The work is devoted to the investigation of virus quasispecies evolution and diversification due to mutations, competition for host cells, and cross-reactive immune responses. The model consists of a nonlocal reaction-diffusion equation for the virus density depending on the genotype considered as a continuous variable and on time. This equation contains two integral terms corresponding to the nonlocal effects of virus interaction with host cells and with immune cells. In the model, a virus strain is represented by a localized solution concentrated around some given genotype. Emergence of new strains corresponds to a periodic wave propagating in the space of genotypes. The conditions of appearance of such waves and their dynamics are described.

The West-African variety of Sorghum bicolor leaf sheath (SBLS) Jobelyn® is a natural remedy, which has gained international recognition for its anti-anemic effect and energy boosting qualities in debilitating diseases. The widespread use of traditional medicine in the region usually confirms its safety, but not its efficacy or deep assessment of their pharmacological properties. The other major issue for herbal-based treatments is the lack of definite and complete information about the composition of the extracts. Despite limitations, efforts have been made in isolation and characterisation of active compounds in this specie of sorghum showing various subclasses of flavonoids including apigeninidin, a stable 3-deoxyanthocyanidin and potential fungal growth inhibitor, which accounts for 84% of the total extract. Non-clinical in vitro and in vivo studies support previous indications that this variety of Sorghum bicolor possesses several biologically active compounds with potent antioxidant, anti-inflammatory, anti-aging and neuro-protective properties. Clinical studies show that SBLS has the ability to boost hemoglobin concentrations in anemic conditions and most remarkably to increase CD4 count in HIV-positive patients. The multiple effects and high safety profiles of this extract may encourage its development as a therapeutic agent for the treatment of anemia, chronic inflammatory conditions or in the symptomatic management of HIV infections. This review describes the potential therapeutic aspects of SBLS extract and its potential benefits.

The relationship of the animal with its environment has been of longstanding interest in philosophy and science. Here I provide a brief introduction to concepts that place an emphasis on mutualism as the basis of organism - environment interaction, in contrast to the long standing view that the environment exerts an instrumental role in shaping the organism. Two influential theories have been von Uexküll’s theory of umwelt and Gibson’s theory of affordances. The former envisioned the animal as immersed in its surroundings (umwelt) to form a functional unit. In a similar manner, the latter theory describes a unity between 1) environmental information that provides the animal with opportunities for action (affordances) and 2) the ability of the animal to perceive and engage with those affordances. These views have influenced more recent ecological models of the organism as the functional unit of biology and have also influenced models of immune function. In ecological models, agency is seen as the ability of the organism to predict and control its engagement with the environment in order to maintain its integrity. The predominant contemporary model of neural function in which perception and action are understood to operate through Bayes-like active inference complements the concept of agency as proposed by the mutualism models. However, it is suggested that rather than a constant mutualism, encounters between organism and environment range over a dynamic spectrum from dualism to mutualism. It is also suggested that along this spectrum, agency emerges when the balance of instrumentality shifts from the environment to the organism, and that the balance of this relationship can further progress towards a felicitous mutualism. Meaning emerges between environmental information and an agent as opportunity for action. Implications for opportunities to foster agency in animals within our care is noted.

Immune-mediated inflammatory diseases (IMIDs) are characterized by dysregulated immune responses and chronic tissue inflammation. In the setting of inflammatory bowel disease (IBD), dipeptidyl peptidase 4 (DPP4) and gut microorganisms have been proved to interplay, potentially influenced by dietary factors. This rapid review aimed to study the DPP4-gut microbiome link in IBD. A literature search across five databases and two other sources identified seven relevant studies reporting data on DPP4 and gut microbiome, in patients with IBD-related IMIDs or in vitro or in vivo models: one cross-sectional, one in vitro, and five in vivo studies. The findings revealed a significant impact of DPP4 and its substrates, i.e. glucagon-like pep-tide-1/2 (GLP-1/2), on the composition of gut microbiome and on the development of dysbiosis. Increased DPP4 activity is associated with decreased GLP-1/2, increased pathogenic bacteria from Actinobacteria, Bacteroidetes, Deferribacteres, Firmicutes, Fusobacteriota, Proteobacteria, and Verrucomicrobia phyla, and decreased -diversity of beneficial gut microbes, including Clostridiaceae, Lachnospiraceae, and Ruminococcaceae families and short-chain fatty ac-id-producing bacteria like Odoribacter and Butryvibrio spp., with exacerbation of intestinal in-flammation. This overview revealed that understanding the DPP4-gut microbiome association is critical for the development of DPP4-targeted therapeutic strategies to guarantee gut microbiome balance and modulation of immune response in IBD.

Objective: SARS-CoV-2 remains the third most common cause of death in North America. We studied methotrexate and tumor necrosis factor inhibitor (TNFi) effects on neutralization responses post-COVID vaccination, in immune-mediated inflammatory disease(IMID). Methods: Prospective data and sera on adults with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA) and systemic lupus (SLE) were collected at 6 academic centres in Alberta, Manitoba, Ontario, and Quebec between 2022-2023. Sera from two time points were evaluated for each subject. Neutralization studies were divided between 5 laboratories, and each lab’s results analyzed separately using multivariate generalized logit models (ordinal outcomes: absent, low, medium, and high neutralization). Odds ratios (ORs) for methotrexate and TNFi effects were adjusted for demographics, IMID, other biologics and immunosuppressives, prednisone, COVID vaccinations (number/type), and infections in the 6 months prior to sample. Adjusted ORs for methotrexate and TNFi were then pooled in random-effects meta-analyses (separately for ancestral, and Omicron BA1 and BA5 strains). Results: Of 479 individuals (958 samples), 292 (61%) were IBD, 141 (29.4%) RA, and the remainder PsA, SpA and SLE. Mean age was 57 (62.2 % female). For both individual labs and the meta-analyses, adjusted ORs suggested independent negative effects of TNFi and methotrexate on neutralization. The meta-analysis adjusted ORs for TNFi were 0.56 (95% confidence interval, CI 0.39, 0.81) for the ancestral strain and 0.56 (95% CI 0.39, 0.81) for BA5. The meta-analysis adjusted OR for methotrexate was 0.39 (95% CI 0.19, 0.76) for BA1. Conclusions: SARS-CoV-2 neutralization in vaccinated IMID was diminished independently by TNFi and methotrexate. As SARS-CoV-2 circulation continues, ongoing vigilance regarding optimized vaccination is required.

Background: Interleukin-6 is dysregulated in multiple pathological conditions, e.g. cancer and inflammatory diseases. Aim: To investigate new mechanisms for regulation of pathological IL-6 production. Methods: PBMC produce interleukin-6 (IL-6) stimulated by cancer serum factors or specific peptides. Immunoregulatory albumin neo-structures and peptides were identified with 2D-gel electrophoresis and MALDI-TOF-MS analyses. Il-6 and albumin neo-structures were determined by ELISA. Results: Conformational changes of normal serum albumin by proteolytic degradation generates an IL-6 inducing neo-structure, IL-6 inducing factor (IL-6IF), which is immunogenic eliciting production of autoantibodies. IL-6 production induced by IL-6IF and cancer patient sera is inhibited by specific antibodies. The serum concentration of IL-6IF, is significantly higher in advanced cancer stages and its presence is significantly correlated to the survival of the patients. Conclusion: A new mechanism for induction IL-6 synthesis is presented. Based on this mechanism the pathological IL-6 production related to an enhanced proteolytic activity can be diagnosed and selectively inhibited by specific antibodies. Such antibodies have been identified and purified. Thus, the neo-structure, inducing pathological IL-6 production, associated with a reduced survival of cancer patients can be selectively removed by therapeutic administration of antibodies leaving the function of IL-6 needed for the normal activity of the immune system intact.

Background: Tumor mutational burden (TMB) is increasingly recognized as a vital biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment. Despite its growing importance, the effectiveness of TMB as a predictive marker are well established in lung cancer and melanoma but remain ambiguous for breast and prostate cancers. Objective: This study aims to evaluate the role of TMB in predicting response to ICIs across four major cancer types—lung, melanoma, breast, and prostate—and to address the variability in TMB's predictive value in different cancers. Methods: A comprehensive review of the current literature was performed, analysing studies that investigated TMB and its association with ICI therapy outcomes in the specified cancer types. Results: The analysis reveals a strong consensus on the predictive value of TMB in lung cancer and melanoma, where high TMB levels are associated with improved clinical outcomes and better responses to ICIs. In contrast, the evidence for breast and prostate cancers is less conclusive, with variability in results highlighting the need for further research. Specifically, high TMB in these cancers does not consistently predict better responses to ICIs, suggesting that additional biomarkers or refined criteria might be necessary. Conclusion: TMB is a promising biomarker for predicting responses to ICI therapy, particularly in lung cancer and melanoma. However, its predictive value in breast and prostate cancers remains uncertain, underscoring the need for more extensive studies. Future research should focus on standardizing TMB evaluation methods and exploring additional biomarkers to improve treatment personalization and outcomes in these cancer types.

Coronaviruses constitute a global threat to human and animal health. It is essential to investigate the long-distance RNA-RNA interactions that approximate remote regulatory elements in strategies, including genome circularization, discontinuous transcription, and transcriptional enhancers, aimed at rapid replication of their large genomes, pathogenicity, and immune evasion. Based on the primary sequences and modeled RNA-RNA interactions of two experimentally de-fined coronaviral enhancers, we detected via in silico primary and secondary structural analysis potential enhancers in various coronaviruses, from the phylogenetically ancient avian IBV to the recently emerged SARS-CoV-2. These potential enhancers possess a core duplex-forming region that could transition between closed and open states, as molecular switches directed by viral or host factors. The open state would permit the enhancer to pair with remote sequences in the viral genome and modulate the expression of crucial genes involved in viral replication and host immune evasion. Consistently, variations in the predicted IBV enhancer region or its distant targets coincide with cases of viral attenuation possibly driven by decreased expression of the ORF3a immune evasion protein. The annotated enhancer sequences could inform structural prediction tools and antiviral interventions if validated experimentally.

The periodontal ligament (PDL) is a complex connective tissue that connects the tooth root to the dental alveolar bone and plays crucial mechanical roles. PDL also exhibits regenerative roles and regulatory functions to maintain per-iodontium integrity and homeostasis. While PDL exposure to oral microbial pathogens is common, virtually nothing is known regarding viral infections of PDL. In particular, human herpes simplex virus type 1 (HSV-1) persistently infects the oral cavity through infections of the oral epithelium, connective tis-sue and neurons. While the oral spread of HSV-1 is generally asymptomatic, this virus has also been implicated in various oral pathologies. In this study, using a primary cell model derived from PDL (PDL-cells), and whole surgical fragments of PDL, we provide evidence supporting the efficient infection of PDL by HSV-1 and the promotions of cytopathic effects. Infection of PDL by HSV-1 was also associated with an acute innate inflammatory response, as il-lustrated by the production of the antiviral interferons and pro-inflammatory cytokines. Furthermore, this inflammatory response to HSV-1 was exacerbated in the presence of bacterial-derived products, such as peptidoglycans. This work therefore highlights the ability of HSV-1 to infect mesenchymal cells from PDL, suggesting that PDL may serve as a viral reservoir for the perio-dontal spread of HSV-1. Moreover, this raises questions about HSV-1 oral pathogenesis, as HSV-1-associated cytopathic and inflammatory effects may contribute to profound alterations of PDL integrity and functioning.

Recently intraductal carcinoma of the prostate (IDCP) has attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced accessibility to immune cells, which reflect the pathological characteristics of IDCP, may influence the aggressiveness of high-grade prostate cancer.

Background: SARS-CoV-2 Omicron JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used RT-qPCR SGTF as the proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing for diagnosis of JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed Q229K, usually associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: The CDC should consider Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.

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.

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.

Handedness reflects functional body and hemispheric lateralization, proving relevant to contextualize cognitive and behavioral profiles. This study aimed to determine the lateralization of the hands, feet and eyes in patients with various neurological disorders and to test the Edinburgh Handedness Inventory (EHI), a widely used handedness measure. The study design included a literature overview and a clinical study. The overview spanned the literature of the past 50 years since the EHI was developed. Three hundred seventy-four patients with immune-mediated (IM) or noIM neurological diseases and healthy subjects underwent personal and family history of handedness, stressful events and IM diseases, and EHI. The literature overview showed that handedness, which develops under the influence of genetic and acquired factors, is an indirect indicator of hemispheric lateralization; hemispheric lateralization is bidirectionally related to the immune system. In the clinical study, the EHI showed appropriate reliability and structural validity; its scores related to chronological age, onset age, and disease duration and helped distinguish patients with IM disease from other patients and healthy subjects. Therefore, handedness may change over the course of life under the influence of pathology and could predict IM neurological diseases. The EHI is an appropriate measure of handedness.

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.

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.

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.

Similarly to our healthy organs, tumor tissue also generates an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells, alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix, all promoting the epithelial-mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment, so the successful inhibition of tumorous matrix remodeling could further enhance the success of tumor treatment. Numerous publications describe efforts to inhibit tumor matrix components, but the true breakthrough has yet to be achieved. If, on the other hand, we assume that tumorous blood vessels and inflammatory cells are residents of the tumorous stroma, then two steps forward have occurred.

Mincle, a C-type lectin, is expressed predominantly in macrophages, where it plays a role in the macrophage response to various microorganisms such as mycobacteria. Docking is a computational procedure in which various software packages generate different positions at which ligands bind to their receptors. Discovery Studio docking was used in Molegro Virtual Studios. ChemDraw and ChemDraw3D were used for ligand preparation and construction because the protein preparation performed using docking software was a very lengthy process. Mincle plays a novel and non-redundant role in the induction of inflammatory signaling in response to mycobacteria. One disadvantage of Molegro studio docking is that it does not show the metallic atoms with which it interacts but rather shows hydrogen bonding and amino acid interactions. Hypothetically, trehalose dimycolate (TDM) and trehalose dibenzenate (TDB) detected by macrophages ultimately lead to CARD9 signaling, thereby producing pro-inflammatory cytokines and chemokines that have the potential to be used therapeutically.

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.

Modern oncological therapy utilizes various types of immunotherapy. Immune checkpoint inhib-itors (ICIs), chimeric antigen receptor T cells (CAR-T) therapy, cancer vaccines and bispecific an-tibodies are improving patients’ outcomes. However, stimulation of the immune system, benefi-cial in terms of fighting against cancer, generates the risk of harm to other cells in a patient's body. Kidney damage belongs to the relatively rare adverse events (AEs). Best described, but still, su-perficially, are renal AEs in patients treated with ICIs. International guidelines issued by Euro-pean Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) cover the management of immune-related adverse events (irAEs) during ICI therapy. There are scarce data concerning renal adverse drug reactions of other immunotherapeutic methods. This implicates the need for the collection of safety data during ongoing clinical trials and in the re-al-life world to characterize the hazard related to the use of new immunotherapies and manage-ment of irAEs.

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.

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.

Until recently, research on the molecular signatures of HPV-associated head and neck cancers mainly focused on their differences with respect to HPV-negative HNSCCs. However, given the continuing high incidence level of HPV-related HNSCC, the time is ripe to characterize the heterogeneity that exists within these cancers. Here, we review research thus far on HPV-positive HNSCC molecular subtypes, and their relationship with clinical characteristics and HPV integration into the host genome. Different omics data including host transcriptomics and epigenomics, as well as HPV characteristics, can provide complementary viewpoints. Keratinization, mesenchymal differentiation, immune signatures, stromal cells, and oxidoreductive processes all play important roles.

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.

C-C Chemokine receptor type 5 (CCR5) is expressed on the CD4 T cell surface where CXCR4 and CCR5 expressions are controlled differently during the activation of T cells and with the binding of interleukin type-2 (IL-2). IL-2 can upregulate CCR1 and CCR2 in CD45R01 T cells and increase the T lymphocyte chemotaxis toward CC-chemokines. CD4+ T cells are either apart of the T helper 1 or Th1 lymphocytes that release interferon gamma (IFNγ) and lymphotoxin that provide cellular immunity to internal pathogens and T helper cells type 2 (Th2), which secrete interleukins 4 and 5 (IL-4 and IL-5). IL-4 and IL-5 cause an allergic and humoral immune response to parasites. Th2 lymphocytes use CCR3 chemokine receptors. CCR5 and CXCR3 chemokine receptors are specific for CD4+ Th1 and Th2 lymphocytes. CCR5Δ32 is a 32-base-pair deletion of the CCR5 gene. CCR5 is a co-receptor for the entrance of the human immunodeficiency virus-1 (HIV-1). CCR5Δ32 creates a malfunction of the CCR5 protein that can prevent HIV-1 infection. However, the CCR5Δ32 32-base-pair deletion is not prevalent and predominant in many populations worldwide and there also exist more genetic variations of CCR5 known as CCR5-SNPs. An alternative polymorphism was identified based on the CCR5 gene that was identified as a A to G (A/G) point mutation. This point mutation is located at the 59029 locus on the promoter that lowers the expression rate of CCR5. Gurdol et al. found activity at the promoter of CCR5/590029G was 45% lesser than the CCR5/59029A. The genetic variations of CCR5 SNPs also include: 2459G>SNP of CCR5, C101X, CCR5 gene position at -2273, and the A to G SNP mutation found in two South African blacks. Therefore, more studies are needed to find more and varied chemokine polymorphisms that are present in many diverse populations in the world. The aim of this literature review is to describe the immense impact of CCR5 SNP mutations on viral infection susceptibility, on the pathogenesis of chronic conditions, to endorse the increased discovery of more novel CCR5 SNPs, and to show the significant potential of anti-CCR5 therapies to treat multiple diseased conditions.

New coronavirus (SARS-CoV-2) treatments and vaccines are under development to combat the COVID-19 disease. Several approaches are being used by scientists for investigation including 1) various small molecule approaches targeting RNA polymerase, 3C-like protease, and RNA endonuclease and 2) exploration of antibodies obtained from convalescent plasma from patients who have recovered from COVID-19. The coronavirus genome is highly prone to mutations that lead to genetic drift and escape from immune recognition; thus, it is imperative that sub-strains with different mutations are also accounted for during vaccine development. As the disease has grown to become a pandemic, new B-cell and T-cell epitopes predicted from SARS coronavirus have been reported. Using the epitope information along with variants of the virus, we have found several variants which might cause drifts. Among such variants, 23403A>G variant (p.D614G) in spike protein B-cell epitope is observed frequently in European countries such as the Netherlands, Switzerland and France.

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems. Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene-expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window.To this end, we provide an original bioinformatic dissection of the gene-expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient’s derived samples indicated that WNT increased activation and a peculiar immune-microenvironment identify subjects with nodal involvement.In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939, a specific WNT pathway inhibitor, has in re-educating a tumour permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in nodes-positive disease.

Obesity is a complex disease increasing risk of other pathologies. Its prevention or long-term weight loss maintenance is problematic. Gut microbiome is considered a potential obesity modulator. The objective of the present study was to summarize recent findings regarding relationships between obesity, gut microbiota and diet, with emphasis on dietary fiber and resistant starch. Composition of the human gut microbiome and methods of its quantification are described. Products of the gut microbiome metabolism, such as short-chain fatty acids and secondary bile acids including their effects on the gut microbiota, intestinal barrier function and immune homeostasis are discussed in the context of obesity. Importance of dietary fiber and resistant starch is emphasized as far as effects of the host diet on the composition and function of the gut microbiome are concerned. Complex relationships between human gut microbiome and obesity are finally summarized.

pending

White adipose tissue (WAT) and gut are involved as inducers of neuroinflammation when they detect injury and trigger inflammation. The autonomous nervous system innervates both tissues, although the roles of the sympathetic, parasympathetic and enteric nervous systems have not been fully elucidated. Here, we revisited the participation of both types of inflamed peripheral tissue in neuroinflammation. We first analyzed how inflamed peripheral WAT plays a key role in neuroinflammation once metainflammation is installed. Second, we described the impact of insulin resistance (IR) on hypothalamic dysfunction, T2DM and neurodegenerative diseases. Finally, we analyzed the gut-brain axis, examining cell interactions, soluble factors, the sensing of microbes and the role of the intestinal microbiota and mucosal barriers in neuroinflammation. Since intestinal mucosa and secondary lymphoid organs are densely innervated by the sympathetic, parasympathetic, and enteric nervous systems, we analyzed bidirectional crosstalk between different tissues, neurons, and immune systems in healthy and pathological circumstances to restore normal tissues functions, and consequently homeostasis.

Background: Routine childhood vaccination, e.g., for diphtheria-tetanus-pertussis (DTP), might provide an additional protection towards SARS-CoV-2 infection. This concept of heterologous immunity was explored in healthy children receiving both DTP and inactivated SARS-CoV-2 vaccines. Methods: A cross-sectional study was performed on 154 healthy children aged 6–8 years old in Jakarta, Indonesia. Their vaccination status of DTP (including diphtheria-tetanus booster vaccine at 5 years old) and CoronaVac (from 6 years old) were recorded. Peripheral blood samples were collected from all participants, in which anti-diphtheria toxoid IgG, anti-SARS-CoV-2 S-RBD antibodies and T cell-derived IFN-g were measured. Results: Study participants with complete DTP vaccination had significantly higher titer of anti-diphtheria toxoid IgG than the ones without (median=0.9349 versus 0.2113 IU/mL; p<0.0001). Upon stratification based on DTP and CoronaVac vaccination statuses, participants with complete DTP and CoronaVac vaccinations had the highest titer of anti-SARS-CoV-2 S-RBD antibodies (median=1,196 U/mL) and the highest concentration of SARS-CoV-2-specific T cell-derived IFN-g (median=560.9 mIU/mL) among all groups. Conclusion: Healthy children aged 6-8 years old with complete DTP and CoronaVac vaccinations exhibited higher SARS-CoV-2-specific adaptive immune responses, particularly on their T-cell response. This suggests an additional benefit of routine childhood vaccination to generate protection against novel pathogens, presumably via heterologous immunity.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

Mastitis-causing bacteria can establish persistent infections in the mammary gland of commercially important dairy animals despite the presence of strong specific humoral and cellular immune mechanisms. The aim of this study was to encapsulate vitamin D3 by complex coacervation with sulfur-saturated bovine lactoferrin-alginate using microbial transglutaminase-catalyzed crosslinking and investigate the oral administration of encapsulated vitamin D3 in blood serum biomarkers of the immune response in late-lactating dairy goats. Dairy goats (n = 18) in late lactation were randomly assigned to three experimental groups (n = 6), after balancing weight. Dairy goats were orally administered with 0.35 mg vitamin D3/day in the unencapsulated form and 0.35 mg vitamin D3/day in the encapsulated powder form. Another group received the basal diet. The experimental period lasted 6 weeks. The blood serum concentrations of 25-hydroxyvitamin D3 [25-(OH)-D3], lactoferrin, immunoglobulin A (IgA), and interferon-gamma (INF-γ) were measured. The delivery of vitamin D3 to dairy goats resulted in a marked increase of 25-(OH)-D3 concentration in serum while the serum level of lactoferrin also increased. Alternatively, the serum levels of IgA and the immunomodulatory cytokine INF-γ were elevated following supplementation with the encapsulated vitamin D3. Overall, the capsules in the powder form used in this study kept vitamin D3 highly bioavailable.

Avian Influenza viruses (AIVs) has posed a significant pandemic threat since their discovery. This review mainly focuses on the epidemiology, virology, and pathogenesis, and treatments of avian influenza viruses. We delve into the global spread, past pandemics, clinical symptoms, severity, and immune response related to AIVs. The review also discusses various control measures, including antiviral drugs, vaccines, and potential future directions in influenza treatment and prevention. Lastly, by summarizing the insights from the previous pandemic control, this review aims to direct effective strategies for managing future influenza pandemics.

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.

Salmonid alphavirus strain 3 is responsible for outbreaks of pancreas disease in salmon and rainbow trout in Norway. Although the extensive amount of research on SAV3 focused mainly on the heart and pancreas (of clinical importance), tropism and pathogenesis studies of the virus in other salmon tissues are limited. Here, we used a combination of RT-qPCR (Q_nsp1 gene) and in situ hybridization (RNAscope®) to demonstrate the tropism of SAV3 in situ in tissues of Atlantic salmon, employing a challenge model (by cohabitation). In addition, as previous results suggested that pseudobranch may harbor the virus, the change in the expression of different immune genes upon SAV3 infection (RT-qPCR) was focused on the pseudobranch in the current study. In situ hybridization detected SAV3 in the heart, pseudobranch, gills, pyloric caeca, and pancreas after virus infection, with the heart ventricle showing the most extensive infection. Furthermore, the detection of the virus at different adipose tissues associated with the internal organs of the salmon, suggests a specific affinity of SAV3 to adipocyte’s components. The innate immune response to SAV3 in the pseudobranch after infection dominated over the adaptive responses, yet it did not mitigate the infection in that tissue. The early detection of SAV3 in the pseudobranch after infection, along with the persistent low infection over the experimental course, suggests a pivotal role of the pseudobranch in SAV3 pathogenesis in Atlantic salmon.

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n=18) and IDH1 mutant (IDH1-mt) astrocytoma (n=12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical mem-braneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vascula-ture are shown to have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Overproduction of lipids by the tumor is suspected to be due to a combination of two processes: i) dysfunctional oxidative phosphorylation in mitochondria that causes metabolic backup and ac-cumulation of acetyl-CoA, as well as ii) the overproduction of pyruvate due to the tumor cell reli-ance on overactive glycolysis. Tumor cells use lipids for structural components but cannot use them for energy if their oxidative phosphorylation is dysfunctional, which seems to be the case in the tumor cells we examined. This lipid-rich environment, however, offers tumor cells certain advantages: protection from the immune system, non-lipophilic drugs, and oxidative stress. Our research highlights the significant presence of lipid overproduction in both IDH1-wild type glio-blastoma and IDH1-mutant astrocytoma tumors, leading to diverse lipid accumulations in var-ious cellular compartments and structures. This lipid excess stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune re-sponses, non-lipophilic drugs, and free radicals.

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.

Targeted cancer therapy has grown exponentially in the last decade, representing the largest frontier in the modern concept of precision medicine. This renaissance is largely due to our rapidly evolving ability to biochemically harness our immune systems to target cancer-specific antigens. Combined with an increasing armamentarium of surgical and non-invasive techniques for cancer mitigation we have upgraded cancer therapy from a non-specific assault on cell-division to a multi-modal, targeted approach. This renaissance has resulted in an increase in the perioperative footprint of patients with advanced cancer. The scope of the perioperative clinician has evolved from one of passive/reactive management of complications to a proactive approach that starts in the preoperative optimization phase and continues into the postoperative period. The perioperative world should not exist in a silo, and thus involvement of the oncology team is paramount. To provide safe oncologic care, it is essential to be up to date in newer cancer therapies, lest we act on erroneous and/or outdated information. Oncologists should weigh in on immune status, recent chemotherapeutic exposures, and potentially evolving toxicities. These might involve critical changes to perioperative infectious prophylaxis, steroid administration, and coagulopathy management. First, patients living beyond the typical life-expectancy for their cancer will carry a high burden of cancer-related downstream effects. General metabolic issues will include malnutrition, cachexia, and gastric outlet obstruction. Severe protein-calorie malnutrition, as well as hepatic and renal dysfunction can impact the metabolism and clearance of drugs. The cardiovascular, endocrinologic, pulmonary, and central nervous system implications of new cancer therapies will be discussed extensively below. Second, we have to enhance our ability to manage a cancer population who may be experiencing increasing novel chemotherapeutic toxicities. Newer agents differ from historical agents, which were blunt-force tools aimed at nonspecific destruction of cell-division. These drugs are efficacious but physiologically costly. Newer immunogenic therapies have a slightly improved acute safety profile, and a more complex chronic toxicity profile that may be overt or insidious. Chronic toxicities can present overtly or as a smoldering undertone to other active medical conditions such as sepsis, pneumonia, failure to thrive, or renal failure. The new therapies discussed in this review occur in the context of an overall increasingly multi-faceted cancer care machine. An example is screening for esophageal cancer in patients with Barrett's esophagus, or periodic chest CTs for patients with a strong history of tobacco use. These interventions are more likely to detect disease while it is still resectable, and resections will commonly accompany neo-adjuvant therapy. These approaches commonly involve new immunotherapies whose efficacy is higher-yield with a lower disease burden. In a recent example, the immune-checkpoint inhibitors (ICIs) ipilimumab plus nivolumab have significantly increased survival rate for squamous cell esophageal cancer when combined with standard chemotherapy. Surgical resection has evolved to one that often accompanies neoadjuvant chemo and radiation. The increasing efficacy of this approach may de-necessitate many major resections, and increase the number of sub-anatomic resections and minimally invasive procedures. Improved techniques - notably for hepatectomy, whipple procedure, prostatectomy, nephrectomy - have increased the safety profile and decreased the perioperative physiologic burden. This has enabled a broader subset of patients (due to cancer burden or due to medical comorbidities) to qualify for the operation, and increased the involvement of anesthesia and their perioperative services. With an increase in surgical candidacy comes an increase in post-surgical complications, and post-surgical maintenance such as drains, embolizations, imaging studies, etc. In the non-OR anesthesia realm, there have been considerable advancements in cancer “micro-treatments” such as hepatic metastasis embolization, tumor ablation, and peri-tumor vascular embolization. There are an ever-increasing number of IR-guided embolizations for bleeding tumors, aspiration of malignant effusions, and drainage of abscesses. This review serves to provide insight into new categories of chemotherapy and their perioperative implications.

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.

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.

Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate immune system and in particular the interferon response form the important first line of defense against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate immune evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate immune evasion on the pathology caused by the viral infection is less prevalent in literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, the influence of antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host immune evasion in the pathogenesis of emerging viruses belonging to the coronaviruses, alphaviruses and flaviviruses.

This research aims to apply Artificial Intelligence (AI) methods, specifically Artificial Immune Systems (AIS), to design an optimal control strategy for a multivariable control plant. Two specific industrial control approaches are investigated: I-PD (Integral-Proportional Derivative) and PI-D (Proportional-Integral Derivative) control. The motivation for using these variations of PID controllers is that they are functionally implemented in modern industrial controllers, where they provide precise process control. The research results in a novel solution to the control synthesis problem for the industrial system. In particular, the research deals with the synthesis of I-P control for a two-loop system in the technological process of a distillation column. This synthesis is carried out using the AIS algorithm, which is the first application of this technique in this specific context. Methodological approaches are proposed to improve the performance of industrial multivariable control systems by effectively using optimization algorithms and establishing modified quality criteria. The numerical performance index ISE justifies the effectiveness of the AIS-based controllers in comparison with conventional PID controllers (ISE₁ = 1.865, ISE₂ = 1.56). The problem of synthesis of the multi-input multi-output (MIMO) control system is solved, considering the interconnections due to the decoupling procedure.

The neurologic effects of long-COVID are a therapeutic challenge. This article discusses the immunologic manifestations of long-COVID and proposes a non-androgenic, synthetic analog of dehydroepiandrosterone (DHEA), bromo-epi-androsterone (BEA), as a candidate for clinical trials for this exigent collection of neurologic conditions. Moreover, because there is an association between long-COVID and Alzheimer’s disease, the evaluation of BEA in long-COVID may serve as a proxy for its effect on neuroinflammatory biomarkers of Alzheimer’s disease that are shared with long-COVID.

Aim: To evaluate the clinical findings of glucose 6 phosphate dehydrogenase(G6PD) and pyruvate kinase(PK) deficiency in prolonged jaundice. To determine whether systemic-immune-inflammation index(SII), neutrophil-to-lymphocyte ratio(NLR) and platelet-to-lymphocyte ratio (PLR) can be used in the diagnosis of neonatal prolonged jaundice. Methods: In full term neonates with hyperbilirubinemia who were admitted to Medicine Hospital between January 2019 and January 2024 with the complaint of jaundice, 167 infants with a serum bilirubin level above 10 mg/dL, whose jaundice persisted after the 10th day, were included in the study. Results: G6PD was negatively correlated with NLR, SII, age, and Hct. There was a negatively poor correlation between G6PD and NLR and a negatively moderate correlation between G6PD and SII when adjusted for age and Hct. PK showed no significant correlation with G6PD, NLR, PLR, SII, age, and Hct. A linear relationship was observed between G6PD and SII and NLR. Conclusions: NLR and SII can be easily calculated in the evaluation of prolonged jaundice in G6PD deficiency has a considerable advantage. NLR and SII levels may contribute by preventing further tests for prolonged jaundice and regulating its treatment. It may be useful to form an opinion in emergencies and in the early period.

Background: Bacteria, among the earliest life forms on Earth, are integral to both human health and environmental ecosystems. They contribute to essential processes such as digestion, nutrient absorption, and immune defense, and play key roles in the biogeochemical cycles that sustain life. Objective: This paper explores the indispensable role of bacteria in human life and environmental health, emphasizing their contributions to digestion, nutrient absorption, immune protection, and ecosystem functioning. It also discusses advances in understanding the human microbiome and their implications for health and therapeutic interventions. Methods: The study reviews existing literature on the human microbiome, probiotics, and the role of bacteria in environmental nutrient cycling. It analyses experimental evidence and case studies, particularly focusing on the impact of fecal microbiota transplantation (FMT) as a therapeutic tool. Metagenomic analysis techniques are examined to highlight the diversity and functionality of gut bacteria. Results: Bacteria are found to be essential for breaking down food, providing vital nutrients, and protecting against pathogens. They play a critical role in maintaining a healthy immune system and are involved in the biogeochemical cycles necessary for ecosystem health. Metagenomic analysis reveals significant variations in bacterial populations associated with health and disease, emphasizing the importance of a balanced microbiota. FMT shows promise as an effective treatment for various diseases, including gastrointestinal, metabolic, and neurological disorders. Conclusions: Bacteria are crucial for human health and environmental stability. Maintaining a balanced microbiota is vital for overall well-being, and interventions such as probiotics and FMT can offer significant health benefits. Future research should focus on further understanding the complex interactions between bacteria and their hosts to develop targeted therapies for various health conditions.

Cellular senescence has recently been recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies such as radiation, chemotherapy, and targeted agents. While such therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis and normal tissue toxicity, TIS has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), with a particular focus on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Via the SASP, the formation of SnCs may alternately mediate resistance or response to conventional therapy. Further, toward fulfilling the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as a source of antigen to potentiate anti-tumor immunity. This new view suggests treatment strategies based on inducing TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, toward enhancing the benefits of cancer treatment.

Background: In recent years, whole blood parameters and derivatives have been used as prognostic criteria in the course of the disease in various diseases. The prognostic nutritional index (PNI), the systemic immune-inflammation index (SII), the neutrophil-lymphocyte ratio (NLR) have been adapted as an indicator of inflammation and have been widely studied to define the severity of inflammation in some diseases. The aim of this study was to evaluate the relationship between parameters such as NLR, SII, PNI, controlling nutritional status (CONUT) score, nutritional risk index (NRI) and with immunonutrition status and disease activity in patients with ischemic stroke of small vessel, large vessel and other etiologies. Methods: We retrospectively evaluated the records of 1454 consecutive ischemic stroke patients hospitalized in the emergency department of Gaziosmanpasa Education and Research Hospital from 2019 to 2023. Results: Of the 1350 SVO patients included in the study, 58.8% had small vessel, 29.3% had large vessel and 11.9% had other etiologies. There was a significant difference between the 3 etiology groups for PNI and CONUT. The median PNI was 47.03 (41.33-52.85) in the other etiology group, 35.29 (33.69-37.25) in the small vessel group, and 34.11 (30.23-36.87) in the large vessel group. The CONUT median was 5(5-6) in the small vessel group, 5(4-6) in the large vessel group and 4(4-4) in the other etiology group. In addition, CONUT and PNI were also found to be independent risk factors for death. A negative significant correlation was observed between PNI and NLR (r:-0.692), SII (r:-0.591), CONUT (r:-0.685). Significant correlations were observed between CONUT and NLR (r:0.402), SII (r:0.312). Conclusion: PNI and SII were significantly associated with disease activity. PNI, CONUT and NRI as a more accurate prognostic indicator of nutritional status in patients with ischemic stroke of small vessel, large vessel and other etiologies. NLR and SII may be important predictive markers in the course and prognosis of stroke.

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.

By conjugating a radioantigen (o-quinone) with a protein - Esherichia coli endotoxin, a stable polyantigen complex-protein-quinoid radioantigen (BChA) - o-quinone imine (C6H10O-NH - protein) was obtained, including haptenic (o-quinone) and protein part of the antigenic complex (Esherichia coli endotoxin). Using the above components (hyperimmune antiradiotoxic serum, ethanol extract of the Vita-Force apiphitopreparation, metabolic products of Bifidobacterium bifidum, Bacillus subtilis and a highly dispersed fraction of bentonite), a polyfunctional composition «Polyapisogen» was compiled, including polyglobulins (500 cm3 per 1 L),500 cm3 of 4% ethanol extract of the Vita-Force apiphitopreparation, in which a highly dispersed fraction of bentonite (20 g), metabolism products (2 g powder) and Bacillus subtilis metabolism products (4 g) are dissolved. The polyfunctional preparation obtained by the above-described technology is used as an activator of the immune system against the background of its imbalance induced by agents of a radiogenic nature. It was found that a single subcutaneous injection of the drug at a dose of 25 mg / kg of live weight (dry matter basis) had a radioprotective effect increasing the survival rate of affected animals upto 75%. The studies carried out can serve as a basis for the creation of polyfunctional radioprotective, immunoprotective and bioprotective agents not only for isolated, but also for combined lesions of the body by agents of radiogenic and non-radiogenic nature using polyglobulins, convalescent serums, bee products, metabolic products of probiotic microorganisms and mineral sorbents.

Due to slow progression and susceptibility to radical forms of treatment low-grade PC is associ-ated with high overall survival (OS). With the clinical progression of PC the therapy is getting more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by i.e. immune evasion through Treg cells, synthesis of immunosuppressive mediators, and defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of the tumor and eliminate the immunosuppres-sive properties of TME. In the settings of PC treatment, this can be commonly achieved with radi-ation therapy (RT). Also, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), or irreversible electroporation (IRE) were shown to boost anti-cancer response. Nevertheless, the present guide-lines restrict their application to localized and low-grade PC. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.

Several COVID-19 platforms have been licensed across the world thus far, but vaccine platforms research that can lead to effective antigen delivery is still ongoing. Here, we constructed AdCLD-CoV19 that could modulate humoral immunity by harboring SARS-CoV-2 antigens onto a chimeric adenovirus 5/35 platform that was effective in cellular immunity. By replacing the S1/S2 furin cleavage sequence of the SARS-CoV-2 Spike (S) protein mounted on AdCLD-CoV19 with the linker sequence, high antigen expression was confirmed in various cell lines. The high levels of antigen expression contributed to antigen-specific antibody activity in mice and non-human primates (NHPs) with single vaccination of AdCLD-CoV19. Furthermore, the adenovirus-induced Th1 immune response was specifically raised for the S protein, and these immune responses protected the NHP against live viruses. While AdCLD-CoV19 maintained neutralizing antibody activity against various SARS-CoV-2 variants, it was reduced to single vaccination for β and ο variants, and the reduced neutralizing antibody activity was restored with booster shots. Hence, AdCLD-CoV19 can prevent SARS-CoV-2 with single vaccination, and the new vaccine administration strategy that responds to various variants can maintain the efficacy of the vaccine.

Migraine is a primary headache disorder characterized by unilateral throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This review article discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

Immune reconstitution inflammatory syndrome (IRIS) presents as an exaggerated immune reaction that occurs during dysregulated immune restoration in immunocompromised patients in late-stage HIV infection who commenced antiretroviral treatments. Virtually, any opportunistic pathogen can provoke this type of immune restoration disorders. In this review, we focus on recent development in the identification of risk factors for Cryptococcal IRIS and on advancements in our understanding of C-IRIS immunopathogenesis. We overview new findings in blood and cerebrospinal fluid which can potentially be useful in the diagnosis of cryptococcal meningitis IRIS. We assess the utility of these biomarkers to identify putative host-based targets, which may justify a clinical need for improvement in monitoring a patient’s laboratory results and adjusting treatment modalities in AIDS patients co-infected with Cryptococcus.

White shrimps are susceptible to outbreaks of vibriosis because they do not have any adaptive immune system, they only have a non-specific innate immune system. The administration of EPS from microalgae Porphyridium cruentum (synonym: P. purpureum) on shrimps Litopenaeus vannamei was investigated to determine the effect of this immunostimulant on their non specific immune response and to test if EPS can be used as a protective agent for shrimp related to Vibrio infection. EPS was given to shrimps by immersion method on day 1 and booster on day 8. Shrimp hemocytes were taken on day 1 (EPS administration), day 7 (no treatment), day 8 (EPS booster) and day 9 (Vibrio infection) and tested for their immune response on each treatment. Result shows an increase in values ​​of all immune parameters in line with the increasing EPS concentration, except the Differential Haemocyte Count (DHC). In detail, an increase was noted in total hemocytes (THC) value, Phagocytotic Activity (PA), Respiratory Burst (RB) in line as the EPS concentration increase. Although there is a decrease after the infection, the value obtained is not lower than the control value. These results indicate that EPS from Porphyrydium enhances immune parameters in shrimp rapidly and has the ability as an immunostimulant or an immunomodulator. It is a good modulator for the non specific immune cells of Pacific white shrimps, and it can be used as a preventive agent against Vibrio.

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.

Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, are responsible for approximately 2.65 million deaths per year. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: 1) Supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; 2) Supplementation above the RDA, but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and 3) Public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.

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.

Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial-mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play a pivotal role in seeding metastases and their presence in cancer patients indicates an adverse prognostic factor. Moreover, cancer cells in hybrid E/M phenotypes tend to be more associated with stemness which endows them with tumor-initiation ability and therapy resistance. Most recently, cells undergoing EMT have been shown to promote immune suppression for better survival. A systematic understanding of the emergence of hybrid E/M phenotypes and the connection of EMT with stemness and immune suppression would contribute to more effective therapeutic strategies. In this review, we first discuss recent efforts combining theoretical and experimental approaches to elucidate mechanisms underlying EMT multi-stability (i.e. the existence of multiple stable phenotypes during EMT) and the properties of hybrid E/M phenotypes. Following we discuss non-cell-autonomous regulation of EMT by cell cooperation and extracellular matrix. Afterwards, we discuss various metrics that can be used to quantify EMT spectrum. We further describe possible mechanisms underlying the formation of clusters of circulating tumor cells. Last but not least, we summarize recent systems biology analysis of the role of EMT in the acquisition of stemness and immune suppression.

The article titled "Immunoglobulins and Its Applications" provides a comprehensive overview of the structure, function, and therapeutic significance of immunoglobulins, also known as antibodies. These vital proteins, produced by plasma cells in response to immunogens, are essential components of the immune system, playing a critical role in recognizing and neutralizing pathogens such as bacteria and viruses. The article elaborates on the five primary classes of immunoglobulins (IgA, IgD, IgE, IgG, and IgM), each distinguished by its unique structural and functional properties. It discusses the molecular composition of immunoglobulins, highlighting the significance of their variable and constant regions in antigen binding. The paper also explores the diverse immune functions mediated by these proteins, including precipitation, agglutination, and neutralization of antigens. Additionally, the article emphasizes the therapeutic applications of immunoglobulins, particularly in treating immune deficiencies and other diseases. Advances in monoclonal antibody technology have significantly expanded the utility of immunoglobulins in both research and medicine, leading to the development of innovative therapeutic approaches such as humanized monoclonal antibodies and bifunctional antibodies. This comprehensive analysis underscores the critical role of immunoglobulins in both natural immunity and therapeutic interventions.

There is currently no effective treatment strategy for the recurrent/metastatic adenoid cystic carcinoma (R/M ACC). Furthermore, recent single-agent and combination immunotherapy trials have failed in unselected ACC cohorts unlike non-ACC salivary gland cancers. Genomic profiling revealed no actionable targets but NOTCH1 and KDM6A frameshift and CTCF splice site mutations (no MYB/L fusion) with a low TMB, MSS and negative PD-L1. We recommended anti-PD-1 plus anti-CTLA-4 combination based on TMB 2-fold greater than median TMB in ACC, tumor harboring multiple immunogenic frameshift or splice site mutations, and PD-L1 negativity. Accordingly, we achieved a complete response in a radiotherapy and chemotherapy-refractory patient with locally recurrent lacrimal gland ACC and lung metastasis following personalized immunotherapy in combination with integrative therapeutics. Therefore, it is crucial to assess not only conventional immune biomarkers but also patient-specific parameters.

The ubiquitin proteasome system (UPS) utilizes an orchestrated enzymatic cascade of E1, E2, and E3 ligases to add single or multiple ubiquitin-like molecules as post-translational modification (PTM) to proteins. Ubiquitination can alter protein functions and/ or marks ubiquitinated proteins for proteasomal degradation but deubiquitinases (DUBs) can reverse protein ubiquitination. While the importance of DUBs as regulatory factors in the UPS is undisputed, many questions remain on DUB selectivity for protein targeting, their mechanism of action, and the impact of DUBs on the regulation of diverse biological processes. Furthermore, little is known about the expression and role of DUBs in tumors of the human central nervous system (CNS). In this comprehensive review, we have used publicly available transcriptional datasets to determine the gene expression profiles of 99 deubiquitinases (DUBs) from five major DUB families in seven primary pediatric and adult CNS tumor entities. Our analysis identified selected DUBs as potential new functional players and biomarkers with prognostic value in specific subtypes of primary CNS tumors. Collectively, our analysis highlights an emerging role for DUBs in regulating CNS tumor cell biology and offers a rationale for future therapeutic targeting of DUBs in CNS tumors.

Neutrophils are the most abundant immune cells and make up about 70% of white blood cells in human blood and play a critical role as the first line of defense in the innate immune response. They also help regulate the inflammatory environment to promote tissue repair. However, in cancer, neutrophils can be manipulated by tumors to either promote or hinder tumor growth depending on the cytokine pool. Studies have shown that tumor-bearing mice have increased levels of neutrophils in peripheral circulation, and that neutrophil-derived exosomes can deliver various cargos, including lncRNA and miRNA, which contribute to tumor growth and degradation of extracellular matrix. Exosomes derived from immune cells generally possess anti-tumor activities and induce tumor-cell apoptosis by delivering cytotoxic proteins, ROS generation, H2O2 or activation of Fas-mediated apoptosis in target cells. Engineered exosome-like nanovesicles have been developed to deliver chemotherapeutic drugs precisely to tumor cells. However, tumor-derived exosomes can aggravate cancer-associated thrombosis through the formation of neutrophil extracellular traps. Despite the advancements in neutrophil-related research, a detailed understanding of tumor-neutrophil crosstalk is still lacking and remains a major barrier in developing neutrophil-based or targeted therapy. This review will focus on the communication pathways between tumors and neutrophils, and the role of neutrophil-derived exosomes (NDEs) in tumor growth. Additionally, potential strategies to manipulate NDEs for therapeutic purposes will be discussed.

The successful vaccination implies the induction of effective specific immune responses. We intend to find biomarkers among various immune cell subpopulations, cytokines and antibodies which could be used to predict the levels of specific antibody- and cell-mediated responses after measles-mumps-rubella vaccination. We measured 59 baseline immune status parameters (frequencies of 42 immune cell subsets, levels of 13 cytokines, immunoglobulins) before vaccination and 13 response variables (specific IgA and IgG, antigen-induced IFN-γ production, CD107a expression on CD8+ T lymphocytes, and cellular proliferation levels by CFSE dilution) 6 weeks after vaccination for 19 individuals. Statistically significant Spearman correlations between some baseline parameters and response variables were found for each response variable (p&lt;0.05). Due to the low number of observations relative to the number of baseline parameters and missing data for some observations, we utilized three feature selection strategies to select potential predictors of the post-vaccination responses among baseline variables: (a) screening of the variables based on the correlation analysis, (b) supervised screening based on the information of changes of baseline variables at day 7, (c) implicit feature selection is performed using regularization-based sparse regression. We identified optimal multivariate liner regression models for predicting the effectiveness of vaccination against measles-mumps-rubella using the baseline immune status parameters. It turned out that the sufficient number of predictor variables ranges from one to five depending on the response variable of interest.

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.

Since its initial characterization in 2016, the interferon stimulated gene Shiftless (SHFL) has proven to be a critical piece of the innate immune response to viral infection. SHFL expression stringently restricts the replication of multiple DNA, RNA, and retroviruses with an extraordinary diversity of mechanisms that differ from one virus to the next. These inhibitory strategies include the negative regulation of viral RNA stability, translation, and even the manipulation of RNA granule formation during viral infection. Even more surprisingly, SHFL is the first human protein found to directly inhibit the activity of the -1 programmed ribosomal frameshift, a translation recoding strategy utilized across nearly all domains of life and a several human viruses. Recent literature has shown that SHFL expression also significantly impacts viral pathogenesis in mouse models, highlighting its in-vivo efficacy. To help reconcile the many mechanisms by which SHFL restricts viral replication, we provide here a comprehensive review of this complex ISG, its influence over viral RNA fate, and the implications of its functions on the virus-host arms race for control of the cell.

Background/Aim: To evaluate the association between baseline [18F]FDG-PET/CT tumor burden parameters and disease progression rate after first-line target therapy or immunotherapy in advanced melanoma patients. Materials and Methods: 44 melanoma patients who underwent [18F]FDG-PET/CT before first-line target therapy (28/50) or immunotherapy (16/50) were retrospectively analyzed. Whole-body and per-district metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. Therapy response was assessed according to RECIST 1.1 on CT scan at 3 (early) and 12 (late) months. PET parameters were compared with Mann-Whitney test. Optimal cut-offs for predicting progression were defined using the ROC curve. PFS and OS were studied using Kaplan-Meier analysis. Results: Median(IQR) MTVwb and TLGwb were 13.1 mL and 72.4 respectively. Non-responders patients were 38/44, 26/28 and 12/16 at early evaluation, and in 33/44, 21/28 and 12/16 at late evaluation in the whole-cohort, target and immunotherapy subgroup respectively. At late evaluation, MTVbone and TLGbone were higher in non-responders compared to responder patients (all p<0.037) in the whole-cohort and target subgroup and also MTVwb and TLGwb (all p<0.022) in target subgroup. No significant differences were found for immunotherapy subgroup. No metabolic parameters were able to predict PFS. Controversy, MTVlfn, TLGlfn, MTVsoft+lfn, TLG-soft+lfn, MTVwb and TLGwb were significantly associated (all p<0.05) with OS in both the whole-cohort and target therapy subgroup. Conclusion: Higher values of whole-body and bone metabolic parameters were correlated with poorer outcome, while higher values of whole-body, lymph node and soft tissue metabolic parameters were correlated with OS.

SARS-CoV-2 was empirically and computationally found to be of a specific but peculiar evolution. Shell disorder models found that the outer shell (M protein) of SARS-CoV-2 to be among the hardest in its CoV family. The hard outer shell (low M percentage of disorder (PID)) is likely to be related to the SARS-CoV-2 resistance to the antimicrobial enzymes in saliva and mucus, and be responsible for the high-level of viral shedding which has been observed clinically. Experimental studies have also shown that SARS-CoV-2 is more resilient in the environment than many other CoVs, including SARS-CoV-1. Another aspect of the shell disorder models predicts that SARS-CoV-1 is more virulent than SARS-CoV-2 because of higher inner shell disorder (N PID) that helps SARS-CoV-1 replicate faster in vital organs despite being of lesser viral loads in the saliva and mucus, unlike SARS-CoV-2. This has been reaffirmed experimentally, where higher levels (50 folds) of infectious particles were detected in the SARS-CoV-1 samples in comparison with those of SARS-CoV-2. The hard outer shell of SARS-CoV-2 has been found to be associated with burrowing animals, particularly pangolins, which are often in contact with buried feces. For these reasons, the M protein is highly conserved among close relatives of SARS-CoV-2. The phylogenetic tree using M, unlike the genome-wide one, shows that pangolin-CoVs are more closely related to SARS-CoV-2 than bat-RaTG13. Previous phylogenetic studies may have been confused by recombinations that are usually poorly handled. According to the shell disorder models based on the N PID, an attenuated COVID-19 strain is likely to have entered humans via pangolins in 2017 or before, which provides the virus enough time to adapt to humans. This could explain why the SARS-CoV-2 S protein is highly adapted to the human ACE-2. The specific but peculiar evolution has a wide range of clinical, immunological, and epidemiological implications.

Exopolysaccharides or extracellular polysaccharides (EPS, sPS) represent valuable metabolite compound synthesized from red microalgae. It is a non toxic natural agent and can be applied as immunostimulant. Toxicity test of exopolysaccharides from Porphyridium has been done in-vivo using zebrafish (Danio rerio) embryonic model, or the ZET (Zebrafish Embryotoxicity Test). The administration of extracellular polysaccharide or exopolysaccharides (EPS) from microalgae Porphyridium cruentum (synonym: P. purpureum) on shrimps Litopenaeus vannamei was investigated to determine the effect of this immunostimulant on their non specific immune response and to test if this compound can be used as a protective agent for shrimp related to Vibrio infection. For immune response, exopolysaccharides was given to shrimps by immersion method on day 1 and booster on day 8. Shrimp hemocytes were taken on day 1 (EPS administration), day 7 (no treatment), day 8 (EPS booster) and day 9 (Vibrio infection) and tested for their immune response on each treatment. Result shows that the EPS is not toxic as represented by the normal embryonic development and the mortality data. In the Pacific whiteshrimps, it show an increase in values ​​of all immune parameters in line with the increasing EPS concentration, except the Differential Haemocyte Count (DHC). In detail, an increase was noted in total hemocytes (THC) value, Phagocytotic Activity (PA), Respiratory Burst (RB) in line with the EPS concentration increase. These results and other previous studies indicate that EPS from Porphyridium is safe and it enhances immune parameters in shrimp rapidly and has the ability as an immunostimulant or an immunomodulator. It is a good modulator for the non-specific immune cells of Pacific white shrimps, and it can be used as a preventive agent against vibriosis.

Despite the publication in 2009 of a paper on ‘terms and definitions of immune thrombocytopenia’, (ITP) some unresolved issues remain and are reflected by the disagreement in the treatment suggested for primary ITP in adults. Considering that these disagreements could be ascribed to non-shared goals, a ‘consensus’ to classify the different lines of treatment for primary ITP in adults according to their indications and goals was proposed in October 2018 to the XIX annual meeting of the Italian Gruppo di Studio delle Piastrine (GSP), a non-profit platelet study group of scientists and physicians. Having approved the project, 60 potential co-authors and experts in the world were invited to take part to a consensus through e-Delphy method and nine of the 12 who initially accepted the invitation completed the work. Agreement was reached on a classification of four lines of treatment for primary ITP in adults based on their indications and goals. The consensus obtained regarded also the criteria, ‘timing’ included, to consider practicable elective splenectomy in these patients. In our opinion, the classification of the lines of treatment for primary ITP in adults here proposed could facilitate the realization of better shared evidence-based guidelines for the treatment of the disease.

Background: Breast cancer incidence and mortality exhibit a rising trend globally among both premenopausal and postmenopausal women suggesting that there are serious errors in our preventive and therapeutic measures.Purpose: Providing a series of valuable, but misunderstood inventions highlighting the role of increasing estrogen signaling in prevention and therapy of breast cancer instead of its inhibition. Results: 1. Breast cells and breast cancer cells with germline BRCA1/2 mutations similarly show defect in liganded estrogen receptor (ER) signaling demonstrating its role in genomic instability and cancer initiation. 2. In breast cancers, the increased expression of certain receptor family is an effort for self directed improvement of genomic defects, while the weakness or loss of receptors indicates a defect requiring medical repair. 3. ER overexpression in breast cancer cells is capable of strengthening estrogen signaling and DNA repair, while in ER negative tumors, HER2 overexpression tries to upregulate unliganded ER activation and genome stabilization. 4. ER positive breast cancers responsive to endocrine therapy may show a compensatory ER overexpression resulting in a transient tumor response. Breast tumors, non responsive to endocrine therapy, show HER2 overexpression for compensation the complete blockade of liganded ER activation. 5. In breast tumors, somatic mutations serve upregulation of liganded or unliganded activation of ERs helping genome stabilization and apoptotic death. 6. The dynamic communication between breast cancer and its microenvironment is a wonderful collaboration among molecular players fighting for genomic repair and apoptosis in the tumor. 7. In breast cancers, there is no resistance to genotoxic or immune blocker therapies, but rather the non responsive tumor cells exhausted all compensatory possibilities against therapeutic damages. Conclusion: Understanding the behavior and ambition of breast cancer cells may achieve a turn in therapy via applying a supportive care instead of genotoxic measures.

Protein 53 (P53) shows different functions either to support or to contrast malignant growth. P53 history tells that discoveries of molecular features have contributed to the emergence of P53 functions. Conversely, the shift of paradigms demonstrates that P53 functions coexist even if are in conflict with one another. Since 1979, five paradigms have been assembled then deconstructed by taking into account P53 functions of viral protein, oncogene, tumor suppressor gene, transcription factor, apoptotic factor. By summarizing the past five disassembled P53 paradigms, in this investigation the current paradigm involving P53 in the modulation of a composite bio-morphological entity namely, tumor immune microenvironment (TIME) is analyzed. The aims of this investigation were to provide an overview of solid and validated knowledge occurring in all P53 paradigms and to determine P53 abilities to modify TIME through manipulation of viruses. As a result, definitive P53 evidence concerns its genetic localization, amino acids composition, its isoforms and subcellular expression in organelles. P53 “mutome” assembles all mutations affecting this complex protein. Lastly, both categories of tumor promoting and non-oncogenic viruses related to P53 were scrutinized. In conclusion, paradigms teach that P53 is undruggable because its drugs inevitably target all P53 functions.

Esophageal cancer is an extremely deadly tumor that accounts for 5% of all cancer deaths. The two main subtypes of the disease are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). To date, few studies analyse EAC for transcriptional signatures associated with diagnosis and/or prognosis, while most focus on the analysis of transcriptional profiles of ESCC. In this study, we used single-cell RNA sequencing (scRNA-seq) analysis of CD45+ cells enriched from Tumors and matched Non Tumor tissues from therapy naїve patients to identify all types of immune cells present in tumor immune infiltrate and its transcriptional profile. In addi-tion, we analysed the entire transcriptome in a cohort of 23 patients whose tissue biopsies were taken from Tumors and matched with Non Tumor tissue. The transcriptional signatures we obtained were then used to stratify a large cohort of TCGA EAC patients, demonstrating a strong association with their prognosis, as well as the ability to predict a patient's clinical outcome and better define the prognosis of EAC after surgery. In addition, these features may lead patients to effective therapies including immunotherapy approaches.

The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting "nodes" in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being “shared” between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour, before considering future directions in the field.

Objective: Meningococcal meningitis (MM) is an acute, severe respiratory infectious disease caused by Neisseria meningitidis and remains an important cause of morbidity/mortality in children. Immunization with meningococcal vaccine (MV) is the most effective measure to control and prevent the transmission of MM. In this study, in order to support the appropriate use of various MVs in the prevention of MM, the effects of MVs, especially single-dose and inter-booster administered, on inflammatory parameters in

Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived by the interplay between oral microbiota and the host immune response. A comprehensive search of literature published between 2008 and 2023 was conducted to elucidate the association between these two diseases. Preclinical and clinical evidence suggests a bidirectional relationship, with individuals with T1DM exhibiting heightened susceptibility to periodontitis, and vice versa. The review includes recent findings from human clinical studies, revealing variations in oral microbiota composition in T1DM patients, including increases in certain pathogenic species such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans, along with shifts in microbial diversity and abundance. Molecular mechanisms underlying this association involve oxidative stress and dysregulated host immune responses, mediated by inflammatory cytokines such as IL-6, IL-8, and MMPs. Furthermore, disruptions in bone turnover markers, such as RANKL and OPG, contribute to periodontal complications in T1DM patients. While preventive measures to manage periodontal complications in T1DM patients may improve overall health outcomes, further research is needed to understand the intricate interactions between oral microbiota, host response, periodontal disease, and systemic health in this population.

The microbiota–gut–brain axis has garnered increasing attention in recent years for its role in various health conditions, including neuroinflammatory disorders like complex regional pain syndrome (CRPS). CRPS is a debilitating condition characterized by chronic neuropathic pain, and its etiology and pathophysiology remain elusive. Emerging research suggests that alterations in the gut microbiota composition and function could play a significant role in CRPS development and progression. Our paper explores the implications of microbiota in CRPS and the potential therapeutic role of boron (B). Studies have demonstrated that individuals with CRPS often exhibit dysbiosis, with imbalances in beneficial and pathogenic gut bacteria. Dysbiosis can lead to increased gut permeability and systemic inflammation, contributing to the chronic pain experienced in CRPS. B, an essential trace element, has shown promise in modulating the gut microbiome positively and exerting anti-inflammatory effects. Recent preclinical and clinical studies suggest that B supplementation may alleviate neuropathic pain and improve CRPS symptoms by restoring microbiota balance and reducing inflammation. Our review highlights the complex interplay between microbiota, inflammation, and neuropathic pain in CRPS and underscores the potential of B as a novel therapeutic approach to target the microbiota–gut–brain axis, offering hope for improved management of this challenging condition.

Malignant neoplasms arising from the gastrointestinal (GI) tract are among the most common cancer types with a high mortality rate. Despite advances in treatment in a small subgroup harboring targetable mutations, the outcome remains poor, accounting for one in three cancer-related deaths observed globally. As a promising therapeutic option in various tumor types, immunotherapy with immune checkpoint inhibitors has also been evaluated in GI cancer, albeit with limited efficacy except for a small subgroup expressing microsatellite instability. In the quest for more effective treatment options, energetic efforts have been placed to evaluate the role of several immunotherapy approaches comprising of cancer vaccines, adoptive cell therapies and immune checkpoint inhibitors. In this review, we report our experience with personalized dendritic cell cancer vaccine and cytokine-induced killer cell therapy in three patients with GI cancers and summarize current clinical data on combined immunotherapy strategies.

The SARS-CoV-2 virus, which is responsible for the COVID-19 pandemic which emerged and spread, has sparked intense research on its spike protein, which is essential for viral entrance into host cells. Viral reproduction and transmission, host immune response regulation, receptor recognition and host cell entrance mechanisms, as well as structural and functional effects have all been linked to mutations in the spike protein. Spike protein mutations can also result in immune evasion mechanisms that impair vaccine effectiveness and escape, and they are linked to illness severity and clinical consequences. Numerous studies have been conducted to determine the effects of these mutations on the spike protein structure and how it interacts with host factors. These results have important implications for the design and development of medicines and vaccines based on spike proteins as well as for the assessment of those products' efficiency against newly discovered spike protein mutations. The paper gives a general overview of how spike protein mutations are categorized and named, as well as the genomic and phylogenetic techniques that have been used to track their genesis and dissemination. Additionally, it looks at the links between spike protein mutations and clinical outcomes, illness severity, unanswered problems, and future research prospects. Additionally, explored are the effects of these mutations on vaccine effectiveness as well as the possible therapeutic targeting of spike protein mutations.

A key in controlling the SARS-CoV-2 pandemic is the assessment of the immune status of the population. We explored the utility of SARS-CoV-2 virus-like particles (VLPs) as antigens to detect specific humoral immune reactions in an enzyme-linked immunosorbent assay (ELISA). For this purpose, SARS-CoV-2 VLPs were produced from an engineered cell line and characterized by western blot, ELISA and nanoparticle tracking analysis. Subsequently, we collected 42 serum samples from before the pandemic (2014), 89 samples from healthy-, and 38 samples from vaccinated subjects. Seventeen samples were collected less than three weeks after infection, and 44 samples more than three weeks after infection. All serum samples were characterized for their reactivity with VLPs and the SARS-CoV-2 N- and S-protein. Finally, we compared the performance of the VLP-based ELISA with a certified in vitro diagnostic device (IVD). In the applied set of samples, we determined a sensitivity of 95.5 % and a specificity of 100 % for the certified IVD. There were 7 samples with an uncertain outcome. Our VLP-ELISA showed superior performance with a sensitivity of 97.5 %, a specificity of 100 %, and only 3 uncertain outcomes. This result warrants further research to develop a certified IVD based on SARS-CoV-2 VLPs as an antigen.

The rate of technical innovation, system interconnection, and advanced communications undoubtedly boost distributed energy networks' efficiency. However, when an additional attack surface is made available, the possibility of an increase in attacks is an unavoidable result. The energy ecosystem's significant variety draws attackers with various goals, making any critical infrastructure a threat, regardless of scale. Outdated technology and other antiquated countermeasures that worked years ago cannot address the complexity of current threats. As a result, robust artificial intelligence cyber-defense solutions are more important than ever. Based on the above challenge, this paper proposes an ensemble transfer learning spiking immune system for adaptive smart grid protection. It is an innovative Artificial Immune System (AIS) that uses a swarm of Evolving Izhikevich Neural Networks (EINN) in an Ensemble architecture, which optimally integrates Transfer Learning methodologies. The effectiveness of the proposed innovative system is demonstrated experimentally in multiple complex scenarios that optimally simulate the modern energy environment. In this way, the proposed system fully automates the strategic security planning of energy networks with computational intelligence methods. It allows the complete control of the digital strategies of the potential infrastructure that frames it, thus contributing to the timely and valid decision-making during cyber-attacks.

To understand lung damage caused by COVID-19, we deduced two-phase lung damage mechanisms. After the lungs are infected with SARS-CoV-2 virus, the affected lung tissue swells and surface properties of pulmonary capillaries change, resulting in an increased flow resistance of affected capillaries. If a sufficient number of capillaries are affected by the infection, the swelling and increased cell wall adhesion collectively raise pulmonary vascular resistance. The increased vascular resistance further increases the dwell times of WBCs in affected capillaries and nearly capillaries. When pulmonary pressure is sufficiently higher, WBCs are forced to squeeze into interstitial spaces or alveolar spaces when local pressures are higher than what the capillaries can withstand. When more and more WBCs are dynamically retained, the flow resistance of more capillaries rises, pulmonary vascular resistance rises, and pulmonary pressure rises. The rise in the pulmonary pressure in turn results in elevated capillary pressures. When capillary pressures around the alveoli are sufficiently high, they cause interstitial pressures to change from normally negative values to positive values. The positive pressures cause fluid leakage to the alveolar space and thus degrade lung function. Tissue swelling, and occupation of WBCs in interstitial spaces and alveolar spaces further reduce compressible volume, and thus cause further rise in the pulmonary vascular resistance and pulmonary pressure. When the pulmonary pressure has reached a critical point as in the second phase, the blood breaks capillary walls and squeezes through interstitial spaces to reach alveolar spaces, resulting in irreversible lung damages. The available free volume in the thorax cage, organ usable capacities, temperature and humid are expected to have great impacts on degree of lung damages. The free volume in the thorax cage, lung usable surplus capacity, and other organ usable capacities determine the arrival time of last-phase irreversible damage. The mechanisms imply that the top priority for protecting lungs is maintaining pulmonary micro-circulation and preserving organ functions in the entire disease course while controlling viral reproduction should be stressed in the earliest time possible. The mechanisms also explain leukecytes are recruited and migrated into inflamed tissues by increasing their dwell times caused by increased local flow resistance.

Breast implant surgery has evolved significantly, yet challenges such as capsular contracture remain a persistent concern. This review presents an in-depth analysis of recent advancements in understanding the immune mechanisms and clinical implications associated with breast implants. The article systematically examines the complex interplay between immune responses and capsular fibrosis, emphasizing the pathophysiological mechanisms of inflammation in the etiology of this fibrotic response. It discusses innovations in biomaterial science, including the development of novel anti-biofilm coatings and immunomodulatory surfaces designed to enhance implant integration and minimize complications. Emphasis is placed on personalized risk assessment strategies, leveraging molecular insights to tailor interventions and improve patient outcomes. Emerging therapeutic targets, advancements in surgical techniques, and the refinement of post-operative care are also explored. Despite notable progress, challenges such as variability in immune responses, long-term efficacy of new interventions, and ethical considerations remain. Future research directions are identified, focusing on personalized medicine, advanced biomaterials, and bridging preclinical findings with clinical applications. As we advance from bench to bedside, this review illuminates the path forward, where interdisciplinary collaboration and continued inquiry weave together to enhance the art and science of breast implant surgery, transforming patient care into a realm of precision and excellence.

The Influenza A Virus (IAV) represents an enveloped, positive-sense and single-stranded RNA-based virus that infects mammals mainly via the respiratory system, although other bodily systems are also infected and undergo various extents of inflammatory pathogenesis. There are two well-known strains of IAV that cause life-threatening disease in mammals; H1N1 and H5N1, and the first strain caused the 1918 IAV H1N1 pandemic that claimed between 30 and 50 million human lives. Due to the significant ability of IAV to evade important immune recognition, the virus was observed to favour the onset of secondary microbial infections (i.e. bacterial or fungal), as the overall performance of the immune system became transiently weakened during the viral infection. During the IAV H1N1 pandemic, many patients died as a result of bacterial pneumonia, as pathogenic bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae, gained a wider opportunity to colonise and infect vital areas of the lower respiratory tract, and such a phenomenon led to the excessive, prophylactic usage of antibiotics due to the increased levels of panic, which in turn favoured the natural selection of bacteria with genes that became resistant to such antibiotics. Antibiotics might be required for usage solely when bacteria are known to be colonising vital areas of the human body, and this aspect is tricky, as microbial colonisation as such is asymptomatic and screening is consequently rare. Recently, new variants of the avian IAV H5N1 strain were transmitted from live, infected birds to mammals, including humans in some isolated cases, and given that there have already been several zoonotic spillover events overall since the beginning of 2023, we are rapidly approaching the time when a zoonotic spillover into humans will mark the first epidemic outbreak of the avian flu in humans. A lethality rate of approximately 60% was projected by the World Health Organization, as the virus was shown to favour the development of life-threatening hyper-inflammatory responses at the levels of alveolar tissues constituted by Type II pneumocytes. There are hints that novel variants of H5N1 are capable of infecting the intestinal layer, as recently, two dolphins died as a result of ingesting infected birds within the area of the British Isles. IAV is known to suppress the production and transmission of Type I Interferons by expressing various non-structural proteins (NSPs), such as NSP1, which was found to be also packaged into exosomes and transmitted to neighbouring uninfected cells, thereby preventing them from responding to the virus in the first place. Additionally, it was determined that NSP1 induces the apoptosis of the cells it is produced in and the neighbouring ones it enters via induced paracrine signalling, and such an aspect may only emphasise upon the critical role that early innate immune stimulation plays in preventing the development of severe respiratory illness afterward, given the context of increased viral ability of suppressing the production of first-line and second-line signals. A more pronounced rate of innate immune evasion would probably be observed in H5N1 IAV infection than in the infection caused by recent variants of H1N1 IAV. The H5N1 strain of IAV was also found to secrete a higher concentration of NSP1 than SARS-CoV-2, indicating the existence of an association to the greater mortality rate of H5N1 IAV infection. A direct, prophylactic stimulation of the interferon system using a reduced oral or nasal dosage of recombinant anti-inflammatory and anti-viral interferon glycoproteins may represent the most viable approach to prevent an emergence of a life-threatening H5N1 IAV pandemic. A similar non-invasive approach could be developed for a Marburg Virus (MARV) and a Nipah Virus (NiV) infection of humans, as risks of the emergence of a Marburg epidemic and also of a Nipah epidemic may be substantial at this stage as well. Clinical testing of clinical approaches as such could be of critical importance at the moment. Animals could also benefit from related clinical approaches. Somatic natural and adaptive lymphocytes treated with IFN I and III could also constitute a substantial approach of immunisation and heavily favour an indefinite shift in the evolutionary battle between the host organism and microbes of public health concern, as IFN I and III could improve the immunity of T-lymphocytes against HIV infection and even improve the performance of the mentioned types of immune cells during other types of infections. Likewise, a combination of all intellectual and clinical efforts implicating a shift of scientific and medical focus toward natural immunity in vaccine-related research could be a wise method in making the best efforts to prevent or alleviate the effects of a possible future pandemic, given the highly significant and diverse abilities of microbial “intelligence” to effectively hijack the natural immune system, many times causing severe implications upon the quality of the overall immune response against such microbes.

Hashimoto's thyroiditis (HT) is essentially featured by self-tissue destruction by means of the adaptive immune responses that evade immune regulation. Vitamin D carries out an immunomodulatory role that appears to promote immune tolerance. The aim of this study is to elaborate a narrative review about the relationship between vitamin D status and HT and the role of vitamin D supplementation to reduce HT risk by modulating the immune system. There is an extensive literature confirming that vitamin D levels are significantly lower in HT patients compared to healthy people. On the other hand, after the supplementation with cholecalciferol in patients with HT and vitamin D deficiency, thyroid autoantibody titer decreased significantly, However, there are no conclusive results on the effect of vitamin D supplementation on the thyroid function. The confirmation of the beneficial effects of vitamin D in the prevention and treatment of autoimmune thyroid diseases require additional randomized, double-blind, placebo-controlled trials with longer follow-up.

Sepsis is a life-threatening complication of an infectious process that results from excessive and uncontrolled activation of the host's pro-inflammatory immune response to a pathogen. Lipopolysaccharide (LPS), also known as endotoxin, which is a major component of the Gram-negative bacteria outer membrane, plays a key role in the development of Gram-negative sepsis and septic shock in humans. To date, no specific and effective drug against sepsis has been developed. This review summarizes data on LPS-binding proteins from marine invertebrates (ILBPs), that inhibit LPS toxic effects, and are of interest as potential drugs for the sepsis treatment. The structure, physicochemical properties, antimicrobial and LPS-binding/neutralizing activity of these proteins and their synthetic analogues are considered in details. Problems that arise during clinical trials of potential anti-endotoxic drugs are discussed.

Thirteen benzylethylenearyl ureas and one carbamate have been designed, synthesized and biologically evaluated as regards their antiproliferative activity on tumor cell lines HEK-293 and A-549 and on the immune and endothelial Jurkat T cells and HMEC-1, respectively. A relationship between the structure of the synthetic compounds and their antiproliferative activity has been established. Compounds C.1, C.3, C.12 and C.14 were chosen for further biological studies in order to determine their potential as oncoimmunomodulating agents. Some compounds exhibited significant inhibitory effects on both total PD-L1 and VEGFR-2 in HT-29 cell line, showing urea C.12 active against both targets. Some compounds could reduce more than 50% of cancer living cells, compared to non-treated ones, when assessed in co-cultures using HT-29 and THP-1 cells. In addition, these compounds showed no effect on the immune cell viability and significantly reduce CD11b expression, which is a promising target for immune modulation in anti-cancer therapies.

A major advance of drug discovery and targeted therapy directed to cancer cells may be achieved by exploitation and immunomodulation of their unique biological property. This re-view summarizes our efforts to develop novel chemo-thermo-immuno-therapy (CTI therapy) by conjugating a melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine), with magnetite nanoparticles (MNP). In our approach, NPrCAP provides a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It also functions as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Moreover, utilization of MNP is a platform to develop thermo-immunotherapy because of heat shock protein (HSP) generation upon exposure to an alternating magnetic field (AMF). The feasibility of our approach was successfully shown in experimental in vivo and in vitro mouse melanoma models and in preliminary clinical trials to a limited number of advanced melanoma patients.

Autism Spectrum Disorder etiopathogenesis is still unclear and no effective preventive and treatment measures have been identified. Research has focused on the potential role of neuroinflammation and kynurenine pathway. Here we review the nature of these interactions. Pre-natal or neonatal infections would induce microglial activation, with secondary consequences on behavior, cognition and neurotransmitter networks. Peripherally, higher levels of pro-inflammatory cytokines and anti-brain antibodies have been identified. Increased frequency of autoimmune diseases, allergies, and recurring infections have been demonstrated both in autistic patients and in their relatives. Genetic studies, also, have identified some important polymorphisms in chromosome loci related to human leukocyte antigen (HLA) system. The persistence of immune-inflammatory deregulation would lead to mitochondrial dysfunction and oxidative stress, creating a self-sustaining cytotoxic loop. Chronic inflammation activates kynurenine pathway with increase in neurotoxic metabolites and excitotoxicity, causing long-term changes in glutamatergic system, trophic support and synaptic function. Furthermore, overactivation of kynurenine’s branch induces depletion of melatonin and serotonin worsening ASD symptoms. In this scenario, kynurenine pathway appears as a pharmacological target to treat and prevent ASD. Thus, in genetically predisposed subjects aberrant neurodevelopment may derives from a complex interplay between inflammatory process, mitochondrial dysfunction, oxidative stress and kynurenine pathway overexpression. To validate previous hypothesis a new translational research approach is necessary.

To understand great disparities in disease outcomes between CIVID-19 patients, we explore infection and host responses in kinetics. From existing data, we deduced a model that the lungs are damaged by rapidly rising flow resistance as a result of retaining white blood cells in lung tissues. The retention of white blood cells is initially triggered by viral infection but aggravated by injuries caused by low temperature. Lungs are initially damaged by fluid leakage, rapidly followed by extruding blood into alveolar spaces. The step of blood extruding is predicted to take place in a very short time. Our simulations show that as little as 0.1% retention of white blood cells in the lungs can lead to their failure in 5 to 10 days. The small degrees of imbalance implies that this imbalance could be corrected by a large number of factors that are known to reduce flow resistance. The model implies that the top priority is maintaining blood micro-circulation and preserving organ functions in the entire disease course, especially after the virus has spread the whole lungs. From exploring a large number of hypothetical infection modes, we propose preventive, mitigating and treatment strategies for ultimately ending the pandemic. The first strategy is avoiding exposures that could result in widespread damages to lungs and taking post exposure mitigating measures that would reduce disease severity. The second strategy is reducing death rate and disability rate from the current levels to one tenth for infected patients by using multiple factors health optimization method. The double reduction strategies are expected to generate a series of chain reactions that favor mitigating or ending the pandemic. Some reactions include a big reduction of the amount of viral discharges from infected patients into the air, the avoidance of panic, chronic stress and emotional distress, and cross-infections which are expected in quarantines. The double reductions would have a final effect of ending the pandemic.

Tuberculosis cause of death worldwide and the leading cause from a single infectious agent, ranking above Human immunodeficiency virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS). The aim of this study is to ascertain the trend of tuberculosis prevalence and the effect of HIV prevalence onl Tuberculosis case in some West African countries from 2000 to 2016 using count panel data regression models. The data used annual HIV and Tuberculosis cases spanning from 2000 to 2016 extracted from online publication of World health Organization (WHO). Panel Poisson regression model and Negative binomial regression model for fixed and random effects were used to analyzed the count data, the result revealed a positive trend in TB cases while increased in HIV cases leads to increase in TB cases in West African countries. Among the competing models used in this study, Panel Negative Binomial Regression Model with fixed effect emerged the best model with log likelihood value of -1336.554. This study recommended that Government and NGOs need more strategies to fight against HIV menace in West Africa as this will in turn reduced TB cases in West Africa.

In Sub-Saharan African Countries such as Nigeria with high prevalence rate, Child HIV/AIDs acquired through Mother-to-Child transmission (MTCT) can be largely prevented by using a well-established prevention programme and scheme. This study examined factors that can enhanced Prevention of Mother-to-Child transmission (PMTCT) in Nasarawa State. To achieve this, structured questionnaire were used to collect data from one hundred and sixteen (116) women attending two (2) primary facilities and two (2) secondary facilities in the State. This study utilized methods of Poisson Regression, Negative Binomial Regression and Logistic Regression Analyses. Results revealed that women with at least a secondary school education, women with husband in military and women with perceived confidentiality of their HIV status significantly enhanced PMTCT of HIV in Nasarawa State while significant proportion of the women attest to the fact that drugs are available in the facilities (p-value=0.0000<0.05) . Other factors include mother income level, willingness to continue with PMTCT programme and women in support group can also enhanced PMTCT though they are not significant. This study recommends that the factors identified should be explored by NGOs, Ministry of Health and, Support groups and other relevant agencies since they have the capacity to enhanced PMTCT of HIV in Nasarawa State, Nigeria.

Extracellular vesicles (EV) released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP), by which immune evasion can be established. Heat shock proteins (HSPs) are an evolutionarily conserved family of molecular chaperones, which stabilize proteins, minimize protein misfolding and aggregation within the cell, besides facilitating protein translocation, refolding and degradation. (i) Releases of extracellular HSPs (ex-HSP) and EV-associated HSPs (EV-HSP) are essential in RASP, by which molecular cotransfer of HSPs with oncogenic factors into recipient cells can promote cancer progression and resistance against stress such as hypoxia, radiation, chemicals, and immune system. (ii) RASP of tumor cells can eject anticancer drugs, molecularly targeted therapeutics, and immune checkpoint inhibitors with EVs. (iii) Cytotoxic lipids can be also released from tumor cells as RASP. Nevertheless, ex-HSP and EV-HSP can play immunostimulatory and immunosuppressive roles by binding to receptors such as LRP1/CD91/A2MR, scavenger receptors, and toll-like receptors expressed on recipient cells. Liquid biopsy of HSPs in body fluids may be useful in diagnosis, prognosis, and treatment in cancer. Regarding HSP90-targeted therapeutics, we summarize the pros, cons, and problem solutions in this review. Although production of HSPs are canonically induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), recent studies discovered that production of HSPs is also regulated by matrix metalloproteinase 3 (MMP3) and heterochromatin protein 1 (HP1) and production of cochaperone CDC37 is reciprocally regulated by myeloid zinc finger 1 (MZF1) and SCAN-D1.

The resurgence of mpox, particularly in regions where the virus was previously non-endemic, has reignited interest in the cross-protective potential of smallpox antibodies. Given the genetic similarity between the mpox virus and variola virus (the causative agent of smallpox), antibodies generated against smallpox may offer a degree of protection against mpox. This study investigates the presence of smallpox and mpox antibodies in human immunoglobulin preparations containing IgG against both mpox virus and vaccinia virus using ELISA techniques. The implications of these findings for post-exposure prophylaxis (PEP) are discussed in light of the recent mpox outbreaks in Africa, as reported by the World Health Organization (WHO). Current data suggest that smallpox vaccination, even decades after eradication, may confer substantial protection against mpox, thereby serving as a critical tool in managing emerging outbreaks. Further the presence of mpox antibodies in immunoglobulin preparations was also significant. These findings strongly suggest the potential use of intravenous immunoglobulins preparation as possible therapeutic strategy. Particularly it also underscores the need for further research into the development of targeted post-exposure prophylaxis strategies that leverage the cross-reactivity of orthopoxvirus antibodies.

This is a brief critique of the functions—particularly olfactory functions—specified for the “Chemosensory Protein” (CSPs) molecule family. On the basis of these proteins’ presence in the sensory antennal lymph of locusts, odor chemosensory ligand binding functions have been hypothesized. According to this hypothesis, the entire protein molecule superfamily is referred to as “CSPs”. However, new information and developments in the field of CSP molecular research, such as the expression of CSP genes in the gut, brain, fat body, wings, epidermis, and pheromone gland, as well as gene expression profiling from most early developmental stages—that is, CSP expression well in advance of the appearance of chemical sense nerve cells—strongly suggest that the protein molecule has other roles that are unrelated to chemosensing. Moreover, CSPs are found in bacterial microbial prokaryote organisms in addition to insects and all other arthropods. Thus, we examine the molecule’s name, definition, RNA editing, protein structure, lipid binding properties, DNA interaction, and evolutionary characteristics in brief before referring to this protein family as “Chemosensory Proteins”. As a means of renaming this protein family, this review article discusses the latest findings (“CSP” is attached to the tail of bigger intracellular proteins) and attempts to compel all the data. Because of its highly conserved molecular distinctive feature (four adjacent cysteines), we propose renaming “CSPs” as “4CSPs” (4 Cysteines Soluble Proteins) and use at least for abbreviations for distinctive animal proteins the common peptide 5-letter code, such as “Bommo-4CSPs”.

SARS-CoV-2 virulence is known to increase with lowering of environmental temperature and solar ultraviolet radiation; therefore, we have focused our real-world nationwide study concerning with COVID-19 trends and dynamics on the coldest seasons of the year in Italy, the Western country hardest hit at the onset of the pandemic, comparing the autumn-winter of 2020 (before mass vaccination but when the emergency machinery was fully operative in terms of tracing and swabs) with the autumn-winter of 2021 (after mass vaccination), and analyzing the mortality burden by age groups and life stages in the years 2019 (pre-COVID-19), 2020 (before mass vaccination) and 2021 (after mass vaccination). Methods: During the state of national health emergency, the Civil Defense Department released the aggregate data coming from the Higher Institute of Health, the Ministry of Health, the Italian Regions, and the Independent Provinces, to inform the population (58.85 million people) about the pandemic situation, daily. Among these data there were the number of contagions, performed swabs, hospitalizations in Intensive Care Units (ICU), non-ICU patients, and deaths. By means of a team effort, we have collected and elaborated all these data, comparing the COVID-19 pandemic in Italy during the autumn-winter of 2020 with the autumn-winter of 2021. Moreover, we have extracted from the database of the National Institute of Statistics the total number of annual deaths in Italy during the years 2019, 2020 and 2021, comparing them to each other in order to evaluate the mortality burden attributable to COVID-19. Results: From the autumn-winter of 2020 to the autumn-winter of 2021, the contagions increased by ≈285%, however against a ≈290% increase in the performed swabs; therefore, the mean positivity rate passed from 8.74% before mass vaccination to 8.59% after mass vaccination. The unprecedent vaccination campaign allowed a ≈251% abatement in COVID-19 deaths, and a reduction of ≈224% and ≈228% in daily ICU and non-ICU hospitalizations due to COVID-19, respectively. Regarding COVID-19 deaths, in 2020 there was a mortality excess of ≈14.3% quantifiable in 105,900 more deaths compared to 2019, the pre-COVID-19 year; 103,183 out of 105,900 deaths occurred in older adults (≥60 years), which is equivalent to ≈97.4%, while in adults over 50, the segment of population just below older adults, in 2020 there were 2807 more deaths than in 2019. Surprisingly, from the analysis of our data, it is emerged that under the age of 40 in the years 2019, 2020 and 2021 there were 7103, 6808 and 7165 deaths, respectively. This means that in subjects under 40 during 2020 there were 295 fewer deaths than in 2019, while during 2021 there were 357 more deaths than in 2020, equivalent to ≈5.2% more. Conclusions: COVID-19 is a potential life-threatening disease mainly in older adults, as they are the most vulnerable due to inherent immunosenescence and inflammaging. Extensive vaccination in this segment of population with up-to-date vaccines is the means to reduce deaths, hospitalizations, and ICU pressure in the public interest. In the event of future threats, a new mass vaccination campaign must not be implemented without taking into account the individual age; it should primarily be aimed at people over 60 and at patients of any age with immune deficits, and secondly at people over 50. COVID-19 vaccination shows a favorable benefit-risk balance in older adults, while this balance falls under the age of 40; this younger segment of population should be therefore exempt from any mandatory vaccination.

Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut-brain-microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother’s obesity as potentially environmental factors of ASD. The purpose of the present analysis is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.