A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development. In this study, miR-1 potential role in early cardiac chamber differentiation is analyzed through specific signaling pathways. For this, we performed in chick embryos functional experiments by means of miR-1 microinjections into the posterior cardiac precursors -of both primitive endocardial tubes- committed to sinoatrial region fates. Subsequently, embryos were subjected to whole mount in situ hybridization, immunohistochemistry and RT-qPCR analysis. As a relevant nov-elty, our results revealed that miR-1 increases Tbx5, Gata4 and AMHC1, while this microRNA diminishes Mef2c expression, during early differentiation of cardiac sinoatrial region. Further-more, we observed in this developmental context that miR-1 upregulates CRABPII and RARß, and downregulates CRABPI, which are three crucial factors in retinoic acid signaling pathway. Interestingly, we also noticed that miR-1 directly interacts with HDAC4 and Calmodulin, as well as with Erk2/MAPK1, which are three key factors actively involved in Mef2c regulation. Our study shows, for the first time, a key role of miR-1 as an epigenetic regulator in early differenti-ation of cardiac sinoatrial region through orchestrating opposite actions between retinoic acid and Mef2c, fundamental to properly assign cardiac cells to their respective heart chambers. A better understanding of those molecular mechanisms modulated by miR-1 will definitely help in fields applied to therapy and cardiac regeneration and repair.

Gestational Diabetes Mellitus (GDM) is related with adverse outcomes for both the mother and the offspring. Immune and senescence play a crucial role in GDM progression. This study aims to explore the diagnostic significance of immune-related senescence (IRS) genes in GDM. We used weighted gene co-expression network analysis (WGCNA) and single sample gene set enrichment analysis (ssGSEA) to compute the immune score and aging score in control and GDM samples. Machine learning identified core IRS genes. Then we performed unsupervised cluster analysis in GDM patients to explore immune infiltration. Finally, we validated the core genes in clinical samples. We used the intersection of MEblack module from WGCNA and differentially expressed genes (DEGs) to obtain the potential genes. Next, a univariate logistic regression model including 23 potential genes were constructed, and these genes were filtered by least absolute shrinkage and selection operator (LASSO) algorithm. There were 5 potential genes (COX17, RRAS2, RRAGC, CECR1, and TACC2), which defined as biomarkers, remained eventually, and the efficacy of these biomarkers was evaluated by nomogram. Finally, the results from both qRT-PCR and western blot analyses demonstrated CECR1 was down-regulated, while TACC2 was up-regulated in GDM placental tissue. Our study identified CECR1 and TACC2 as diagnostic biomarkers for GDM associating with immune and senescence, providing a new perspective on GDM progression.

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.

Objective: To examine the associations between menstruation features and symptoms and hormone-immune-metabolic biomarkers. Methods: Forty-one women completed questionnaires assessing characteristic menstruation symptoms, duration of menstrual cycle and number of pads used/day and completed the Daily Record of Severity of Problems (DRSP) during the consecutive days of their menstrual cycle. Menses-related symptoms (MsRS) were computed from the sum of 10 pre- and post-menses symptoms and the menstruation blood and duration index (MBDI) was computed based on the daily number of pads and duration of menses. We assayed serum levels of various biomarkers at days 7, 14, 21, and 28 of the subjects’ menstrual cycle. Results: MBDI was significantly associated with a) MsRS including low abdominal cramps, and gastro-intestinal (GI) and pain symptoms (positively); b) plasma levels of haptoglobin (Hp), CCL5, insulin growth factor (IGF)-1, and plasminogen activator inhibitor (PAI)1 (all positively); and c) estradiol and paraoxonase (PON)1 arylesterase activity (both inversely). MsRS were significantly predicted by CCL5 and IGF-1 (both positively) and progesterone (inversely). Low-abdominal cramps, and gastro-intestinal and pain symptoms were associated with lower progesterone levels. The MBDI+MsRS score was significantly predicted by the cumulative effects of (in descending order of importance): Hp, IGF-1, PON1 arylesterase, estradiol and PAI. Conclusion: Menstruation-related features including estimated blood loss, duration of menses, cramps, pain and GI symptoms are associated with hormone-immune-metabolic biomarkers, which mechanistically may explain those features. Women with an increased MBDI+MsRS index ≥ 0.666 percentile may be considered to have menstruation-related distress, including dysmenorrhea symptoms.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track response to therapy, and parse causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).

Immune disorders, characterized by dysregulation at cellular and inflammatory levels, result from a complex interplay of genetics and environmental factors that lead to an abnormal immune response against autoantigens, triggering tissue damage. Recent research highlights reactive antibodies as key players in autoimmune diseases and graft rejection, but the complexity of their determination limits their use in clinic. Hence, we studied the specific binding profile of serological antibodies against a panel of cellular membranes in order to determine whether this antigenic panel could be used to diagnose specific immune disorders in humans. For this purpose, cell membrane microarrays of spleen, liver, and kidney tissues of monkey, rat, and human were developed, and human sera were analyzed, including healthy controls, patients with autoimmune disorders, and kidney transplant patients. A significant increase in antibody reactivity against specific monkey kidney and spleen membranes was observed in the serum of patients with lupus nephritis, while kidney transplant patients showed a significant enhancement against human tissues and Human embryonic kidney 293 cells. These results show the potential importance for clinical and basic research purposes of studying the presence of specific IgG against membrane antigens in the serum of patients as potential biomarkers of immune disorders.

Immune checkpoint blockade (ICB) has revolutionized the prognosis of several advanced-stage solid tumors. However, its success has been far more limited in hematological malignancies and is mostly restricted to classical Hodgkin lymphoma (cHL) and primary mediastinal B cell lymphoma (PMBCL). In patients with non-Hodgkin lymphoma (NHL), response to PD-1/PD-L1 ICB monotherapy has been relatively limited, although some subtypes are more sensitive than others. Numerous predictive biomarkers have been investigated in solid malignancies, such as PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability (MSI), among others. This case-illustrated review aims to appraise the current knowledge on PD-1/PD-L1 ICB efficacy in lymphoid malignancies, when used either as monotherapy or combined with other agents, and describes potential biomarkers of response in this specific setting.

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.

Objective: A previous study showed that schizophrenia is accompanied by lowered levels of trace/metal elements including cesium. There are no data whether changes in cesium, rubidium and rhenium are associated with activated immune-inflammatory pathways, cognitive impairments, and the symptomatology of schizophrenia. Methods: This study measured cesium, rubidium, and rhenium, cognitive impairments (using the Brief Assessment of Cognition in Schizophrenia) and the cytokines/chemokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and CCL11 (eotaxin) in 120 schizophrenia patients and 54 healthy controls. Severity of illness was assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) Scale and the Hamilton Depression Rating Scale (HAM-D). Results: Serum cesium was significantly lower in schizophrenia patients as compared with controls. Serum cesium was significantly and inversely associated with CCL11 and TNF-α, but not IL-1β. Moreover, there were significant inverse associations between serum cesium levels and the BPRS, FF, HAM-D and SANS scores and positive correlations between cesium and neurocognitive probe results including the Tower of London, Symbol Coding, Controlled Word Association, Category Instances, Digit Sequencing Task, and List Learning tests. Conclusion: The results suggest that lowered serum cesium levels may play a role in the pathophysiology of SCZ, specific symptom domains including negative, depressive and fatigue symptoms, neurocognitive impairments (spatial working, episodic and semantic memory and executive functions) and neuro-immune pathways as well.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying non-invasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small non-coding RNA such as microRNA and transfer RNA-derived fragments (tRF). Here we performed small-RNA next-generation sequencing for urine EVs, serum EVs and serum supernatant from 41 patients with non-muscle invasive BC (27 stage Ta, 14 stage T1) and 15 non-cancer patients (NCP) with benign cystoscopy findings. Serum and urine samples were collected before transurethral resection of bladder tumors (TUR-b) and at routine postsurgery check-ups. Expression levels of tRFs in presurgery samples were compared to those at postsurgery check-ups and to NCPs. To strengthen the reliability of our results, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between BC patients with stage T1 disease and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing presurgery to postsurgery samples, and four DEtRFs were found when comparing presurgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC.

Immune checkpoint inhibitors (ICI) are a promising form of immunotherapy that has significantly changed the therapeutic landscape for many advanced cancers. They have shown unique clinical benefit against a broad range of tumour types and a strong overall impact on survival in studied patient populations. However, there are still many limitations holding back this immunotherapy from reaching its full potential as a possible curative option for advanced cancer patients. A great deal of research is being undertaken in the hope of driving advancements in this area, building a better understanding of the mechanisms behind immune checkpoint inhibition and ultimately developing more effective, safer, and wider-reaching agents. Taking into account the current literature on this topic, this review aims to explore in depth the basis of the use of ICIs in the treatment of advanced cancers, evaluate its efficacy and safety, consider its current limitations, and finally reflect on what the future holds for this very promising form of cancer immunotherapy.

At present, there are still no specific therapeutic drugs and appropriate vaccines for Dengue. Therefore, it is very important to explore distinct clinical diagnostic indicators. In this study, we combined differentially expressed genes (DEGs) analysis and weighted co-expression network analysis (WGCNA) to screen a stable and robust biomarker which can be used to distinguish three clinical stages of Dengue and severity of Dengue. CD38 can distinguish excellently Early Acute, Late Acute, Convalescent stages for Dengue patients, and ZNF595 can discriminate DHF from DF in whole acute stages. We also found that three clinical stages can be discriminated based on the fractions of Plasma cells, activated memory CD4+ T cells, and Monocytes. In different clinical stages different immune cells function positively. Negative inhibition of viral replication based on Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene set enrichment analysis (GSEA), up-regulated autophagy genes and impairing immune system are potential reasons resulting in dengue hemorrhagic fever (DHF).

Background: Aberrations in endothelial cells, immune and oxidative pathways are associated with atherosclerosis (ATS) and unstable angina (UA). The role of trace elements, minerals, and the endogenous opioid system (EOS) in UA are less well established. Methods: We measured lipid, insulin resistance (IR), and immune, trace element (copper and zinc), mineral (magnesium, calcium), EOS (β-endorphin and mu-opioid receptor (MOR)) and antioxidant (vitamin D3) biomarkers in patients with ATS (n=60) and UA (n=60) and healthy controls (n=58). Results: ATS patients showed increased atherogenic and IR indices, IL-6, IL-10, β-endorphin, copper and magnesium, and lower zinc than healthy controls. Logistic regression showed that UA was significantly discriminated from ATS without UA with an accuracy of 85.5% using calcium, IL-10, β-endorphin, MOR, triglycerides, IR (all positively), and copper and vitamin D3 (inversely). Neural networks showed that UA was discriminated from ATS without UA with an area under the ROC curve of 0.942 using MOR, β-endorphin, calcium, insulin resistance, vitamin D3 and copper as input variables. We found that 50.0% of the variance in IR was explained by the regression on copper, IL-10, IL-6 (all positively), and zinc (inversely), while 32.9% of the variance in the atherogenic index of plasma was explained by copper, IL-10 (both positively), and magnesium (inversely). Conclusion: UA is not only mediated by insulin resistance, atherogenicity, and immune disorders, but also by aberrations in the endogenous opioid system and trace elements as well as lowered antioxidant levels. Copper appears to play a key role in IR and atherogenicity.

Immunological aging type definition requires establishing reference intervals from the distribution of immunosenescence biomarkers conditional on age. For 1,605 individuals (18–97 years), we determined the comprehensive IMMmune Age indeX IMMAX from flow cytometry-based blood cell sub-populations, and identified age-specific centiles by fitting generalized additive models for location, scale and shape. The centiles were uncorrelated with age, and facilitated the categorization of individuals as immunologically slow or fast aging types. Using its 50th percentile as reference, we rescaled IMMAX to equivalent years-of-life (EYOL), and computed the immunological age gap as difference between EYOL and chronological age. Applied to preliminary baseline and follow-up measurements from 53 participants of the Dortmund Vital Study (Clinical-Trials.gov Identifier: NCT05155397), the averaged changes in IMMAX and EYOL conformed to the 5-year follow-up period, whereas no significant changes occurred concerning IMMAX centiles and age gap. This suggested that the participants immunologically adapted to aging, and kept their relative positions within the cohort. Sex was non-significant. Methodical comparisons indicated that future confirmatory analyses with the completed follow-up examinations could rely on percentile curves estimated by simple linear quantile regression, while the selection of the immunosenescence biomarker will greatly influence the outcome, with IMMAX representing the preferable choice.

Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient's quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, until now, diagnoses and treatments are conducted according to clinical symptoms. Objective and biological validation are lacking. This may result in a poor outcome for patients with depressive disorder. Research has been conducted to identify the biomarkers that are related to depressive disorder. Cumulative evidence has revealed that certain immunologic biomarkers in-cluding brain-derived neurotrophic factor (BDNF) and cytokines, gastrointestinal biomarkers, hormones, oxidative stress, and certain hypothalamus-pituitary axis biomarkers are associated with depressive disorder. This article reviews the biomarkers related to the diagnosis and treatment of pediatric depressive disorders. To date, clinical biomarker tests are not yet available for diagnosis or for the prediction of treatment prognosis. However, cytokines such as Interleukin-2, interfer-on-gamma, tumor necrosis factor-alpha, and BDNF have shown significant results in previous studies of pediatric depressive disorder. These biomarkers have the potential to be used for diagnosis, prognostic assessment, and group screening for those at high risk.

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

The rapid growth of the global wearable technologies market is projected to reach $61.30 billion by 2030 which reflects a shift towards personalised health monitoring embedded in everyday activities. This paper explores the potential of embroidered interdigitated transducer (IDT)-based sensors for non-invasive, continuous monitoring of human biomarkers, particularly glucose levels, in human sweat. The study employs innovative embroidery techniques to create flexible fabric-based sensors with gold-coated IDTs. Experimental results demonstrate the sensor’s capability to detect water droplets and glucose concentrations, showcasing promising applications for health monitoring. The embroidered IDT-based sensors offer a unique approach for seamless integration into clothing, paving the way for personalised, continuous health data capture.

Chronic kidney disease patients treated by hemodialysis present a high cardio-vascular morbidity and mortality. There is an imperative need for novel biomarkers in identifying and to offer possible therapeutically intervention in these patients. We performed a prospective observational cohort study on 77 patients in the period October 2021 – October 2023. We measured serum plasma levels of Interleukin 1-Beta, Galectin 3, human suppression of tumorigenicity factor 2, bone morphogenetic protein 2 and fibroblastic growth factor 23 at the inclusion. We evaluated the correlations of these biomarkers with cardiac function and structure evaluated by echocardiography. Mean age was 61.02 (±11.81) years, 45 (56.2%) males and with a dialysis vintage of 4.95 (2.4-7.8) years. Median ejection fraction was 51 (43-54 %) and more than two thirds of the patients presented valvular calcifications. Overall mortality was 22%. Interleukin 1-Beta correlated positively with ejection fraction and global longitudinal strain and negatively with left atrium diameter and left ventricle tele systolic diameter. Galectin 3 values negatively correlated with aortic valve fibrosis and mitral valve calcifications and human suppression tumorigenity factor 2 negatively correlated with mitral valve calcifications. Some of these novel biomarkers could be used to better asses the cardio-vascular disease in patients on maintenance hemodialysis.

Depression is the commonest mental disorder worldwide. Both antidepressants and psychotherapy are effective in treating depression, but response to these treatments is often incomplete. Yoga-based interventions (YBIs) have emerged as a promising adjunctive treatment for depression. Recent research has attempted to identify the biological mechanisms associated with the antidepressant actions of YBIs. In this scoping review, conducted according to the PRISMA-ScR guidelines, the PubMed and Scopus databases were searched to retrieve research on biomarkers of response to YBIs in patients with depression. Eleven studies were included in the review. Based on these studies, YBIs may improve depression through beneficial effects on systemic inflammation, stress axis regulation, cardiac autonomic functioning, and possibly reductions in oxidative stress-related cellular damage. Increases in brain-derived neurotrophic factor (BDNF) may represent a final common pathway upon which these processes converge. Though these results are theoretically plausible, they should be interpreted with caution due to certain methodological limitations in the existing research. Replication of these results and improvements in study methodology, and the evaluation of other biomarkers relevant to the pathophysiology of depression, could further elucidate the mechanism of action of YBIs in this disorder, and identify which patients would benefit most from this treatment approach.

Abstract: COVID-19 in 2020 brought challenges to the Brazilian public health system with an emerging virus with respiratory contagion called SARS-CoV-2. There are few studies in Brazil and in some countries, on the increased incidence of certain viral respiratory infections, includ-ing H1N1 and coronavirus and their association with low levels of vitamin D, zinc and iron. The aim of this study was to demonstrate that the deficit of vitamin D, zinc and iron has an impact on the infectious process of patients with COVID-19 and to establish new forms of prevention for the worsening of COVID-19 in the human body. Data were collected from medical records and test results from patients being followed up during the treatment period for COVID-19. Patients with low blood levels of vitamin D, zinc and iron during the treatment period of COVID-19 had a higher percentage of worsening and complications requiring hospitalization in intensive care beds. The ingestion of vitamin D, zinc and iron in the treatment period of patients with COVID-19 in addition to being an immunological protector against SARS-CoV-2 and alleviating the process of worsening the disease can also act as a biomarker in cases of this disease.

Immune checkpoint inhibitors (ICI’s) are in the forefront of advanced Non Small Cell Lung Cancer (NSCLC) treatment. Still, only 27- 46% of patients respond to initial therapy with ICI’s and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4%-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post-hoc analyses of several clinical trials. Future research of ICI rechallenge for NSCLC should focus on better patient stratification, to reflect the underlying biology of immunotherapy resistance more accurately.

Urea cycle disorders (UCDs) are common inborn errors of metabolism, with an incidence of one in 30,000 births. They are caused by deficiencies in any of six enzymes and two carrier proteins, the most common being Ornithine Transcarbamylase Deficiency (OTCD). OTCD results in impairment to excrete nitrogen, causing toxic buildup of ammonia with resultant encephalopathy. Hyperammonemia (HA) induces the conversion of glutamate to glutamine in the brain. Excess glutamine in the brain causes osmotic changes cerebral edema, changes in astrocyte morphology, and cell death. Acute symptoms of HA include vomiting, hyperventilation, seizures, and irritability. Long-term neurological changes include deficits in working memory and executive function. To date, there are no predictors of prognosis of infants with neonatal onset OTCD outside of plasma ammonia level at presentation and duration of hyperammonemic coma. We provide a comprehensive analysis of a 16-year-old male with neonatal onset of OTCD as an example of how brain biomarkers may be useful to monitor disease course and outcome. This male presented at 8 days post natal with plasma ammonia and glutamine of 677 and 4024 micromol/L and had a missense mutation in Exon 4 (p.R129H). Treatment included protein restriction, sodium benzoate, and citrulline, arginine, and iron. He suffered recurrent acute hyperammonemic episodes despite compliance, triggered by infections or catabolic stressors. We discuss the long-term effects of the hyperammonemic episodes by following MRI based disease biomarkers.

Introduction: Substance-induced psychotic disorder (SIPD) is a mental health condition linked to the use of a psychotropic substance whose pathogenesis has not been totally clarified. The present retrospective observational study has the objective to identify differences in clinical features and peripheral biomarkers in SIPD patients according to the main substance of abuse.Methods: A total sample of 218 patients was divided in 3 groups according to the type of consumed substance: alcohol, cannabis and psychostimulants. The 3 groups were compared for continuous variables by one-way analyses of variance (ANOVAs) and for qualitative variables by χ² tests. After removing alcohol-induced psychotic disorder group, the same analyses were repeated. Statistically significant variables from these latter analyses were included in a binary logistic regression model to confirm their reliability as predictors for cannabis- or psychostimulants-induced psychotic disorders. Results: Psychotic cannabis abusers were younger (p<0.01) and had an earlier age at onset (p<0.01). On the contrary, alcohol consumers resulted to have a longer duration of illness (p<0.01), more previous hospitalizations (p=0.04), more frequent medical comorbidity (p<0.01), higher mean Modified Sad Person Scale scores (p<0.01). Finally, psychostimulant abusers had more frequently a lifetime history of poly-substance use disorders (p<0.01). Binary logistic regression revealed that higher mean Brief Psychiatric Rating Scale scores (p<0.01) higher sodium (p=0.012) and haemoglobin(p=0.040) plasma levels were predictors of cannabis misuse in SIPD patients.Conclusions: Different clinical factors and biochemical parameters con be associated to SIPD according to the main substance of abuse, thus requiring a specific management by clinicians.

Lung cancer is the leading cause of cancer related mortality worldwide. In order to improve its overall survival, early diagnosis is required. Since current screening methods still face some pitfalls, such as high false positive rates for low-dose computed tomography, researchers are still looking for early biomarkers to complement existing screening techniques in order to provide a safe, faster and more accurate diagnosis. Biomarkers are biological molecules found in body fluids, such as plasma, that can be used to diagnose a condition or disease. Metabolomics has already shown to be a powerful tool in the search for cancer biomarkers since cancer cells are characterised by impaired metabolism, resulting in an adapted plasma metabolite profile. The metabolite profile can be determined using nuclear magnetic resonance, or NMR. Although metabolomics and NMR metabolite profiling of blood plasma are still under investigation, there is already evidence for its potential for early-stage lung cancer diagnosis, therapy response, and follow-up monitoring. This review highlights some key breakthroughs in this research field, where the most significant biomarkers will be discussed in relation with their metabolic pathways and in light of the altered cancer metabolism.

In spite of prevalence gaps in several micronutrients supporting immune function, significance of their deficits/supplementation for efficacy of vaccines is underinvestigated. Thus, influence of supplementation combining vitamins C and D, zinc, selenium and manganese, and N-acetyl-cysteine on mouse IgG responses and underlying mechanisms to seasonal quadrivalent influenza vaccine (QIV) was investigated. QIV was given in two doses (28 days apart). The supplementation starting 5 days before the first injection increased the total serum IgG titre, through stimulation of germinal centre (GC) reaction in secondary lymphoid organs (SLOs), as indicated by increase in the frequency of GC B cells and follicular CD4+ T helper (Th) cells, and IL-21-producing Th cells. Additionally, the supplementation “optimized” IgG response following the second QIV injection by supporting more favorable (in respect to virus clearance) IgG2a response through favoring Th1 differentiation as indicating by Th1 (INF-γ) /Th2 (IL-4) signature cytokine level ratio upon QIV restimulation in SLO cell cultures. This most likely reflected partly their antioxidant action (as indicated by redox status analyses) on Th cell differentiation. Thus, the study forms solid base for further research aimed at repurposing use this safe and inexpensive micronutrient combination as an adjuvant for virus influenza vaccine.

Meningitis is a severe disease associated with death in children under five with highest rates of infections under age of one. Vaccines for Neisseria meningitides and Haemophilus influenza are used to prevent the main causative agents of meningitis. Administration of H. influenzae type b (Hib) vaccine is recommended at 2, 4 and 6 months with a booster dose at 18 months. N. meningitidis has two commercially available vaccines, the pure polysaccharide is recommended at 24 months meanwhile the protein-conjugated vaccines at 12 months. We sought in this study to examine if coadministering the vaccines for the two main meningitis causing bacteria might be synergistic as a preliminary step towards the possibility of shuffling immunization schedule. So, we coadministered Hib vaccine with commercially available vaccines either quadrate (ACWY) polysaccharide meningococcal (Men) or conjugated meningococcal (Nim) vaccines in Balb/C mice (n = 6/group) and compared to each vaccine administered separately and controls. Thirty-five days post immunization, we measured specific antibodies titers. Hib vaccine increased Men antibody titers significantly for serotypes Y and W. When Hib vaccine was coadministrated with Nim, antibody titer for Y, W and A significantly increased. For serotype C, there was no significant difference in antibody titers among immunized groups. As for effect of meningococcal vaccines on Hib, Men significantly increased Hib antibody titers while Nim had no effect. Collectively, our data suggested that coadministration of Hib and Men or Nim vaccines was safe and had synergistic effect on immune responses elicited to both vaccines. Further studies are needed before immunization schedule modifications. Such immunization schedule recommendation should provide better protection against this life-threatening disease in young children.

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

Oncolytic virotherapy is a promising immunotherapy approach for cancer treatment, utilizing viruses to preferentially infect and eliminate cancer cells while stimulating immune responses. In this review we synthesize current literature on the molecular circuits of immune sensing and response to oncolytic virotherapy; focusing on viral DNA or RNA sensing by infected cells, cytokine and danger-associated signal sensing by neighboring cells, and subsequent downstream activation of immune pathways. The sequential sense-and-response mechanisms involve the triggering of molecular sensors by viruses or infected cells to activate transcription factors and related genes for a breadth of immune responses. We describe how molecular signals induced in the tumor upon virotherapy can trigger diverse immune signaling pathways, activating both antigen-presenting cell-based innate and T cell-based adaptive immune responses. Insights into these complex mechanisms provide valuable knowledge for enhancing oncolytic virotherapy strategies.

Lung cancer remains the main cause of global cancer-related deaths. Currently low-dose computed tomography (LD-CT) shows a 20% reduction of mortality. However, its clinical suitability is hindered by cost, radiation, and some false positives. Thus, the discovery non-invasive and less-expensive biomarker is urgent needed. In this scenario, proteins released in biological fluids could be considered interesting biomarkers for their role in cancer development. We conducted a pioneering case-control pilot study aimed at assessing the usefulness of Raf Kinase Inhibitory Protein (RKIP) and its phosphorylated form (pRKIP) as potential early-stage lung cancer biomarkers. Urine and Blood samples of two consecutive and independent cohorts of lung cancer patients and healthy controls were screened by means of a novel experimental ELISA assay designed to evaluate both forms of the biomarker. Although urinary levels of RKIP were not statistically different between the lung cancer group and high-risk healthy group, serum ones instead increased significantly in early stage LC patients and permitted to discriminate LC patients from both low-risk (HS) and high-risk healthy subjects (HR-HS) with an overall 93% accuracy (AUC 0.93) when LC was compared to HS and 74% (AUC 0.73) when it was compared to high-risk group. Of note, the analysis of RKIP/pRKIP ratio also showed a high accuracy (90% - AUC 0.95) in discriminating LC patients from HS and more importantly, it allowed to identify LC patients compared to HR-HS, with a higher accuracy (79% - AUC 0.79) than RKIP alone. We hypothesize that serum RKIP levels may be correlated to the activation of the immune systems against the tumor during the first phases of its development. Our study identified a preliminary, non-invasive, RKIP and pRKIP profile able to discriminate with high specificity and sensitivity the early-stage lung cancer patients from high-risk Healthy Subjects. These results, although preliminary, suggest the utility of measuring RKIP/pRKIP as potential new screening test for lung cancer and provide the basis for future validation studies.

Genome-wide association studies (GWAS) have successfully revealed numerous susceptibility loci for obesity. PREDATORR study (2014) shows that in Romania, 34,6% of adults aged 20-79 y/o are overweight, 31,4% are obese with a high risk of cardiometabolic complications, a number that puts almost 67% of Romania's population in the abnormal weight group. Our study aims to investigate the current staus of genetic foundation in metabolic disease associated with obesity, applied to a pilot group of patients specifically examining the impact of known polymorphisms and their haplotype of six food intake-regulating genes: leptin (LEP), leptin receptor (LEP-R), serotonin receptor (5HTR2A), ghrelin (GHRL), neuropeptide Y (NPY) and fat-mass and obesity-associated (FTO) with the following polymorphisms: LEP A-2548G, LEPR A-223G, 5HTR2A G-1439A, GHRL G-72T, NPY T-29063C, FTO A-T and body mass index (BMI). A notable link between the LEP-2548 rs7799039 gene's AG genotype and the risk of obesity was observed, particularly pronounced in males aged 40-49, with an approximately sevenfold increased likelihood of obesity. The 5HTR2A rs6311 AA genotype was associated with a higher BMI, not statistically significant. The FTO rs9939609 gene's AA genotype emerged as a significant predictor of obesity risk. Besides these significant findings, no substantial associations were observed with the LEPR, 5HTR2A, GHRL and NPY genes. Haplotype association analysis showed a suggestive indication of GRGMLA (rs7799039, rs1137101, rs6311, rs696217, rs16139, rs9939609 sequence) haplotype with susceptibility effect towards obesity predisposition. Linkage disequilibrium (LD) analysis showed statistically significant associations between LEP and LEPR gene (p = 1e-04), LEP and GHRL gene (p = 0.0047), GHRL and FTO gene (p=0.03). The outcomes of this study, to our knowledge, one of the very few on the Romanian population, aimed to be a starting point for further research on the targeted interventional strategies to reduce cardiometabolic risks.

Fermented foods have long been known to have immunomodulatory capabilities and fermentates derived from the lactic acid bacteria of dairy products can modulate the immune system. We have used skimmed milk powder to generate novel fermentates using Lb. helveticus strains SC234 and SC232 and we demonstrate here that these fermentates can enhance key immune mechanisms that are critical to the immune response to viruses. We show that our novel fermentates SC234 and SC232 can positively impact on cytokine and chemokine secretion, nitric oxide (NO) production, cell surface marker expression, and phagocytosis in macrophage models. We demonstrate that fermentates SC234 and SC232 increase the secretion of cytokines IL-1β, IL-6, TNF-α, IL-27, and IL-10, promote an M1 proinflammatory phenotype for viral immunity via NO induction, decreases chemokine expression of Monocyte Chemoattractant Protein (MCP), increasing cell surface marker expression, and enhance phagocytosis in comparison to their starting material. These data suggest that these novel fermentates have potential as novel functional food ingredients for the treatment, management and control of viral infection.

A proportion of osteoarthritis (OA) patients are unsatisfied with post-operative outcomes following total joint replacement surgery (TJR), with insufficient pain relief or poor functional improvement. Predicting those will have poor outcomes would be beneficial for patients and clinicians. The aim of this study was to determine the relationship between baseline anthropometric data and the concentration of pre-operative serum and peri-operative synovial fluid (SF) cytokines with 7-month post-operative outcomes in a cohort of knee and hip OA patients. 160 OA patients were recruited who were scheduled for TJR. The concentration of 24 cytokines were measured in blood and SF by multiplex assay. EQ5Dindex health status was assessed pre-operatively and at 7-months post-operatively. 13% of patients were identified as non-responders based on EQ5Dindex. Compared to responders, non-responders were of higher BMI, had greater waist and hip circumference and had higher levels of SF leptin but lower levels of SF Resistin (p&lt;0.05). Linear regression analysis found a significant relationship between pre-operative body weight and post-operative response (ΔEQ5Dindex; r=0.222, p=0.049). The combination of body weight with SF amphiregulin and SF IL-6 provided an improved predictive model of post-operative response (r=0.470, p=0.035).

Antler is the fastest growing tissue. Because is based on proto-oncogenes, to avoid the risk of cancer, antlers evolved strong anticancer mechanisms, and thus its extract (DVA) is effective also against the few human tumours studied so far. We assessed whether DVA is a general anticancer compound testing direct effects in cells of different tumours: glioblastoma (GBM), colorectal and breast cancer, and leukaemia. DVA reduced viability of tumour but not healthy cells. Mobility decreased at least at the longest test (72 h). Intraperitoneal/oral 200 mg DVA/kg administration in GBM xenograft mice for 28 d reduced tumour weight 66.3% and 61.4% respectively, and also spleen weight. In addition, tumours treated with DVA showed symptoms of liquefactive necrosis. Serum cytokines showed DVA up-regulated factors related with tumour fighting and down-regulated those related with inducing immune tolerance to the tumour. DVA shows general anticancer effects in the lines tested and, in GBM mice, also strong indirect effects apparently mediated by the immune system.

Abstract: Lipidic carriers employed for the entrapment, encapsulation and precise targeting the bioactive compounds offer significant advantages to the biomedical, pharmaceutical, nutraceutical and cosmeceutical industries. These lipid and phospholipid-based vesicles can improve the solubility, permeation, pharmacokinetics, pharmacodynamics and bioavailability of the encapsulated material. As a matter of fact, nano-sized phospholipid vesicles have attained the highest success rate in commercialization among the available drug encapsulation technologies. Nevertheless, developing industrially acceptable products still remains a challenge. Among the main disadvantages of conventional lipidic carriers are their instability in the biological environments, and their sensitivity to changes in the pH, temperature and enzymes. To overcome these problems, the new generation of phospho/lipid-based carrier systems was developed using ingredients from microorganisms living in extremely harsh environments (i.e., archeaeobacteria). The present entry aims to review unique features of archaeolipids and recent developments in their application for the encapsulation of genetic material as well as their role and function as adjuvants and vaccine candidates.

Fowlpox virus (FPV) has been used as a vector for many years. To date, surprisingly, very little data exist on the persistence of fowlpox vaccines in chicken tissues, or what kind of immune cells respond to the vaccination at the site of inoculation. Although both humoral and cellular mediated immunity (CMI) play a part in overall immunity against FPV, little is known regarding the cell-mediated immune responses to FPV infection. The main aim of this paper was to measure persistence of the recombinant fowlpox vaccine in the skin tissues following vaccination. The results showed that the recombinant FPVs do not persist for long, and are cleared by 6 days post-vaccination (dpv). The response of immune cells (macrophages, B cells, CD4+ and CD8+ T cells) that infiltrating the site of vaccination was estimated.

Introduction: The repertoire of microRNAs (miRNAs) in thyroid carcinomas starts to be elucidated. Among differentiated thyroid carcinomas (DTC), papillary thyroid carcinoma (PTC) is the most common. The assessment of miRNAs expression may contribute to refine the pre-surgical diagnosis, in order to obtain a personalized and more effective treatment of patients. Aims: This study aims to evaluated 1) miRNAs expression in a series of DTC, and the association with the presence of selected genetic mutations, in order to improve diagnosis and predict biologic behavior of DTC/PTC. 2) the reliability of molecular tests in Ultrasound-guided Fine Needle Aspiration Cytology (US-FNAC) for a more precise preoperative diagnosis. Material and methods: This series includes 176 samples (98 cytology samples and 78 formalin-fixed paraffin embedded (FFPE) tissues) obtained from 106 patients submitted to surgery, being 13 benign lesions (controls) and 93 DTCs (cases). The microRNA expression was assessed for miR-146b, miR-221, miR-222, and miR-15a by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and the results were analyzed using the 2- ΔΔCT method, using miR16 as an endogenous control. The discriminative ability of miRNAs expression regarding PTC diagnosis was evaluated using the area under the Receiver Operating Characteristic Curve (AUC). The association of miRNAs expression, clinicopatological features and genetic alterations (BRAF, RAS and TERTp) was evaluated in PTCs. Results/Discussion: All the analyzed miRNAs showed a tendency to be over expressed in DTCs/PTCs when compared with benign lesions, both in cytology and histology samples. In cytology, miRNAs expression levels were higher in malignant than in benign tumors. In histology, corresponding discriminative abilities regarding PTC diagnosis were: miR-146b (AUC0.94, 95%CI 0.87-1), miR-221 (AUC0.79, 95%CI 0.68-0.9), miR-222 (AUC0.76, 95%CI 0.63-0.89) and miR-15a (AUC0.85, 95%CI 0.74-0.97). miR-146b showed 89% sensitivity (se) and 87% specificity (sp); mi-R221 se=68.4, sp=90; miR222 se=73, sp=70, and mi-R15a se=72, sp=80. MicroRNAs were associated with aggressive clinicopathological features and tumor progression in PTCs (p &lt; 0.05), particularly for miR-222. Our data reveals a significant association between higher expression levels of miR-146b, miR-221 and miR-222, with the presence of BRAF mutation (p&lt;0.001), and miR-146b (p=0.016) and miR-221 (p=0.010) with the presence of RAS mutation, suggesting an interplay of these mutations with miRNAs expression. Although this study has a relatively small sample size, over expression of miRNAs in cytology may contribute to a more precise preoperative diagnosis. The miRNAs showed a good discriminative ability in PTC diagnosis. The association between the miRNAs expression profile and genetic alterations results could be useful for an accurate diagnosis of DTCs/PTCs in FNAC.

In February 2004, the Food and Drug Administration (FDA) was the first to approve the combination of cisplatin (CDDP) and pemetrexed (PEM) as standard first-line chemotherapy for untreated, unresectable malignant pleural mesothelioma (MPM). However, after that approval, no progress was made in the standard first-line treatment of MPM for almost 15 years. Positive results from a phase 3 study (Mesothelioma Avastin Cisplatin Pemetrexed Study: MAPS) verifying the effect of bevacizumab, an anti-angiogenesis agent added to CDDP/PEM for unresectable MPM, were published in The Lancet in December 2015; however, this did not lead to approval by national drug regulatory agencies. Furthermore, no second-line treatment was established for cases refractory to CDDP/PEM. In August 2018, the Pharmaceuticals and Medical Devices Agency of Japan was the first in the world to approve monotherapy with nivolumab, an immune checkpoint inhibitor (ICI), for previously unresectable, advanced, or recurrent MPM. Following Japan, in October 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of previously untreated, unresectable MPM. In this article, we review the transition of drug treatment for MPM, in light of the historical background, focusing on the benefits of ICIs.

Fibrosis is an important health problem and its pathogenetic activation is still largely unknown. It can develop either spontaneously or, more frequently, as a consequence of various underlying diseases, such as chronic inflammatory autoimmune diseases. Fibrotic tissue is always characterized by mononuclear immune cells infiltration. The cytokine profile of these cells shows clear proinflammatory and profibrotic characteristics. Furthermore, the production of inflammatory mediators by non-immune cells, in response to several stimuli, can be involved in the fibrotic process. It is now established that defects in the abilities of non-immune cells to mediate immune regulation may be involved in the pathogenicity of a series of inflammatory diseases. The convergence of several, not yet well identified, factors results in the aberrant activation of non-immune cells, such as epithelial cells, endothelial cells and fibroblasts, that producing pro-inflammatory molecules, exacerbate the inflammatory condition leading to the excessive and chaotic secretion of extracellular matrix proteins. However, the precise cellular mechanisms involved in this process have not yet been fully elucidated. In this review we explore the latest discoveries on the mechanisms that initiate and perpetuate the vicious circle of abnormal communications between immune and non-immune cells, responsible for fibrotic evolution of inflammatory autoimmune diseases.

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

Background: Oral cancer (OC) is serious health concerning issue that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft palate. The goal of this study is to look into new biomarkers and important pathways that might be used as diagnostic biomarkers and therapeutic candidates in OC. Methods: Publicly available repository the Gene Expression Omnibus (GEO) was responsible to collect OC-related datasets. GSE74530, GSE23558, and GSE3524 microarray datasets were collected to apply analysis. Minimum cut-off criteria of |log fold-change (FC)| > 1 and adjusted p < 0.05 were applied to figure out the up-regulated and down-regulated differential expression genes (DEGs) from the three datasets. After that only common DEGs in all three datasets were collected to apply further analysis. Gene ontology (GO) and Pathway analysis were implemented to explore the functional behaviors of DEGs. Then protein-protein interaction (PPI) networks were built to identify the most performed genes, clustering algorithm was also implemented to identify complex parts of PPI. TF-miRNA networks were also constructed to study deeply about OC-associated DEGs. Finally, top gene performers from PPI networks were used to apply drug signature analysis. Results: After applying filtration and cut-off criteria 2508, 3377, and 670 DEGs were found for GSE74530, GSE23558, and GSE3524 respectively, and 166 common DEGs were found in every dataset. The GO annotation remarks that most of the DEGs were associated with the terms of type I interferon signaling pathway. The pathways of KEGG reported that the common DEGs are related to the Cell cycle and Influenza A. The PPI network holds 88 nodes and 492 edges and CDC6 had the highest number of connections. 4 clusters were identified from the PPI. Drug signatures doxorubicin and resveratrol showed high significance according to the hub genes. We anticipate that our bioinformatics research will aid in the definition of the pathophysiology and the development of new therapies for OC.

Mild TBI (mTBI) accounts for most TBI cases, the leading cause of morbidity and mortality worldwide. Despite their high incidence, mTBI pathophysiology remains largely unknown. Recent studies have shown that the inflammatory response is activated early after mTBI and can persist for several weeks or months. However, limited evidence on the utility of inflammatory biomarkers as predictors of clinical outcomes in mTBI was previously provided. Thus, this study aims to provide an overview of the current knowledge on the role of inflammation in the pathogenesis of mTBI and the potential of some inflammatory biomolecules as biomarkers of mTBI. Thus, it was shown that the increase of IL-6, TNF-α, and IL-1β plasma levels could be implicated in the development of the early post-concussion symptoms. On the other hand, the persistence of the increased plasmatic concentrations of IL-10 and IL-8 for as long as six months following the brain injury event could suggest chronic inflammation leading to neuroinflammation and late or persistent symptoms. In this context, our findings showed that the inflammatory biomarkers could be relevant in diagnosing or predicting recovery or long-term outcomes of mTBI.

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

Despite increasing research efforts, there is a lack of consensus on defining aging or health. To understand the underlying processes, and to foster the development of targeted interventions towards increasing one’s health, there is an urgent need: (1) to find a broadly acceptable and useful definition of health, based on a list of features (which may or may not be molecular); (2) to operationalize features of health so that it can be measured; (3) to identify predictive biomarkers and (molecular) pathways of health, and (4) to suggest interventions, such as nutrition and exercise, targeted at putative causal pathways and processes. Based on a survey of the literature, we propose to define health as a state of an individual characterized by the core features of (a) physiological function, (b) cognitive function and (c) physical function, amended, specifically in case of humans, by (d) lack of disease, and by (e) reproductive function. Often used concepts such as lack of frailty, allostatic load, or self-reported health (in case of human), and indices such as the Healthy Aging Index can be viewed as projections or surrogates of our definition. We further define aging as the set of all processes in an individual that reduce its “wellbeing”, that is, its health or survival or both. We define biomarkers of health by their attribute of predicting future health better than chronological age. We define healthspan pathways as molecular features of health that relate to each other, specifically by belonging to the same molecular pathway. Our conceptual framework may integrate diverse operationalizations of health and guide precision prevention efforts that are a key to reducing the need for medical and nursing care.

Introduction: A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). Material and Methods: The study analysed articles published in JCR journals from 2019 to 2024, including retrospective, prospective, case-control, or cross-sectional studies. It combined MESH and free terms for "Epileptogenesis" and "Neuroinflammation" and included searches for biomarkers previously reported in narrative reviews. Results: The study analysed 243 articles related to epileptogenesis and neuroinflammation, with 356 from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 52 evaluated by authors. 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. This systematic review provides acceptable support for five biomarkers: TNF-a and some of its soluble receptors (sTNFr2), HMGB1 and TLR-4, CCL2 and IL-33. Discussions: Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control levels of epileptic patients. Their value will be better defined by future studies.

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

Cervical cancer (CC) is the most common cancer in women worldwide and is almost always associated with repeated infections by human papillomavirus (HPV). Screening by traditional tests combined with biomarker identification techniques for low- or high-grade injuries, are becoming increasingly important in diagnosis and prognosis, avoiding countless deaths. This article explores existing literature on the main serum biomarkers and the identification of biomarkers associated with the oncogenesis of HPV expression in the identification of pre-cancerous lesions and of CC for an effective treatment, with reduction of recurrence, as well as we explain strategies for the development of biomarkers based on DNA, proteins and other markers. We also describe how markers of chromosomal instability host DNA, promoting hypo- or hypermethylation of DNA, as well as polymorphisms and epigenetic events in the p53 gene. Finally, we discuss changes in gene expression using cDNA microarray techniques and changes in the expression of proteins and markers identified through mass spectrometry.

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

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.

Lymphangioleiomyomatosis (LAM) is a cystic pulmonary disorder that has been known to primarily affect women of childbearing age. The disorder can develop with mutations in the tuberous sclerosis (TSC) genes TSC1 & TSC2 but may arise by other irregular cases in the lack of these mutations. LAM can manifest in a wide variety of ways and generally compounded in symptoms of other lung disorders such as bronchitis, emphysema, & asthma. However, due to lack of effective diagnostic methods, biomarkers of LAM leading to a treatment for the disorder are currently unmet. Using integrative dating analytics and bioinformatics approaches; this study used publicly available microarray data to identify biomarkers in LAM. The results showed important differential expressed genes (DEGs) including: CDH2, CXCL6, ANXA10, MFAP5, RPS4Y1, DCBLD2, PAPPA, TFPI2, SERPINE1, LOX, MYH11, RGS1, SEPP1, TMOD1, ID1, SFTPB, CDH1, HTR2B, OGN, and IGLC1. Furthermore, gene – network and gene ontology (GO) analysis were conducted to show the importance of these genes from a molecular understanding. Taken together, the results revealed could serve as diagnostic and prognostic biomarkers with LAM patients.

Abstract Precision medicine is essentially based on reliable and non-invasive biomarkers. Aim of this review has been to describe the newest biomarkers in the field of kidney transplantation and the kidney rejection, one of the commonest and severe complications. Standard of care tools to identify acute rejection are largely full of errors and of drawbacks. In recent years new and reliable biomarkers have been found. They are avoid of risks, non-invasive and able to detect rejection even in those frequent cases in which acute rejection are clinically asymptomatic and not otherwise identifiable. In recent years several biomarkers have been identified. Very recently have been found new relevant biomarkers able to diagnose rejection with high positive predictive value and low negative predictive value. These are the donor derived cell free DNA found in the recipient, the gene expression profile of the donor found in the recipient and the urinary cytokines that express modification in the graft tissue. The aim of this study has been to find the most recent findings in the literature on this topic and to describe the utility and possible limitation of such new biomarkers on kidney rejection.

Predominantly antibody deficiencies (PAD) represent the most common type of primary immu-nodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifesta-tions, complications and outcome. Considering that the prevalence of PAD in Greece is unknown and there is limited knowledge on clinical and laboratory characteristics of affected patients, we conducted a nationwide study, including 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed and/or followed-up between April 2007 to September 2023. Furthermore, we classified our cohort into five Groups according to their medical history, im-munoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficien-cy (CVID), 12 with CVID-like disease (with a history of a previous B-cell depletion immunother-apy for autoimmune or malignant disease), seven with combined IgA and IgG subclass deficien-cies, five with immune dysregulation syndrome and CTLA4 defects, and six with unclassified hypogammaglobulinemia. We demonstrated a remarkable delay of PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). Family history of PAD was only 11.8%, with the majority of patients considered sporadic cases. Most patients were diag-nosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant auto-immune cytopenias. Interestingly, ten patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%) and atopy (24.2%), while 39 patients (25.5%) developed bronchiectasis and 16 (10.5%) granulomatous dis-ease. Patients with CTLA4 defects displayed a variable clinical phenotype at diagnosis, with four patients diagnosed during a work-up of re-current infections, while one also displayed a massive splenomegaly. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and appropriate management of affected patients

Increasing evidence points to host Th17 inflammatory responses as contributing to the severe lung pathology and mortality of lower respiratory tract infections from coronaviruses. This includes host inflammatory and cytokine responses to COVID-19 caused by the SARS-2 coronavirus (SARS CoV2). From studies conducted in laboratory animals, there are additional concerns about immune enhancement and the role of potential host immunopathology resulting from experimental human COVID-19 vaccines. Here we summarize evidence suggesting there may be partial overlap between the underlying immunopathologic processes linked to both coronavirus infection and vaccination, and a role for Th17 in immune enhancement and eosinophilic pulmonary immunopathology. Such findings help explain the link between viral-vectored coronavirus vaccines and immune enhancement and its reduction through alum adjuvants. Additional research may also clarify links between COVID-19 pulmonary immunopathology and heart disease.

Fermented foods and ingredients, including fermentates derived from lactic acid bacteria (LAB) in dairy products, can modulate the immune system. Here we describe the use of reconstituted skimmed milk powder to generate novel fermentates from Lactobacillus helveticus strains SC232, SC234, SC212, and SC210, and from Lacticaseibacillus casei strains SC209 and SC229, and demonstrate using in vitro assays that these fermentates can differentially modulate cytokine secretion by bone marrow derived dendritic cells (BMDCs) when activated with either the viral ligand, loxoribine, or an inflammatory stimulus, lipopolysaccharide. Specifically, we demonstrate that SC232 and SC234 increase cytokines IL-6, TNF-α, IL-12p40, IL-23, IL-27 and IL-10, and decreased IL-1β in primary bone marrow derived dendritic cell (BMDCs) stimulated with a viral ligand. In contrast exposure of these cells to SC212 and SC210 resulted in increased IL-10, IL-1β, IL-23, and decreased IL-12p40 following activation of the cells with the inflammatory stimulus LPS. Interestingly SC209 and SC229 had little or no effect on cytokine secretion by BMDCs. Overall, our data demonstrates that these novel fermentates have specific effects and can differentially enhance key immune mechanisms that are critical to viral immune responses, or can suppress responses involved in chronic inflammatory conditions, such as Ulcerative Colitis (UC), and Crohn’s disease (CD).

The aging populations observed across numerous countries worldwide necessitate a thorough exploration of interventions aimed at promoting healthy aging. As individuals age, they undergo significant physiological changes that impact their functional capacity and often necessitate increased reliance on external support systems. Enhancing the autonomy and well-being of elderly individuals emerges as a critical imperative, serving not only individual interests but also broader societal goals. This review investigates various interventions designed to optimize the health and independence of aging populations, offering insights into effective strategies for promoting healthy aging and mitigating the societal burdens associated with an aging demographic.

MicroRNAs (miRNAs) are single-stranded, noncoding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and dog diseases. Most cancers tested, to date, have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process. Based on this evidence, numerous miRNAs have been suggested as potential cancer biomarkers for both diagnosis and prognosis. miRNA-based therapies have also been tested in different cancers and have provided measurable clinical benefits to patients. In addition, understanding miRNA biogenesis and regulatory mechanisms in cancer can provide important knowledge about resistance to chemotherapies, leading to more personalized cancer treatment. In this review, we have comprehensively summarized the importance of miRNA in human and dog cancer research. We have discussed the current state of development and potential for miRNA as both a diagnostic marker and a therapeutic target.

Renal clear cell carcinoma (ccRCC) comprises over 75% of all renal tumors and arises in the epithelial cells of the proximal convoluted tubule. Molecularly ccRCC is characterized by copy number alterations (CNAs) such as the loss of chromosome 3p and VHL inactivation. Additional driver mutations (SETD2, PBRM1, BAP1, and others) promote genomic instability and tumor cell metastasis through the dysregulation of various metabolic and immune-response pathways. Many researchers identified mutation, gene expression, and proteomic signatures for early diagnosis and prognostics for ccRCC. Despite a tremendous influx of data regarding DNA alterations, gene expression, and protein expression, the incorporation of these analyses for diagnosis and prognosis of RCC into the clinical application has not been implemented yet. In this review, we focused on the molecular changes associated with ccRCC development, along with gene expression and protein signatures, to emphasize the utilization of these molecular profiles in clinical practice. These findings, in the context of machine learning and precision medicine, may help to overcome some of the barriers encountered for implementing molecular profiles of tumors into the diagnosis and treatment of ccRCC.

Aluminum, a contentious trace element found in the environment, has been demonstrated to have harmful effects on both humans and animals. In contrast, Sempervivum tectorum, an evergreen plant, has been found to offer numerous beneficial effects for both humans and animals. Therefore, this study aims to assess the protective effect of S. tectorum on certain reproductive biomarkers in male rats exposed to aluminum. Thirty-five Wistar rats were randomly divided into five groups: NTC (no-treatment control) received distilled water; NC (negative control) received drinking water containing 1 mg/L aluminum sulfate (AS); E1 received 1 mg/L AS along with an 8% S. tectorum extract; PC (positive control) received only 8% S. tectorum extract; E2 received 1 mg/L AS for three months followed by 8% extract for one month. The study analyzed testosterone, LH, FSH, body weight, and the histological structure of the testis, epididymis, and prostate, as well as the levels of zinc, manganese, copper, and iron in these organs. Significant decreases in body weight, testis, and epididymis size were observed in the aluminum-exposed groups compared to the control, whereas these decreases were not significant in the S. tectorum-treated groups compared to the control. Aluminum exposure led to significant decreases in testosterone and LH levels, with FSH levels showing a non-significant decrease in males, which were mitigated significantly by the administration of the plant extract. Histological analysis revealed alterations in the testis, epididymis, and prostate of the AS-exposed groups, including necrosis of seminiferous tubule epithelium and Leydig cells in the testis, and basal epithelial necrosis in the epididymis and prostate. Aluminum levels increased in all organs studied, while levels of zinc, copper, iron, and manganese decreased, showing a negative and significant correlation with aluminum levels. The aqueous extract of S. tectorum demonstrated a protective effect on certain studied biomarkers in male rats affected by aluminum exposure.

Brain tumors still remain a deadly cancer that, in most cases, is difficult to diagnose at an earlier stage. Therefore, it is necessary to develop rapid, sensitive methods for detecting cancer biomarkers. Such a biomarker may be a microRNA which expression level in body fluids is strongly correlated with cancer. Numerous studies have demonstrated changes in the expression of microRNAs in cerebrospinal fluid and blood samples collected from patients with brain tumors. These new biomarkers have the potential to help diagnose brain cancers at an early stage, avoiding the most invasive procedures. This review discusses the functional role of microRNAs and the prospects for their use as diagnostic biomarkers in patients with brain tumors.

Multiple Sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves the intricate interplay of different immune cells going awry leading to inflammation, demyelination, and neurodegeneration. Its diagnosis is quite arduous because of the baffling number of symptoms it elicits and the varied clinical manifestation it presents. The simplified criteria (in form of Macdonald’s Criteria) which have got modified several times is now the single most important criteria accepted by neurology bodies for diagnosing MS. Biomarkers from time to time have been explored to simplify the diagnosis and prognosticate MS along with anecessity to monitor treatment outcome. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and rapidly measured, their specificity, safety, and their ability to yield precise results. Biomarkers are classified into various categories including predictive, diagnostic, prognostic, related to disease activity, and monitoring treatment outcome. Each representative of the disease activity category reflects a variety of pathological processes of MS such as neuroaxonal loss, gliosis, demyelination, disability progression, remyelination, etc. This review discusses several promising serum and cerebrospinal fluid biomarkers and imaging biomarkers used in clinical practice. Myelin oligodendrocyte glycoprotein antibody disease which is recently recognized as a definite disease will also be discussed. Furthermore, it sheds light on the criteria and the challenges a biomarker faces to be considered as a standard one.

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

Blood biomarkers represent a promising future for studying cognitive impairment, particularly in Alzheimer's Disease (AD), as they offer a non-invasive alternative to cerebrospinal fluid tests and have potential as population screening tools. However, the relationships between these biomarkers and specific cognitive functions, as well as their utility in predicting longitudinal cognitive decline, are not yet fully understood. This descriptive review surveys the literature from 2018 to 2023, focusing on the associations between Amyloid-β, Total Tau, Phosphorylated Tau (p-tau), Neurofilament Light (Nfl), and Glial Fibrillary Acidic Protein (GFAP) with cognition. The reviewed studies are heterogeneous, varying in design and population (mixed, cognitively impaired, or unimpaired), and show results that are sometimes conflicting. Generally, cognition positively correlates with Aβ levels, especially when evaluated through the Aβ42/Aβ40 ratio. In contrast, Tau, Nfl, and GFAP levels typically show a negative correlation with cognitive performance. While p-tau measures tend to show stronger associations with cognitive functions than other biomarkers, no single blood marker has emerged as predominantly associated with a specific cognitive domain. These findings add to our understanding of the complex relationship between blood biomarkers and cognitive performance and underscore their potential utility in clinical evaluations of cognition.

Acute kidney injury (AKI) is a clinical syndrome where a rapid decrease in kidney function and/or urine output is observed, which may result in the imbalance of water, electrolyte and acid base, and is associated with poor prognosis and prolonged hospitalization. Therefore, early diagnosis and treatment to avoid the severe AKI stage is important. While several biomarkers, such as urinary L-FABP and NGAL, can be clinically useful, there is still no gold standard for early detection of AKI and there are limited therapeutic options against AKI. miRNAs are non-coding and single-stranded RNAs that silence their target genes in the post-transcriptional process and are involved in a wide range of biological processes. Recent accumulated evidence has revealed that miRNAs may be potential biomarkers and therapeutic targets for AKI. In this review article, we summarize the current knowledge about miRNAs as promising biomarkers and potential therapeutic targets for AKI, as well as the challenges in their clinical use.

nutrition, macro and micronutrients, bone health, exercise, exogenous and endogenous microRNA, epigenetics

Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocytes-derived and TAMs-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer.

Ulcerative colitis (UC) is one of the two disorders known as inflammatory bowel diseases (IBD) along with Crohn’s disease (CD), with complex pathogenesis, requiring costly invasive investigations. Objective: to examine the most recent biomarkers proposed for UC diagnosis; to establish the strategy used to make the differential diagnosis between UC and CD relying on these biomarkers, also adding the benefit of finding new non-invasive tools in managing this condition. The search was performed in a single database (Web of Science) using the specific keywords „ulcerative colitis”, „biomarkers” and „diagnosis” for the last five years. Study eligibility criteria: clinical trials on adults and pediatric patients with ulcerative colitis compared with Crohn’s disease. Results: We selected 57 studies, randomized controlled trials (RCTs) and clinical case series (CCS), summarizing the latest most specific biomarkers in diagnosis of UC. Limitations: we considered RCTs and CCS from one database, limited to the search topics. Our findings indicate a important number of potential biomarkers with diagnostic value, which bring the advantage of a non-invasive method to approach this challenging disorder.

Objective: The aim of study is to find key genes and enriched pathways associated with lung cancer. Participants and Methods: Differentially expressed genes (DEGs) data of 54674 genes based on stage, tumor and status of lung cancer was taken from 66 patients of African American (AAs) origin. 2392 DEGs were found based on stage, 13502 DEGs were found based on tumor, 2927 DEGs were found based on status having p value (p<0.05). Results: Total 33 common DEGs were found from stage, tumor and status of lung cancer. Gene ontology (GO) and KEGG pathway enrichment analysis was performed and 49 significant pathways were obtained, out of which 10 pathways were found to be exclusively involved in lung cancer development. Protein-protein interaction (PPI) network analysis found 69 nodes and 324 edges and identified 10 hub genes based on their highest degrees. Module analysis of PPI found that ‘Viral carcinogenesis’, ‘pathways in cancer’, ‘notch signaling pathway’, ‘AMPK signaling pathways’ had a close association with lung cancer. Conclusion: These identified DEGs regulate other genes which play important role in growth of lung cancer. The key genes and enriched pathways identified can thus help in better identification and prediction of lung cancer.

SARS-CoV-2 infection can lead to life-threatening clinical manifestations. Patients with cardiovascular disease (CVD) are at higher risk for severe courses of COVID-19. However, strategies to predict the course of SARS-CoV-2 infection in CVD patients at the time of hospital admission are still missing. Here, we investigated whether this prediction is achievable by prospectively analysing the blood immunophenotype of 94 participants, including 20 uninfected and 37 acutely SARS-CoV-2-infected CVD patients and 37 healthy donors, using a 36-colour spectral flow cytometry panel. Unsupervised data analysis revealed little differences between healthy donors and CVD patients, whereas the distribution of the cell populations changed dramatically in SARS-CoV-2-infected CVD patients. The latter had more mature NK cells, activated monocyte subsets, central memory CD4+ T cells, and plasmablasts but fewer dendritic cells, CD16+ monocytes, innate lymphoid cells, and CD8+ T cell subsets. Moreover, we identified an immune signature characterised by mucosal-associated invariant T (MAIT) cells, intermediate effector CD8+ T cells, and natural killer T (NKT) cells that is predictive for CVD patients with a severe course of COVID-19. Thus, intensified immunophenotype analyses can help identify patients at risk of severe COVID-19 at hospital admission, improving clinical outcomes through specific treatment.

Postpartum depression (PPD) is a disorder that impairs the formation of the relationship between mother and child, and reduces the quality of life for affected women to a functionally significant degree. Studying markers associated with PPD can help in early detection, prevention, or monitoring treatment. The purpose of this paper is to review biomarkers linked to PPD and to present selected theories on the pathogenesis of the disease based on data from biomarker studies. The complex etiology of the disorder reduces the specificity and sensitivity of markers, but they remain a valuable source of information to help clinicians. The biggest challenge of the future will be to translate high-tech methods for detecting markers associated with postpartum depression into more readily available and less costly ones. Population-based studies are needed to test the utility of potential PPD markers.

Cutaneous T cell lymphomas (CTCLs) are caused by malignant clonal proliferation of skin-tropic T cells. Most patients have an indolent disease course managed with skin-directed therapies, while some entities, or in advanced stages of disease, have aggressive progression and poor survival. To efficiently treat CTCL consistent entity markers are needed to prevent the delay in diagnosis and to provide disease specific treatment to patients. Recently, the introduction of high throughput parallel sequencing methods resulted in identification of numerous genetic and ep-igenetic alterations affecting the transcriptome of CTCL cells. In this review, most relevant genes, including TOX, CADM1, PLS3, DNM3, CXCL13, PD-1, BCL11B and TMEM244 are reported that are specifically expressed in CTCL. Upon verification their specificity and sensitivity in larger studies, their altered expression will be able to be recognized as novel biomarkers, that can im-prove the early diagnosis of CTCL.

The development of biosensors with high sensitivity and low-detection limits provides a new direction for medical and personal care. Graphene and graphene derivatives have been used to prepare various types of biosensors due to their excellent sensing performance (e.g. high specific surface area, extraordinary electronic properties, electron transport capabilities and ultrahigh flexibility). This perspective review focuses on graphene-based biosensors for quantitative detection of cancer related biomarkers such as DNA, miRNA, small molecules and proteins by integrating with different signal outputting approaches including fluorescent, electrochemistry, surface plasmon resonance, surface enhanced Raman scattering etc. The article also discussed their challenges and potential solutions along with future prospects.

Immune Checkpoint Inhibitors are monoclonal antibodies that are used to treat over one in three cancer patients. While they have changed the natural history of disease, prolonging life and preserving quality of life, they are highly active in less than 40% of patients, even in the most responsive malignancies such as melanoma, and cause significant autoimmune side effects. Licenced biomarkers include tumour Programmed Death Ligand 1 expression by immunohistochemistry, microsatellite instability, and Tumour Mutational Burden, none of which are particularly sensitive or specific. Emerging tumour and immune tissue biomarkers such as novel immunohistochemistry scores, tumour, stromal and immune cell gene expression profiling, and liquid biomarkers such as systemic inflammatory markers, kynurenine/tryptophan ratio, circulating immune cells, cytokines and DNA are discussed in this review. We also examine the influence of the faecal microbiome on treatment outcome and its use as a biomarker of response and toxicity.

Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g. ill/critically ill, post-trauma, sepsis, exhausted athletes) it is currently difficult to determine whether glutamine parenteral or enteral supplementation should be recommended based on the amino acid plasma concentration (glutaminemia). Although the beneficial immune based effects of glutamine supplementation is already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review on how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism, action and important issues related to the effects of glutamine supplementation in catabolic situations.

Type2 diabetes(T2D) is a pervasive modern disease, classified as a metabolic disorder marked by hyperglycemia, hyperinsulinemia, and life-long threatening cardiovascular morbidities. Subclinical inflammation stands as the primary pathogenetic factor propelling T2D progression, correlated with heightened levels of proinflammatory cytokines. Immune cells serve as the prominent sources of cytokine production, and under diabetic conditions, they tend toward a proinflammatory phenotype, fostering chronic inflammation. This review zeroes in on the disrupted homeostasis characteristic of diabetic conditions, encompassing cytokines, hormones, and their interplay with altered immune function, all contributing to the onset of diabetic cardiovascular complications.

Intratumoral immune cytolytic activity (CYT), measured as the geometric mean of the expression of Granzyme-A (GZMA) and Perforin-1 (PRF1), has emerged as a critical factor in cancer immunotherapy, with significant implications for patient prognosis and treatment outcomes. Here, we review how different immune checkpoint pathways, the composition of Tumor Microenvironment (TME), antigen presentation and metabolic pathways, all regulate CYT. We also discuss the various methods through which CYT can be assessed. The detection and analysis of tumor-infiltrating lymphocytes using flow cytometry or immunohistochemistry provide important information on the immune cell populations within the TME. Gene expression profiling and spatial analysis techniques, such as multiplex immunofluorescence and imaging mass cytometry, allow researchers to study CYT in the context of the TME. We further report the significant clinical implications that CYT has, as its increased levels are associated with positive clinical outcomes and a favorable prognosis. Moreover, CYT can be used as a prognostic biomarker and aid in patient stratification. Measuring CYT through different methods offers promising paths for improving treatment responses. Overall, we highlight that the understanding and modulation of CYT levels is critical for improving cancer immunotherapy. Research into CYT and the factors that influence it has the potential to transform cancer treatment and improve patient outcomes.

Polyphenols, long-used components of medicinal plants, have drawn great interest in recent years as potential therapeutic agents because of their safety, efficacy, and wide range of biological effects. Approximately 74% of the world's population still uses plant-based medicines, indicating the ongoing significance of phytochemicals for human health. The study emphasizes the growing body of research examining the role of polyphenols in uncovering their anti-adipogenic and anti-obesity properties. Functions of polyphenols including phenylpropanoids, flavonoids, terpenoids, alkaloids, glycosides, and phenolic acids are distinct due to changes in chemical diversity, and structural characteristics. This review methodically investigates the mechanism of how naturally occurring polyphenols mediate obesity and metabolic function. To this end, hormonal control of hunger has the potential to inhibit pro-obesity enzymes such as pancreatic lipase, the promotion of energy expenditure, and the modulation of adipocytokine production. Specifically, polyphenols affect insulin, a hormone that is essential for regulating blood sugar, and they also play a role in part in a complex web of factors that affect the progression of obesity. This review also explores the immunomodulatory properties of polyphenols, providing insight into their ability to improve immune function. The effects of polyphenols on gut health, improving the number of commensal bacteria, cytokine production suppression, and immune cell mediation, including natural killer cells and macrophages. Taken together, continuous studies are required for prudent and precise mechanisms underlying polyphenols' therapeutic potential in obesity and immunomodulation. In the interim, this review emphasizes the holistic approach to health and promotes the consumption of a wide range of foods and drinks high in polyphenols. This review lays the groundwork for future developments, indicating that the components of polyphenols and their derivatives may provide the answer to urgent worldwide health issues. This compilation of the body of knowledge paves the way for future discoveries in the global treatment of pressing health concerns in obesity and metabolic diseases.

COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2-rs5743708, TLR4-rs4986790, TLR4-rs4986791, CD14-rs2569190, CARD8-rs1834481, IL18-rs2043211 and CD40-rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18-rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2-rs5743708 or the TLR4-rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data supports the notion that the host’s genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18-rs1834481, TLR2-rs5743708 and TLR4-rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype.

Dendritic cells (DCs) are the professional antigen-presenting cells that recognize and present antigens to naïve T cells to induce antigen-specific adaptive immunity. Among the T-cell subsets, T helper type 2 (Th2) cells produce the humoral immune responses required for protection against helminthic disease by activating B cells. DCs induce a Th2 immune response at a certain immune environment. Basophil, eosinophil, mast cells, and type 2 innate lymphoid cells also induce Th2 immunity. However, in the case of DCs, controversy remains regarding which subsets of DCs induce Th2 immunity, which genes in DCs are directly or indirectly involved in inducing Th2 immunity, and the detailed mechanisms underlying induction, regulation, or maintenance of the DC-mediated Th2 immunity against allergic environments and parasite infection. A recent study has shown that a genetic defect in DCs causes an enhanced Th2 immunity leading to a severe atopic dermatitis. We summarize the Th2 immune-inducing DC subsets, the genetic and environmental factors which involved in DC-mediated Th2 immunity, and current therapeutic approaches for Th2-mediated immune disorders. This review is to provide an improved understanding of DC-mediated Th2 immunity and Th1/Th2 immune balancing, leading to control over their adverse consequences.

A parallel between defense powers of sovereign nations and effective immunity that guards health is relevant to demonstrate vulnerability of immune system under external forces (vaccines, drugs). History demonstrated that sovereignty (power within) of small nations often threatened or destroyed by military might of powerful nations (power without) who use false-flags and propaganda for motives that are financial-control-driven. Similarly, we propose that body’s complex immune neuroplasticity (power within, adaptive, horizontal) is stretched-thin and weakened by the external forces, particularly by vaccination of the unborn/newborn or immune-compromised individuals. Validity of genomics (innate, perpendicular) as origins of ‘hereditary’ diseases (eg, allergies, diabetes, cancers) that for a century dominated research and treatment is also challenged. In conclusion, we propose that the pressure/power from within creates life with potential to sustain health, while the pressure/power from without, weaken and destroy life.

Febrile infections are a common cause of presentation to the emergency department (ED) in chil-dren. While viral infections are usually self-limiting, sometimes bacterial illnesses may lead to sepsis and severe complications. Inflammatory biomarkers such as C reactive protein (CRP) and procalcitonin are usually the first blood exams performed in the ED to differentiate bacterial and viral infections; the better understanding of immunochemical pathways has nowadays led to the discovery of new and more specific biomarkers that could play a role in the emergency setting. The aim of this narrative review is to provide the most recent evidence on biomarkers and predictor models combining them for serious bacterial infections (SBI) diagnosis in febrile children. Litera-ture analysis showed that inflammatory response is a complex mechanism in which many bio-chemical and immunological factors contribute to host response in SBI. CRP and procalcitonin still represent the most used biomarkers in the pediatric ED for the diagnosis of SBI. Their sensibility and sensitivity increase when combined and for this reason it is reasonable to take them both into consideration in the evaluation of a febrile children. The potential of machine learning tools, who represent a real novelty in medical practice, in conjunction with routine clinical and biological in-formation, may improve accuracy of diagnosis and target therapeutic options in SBI. However, studies on this matter are not yet validated in younger populations, making their relevance in pe-diatric precision medicine still uncertain. More data from further researches are needed to improve clinical practice and decision making using these new technologies.

Abstract: Background: COVID-19 is a respiratory disease that eventually became pandemic with 300 million people infected around the world. Alongside the improvement in COVID-19 management and vaccine development, identifying biomarkers for COVID-19 has recently reported to help in early prediction and managing severe cases which might improve outcome. The Aim of our study was to find out if there is any correlation between clinical severity and elevated hematological and biochemical markers in Covid-19 patients and its effect on the outcome Methods: We have collected data retrospectively of socio-demographic, medical history, biomarkers, and diseases outcome from five hospitals and health institutions in the Kingdom of Saudi Arabia. Results: Pneumonia was the most common presentation of COVID 19 in our cohort. All biomarkers (D-Dimer, CRP, troponin, LDH and ferritin) except for the mean lowest white blood cells were found to have significant correlation (p<0.05) with worse COVID-19 disease outcomes. There was a sig-nificant association between the inflammatory biomarkers and the disease severity of COVID 19 patients (p<0.001). Patients with evidence of severe respiratory disease particularly who required mechanical ventilation (MV) had higher biomarkers, when compared to those with stable respiratory condition (p<0.001). Conclusion: Identifying biomarkers predicts outcome for COVID-19 patients and may significantly help in the management.

Epilepsy is one of the most common disorders of the central nervous system, impacting nearly 50 million people around the world. Heterogeneous in nature, epilepsy presents in children and adults alike. Currently, surgery is the only treatment that can cure epilepsy. However, not all individuals are eligible or have successful outcomes. Difficulty in accessing samples of human brain tissue along with advances in sequencing technology have driven researchers to investigate sampling liquid biopsies in blood, serum, plasma, and cerebrospinal fluid within the context of epilepsy. Liquid biopsies provide minimal or non-invasive sample collection approaches and can be assayed relatively easily across multiple time points, unlike tissue-based sampling. Various efforts have investigated circulating nucleic acids from these samples including microRNAs, cell-free DNA, transfer RNAs, and long non-coding RNAs. Here, we review nucleic acid-based liquid biopsies in epilepsy to improve understanding of etiology, diagnosis, prediction, and therapeutic monitoring.

Background: Identification of cancer biomarkers that are differentially expressed (DE) under two biological conditions is an important task in many microarray studies. There exist several methods in the literature in this regards and most of these methods designed especially for unpaired samples, which does not satisfy the requirements of paired samples where the gene expressions are taken from the same patients before and after treatment. Furthermore, the traditional biomarker identification methods based on either p-values or fold change (FC) values. However, sometimes, p-value based results do not comply with FC based results due to the smaller variance of gene expressions. There are some methods that combine both p-values and FC values to solve this problem. But, these methods also show weak performance for small-sample case in presence of outlying expressions. To overcome this problem, in this paper an attempt is made to develop a hybrid robust SAM-FC approach by combining rank of FC values and rank of p-values based on SAM statistic using minimum β-divergence method, which is designed for paired samples. This method introduces a weight function known as β-weight function. This weight function produces larger weights corresponding to usual/normal expressions and smaller weights for unusual/outlying expressions. The β-weight function plays the significant role on the performance of the proposed method. Results: The proposed method uses β-weight function as a measure of outlier detection by setting β=0.2. We unify both classical and robust estimates using β-weight function such that maximum likelihood estimators (MLEs) are used in absence of outliers and minimum β-divergence estimators are used in presence of outliers to obtain reasonable p-values and FC values in the proposed method. We examined the performance of proposed method in a comparison of some popular methods (t-test, SAM, LIMMA, Wilcoxon, WAD, RP and FCROS) using both simulated and real gene expression profiles for both small-and large-sample cases. From the simulation and a real spike in data analysis results we observed that the proposed method outperforms other methods for small-sample case in presence of outliers and it keeps almost equal performance with other robust methods (Wilcoxon, RP and FCROS) otherwise. From a head-and-neck cancer (HNC) dataset the proposed method identified 2 genes (CYP3A4, NOVA1) that are significantly enriched in linoleic acid metabolism, drug metabolism, steroid hormone biosynthesis and metabolic pathways. The survival analysis through Kaplan-Meier curve revealed that combined effect of these 2 genes has prognostic capability and they might be promising biomarker of HNC. Moreover, we retrieved the 12 candidate drugs based on gene interaction from glad4u and drug bank databases. Conclusion The identified drugs showed statistical significance and critical role of the proteins indicate that these proteins might be therapeutic target in cancer. Thus, elucidating the associations between the drugs identified in the present study require further investigations.

Abstract: The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-45 spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness.

Diabetes mellitus – type 2 (DM2) is a hypercoaguable state with enhanced platelets (PLTs) activation and increased clotting factor production. Simultaneously, the fibrinolytic cell system is inhibited due to formation of clots with high resistance to fibrinolysis. The stages of PLTs "activation" have been well-characterized microscopically, morphometrically and nanomechanically (by light microscope, transmisiion electron microscope - TEM, scanning electron microscope - SEM and atomic force microscope - AFM). Thrombocytes in "acivated" (pro-coagulant) state play central role in two main biological processes: hemostasis and repair of vascular vessels. Pro-coagulant PLTs participate in generation of thrombin and in development of fibrin fibers in the clot matrix. Enhanced PLTs reactivity in dibetic- (diabetes mellitus - DM2) patients is considered as a "pro-thrombotic" state. In the retrospective- and prospective- studies on the topic, the higher are the PLTs' hematometrical indices: PLTs (count), MPV (mean platelet volume), PDW (platelet distribution width), PCR (plateletcrit), as well as PLTs/Ly ratio. The PLТs parameters/indices are usefull biomarkers in early diagnosis and prognosis of DM2. The precise studies of PLTs' state of activation during DM2 might be useful for creation of new diabetes (DM2) treatment strategies and effective medicines. Using the amount of blood glucose, attached to hemoglobin (HbA1c values) as markers of glycemic control in diabetic patients, researchers have observed association between MPV and medications as Insulin, Metformin, sulphonyl ureas. Computational modellng of PLTs' activation in DM2 is also a controlling factor for thrombocyte distribution and margination in bood vessels, associated with micro- and macrovascular disease in DM2. PLTs-derived miRNAs are novel molecular biomarkers for diagnosis and prognosis of DM2, insulin resistance and diabetes complications. We have proposed (2010) oleic acid (OA) as a substance suppressing "PLT hyperactivation" and inhibiting “thrombocyte aggregation”. Antiplatelet agents, natural plant products including, could be effective in the prevention and the secondary treatment of micro- and macrovascular complications in the type 2 Diabetes mellitus. Our proposal on following up of a combination of hematological-, hemorheological- and hemostatic parameters (indices) as a new way in diagnosis, treatment, predicting and management of DM2 and its related vascular complications, probably could be more explored in future studies.

Exosomes are nano-sized extracellular vesicles excreted by mammalian cells that circulate freely in the bloodstream of living organisms. Exosomes have a lipid bilayer that encloses genetic material used in intracellular communication (e.g., double-stranded DNA, micro-RNAs, and messenger RNA). Recent evidence suggests that dysregulation of this genetic content within exosomes has a major role in tumor progression and in the surrounding microenvironment. Motivated by this discovery, we focused here on using exosomal biomarkers as a diagnostic and prognostic tool for cancer. In this review, we discuss recently discovered exosome-derived proteomic and genetic biomarkers used in cancer diagnosis and prognosis. Although several genetic biomarkers have been validated for their diagnostic values, proteomic biomarkers are still being actively pursued. We discuss both commercial technologies and emerging technologies for exosome isolation and analysis.

Immune checkpoint inhibition therapy (ICIT) is an emerging field in oncology especially opening new horizons to chemotherapy refractory patients. This paper provides deep insight into immune related adverse events (irAEs) posing a major challenge and drawback to ICIT, and presents right management strategies for very complex complications. Moreover, for the first time in literature, a non-linear mathematical model is introduced to measure the ICIT success rate and to decide about the optimum ICIT duration. Furthermore, a strategy is presented to overcome or to delay the progression after initial good response in a subset of patients.

Background: First episode psychosis (FEP), schizophrenia and affective disorders are accompanied by activation of the immune inflammatory response system (IRS). The compensatory immune-regulatory reflex system (CIRS) is a regulatory immune response that is induced by the IRS but exerts negative feedback through, for example, increased levels of anti-inflammatory cytokines such as IL-4, IL-13 and IL-10. Different phenotypes of schizophrenia may exhibit distinct IRS and CIRS immune profiles.Aims: This study aims to examine the IRS and CIRS components, including macrophagic M1, T-helper (Th)-1, Th-2, Th-17 and T-regulatory (Treg) phenotypes, in antipsychotic-naïve FEP patients before and after risperidone treatment.Methods: We included 31 antipsychotic-naïve FEP patients who had measurements of IRS and CIRS biomarkers before and after treatment with risperidone for 10 weeks, and 22 healthy controls.Results: Antipsychotic-naive FEP patients showed interrelated increments in M1, Th-1, Th-2, Th-17 and Treg phenotypes and a relatively greater IRS response (especially granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL-12) as compared with the CIRS response (IL-4, IL-13, IL-5 and IL-10). Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with negative, psychotic, affective and excitation symptom dimensions. Treatment with risperidone significantly suppressed the IRS and CIRS. Baseline levels of CIRS biomarkers, especially higher soluble tumor necrosis factor receptor-1 and IL-10 predicted clinical improvement during treatment.Discussion: Our findings indicate that FEP is characterized by robust IRS (M1 + Th-1 + Th-17) and CIRS responses, suggesting that monocytes, macrophages, Th-1, Th-2, Th-17 and Treg cells are activated. The findings indicate that a) FEP patients are prone to the detrimental effects of M1, Th-1, Th-17 and Th-2 cells, which may contribute to long-lasting abnormalities in brain circuitry; and b) in FEP, the CIRS may contribute to recovery from the acute phase of illness. Enhancing the CIRS is a new drug target to treat FEP.

Iron deficiency in the fetal and neonatal period (perinatal iron deficiency) bodes poorly to neuro-development. Given its common occurrence and the negative impact on brain development, a screening and treatment strategy that is focused on optimizing brain development in perinatal iron deficiency is necessary. Pediatric societies currently recommend a universal iron supple-mentation strategy for full-term and preterm infants that does not consider individual variation in the body iron status and could lead to under-treatment or over-treatment. Moreover, the focus is on hematological normalcy and not optimal brain development. Several serum iron indices and hematological parameters in the perinatal period are associated with risk of abnormal neurodevelopment, suggesting their potential use as biomarkers for screening and monitoring treatment in infants at risk for perinatal iron deficiency. A biomarker-based screening and treatment strategy that is focused on optimizing brain development will likely improve outcome in perinatal iron deficiency.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological biomarkers of LongC, we investigated the soluble proteins present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected from 2020-2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1b was significantly increased in both nLongC and Cov and IL-8 elevated in only nLongC. Both brain-derived neurotropic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.

Biomarkers play key roles in diagnosis, risk assessment, treatment and supervision of car-diovascular diseases (CVD). Optical biosensors and assays are valuable analytical tools answering the need for fast and reliable measurements of biomarkers levels. This review presents a survey of recent literature with a focus on the past 5 years. The data indicates continuing trends towards multiplexed, simpler, cheaper, faster and innovative sensing while newer tendencies concern minimizing the sample volume or using alternative sam-pling matrices such as saliva, for less invasive assays. The use of enzyme mimicking activity of nanomaterials gained ground in comparison to their more traditional roles as signaling probe, immobilization support for biomolecules or for signal amplification. The growing use of aptamers as replacements for antibodies prompted emerging applications of DNA am-plification and editing techniques. Optical biosensors and assays were tested with larger sets of clinical samples and compared with the current standard methods. The ambitious goals on the horizon for CVD testing include the discovery and determination of relevant biomarkers with the help of artificial intelligence, more stable specific recognition elements for biomarkers and fast, cheap readers and disposable tests to facilitate rapid testing at home. As the field is progressing at an impressive pace the opportunities for biosensors in the optical sensing of CVD biomarkers remain significant.

There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised intermediate grade prostate cancer. There has therefore been a major focus on identifying molecular biomarkers that can add prognostic value to existing markers, including investigation of DNA methylation, which has a known role in tumorigenesis. In this review, we will provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis, and highlight the advances that have been made in this field. We cover the numerous studies into well-established candidate genes, and explore the technological transition that has enabled hypothesis-free genome-wide studies and the subsequent discovery of novel prognostic genes.

This overview initially describes insect immune reactions and then brings together present knowledge of the interactions of vector insects with their invading parasites and pathogens. It is a way of introducing this special issue with subsequent papers presenting the latest details of these interactions in each particular group of vectors. Hopefully, this paper will fill a void in the literature since brief descriptions of vector immunity have now been brought together in one publication and could form a starting point for those interested and new to this important area. Descriptions are given on the immune reactions of mosquitoes, blackflies, sandflies, tsetse flies, lice, fleas and triatomine bugs. Cellular and humoral defences are described separately but emphasis is made on the co-operation of these processes in the completed immune response. The paper also emphasises the need of great care in extracting haemocytes for subsequent study as appreciation of their fragile nature is sometimes overlooked with non-sterile media, smearing techniques and excessive centrifugation sometimes used. The potential vital role of eicosanoids in the instigation of many of the immune reactions described is also discussed. Finally, the priming of the immune system, mainly in mosquitoes, is considered and one possible mechanism is presented

The innate immune system is the first line of defense against pathogens. It’s composition includes barriers, mucus and other substances as well as phagocytic and other cells. The purpose of the paper is to analyze in general grounds the immune system and the body immunity to cancer. Simple ideas and the qualitative theory of differential equations are used along with general principles such as the minimization of the pathogen load and economy of resources. In the simplest linear model, the annihilation rate of pathogens in any tissue should be greater than the pathogen’s average rate of growth. When nonlinearities are added, a reference value for the number of pathogens is set, and a stability condition emerges, which relates strength of regular threats, barrier height and annihilation rate. On the other hand, in cancer immunity, the linear model leads to an expression for the lifetime risk, which accounts for both the effects of carcinogens (endogenous or external) and the immune response. The stability condition allows a comparison of immunity in different tissues. The way the tissue responds to an infection shows a correlation with the way it responds to cancer. These statements are formulated at the qualitative level, but may and deserve to be quantitatively checked.

Diabetes is a prevalent global health issue associated with significant morbidity and mortality. Diabetic retinopathy (DR) is a well-known inflammatory, neurovascular complication of diabetes and a leading cause of preventable blindness in developed countries among working-age adults. However, the ocular surface components of diabetic eyes are also at risk of damage due to uncontrolled diabetes, which is often overlooked. Inflammatory changes in the corneas of diabetic patients indicate that inflammation plays a significant role in diabetic complications, much like in DR. The eye´s immune privilege restricts immune and inflammatory responses, and the cornea and retina have a complex network of innate immune cells that maintain immune homeostasis. Nevertheless, low-grade inflammation in diabetes contributes to immune dysregulation. This article aims to provide an overview and discussion of how diabetes affects the ocular immune system’s main components, immune-competent cells, and inflammatory mediators. By understanding these effects, potential interventions and treatments may be developed to improve the ocular health of diabetic patients.

Extracellular vesicles (EV), including exosomes and microvesicles, are released from various cells and alter recipient cell phenotypes and fates by their biomolecules. Here we review current knowledge about tumor EVs and how they prompt malignant cell communication with tumor-associated cells, such as cancer-associated fibroblasts, tumor endothelial cells, and immune cells. We delineate the major pathways and molecular players that influence each step of cancer initiation, progression, and resistance. Of note, cancer exosomes involve immunosuppression by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Moreover, tumor exosomes can induce the apoptosis of killer T cells and immune checkpoint of dendritic cells and attenuate natural killer cells. An in-depth understanding of EV biology is essential to ensure the clinical development of exosome/EV-based therapeutic products, which will be of benefit to exosome manipulation in cancer management.

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

Cancer risk is known to increase tremendously when the immune system is suppressed, e.g., as observed in young organ-transplant recipients and AIDS patients. Based on such data, it may be hypothesized that the main reason for the development of clinical cancer is the weakening or suppression of the immune system, and that uncontrolled multiplication of cancer cells occurs when some aspects of the immune system fall below certain critical levels. Therefore, cancer may be prevented and treated by boosting these critical aspects of the immune system so that they are maintained above the critical levels. If multiple immune system boosting interventions are utilized, more aspects of the immune system would be boosted, increasing the likelihood of enhancing the critical aspects of the immune system and generating a cancer preventive and/or therapeutic effect. Clinical trials are needed to validate this approach for cancer prevention and treatment. If validated, the proposed approach could result in a major reduction of the death and suffering caused by cancer in the world.

Phospholipases are a family of lipid altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote g-coupled protein activity, and modulate membrane fluidity that mediate cellular function. Phospholipases and the bioactive lipids they produce are important regulators on immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis.

The dominant paradigm holds that spontaneous and therapeutically induced anti-tumor responses are mediated mainly by CD8 T cells and directed against tumor-specific antigens (TSAs). The presence of specific TSAs on cancer cells can only be proven by mass spectrometry analyses. Bioinformatic predictions and reverse immunology studies cannot provide this type of conclusive evidence. Most TSAs are coded by unmutated non-canonical transcripts that arise from cancer-specific epigenetic and splicing aberrations. When searching for TSAs, mass spectrometry analyses must therefore interrogate not only the canonical reading frame of annotated exome but all reading frames of the entire translatome. The majority of aberrantly expressed TSAs (aeTSAs) derive from unstable short-lived proteins that are good substrates for direct MHC I presentation but poor substrates for cross-presentation. This is an important caveat because cancer cells are poor antigen-presenting cells and the immune system therefore depends on cross-presentation by dendritic cells (DCs) to detect the presence of TSAs. We therefore postulate that, in the untreated host, most aeTSAs are undetected by the immune system. We present evidence suggesting that vaccines inducing direct aeTSA presentation by DCs represent an attractive strategy for cancer treatment.

Functional copy number alterations (fCNAs) are DNA copy number changes with concordant differential gene expression. These are less likely to be bystander genetic lesions and could serve as robust and reproducible tumor biomarkers. To identify candidate fCNAs in neuroendocrine tumors (NETs), we integrated chromosomal microarray (CMA) and RNA-seq differential gene expression data from 31 pancreatic (pNET) and 33 small bowel neuroendocrine tumors (sbNET). Tumors were resected from 47 early disease progression (24 months) patients. Candidate fCNAs that accurately differentiated these groups in this discovery cohort were then replicated using fluorescence in situ hybridization (FISH) on formalin-fixed, paraffin-embedded (FFPE) tissues in a larger validation cohort of 60 pNETs and 82 sbNETs (52 early and 65 late disease progression samples). Logistic regression analysis determined the predictive ability of these biomarkers as well as the assay performance metrics of sensitivity, specificity, and area under the curve. Our results indicate that copy number changes at chromosomal loci 4p16.3, 7q31.2, 9p21.3, 17q12, 18q21.2, and 19q12 may be used as diagnostic and prognostic NET biomarkers. This involves a rapid, cost-effective approach to determine primary tumor site for patients with metastatic liver NETs and to guide risk stratified therapeutic decisions.