehensive clinical trials are needed to confirm its long-term biocompatibility in humans. Furthermore, the best methods for incorporating sericin into existing graft materials are still under investigation, and potential allergic reactions or immune responses to sericin need further study.

During one of the worst global health crises, millions of people were vaccinated against SARS-CoV-2. In rare cases, new onset systemic inflammatory diseases were reported with temporal coincidence to the vaccination. We describe a case of severe Eosinophilic Granulomatosis with Polyangiitis (EGPA) in a young asthmatic woman, occurring after a 2nd dose of mRNA-1273 vaccine. She presented with multisystem EGPA with cardiac and central nervous system involve-ment, complicated by secondary immune thrombocytopenia (ITP). We review the reported cases of EGPA coinciding with SARS-CoV-2 mRNA vaccination. All potentially vaccine-related EGPA cases reported so far occurred within 14 days from immunization. EGPA is very rare with an incidence of 1:1’000’000 inhabitants and the number of reported post-vaccination EGPA cases lies within the expected incidence rate for the period. While we cannot prove a causal relationship between the vaccine and EGPA onset, the temporal relationship with the vaccine immune stimulation is intriguing, in a disease occurring almost always in adults with asthma and/or chronic rhinosinusitis and driven by an aberrant Th2 lym-phocyte activation with hypereosinophilia. Nevertheless, cases of inflammatory diseases emerging in the context of vaccination remain rare and the benefits of preventing severe Covid presentations with SARS-CoV-2 mRNA vaccines remains unquestionable.

In several mammalian species including humans, complex stimulation patterns such as cognitive challenge and physical exercise lead to improvements in organ function, organism health and performance, as well as possibly longer lifespans. The hypothesis is presented here that activity-dependent transcriptional programs, induced by these environmental stimuli, temporarily and lightly de-differentiate somatic cells such as neurons and muscle cells into a state that resembles functionally younger cells to allow cellular remodeling and adaptation of the organism to environmental change. This cellular adaptation program targets several process classes that are heavily implicated in aging, such as mitochondrial metabolism, cell-cell communication, intracellular signaling and epigenetic information processing and leads to functional improvements in these areas. I reverse engineer these activity-dependent gene programs, identify critical molecular nexus points such as CREB, MEF2 and cFos and speculate as to how one might leverage them to prevent and attenuate human aging-related decline of body function, enhance human performance and restore more youthful levels of function and morphology. The findings presented here can serve as a basis for the study and development of effective longevity efforts as the underlying gene programs could be used as markers for treatment success and as targets for therapy development.

Different types of engineered cardiac constructs are being developed nowadays by many research groups. However, the immunological properties of such artificial tissues are not yet clearly understood. Previously, we have studied microfiber scaffolds carrying iPSC-derived cardiomyocytes. In this work, we evaluated the ability of these tissue-engineered constructs to activate the expression of CD28 and CTLA-4 proteins in T-lymphocytes which are early markers of the immune response. For this purpose electrospun PLA nanofibrous scaffolds were seeded with human iPSCs-CM and cultivated for 2 weeks. After, allogeneic mononuclear cells were co-cultured during 48 hours with 3 groups of samples that were tissue-engineered constructs, pure culture of cardiomyocytes and bare scaffolds followed by analysis of CD28/CTLA-4 expression on T-lymphocytes via flow cytometry. PLA scaffolds and concanavalin A (positive control) stimulation statistically significantly increased CD28 expression on CD4+ cells (up to 61.3% and 66.3%) and on CD8+ cells (up to 17.8% and 21.7%). CD28/CTLA-4 expression didn’t increase during co-cultivation of T-lymphocytes with cardiac engineered constructs and iPSC-CM monolayers. Thus, iPSCs-CM in monolayers and on PLA nanofibrous scaffolds didn’t cause T-cell activation, which allows us to expect that such cardiac constructs are not a cause of rejection after implantation.

Osteosarcoma (OSA) is the most common primary malignant bone tumor. More than 40% of patients with OSA have poor prognoses. We aimed to discover a biomarker for patient stratification and therapeutic targets for these high-risk patients. Using Single Sample Gene Set Enrichment Analysis (ssGSEA) and univariate Cox analysis, six hallmarks were identified as significant prognostic factors for overall survival (OS). Three were selected to construct a multivariate Cox model. Then, WGCNA, univariate Cox regression, Kaplan-Meier (KM) survival analyses, and multivariate Cox analyses were combined to filter promising candidates and establish a seven-gene signature to predict OS, whose prognostic value was validated internally and externally. Subsequently, Differential Expression Analysis was conducted between high- and low-risk patients, and the Robust Rank Aggregation algorithm was used to determine the robust DEGs. Metascape was used to perform pathway and process enrichment analyses as well as construct protein-protein interaction (PPI) networks. Finally, RPS28 was identified as an independent risk factor by using univariate and multivariate Cox regression, which was preliminarily validated as a promising therapeutic target by using RNA interference. In conclusion, we might contribute to optimizing risk stratification and an excellent therapeutic target for high-risk patients with OSA.

Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovate therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of MEK-inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM) show only marginal effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers and YAP/TAZ specific drugs give new hope to repeat the success of innovative therapy obtained for CM.

The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment landscape for patients with metastatic non-small cell lung cancer (NSCLC). These achievements inspired investigators and pharmaceutical companies to conduct clinical trials in patients with early-stage NSCLC because both adjuvant and neoadju-vant platinum-based doublet chemotherapies (PT-DCs) showed only a 5% improve-ment in the 5-year overall survival. IMpower010, a phase 3 trial (P3), showed that ad-juvant PT-DC followed by maintenance atezolitumab significantly prolonged dis-ease-free survival than adjuvant PT-DC alone (hazard ratio, 0.79; stage II to IIIA). Since conventional therapies, including chemotherapy and radiotherapy, can promote im-munogenic cell death, which releases tumour antigens from dead tumour cells, ICI combination therapies with conventional therapies are widely proposed. Checkmate 816 trial (P3) indicated a significantly higher pathological complete response rate of neoadjuvant nivolumab/PT-DC combination therapy than neoadjuvant PT-DC alone (odds ratio, 13.9, for stage IB to IIIA). Detection of circulating tumour DNA is highly anticipated for the evaluation of minimal residual disease. Multimodal approaches and new ICI agents are being attempted to improve the efficacy of ICI treatment in phase 2 trials. This review presents the development of perioperative treatment using ICIs in patients with NSCLC while discussing problems and perspectives.

Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English-language publications from 2008 – 2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimizing safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found few, but no serious, adverse events associated with phage therapy. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.

Background. There is strong comorbidity between atherosclerosis (ATS) and depression which is attributed to increased atherogenicity, insulin resistance (IR), and immune and oxidative stress.Aim of the study. To examine the role of the above pathways and mu opioid receptor (MOR), β-endorphin, zinc, copper, vitamin D3, calcium, and magnesium in depression due to ATS / unstable angina (UA).Methods. Biomarkers were assayed in 58 controls and 120 ATS patients divided into those with moderate and severe depression according to the Beck Depression Inventory (BDI)-II score > 19 and > 29, respectively. Results. Neural network and logistic regression models showed that severe depression due to ATS/UA was best predicted by IL-6, UA, MOR, zinc, β-endorphin, calcium and magnesium and that moderate depression was associated with IL-6, zinc, MOR, β-endorphin, UA, atherogenicity, IR, and calcium. These neural networks yielded a significant discrimination of severe and moderate depression with an area under the ROC curve of 0.831 and 0.931, respectively. Using Partial Least Squares analysis, 66.2% of the variance in a latent vector extracted from the ATS/UA clinical features, BDI-II scores, atherogenicity, and IR could be explained by the regression on IL-6, IL-10, zinc, copper, calcium, MOR, and age. The BDI-II scores increased from controls to ATS to UA class III to UA class IV.Conclusions. Depression due to ATS/UA is a reflective manifestation of increased atherogenicity and IR, which are modulated by immune activation, aberrations in the endogenous opioid system, antioxidants, trace elements, and macrominerals.

As the novel COVID-19 disease spreads around the world, the most affected population are those who suffer from the most common chronic diseases, such as obesity, hypertension, and type 2 diabetes, which are quite associated with the so-called age-related diseases. On the other hand, since the Spanish influenza outbreak, humanity has not experienced an infectious disease that synergizes so quickly with chronic diseases, making it mortal for those individuals with comorbidities. In this context, COVID-19 is challenging for health systems all around the world due to the high prevalence of chronic diseases. Nowadays, we are facing the beginning of a new era in which health infectious and chronic diseases meet. Therefore, epidemiologic and biomedical researchers must work together to solve further contingencies, and politicians should direct science-centered decisions on public health. In the present paper, we make an urgent call to learn from the COVID-19 lessons in order to mitigate the chronic diseases prevalence and to address the influence of the infectious diseases on the aging process; since we are about to begin the Decade of Healthy Aging.

We investigated the effect of C. psittaci and H9N2 coinfection on HD11 cells in vitro, expecting to find the potential pathogenesis of airsacculitis caused by co-infection of C. psittaci and H9N2. HD11 cells were infected with C. psittaci and/or H9N2 in a different order, and effects of the co-infection on iNOS expression and activity, NO synthesis, cell phagocytosis, and cytokines levels in HD11 cells were determined. Results showed that C. psittaci and H9N2 can significantly aggravate the mortality of HD11 cells compared to the effects of infection with one pathogen alone. In addition, infection with C. psittaci can increase the replication of H9N2 in HD11 cells, whereas decrease the iNOS level and enzyme activity as well as NO concentration of HD11 cells by H9N2 infection. We also found that C. psittaci infection alone can significantly decrease the phagocytosis of HD11 cells, compared to H9N2 infection alone. Furthermore, infection with C. psittaci can increase the mRNA expressions of type Th2 cytokines IL-6 and IL-10 of HD11 cells by H9N2 infection. All the above data indicated that primary C. psittaci infection is able to aggravate H9N2 invasion by down-regulating functions of HD11 cells

There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors. The A2BAR, coupled to both Gαi and Gαq G proteins, is one of the several G-protein-coupled receptors that are expressed in a significantly higher level in some cancer tissues in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are potentially novel attractive anticancer agents. Several antagonists targeting at the A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various types cancers, and the rationale of using A2BAR antagonists in cancer therapy

In 2011, it was reviewed that there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS. Moreover, the comorbidity between both conditions may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear. This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies that are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicate that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue. In conclusion, based on our review we may posit that shared immune-inflammatory pathways and activated microglia underpin comorbid depression and CFS and that activated microglia are the main orchestrators of this comorbidity. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

Neuromuscular adverse events following cancer treatment with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are relatively rare, yet potentially fatal. Using the PRISMA approach, we performed a systematic review to characterize the clinical presentation, diagnostic workup, and management of neuromuscular disorders (NMDs) in patients treated with nivolumab or pembrolizumab. Sixty-three publications on 85 patients (mean age 66,9 years (range 34–86); male/female 2.6:1; 59% metastatic melanoma) were identified from selected indexing databases until June 2018. Forty-eight patients had received nivolumab and 39 pembrolizumab. The mean number of PD-1 inhibitor treatment cycles prior to onset of symptoms was 3,6 (range 1–28). Symptoms included oculomotor (47%); respiratory (43%), bulbar (35%), and proximal weakness (35%); as well as muscle pain (28%). Diagnoses were categorized as myasthenia gravis (27%), neuropathy (23%), myopathy (34%) and a combination of these (16%). After critical review of the data, however, evidence did not support the stated NMD diagnosis in 13% of cases, while up to 14% of patients had signs of additional NMDs. PD-1 inhibitor associated myasthenia was associated with cardiac complications in almost 30% of patients and with a more rapid clinical progression compared with idiopathic myasthenia. Mortality was high despite adequate treatment strategies including corticosteroid, IV immunoglobulins and plasmapheresis. In conclusion, clinical presentation of NMDs associated with PD-1 inhibitors is often atypical, with significant overlap between myasthenia gravis and myopathy; and cardiac/respiratory complications are common, leading to more severe disease courses than idiopathic myasthenia.

Human adipose stem cell-derived extracellular vesicles (hASC-EVs) are key mediators of paracrine signaling with promising therapeutic applications. Although hASC-EVs are derived from human cells and are less immunogenic, their immunogenicity cannot be completely excluded. Here, we evaluate the immune responses of ICR and C57BL/6 mice to high doses of hASC-EVs for 10 days after injection. Lymphocyte subpopulations are analyzed using flow cytometry at 0.5, 1, 3 and 24 h post injection. In the spleen and blood of C57BL/6 mice, neutrophils sharply increased at 0.5 h and decreased at 3 h following hASC-EV treatment. We observe increased proportions of monocytes, macrophages, and natural killer cells at 3 h but returned to similar level of vehicle control at 24 h post injection in the spleen and blood of ICR mice. Although the in vivo experiments reveal different immune responses to hASC-EV treatment in C57BL/6 and ICR strains, no major changes occur in human peripheral blood mononuclear cell composition after applying hASC-EVs in vitro. In conclusion, unlike those in mice, immune responses to hASC-EVs in humans are not detectable, indicating a minimal risk of fatal side-effects from hASC-EV-based therapies.

Men with non-small cell lung cancer (NSCLC) have a more favorable response to immune-checkpoint inhibitor (ICI) monotherapy, while women especially benefit from ICI-chemotherapy (CHT) combinations. To elucidate such sex differences in clinical practice, we retrospectively analyzed two cohorts treated with either ICI monotherapy (n=228) or ICI-CHT combination treatment (n=80) for advanced NSCLC. Kaplan-Meier analyses were used to calculate progression-free (PFS) and overall survival (OS), influencing variables were evaluated using Cox-regression analyses. No significant sex differences for PFS/OS could be detected in either cohort. Men receiving ICI monotherapy had a statistically significant independent impact on PFS by Eastern Cooperative Oncology Group performance status (ECOG) ≥2 (hazard ratio (HR) 1.90, 95% confidence interval (CI): 1.10-3.29, p=0.021), higher C-reactive protein (CRP; HR 1.06, 95%CI: 1.00-1.11, p=0.037) and negative programmed death-ligand 1 (PD-L1) status (HR 2.04, 95%CI: 1.32-3.15, p=0.001), and on OS by CRP (HR 1.09, 95%CI: 1.03-1.14, p=0.002). In men on ICI-CHT combinations, multivariate analyses (MVA) revealed squamous histology (HR 4.00, 95%CI: 1.41-11.2, p=0.009) significant for PFS; ECOG≥2 (HR 5.58, 95%CI: 1.88-16.5, p=0.002) and CRP (HR 1.19, 95%CI: 1.06-1.32, p=0.002) for OS. Among women undergoing ICI monotherapy, no variable proved significant for PFS, ECOG≥2 had a significant interaction with OS (HR 1.90, 95%CI 1.04-3.46, p=0.037). Women treated with ICI-CHT had significant MVA findings for CRP with both PFS (HR 1.09, 95%CI: 1.02-1.16, p=0.007) and OS (HR 1.11, 95%CI: 1.03-1.19, p=0.004). Although men and women responded similarly to both ICI mono- and ICI-CHT treatment, predictors of response differed by sex.

This paper develops mathematical models examining possible roles of oxytocin and oxytocin receptors in the development of autism. This is done by demonstrating that mathematical operations on normalized data from the Stanford study (K.J. Parker, 2016), which establishes a correspondence between severity of autism in children and their oxytocin blood levels, generates a graph that is the same as the graph of mathematical operations on a normalized theoretical model for the severity of autism. This procedure establishes the validity of the theoretical model and the significance of oxytocin receptors in autism. A steady-state model follows, explaining the constant baseline concentrations of oxytocin observed in the cerebral spinal fluid and blood in terms of the neuromodulation by oxytocin of oxytocin receptors on the magnocellular neurons that produce oxytocin in nuclei in the hypothalamus. The implications of these models for possible roles of oxytocin and oxytocin receptors in autism is considered for several unrelated conditions that may be associated with autism. These are: oxytocin receptor desensitization and down-regulation as factors during labor in offspring autism development; reductions in the oxytocin receptor numbers in the fixed oxytocin receptor expression that occurs before birth; MAST Immune System disease; and the excess number of dendritic spines from lack of pruning observed in brains of autistic people. Research into the feasibility of generating magnocellular neurons and other neurons from adult stem cells is suggested as a way of doing invitro studies of oxytocin and oxytocin receptors to assess the validity of theories presented in this paper.

In order for the body to function properly, it needs not only food, but also nutrients and non-nutritive bioactive compounds that have an immunomodulating effect. This applies not only to healthy people, but especially to people with accompanying chronic diseases, including type 2 diabetes. Unfortunately, the current food industry and the use of highly processed food promote nutritional deficiencies. Many studies confirm their occurrence in patients with type 2 diabetes. The article presents the influence of selected nutrients on the functioning of the immune system, which ensures homeostasis of the body, with particular emphasis on type 2 diabetes. The role of macroelements, microelements, vitamins and selected substances, such as omega-3 acids, coenzyme Q10 and alpha-lipoic acid. The minimum scope of tests that should be performed in patients to directly or indirectly determine the degree of malnutrition in this group of patients is presented.

We conducted many model simulations to understand the causes of the damages of coronavirus (COVID-19) to lung tissue and constructed a diagram showing apparent viral reproduction, immune response and damage accumulation curves. We found that lung damages include virus-caused damage, tissue damage caused by immune responses and tissue damage caused by accumulated wastes. The virus-caused damage is proportional to the phase lag between the viral reproduction curve and the delayed adaptive immune response curve, while waste-induced damage is attributed to imbalance in removing viral, cellular and metabolic by-products. We found that treatment strategies should slow down viral reproduction and speed up immune response, and improve blood micro-circulation in the lungs. Consistent with the strategies, measures are taken to void direct lung infection, strengthen innate responses, promote immune responses, dilute viral concentration in lung tissue, maintain waste removal balance, protect heart and kidneys, control other infections, avoid allergic reactions and other inflammation, etc. We show that medical, dietary, emotional, lifestyle, environmental, mechanical factors, etc. may be simultaneously used to mitigate lung damages and prove that multiple factor health optimization method is magnitudes more powerful than a single factor treatment. Such a method does not depend on molecular specificity and can be used in parallel to antiviral drugs.