The development of inexpensive, fast and reliable screening tests for COVID-19 is, as yet, an unmet need. The present study was aimed at evaluating the usefulness of serum arylesterase activity of paraoxonase-1 (PON1) measurement as a screening test in patients with different severity levels of COVID-19 infection. We included 615 COVID-19 positive patients who were classified as asymptomatic, mildly symptomatic, severely symptomatic, or fatally symptomatic. Results were compared with 50 healthy volunteers, 330 patients with cancer and 343 with morbid obesity. Results showed PON1 activity greatly decreased in COVID-19 compared to healthy vol-unteers; receiver operating characteristics plot showed a high diagnostic accuracy. The degree of COVID-19 severity did not influence PON1 levels. Our results indicated that PON1 determination was efficient for disease diagnosis but not for prognosis. Further, patients with obesity or cancer presented alterations similar to those of COVID-19 patients. As such, elevated levels of PON1 in-dicate the absence of COVID-19, but low levels may be present in various other chronic diseases. The assay is fast and inexpensive. We suggest that PON1 measurement could be used as an initial, high cut-off point screening method, while lower values should be confirmed with the more ex-pensive nucleic acid amplification test.

Purpose: To investigate the alterations in nitro-oxidative stress (OS) and antioxidant status in adolescents with metabolic syndrome (MetS) and whether these alterations occur independently from effects of overweight or obesity.Methods: Blood was collected in 47 adolescents with MetS and 94 adolescents without MetS as assessed with the International Diabetes Federation criteria. The International Obesity Task Force (IOTF) criteria were used to classify the subjects into those with overweight or obesity. We measured nitro-oxidative biomarkers including nitric oxide metabolites (NOx), lipid hydroperoxides (LOOH), and malondialdehyde (MDA), and antioxidant biomarkers, i.e. total radical-trapping antioxidant parameter (TRAP), paraoxonase (PON)-1 activity, thiol (SH-) groups, as well as tumor necrosis factor-α, glucose, insulin, triglycerides, uric acid and high-density lipoprotein cholesterol (HDL-C).Results: Logistic regression analysis showed that increased MDA and NOx and a lowered TRAP/uric acid ratio were associated with MetS. Machine learning including soft independent modeling of class analogy (SIMCA) showed that the top-3 most important features of MetS were increased glucose and MDA and lowered HDL-C. Support vector machine using MDA, glucose, insulin, HDL-C, triglycerides and body mass index as input variables yielded a 10-fold cross-validated accuracy of 89.8% when discriminating MetS from controls. The association between MetS and increased MDA was independent from the effects of overweight-obesity. glucose, insulin, triglycerides and HDL-C.Conclusion: In adolescents, increased MDA formation is a key component of MetS, indicating that increased production of reactive oxygen species with consequent lipid peroxidation and aldehyde formation participate in the development of MetS.

Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy that otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq defined fraction. Finally, we generated a 15-genes prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.

Prostate cancer (PCa) is one of the most prevalent cancers among men in India. Although studies on PCa have dealt with the genetics, genomics, and the environmental influence in causality of PCa, not many studies employing the next generation sequencing (NGS) approaches of PCa have been carried out. In our previous study, we have identified some causal genes and mutations specific to Indian PCa using Whole-Exome Sequencing (WES). In the recent past, with the help of different cancer consortiums such as The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), along with differentially expressed genes (DEGs), many cancer-associated novel non-coding RNAs have been identified as biomarkers. In this work, we attempt to identify DEGs as well as long non-coding RNAs (lncRNAs) associated with signature pathways from an Indian PCa cohort using RNA-sequencing (RNA-seq) approach. From a cohort of 60, we screened 6 patients who underwent prostatectomy; we performed a whole transcriptome shotgun sequencing (WTSS)/RNA-sequencing to decipher the DEGs. We further normalized the read counts using fragments per kilobase of transcript per million mapped reads (FPKM) and analyzed the DEGs using a cohort of downstream regulatory tools, viz. GeneMANIA Stringdb, Cytoscape-Cytohubba, cbioportal to map the inherent signatures associated with PCa. By comparing the RNA-seq data obtained from the pairs of normal and PCa tissue samples using our benchmarked in-house cuffdiff pipeline, we observed some important genes specific to PCa such as STEAP2, APP, PMEPA1, PABPC1, NFE2L2, HN1L and some other important genes known to be involved in different cancer pathways such as, COL6A1, DOK5, STX6, BCAS1, BACE1, BACE2, LMOD1, SNX9, CTNND1 etc. We also identified a few novel lncRNAs such as LINC01440, SOX2OT, ENSG00000232855, and ENST00000647843.1 that need to be characterized further. Deregulation of SOX2OT is observed in various tumors, including lung cancer, gastric cancer, esophageal cancer, breast cancer, hepatocellular carcinoma, ovarian cancer, pancreatic, laryngeal squamous cell carcinoma, osteosarcoma, nasopharyngeal carcinoma, and glioblastoma. It would be interesting to characterize its function in PCa as well. In comparison with publicly available datasets, we have identified characteristic DEGs and novel lncRNAs implicated in signature PCa pathways in an Indian PCa cohort which have perhaps not been reported. As a pilot study, this has set a precedent for us to validate further experimentally, and we firmly believe this will pave a way towards discovery of biomarkers and development of novel therapies.

The combination of statistical learning technologies with large databases of psychophysiological data has appropriately generated enthusiastic interest in future clinical applicability. It is argued here that this enthusiasm should be tempered with the understanding that significant obstacles must be overcome before the systematic introduction of psychophysiological measures into neuropsychiatric practice becomes possible. The nonspecificity of psychophysiological measures complicates their use in diagnosis. Low test-retest reliability complicates use in longitudinal assessment, and quantitative psychophysiological measures can normalize in response to placebo intervention. Ten cautionary observations are introduced and, in some instances, possible directions for remediation are suggested.

Apoptosis, also known as the programmed death of cells, is responsible for maintaining the homeostasis of tissues and this function is carried out by caspases. The process of apoptosis is carried out via two distinct pathways: the extrinsic pathway, which is governed by death receptors, and the intrinsic pathway, also known as the mitochondrial pathway. The BCL-2 protein family encoded by the BCL-2 gene, located at the 18q21.33 chromosomal location, is in charge of regulating the intrinsic pathway, which is responsible for inducing cell death via the permeabilization of the mitochondrial membrane and the release of apoptosis - inducing components. The BCL-2 homology (BH1, BH2, BH3, BH4) domains of this family proteins are crucial for their functioning and their common BH domains allow interactions between members of the same family and can also serve as indications of pro- or anti-apoptotic activity. A direct correlation may be shown between the overexpression of BCL-2 and the postponement of cell death. It has been determined that a change in the expression of BCL-2 is the root cause of a variety of malignancies, including lung, breast, melanoma, and chronic lymphocytic leukemia, Multiple Sclerosis, Diabetes. In this review, we discuss the therapeutic potential of regulating BCL-2 family connections and their relevance to health and disease.

Background: Type 2 diabetes mellitus (T2DM) is associated with increased atherogenicity and inflammatory responses, which may be related to increased levels of high mobility group box 1 (HMGB1) and Dickkopf-related protein 1 (DKK1). Objective: The role of HMGB1 and DKK1 in T2DM is examined in association with lipid and insulin profiles. Methods: Serum HMGB1 and DKK1 were measured in T2DM with and without hypertension and compared with controls. Results: HMGB1 and DKK1 are significantly higher in T2DM irrespective of hypertension. T2DM was also accompanied by increased atherogenicity indices. HMGB1 and DKK1 are significantly correlated with HbA1c, glucose, indices of insulin resistance, β-cell function, and glucose toxicity, and different atherogenic indices. A large part of the variance in the β-cell index (30.5%) and glucose toxicity (34.8%) was explained by the combined effects of HMGB1 and DKK1 and hypertension. We found that 18.3% of the variance of the atherogenic index of plasma was explained by HMGB1 and DKK1 levels and that 31.2% was explained by glucose toxicity, HMGB1 and body weight. Conclusion: The higher serum HMGB1 and DKK1 levels in T2DM patients and the associations with atherogenicity indicate that low grade inflammation and disorders in the Wnt pathways are associated with T2DM and that both HMGB1 and DKK1 may contribute to increased atherogenicity in T2DM. Moreover, both biomarkers may cause more deficits in β-cell function and increase glucose toxicity leading to the development of more inflammation and diabetic complications. HMGB1 and the Wnt pathways are new drug targets in the treatment of T2DM.

Background: Developing patient-centric baseline standards that enable the detection of clinically significant outlier gene products on a genome-scale remains an unaddressed challenge required for advancing personalized medicine beyond the small pools of subjects implied by “precision medicine”. This manuscript proposes a novel approach for reference standard development to evaluate the accuracy of single-subject analyses of metabolomes, proteomes, or transcriptomes. Since distributional assumptions of statistical testing may inadequately model genome dynamics of gene products, the so-called significant results of previous studies may artefactually conflate with real signals. Model confirmation biases escalate when studies use the same analytical methods in the discovery sets and reference standards, as corroboration of results leads to an evaluation of reproducibility confounded with replicated biases rather than a measure of accuracy. We hypothesized that developing method-agnostic reference standards using effect-size and expression-level filtering of results, obtained from multiple discovery methods that are distinct from the one evaluated, would maximize the evaluation of clinical-transcriptomic signals and minimize statistical artefactual biases. We developed and released an R package “referenceNof1” to facilitate the construction of robust reference standards. Results: Since RNA-Seq data analysis methods often rely on binomial and negative binomial assumptions to non-parametric analyses, the differences create statistical noise and make the reference standards method dependent. In our experimental design, the accuracy of 30 distinct combinations of fold changes (FC) and expression levels (EL) were determined for five types of RNA analyses in two different datasets. This design was applied to two distinct datasets: breast cancer cell lines and a yeast study with isogenic biological replicates in two experimental conditions. In addition, the reference standard (RS) comprised all RNA analytical methods with the exception of the method testing accuracy. To mitigate for biased optimization of the RS parameters towards a specific analytical method, similarity between observed results of distinct analytical methods were calculated across all methods (Jaccard Concordance Index). The greatest differences were observed across diametric extremes. For example, filtering out differentially expressed genes (DEGs) using a fold change < 1.2 leads to a 50% increase in concordance between techniques when compared to results with FC > 1.2. Combining this FC cutoff with genes with mean expressions > 30 counts leads to a 65% increase in concordance in comparison to genes with expression levels < 30 counts and with FC < 1.2. Conclusions: We have demonstrated that comparing accuracies of different single-subject analysis methods for clinical optimization requires a new evaluation framework. Reliable and robust reference standards, independent of the evaluated method, can be obtained under a limited number of parameter combinations: fold change (FC) ranges thresholds, expression level cutoffs, and exclusion of the tested method from the RS development process. When applying anticonservative reference standard frameworks (e.g., using the same method for RS development and for prediction), a majority of the concordant signal between prediction and Gold Standard (GS) cannot be confirmed by other methods, which we conclude as biased results. Statistical tests to determine DEGs from a single-subject study generate many biased results that require subsequent filtering for increasing their reliability. Conventional single-subject studies pertain to one or a few measures in one patient over time [1]and need a substantial conceptual framework extension in order to address the tens of thousands of measures in genome-wide analyses of gene products. The proposed referenceNof1 framework addresses some of the inherent challenges in improving transcriptome scale single-subject analyses by providing a robust approach to constructing reference standards. Github: https://github.com/SamirRachidZaim/referenceNof1

Introduction: Lowered thiol or sulfhydryl (-SH) groups and glutathione (GSH) metabolism may be associated with prostate cancer (PCa) and benign prostatic hyperplasia (BPH). The main objectives of this study were to systematically review and meta-analyze the evidence on the associations among -SH groups, GSH, GSH peroxidase (GPx), GSH reductase (GR) and GSH transferase (GST) and PCa/BPH. Methods: Four electronic databases were searched for studies that reported -SH and GSH variables in PCa/BPH and healthy controls (HC) and the data were meta-analyzed by calculating Hedges’s g with 95% confidence intervals. Results: Twenty studies were included in this meta-analysis including 800 PCa and 791 BPH patients and 592 HC. Total -SH (g=-1.750, -2.341/-1.159), GPx (g=-0.789, -1.234/-0.344), GSH (g=-2.219, -4.132/-0.305), and the combination of -SH, GPx, and GSH (g=-1.271, -1.271/-0.800) were significantly lower in PCa patients than in HC. -SH (g=-1.752, -3.123/-0.381) and the combination of -SH, GPx, and GSH (g=-0.813, -1.298/-0.327) were significantly lower in BPH patients than in HC. GPx was significantly lower in PCa than in BPH patients (g=-0.455, -0.896/-0.014). Heterogeneity levels were very high, but Egger’s test showed that none of the biomarkers showed significant publication bias. Conclusion: Thiol/GPx antioxidant defenses are significantly attenuated in patients with PCa while patients with BPH occupy an intermediate risk group position between PCa patients and HC. Those results suggest that reduced thiol-related antioxidant mechanisms play a crucial role in prostatic disorders, especially in PCa. Future research should examine whether thiols/GPx antioxidants are associated with the onset of PCa/BHP.

Patients with transfusion-dependent thalassemia (TDT) show disorders in calcium metabolism. The α-klotho protein is predominantly expressed in tissues that are involved in calcium homeostasis, and lowered levels are associated with bone disease. Aim of the study. To study the associations between low α-klotho status and calcium metabolism in relation to iron status in children with TDT. Methods. α-klotho, calcium, parathyroid hormone (PTH), calcyphosin, vitamin D3, phosphorous, fibroblast growth factor receptor 2 (FGFR2), as well as iron and erythron biomarkers were measured in 60 children with TDT and 30 healthy control children. Results. A meaningful part of TDT patients showed lowered α-klotho levels, and those children also showed low serum total and ionized calcium concentrations. TDT patients showed increased PTH, FGFR2, and calcyphosin and lowered vitamin D3 as compared with healthy children. The α-klotho levels were significantly correlated with total and ionized calcium (positively) and with iron overload biomarkers and the number of blood transfusions (inversely). Partial Least Squares path analysis showed that 40.1% of the variance in serum total calcium could be explained by the regression on α-klotho, vitamin D3 (both positively), and calcyphosin (inversely) and that the effects of the latter are mediated by iron overload and the number of blood transfusions. Conclusion. In TDT, iron overload and its consequences may induce lowered levels of α-klotho which in turn may lead to lower calcium thereby explaining at least in part the effects of TDT on bone metabolism including spontaneous pathological fractures, osteoporosis, osteopenia, and skeletal deformities.

Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results.Aim of the study: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables. Methods: This study recruited 60 children with TDT and 30 healthy children aged 3-12 years old.Results: Zinc was significantly higher in TDT children than in control children, whilst copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children. Conclusion: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.

Background: Hypertension, atherogenicity and insulin resistance are major risk factors of cardiovascular disorder (CVD), which shows a strong comorbidity with major depression (MDD) and bipolar disorder (BD). Activated oxidative and nitrosative stress (O&NS), inflammatory pathways, and increased atherogenicity are shared pathways underpinning CVD and mood disorders. Methods: The current study examined the effects of lipid hydroperoxides (LOOH), superoxide dismutase (SOD), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), and malondialdehyde (MDA) on systolic (SBP) and diastolic (DBP) blood pressure in 96 mood disordered patients and 60 healthy controls. Results: A large part of the variance in SBP (31.6%) was explained by the regression on a z unit-weighted composite score (based on LOOH, AOPP, SOD, NOx) reflecting nitro-oxidative stress toxicity (NOSTOX), coupled with highly sensitive C-reactive protein, body weight and use of antihypertensives. Increased DBP was best predicted (23.8%) by body mass index and NOSTOX. The most important O&NS biomarkers predicting an increased SBP were in descending order of significance: LOOH, AOPP and SOD. Higher levels of the atherogenic index of plasma, HOMA2 insulin resistance index and basal thyroid-stimulating hormone also contributed to increased SBP independently from NOSTOX. Although there were no significant changes in SBP/DBP in mood disorders, the associations between NOSTOX and blood pressure were significant in patients with mood disorders but not in healthy controls. Conclusions: Activated O&NS pathways including increased lipid peroxidation and protein oxidation, which indicates hypochlorous stress, are the most important predictors of an increased BP, especially in patients with mood disorders.

Atopic dermatitis (AD) is a protease-modulated chronic disorder with heterogenous clinical manifestations which may lead to an imprecise diagnosis. So far, there are no diagnostic protease tests for AD. We explored the gingival crevicular fluid (GCF) protease profile of periodontally-healthy individuals with moderate/severe AD compared to healthy controls. An exploratory case-control study was conducted. Matching AD patients (n=6) and controls (n=6) were enrolled at the International Center for Clinical Studies, Santiago, Chile. Complete dermatological and periodontal evaluations (involving the collection of GCF samples) were made. The levels of 35 proteases were analyzed using a human protease antibody array. The GCF levels of zinc-binding ADAM8, ADAM9, MMP8 and Neprilysin/CD10, aspartyl-binding Cathepsin E, and serin-binding Protein convertase9 and uPA/Urokinase proteases were lower in moderate/severe AD patients compared to controls (p<0.05). No inter-group differences in the levels of the other 28 proteases were found. MMP8, Cathepsin E and ADAM9 were the biomarkers with the highest sensitivity and specificity regarding the detection of AD (p < 0.05). The area under receiver operating characteristic (ROC) curve for MMP-8+ADAMP-9 was 0.90. In conclusion, differences in the protease profile between AD and control patients associated with MMP8, Cathepsin E and ADAM9. MMP8, ADAM9 and Cathepsin E may be useful as combined diagnostic and therapeutic biomarkers of moderate/severe AD.

Current diagnoses of mood disorders are not cross validated. The aim of the current paper is to explain how machine learning techniques can be used to a) construct a model which ensembles risk/resilience (R/R), adverse outcome pathways (AOPs), staging, and the phenome of mood disorders, and b) disclose new classes based on these feature sets. This study was conducted using data of 67 healthy controls and 105 mood disordered patients. The R/R ratio, assessed as a combination of the paraoxonase 1 (PON1) gene, PON1 enzymatic activity, and early life time trauma (ELT), predicted the high-density lipoprotein cholesterol – paraoxonase 1 complex (HDL-PON1), reactive oxygen and nitrogen species (RONS), nitro-oxidative stress toxicity (NOSTOX), staging (number of depression and hypomanic episodes and suicidal attempts), and phenome (the Hamilton Depression and Anxiety scores and the Clinical Global Impression; current suicidal ideation; quality of life and disability measurements) scores. Partial Least Squares pathway analysis showed that 44.2% of the variance in the phenome was explained by ELT, RONS/NOSTOX, and staging scores. Cluster analysis conducted on all those feature sets discovered two distinct patient clusters, namely 69.5% of the patients were allocated to a class with high R/R, RONS/NOSTOX, staging, and phenome scores, and 30.5% to a class with increased staging and phenome scores. This classification cut across the bipolar (BP1/BP2) and major depression disorder classification and was more distinctive than the latter classifications. We constructed a nomothetic network model which reunited all features of mood disorders into a mechanistically transdiagnostic model.

Objectives: 1) to demonstrate the anti-inflammatory and anabolic effect of Ozone by determining in serum samples the biochemical levels of IL-6 and IGF-1 in knee osteoarthritis (OA) patients in a real world in Rehabilitation Setting; 2) to evaluate clinical effectiveness by Visual Analog Scale (VAS) and WOMAC scale, and biochemical effect by C-reactive protein (CRP), uric acid and erythrocyte sedimentation rate (ESR). Material and methods: 65 patients with knee OA Kellgren Lawrence (KL) grade 2 or more were analyzed in a retrospective observational study. The study run from January 2018 to September 2021. Inclusion criteria: a) patients 18 years or older; b) with knee OA KL 2º or more; c) biochemical analysis before-and-after treatment; d) pain more than 3 on VAS. Exclusion Criteria: a) previous knee surgery; b) favism; c) pregnancy; d) any other disease that originates lack of collaboration for infiltration. Primary Outcome variables: a) IL-6; b) IGF-1 in diabetes mellitus (DM)/obese and non-DM/non-obese patients; both before-and-after Ozone treatment. Secondary Outcome variables: a) CRP, b) ESR, c) uric acid, d) VAS pain, e) WOMAC pain, function and stiffness. Ozone protocol consisted of 4 sessions (once a week) of an intra-articular infiltration of 20 mL (20µg/mL concentration) of a gas mixture of Oxygen-Ozone 95-5% (produced by Ozone generator Ozonosan-α Plus ®). For biochemical evaluation, SNIBE MAGLUMI ™ IL-6 (CLIA) and SNIBE MAGLUMI ™ IGF-1 (CLIA) kits were used. CRP and uric acid were analyzed by Abbott Alinity c kit; and ESR was evaluated by DIESSE VES MATIC CUBE 30. Results: There is a linear correlation between age and OA severity. IL-6 decreased both in DM and non-DM patients and in all OA KL grades (from 2.7 to 1.59 pg/mL). IGF-1 decreased in total group (OA + DM + obesity) from 112.09 to 107.19 ng/mL. When only knee OA patients were analyzed, Ozone improved IGF-1 levels (from 100.17 to 102.03 ng/mL). Ozone decreased CRP, ESR, uric acid, and improved VAS pain, WOMAC pain, function and stiffness (p<0.05). Conclusions: Ozone is a valid option for the management of knee osteoarthritis in real world Rehabilitation Setting, because of its anti-inflammatory, metabolic and anabolic properties. Ozone downregulates pro-inflammatory IL-6 cytokine. Ozone has a metabolic/hypoglycemic effect on obese/diabetic knee osteoarthritis patients by reducing IGF-1. Ozone has an anabolic effect on non-diabetic/non-obese patients by improving IGF-1. Ozone reduces other biomarkers of inflammation (CRP, ESR and uric acid) and improves, pain, function and quality of life.

The Neurodegenerative Diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to have an exponential growth thanks to numerous advancements in tech, shifts in the understanding of the disease as a phenomenon, and the change of perspective regarding gene editing and the upsides of this action. The aim of this paper is to analyse the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and Amyotrophic Lateral Sclerosis. We intend through this review to focus on the newest treatment, diagnosis and predictions plans regarding this large group of diseases, in order to obtain a better accuracy analysing and spotting the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide future evidence of possible novelty therapies that target the specific genes and could be useful to be taken into consideration when the classical approaches fail to shed light.

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.

Artificial intelligence methods may help in unveliling information hidden in high-dimensional oncological data. Flow cytometry studies of haematological malignancies provide quantitative data with the potential to be used for the construction of response biomarkers. Many computational methods from the bioinformatics toolbox can be applied to these data but have not been exploited in their full potential in leukaemias, specifically for the case of childhood B-cell acute lymphoblastic leukemia. In this paper we analysed flow cytometry data obtained on diagnosis from 54 paediatric B-cell acute lymphoblastic leukemia patients from two local institutions. We constructed classifiers based on the Fisher’s Ratio to quantify differences in expression levels of immunophenotypical markers between patients with relapsing and non-relapsing disease. The distribution of the marker CD38 was found and validated to have a strong discriminating power between both patient cohorts, thus providing a classifier.

Worldwide, the prevalence of surgery under general anaesthesia has increased significantly, on one hand because of modern anaesthetic and pain control techniques, and on the other hand because of better diagnosis and increased complexity of surgical technique. Together with the development of new concepts in the surgical field, the attention of researchers and clinicians turned to minimizing the impact of surgical trauma and offering minimal invasive procedures. This fact is due to the recent discoveries in the field of cellular and molecular mechanisms, that have revealed a systemic inflammatory and pro-oxidative impact that not only lasts in the perioperative period, but also impacts the long term, contributing to more difficult recovery, increased morbidity, and mortality, and finally a negative financial impact. Detailed molecular and cellular analysis have shown an overproduction of inflammatory and pro-oxidative species, that are responsible for an augmentation of the systemic inflammatory status and more difficult postoperative recovery. Moreover, it was shown that there are a series of changes in certain epigenetic structures, the most important being the microRNAs. Based on these findings, a series of modern, targeted therapeutic approaches have been proposed, with the final goal of blocking these mechanisms and reducing the redox state. Recent studies carried out had a positive clinical impact regarding antioxidant therapy and have shown that it can be used in the perioperative period with beneficial clinical impact. This review describes and details the most important molecular and cellular mechanisms that impact the surgical patient undergoing general anaesthesia, and it presents a series of antioxidant therapies that can reduce systemic inflammation.

Ascending aorta aneurysm (AsAA) is a complex disease, currently defined an inflammatory disease. In the sporadic form, AsAA has, indeed, a complex physiopathology with a strong inflammatory basis, significantly modulated by genetic variants in innate/inflammatory genes, acting as independent risk factors and as largely evidenced in our recent studies performed during the last 10 years. Based on these premises, here, we want to revise the impact of reactive oxygen species (ROS) and oxidative stress on AsAA pathophysiology and consequently on the onset and progression of sporadic AsAA. This might consent to add other important pieces in the intricate puzzle of the pathophysiology of this disease with the translational aim to identify biomarkers and targets to apply in the complex management of AsAA, by facilitating the AsAA diagnosis currently based only on imaging evaluations, and the treatment exclusively founded on surgery approaches.

Adjuvant chemotherapy is currently used in all patients with resected pancreatic cancer who are able to begin treatment within 3 months after surgery. Since the recent publication of the PRODIGE 24 trial results, modified FOLFIRINOX has become the standard-of-care in the non-Asian population with localized pancreatic adenocarcinoma following surgery. Nevertheless, there is still a risk of toxicity, and feasibility may be limited in heavily pre-treated patients. In more frail patients, gemcitabine-based chemotherapy remains a suitable option, for example gemcitabine or 5FU in monotherapy. In Asia, although S1-based chemotherapy is the standard of care it is not readily available outside Asia and data are lacking in non-Asiatic patients. In patients in whom resection is not initially possible, intensified schemes such as FOLFIRINOX or Gemcitabine-Nabpaclitaxel have been confirmed as options to enhance the response rate and resectability, promoting research in adjuvant therapy. In particular, should oncologists prescribe adjuvant treatment after a long sequence of chemotherapy +/- chemoradiotherapy and surgery? Should oncologists consider the response rate, the R0 resection rate alone, or the initial chemotherapy regimen? And finally, should they take into consideration the duration of the entire sequence, or the presence of limited toxicities of induction treatment? The aim of this review is to summarize adjuvant management of resected pancreatic cancer and to raise current and future concerns, especially the need for biomarkers and the best holistic care for patients.

Background: Digital clinical measures collected via various digital sensing technologies such as smartphones, smartwatches, wearables, ingestible, and implantable are increasingly used by individuals and clinicians to capture health outcomes or behavioral and physiological characteristics of individuals. Time series classification (TSC) is very commonly used in modeling digital clinical measures. While deep learning models for TSC are very common and powerful, there exist some fundamental challenges. This review presents non-deep learning models commonly used for time series classification in biomedical applications that achieve high performance. Objective: We performed a systematic review to characterize the techniques used in time series classification of digital clinical measures throughout all stages of data processing and model building. Methods: We conducted a literature search on PubMed, and the Institute of Electrical and Electronics Engineers (IEEE), Web of Science, and SCOPUS databases using a range of search terms to retrieve peer-reviewed articles reporting academic research on digital clinical measures in the five year period between June 2016 and June 2021. We identified and categorized research studies based on the types of classification algorithms and sensor input types. Results: We found 452 papers in total from four different databases: PubMed, IEEE, Web of Science Database, and SCOPUS. After removing duplicates and irrelevant papers, 135 articles remained for detailed review and data extraction. Among these, engineered features using time series methods that were subsequently fed into widely-used machine learning classifiers was the most commonly used technique and also most frequently achieved the best performance metrics (77 out of 135 articles). Statistical modeling (24 out of 135 articles) algorithms were the second most common and also second best classification technique. Wavelet-based classification models (8 out of 135 articles) were also common. Electroencephalogram (29 out of 135 articles) was the most common data type used as an input. Accuracy was the most commonly reported performance metric, with 67.65% of articles reporting on accuracy. In this review paper, we provide summaries of signal pre-processing methods, feature engineering and selection methods, time series models, as well as model interpretations. Importantly, we found that about 50% of the papers only report one performance metric, which may result in a skewed view of overall performance. Conclusion: While high time series classification performance has been achieved in digital clinical, physiological, or biomedical measures, no standard benchmark datasets, modeling methods, or reporting methodology exist. There is no single widely used method for time series model development or feature interpretation– many different methods have proven successful.

The Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the time order of alternation. After the deposition of Aβ, the change of tau, NfL and NG is the main alternation and connection to others. The neuro-inflammation, synaptic dysfunction and neuronal injury function is exhibited prior the structural and metabolic changes in the brain following Aβ deposition. The time order of such biomarkers compared to the tau protein is not clear. Despite the close relationship between biomarkers and plaque Aβ deposition, several factors favor one or the other. There is an interaction between the proteins that CSF SNAP-25, VILIP-1 and YKL-40 can predict the brain amyloid burden. The Aβ cascade hypothesis could be the pathway, but not all subjects are converted to AD, even with very high elevated Aβ. The interaction of biomarkers and the time order of change require further research to identify the right subjects and right molecular target for precision medicine therapies.

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression post-transcriptionally by targeting either the 3′ untranslated or coding regions of genes. They have been reported to play key roles in a wide range of biological processes. The recent remarkable developments of transcriptomics technologies, especially next-generation sequencing technologies and advanced bioinformatics tools, allow more in-depth exploration of messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) including miRNAs. These technologies have offered great opportunities for a deeper exploration of miRNA involvement in farm animal diseases, as well as livestock productivity and welfare. In this review, we provide an overview of the current knowledge of miRNA roles in farm animal diseases with a particular focus on diseases of economic importance. In addition, we discuss the steps and future perspectives of using miRNAs as biomarkers and molecular therapy for livestock disease management as well as the challenges and opportunities for understanding the regulatory mechanisms of miRNAs related to disease pathogenesis.

The Matāura River is the sixth largest river system in New Zealand and has long been subject to agricultural, industrial, and residential land use activities. The catchment has geographic and economic value and is of great cultural importance for local Māori, who have concerns over potential adverse impacts that anthropogenic stressors exert on the health of the river. There is a dearth of information on the impacts of these stressors towards the health of native species such as the longfin eel Anguilla dieffenbachii. This study assessed the environmental status of the Matāura River using biological and chemical methodologies incorporating A. dieffenbachii as a bioindicator species for exposure to combined anthroprogenic stressors. A range of biomarker endpoints were measured in caged and wild-caught eels (when available) to characterize site-specific responses to combined anthropogenic stressors. While there was no clear indication of cumulative impacts moving from pristine headwaters to the lower reaches of the Matāura River biomarkers of xenobiotic metabolization were induced in A. dieffenbachia and there was evidence of chemical contamination in sediments and tissues.

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

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.

Metal exposure has been associated with a wide range of adverse birth outcomes and oxidative stress is a leading hypothesis of the mechanism of action of metal toxicity. We assessed the relationship between maternal exposure to essential and non-essential metals and metalloids in pregnancy and oxidative stress markers, and sought to identify windows of vulnerability and effect modification by fetal sex. In our analysis of 215 women from the PROTECT birth cohort study, we measured 14 essential and non-essential metals in urine samples at three time points during pregnancy. The oxidative stress marker 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite 2,3-dinor-5,6-dihydro-15-15-F2t-IsoP, as well as prostaglandin F2α (PGF2α), were also measured in the same urine samples. Using linear mixed models, we examined the main effects of metals on markers of oxidative stress as well as the visit-specific and fetal sex-specific effects. After adjustment for covariates, we found that a few urinary metal concentrations, most notably cesium (Cs) and copper (Cu), were associated with higher 8-iso-PGF2α with effect estimates ranging from 7.3 to 14.9 % for each interquartile range, increase in the metal concentration. The effect estimates were generally in the same direction at the three visits and a few were significant only among women carrying a male fetus. Our data show that higher urinary metal concentrations were associated with elevated biomarkers of oxidative stress. Our results also indicate a potential vulnerability of women carrying a male fetus.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament III protein of astroglia cells which is upregulated in traumatic brain injury (TBI). Here we reported that GFAP is truncated at both the C- and N-terminals by cytosolic protease calpain to GFAP breakdown products (GBDP) of 46-40K then 38K following pro-necrotic (A23187) and pro-apoptotic (staurosporine) challenges to primary cultured astroglia or neuron-glia mixed cells. In addition, with another pro-apoptotic challenge (EDTA) where caspases are activated but not calpain, GFAP was fragmented internally, generating a C-terminal GBDP of 20 kDa. Following controlled cortical impact in mice, GBDP of 46-40K and 38K were formed from day 3 to 28 post-injury. Purified GFAP protein treated with calpain-1 and -2 generates (i) major N-terminal cleavage sites between A-56 and A-75, and (ii) major C-terminal cleavage sites between T-383 and Q-388, producing a limit fragment of 38K. Caspase-6 treated GFAP was cleaved at D-78, R-79, D-266 and A-267, where GFAP was relatively resistant to caspase-3. We also derived a GBDP-38K N-terminal-specific antibody which only labels injured astroglia cell body in both cultured astroglia and mouse cortex and hippocampus after TBI. As a clinical translation, we observed that CSF samples collected from severe human TBI have elevated levels of GBDP-38K as well as two C-terminally released GFAP peptides (DGEVIKES and DGEVIKE). Thus, in addition to intact GFAP, both the GBDP-38K as well as unique GFAP released C-terminal proteolytic peptides species might have the potential in tracking brain injury progression.

The endothelium has multiple functions from maintaining vascular homeostasis, providing nutrition and oxygen to tissues, to evocating inflammation, under adverse conditions, and determining endo-thelial barrier disruption resulting in dysfunction. Endothelial dysfunction represents the typical condition associated with the pathogenesis of all the diseases of cardiovascular system, as well as of diseases of all the other human body’s systems, also including sepsis, acute respiratory distress syn-drome and COVID-19 respiratory distress. Such evidence is leading to identifying potential bi-omarkers and therapeutic targets for preserving, reverting, or restoring endothelium integrity and functionality by early treating its dysfunction. Here, it stresses some strategies for achieving these goals, even if diverse challenges exist and require a significant bench work associated with an in-creased number of clinical studies.

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.

Homologous recombination deficiency (HRD) has become an important prognostic and predictive biomarker for patients with high-grade serous ovarian cancer who may benefit from poly-ADP ribose polymerase inhibitors (PARPi) and platinum-based therapies. HRD testing provides relevant information to personalize patients’ treatment options, and it has been progressively incorporated in diagnostic laboratories. In this study, we evaluated the feasibility of in-house HRD testing deployable in a diagnostic clinical setting, comparing results from two commercially available next-generation sequencing (NGS)-based tumor tests (SOPHiA DDMTM HRD Solution and AmoyDx HRD Focus Panel) with the reference assay from Myriad MyChoice CDx. A total of 85 ovarian cancer samples were subjected to HRD testing. An overall strong correlation was observed across the three assays evaluated, regardless of the different underlying methods employed to assess genomic instability, with the highest pairwise correlation between Myriad and SOPHiA (R=0.87, p-value=3.39x10-19). The comparison of the assigned HRD status to the reference Myriad’s test revealed a positive predictive value (PPV) and negative predictive value (NPV) of 90.9% and 96.3% for SOPHiA’s test, while AmoyDx’s test achieved 75% PPV and 100% NPV. This is the largest HRD testing evaluation using different methodologies and provides a clear picture of the robustness of NGS-based tests currently offered in the market. Our data show that the implementation of in-house HRD testing in diagnostic laboratories is technically feasible and it can be reliably performed with commercial assays. Also, the turnaround time is compatible with clinical needs, being an ideal alternative to offer to a broader number of patients, while still maintaining high-quality standards at more accessible price tiers.

Background: Myometrial invasion (MI) is a parameter currently used in transvaginal ultrasound (TVS) in endometrial cancer (EC) to determine local staging, however, without molecular diagnostics, it is insufficient for selection of high-risk cases, i.e., those with a high risk of lymph node metastases (LNM). Methods: One hundred sixteen consecutive EC patients, who had received 2D transvaginal ultrasound examinations in their preoperative workup and final histopathology results as a reference standard, were included in this prospective study. Univariate and multivariate logistic models of analyzed TVS biomarkers (tumor [T] size, T area [AREA], T volume [SPE-VOL], MI, T-free distance to serosa [TFD], endo-myometrial irregularity, [EMIR], cervical stromal involvement, CSI) were evaluated to assess the relative accuracy of the possible LNM predictors. To avoid a potential bias in assuming linear relations between LNM and continuous predictors, spline functions were applied. Calculations were made in R with the use of libraries splines, glmulti, and pROC. Results: LNM was found in 20 out of 116 (17%) patients. In univariate analysis, only uMI, EMIR, uCSI and uTFD were significant predictors of LNM. Accuracy was 0.707 (AUC 0.684, 95% CI 0.568-0.801) for uMI (p<0.01), 0.672 (AUC 0.664, 95% CI 0.547-0.781) for EMIR (p<0.01), 0.776 (AUC 0.647, 95% CI 0.529-0.765) for uCSI (p<0.01), and 0.638 (AUC 0.683, 95% CI 0.563-0.803) for uTFD (p<0.05). The cut-off value for uTFD was 5.2 mm. However, AREA and VOL revealed significant relation by non-linear analysis as well. Among all possible multivariate models, the one comprising interactions of splines of uTFD with uMI and splines of SPE-VOL with uCSI showed most usefulness. Accuracy was 0.802 (AUC 0.791, 95% CI 0.673-0.91) Conclusions: A combination of uTFD for patients with uMI>50%, and SPE-VOL for patients with uCSI, allows for the most accurate prediction of LNM in EC, rather than uMI alone.

In this study, novel biomarkers in Blood Mononuclear Cells (PBMCs) of Hepatocellular Carcinoma (HCC) patients were identified through microarray data analysis. The problem that prompted the study was the lack of reliable biomarkers for early diagnosis and monitoring of HCC. The purpose of this study was to discover potential biomarkers in PBMCs of HCC patients that can be used for early diagnosis and monitoring of the disease. The main hypothesis was that there are genes that are overexpressed in PBMC of HCC patients compared to healthy individuals. The results showed that genes HBB, WBP2, HBA2, and HBA1 were overexpressed in PBMCs of HCC patients. Additionally, nine genes were found to be upregulated in HCC patients and had a relation between KEGG pathways of RA, suggesting a link between the two diseases. These genes are TLR4, IL1B, CXCL5, IL11, HLA-DQA1, HLA-DRA, LBT, ATP6V1B2 and ATP6V1C1. The Gene ontology analysis revealed biological processes used in the process of how these genes play a role in development of HCC. In conclusion, this study identified potential biomarkers in PBMC of HCC patients that can aid in early diagnosis and monitoring of the disease. The findings of this study have important implications for improving the clinical management of HCC patients.

Systemic lupus erythematosus (SLE) myocarditis is presumed to be rare but associated with ad-verse outcomes. If SLE diagnosis has not previously been established, its clinical presentation is often unspecific and difficult to recognize. Furthermore, there is a lack of data in the scientific literature regarding myocarditis and its treatment in systemic immune-mediated diseases, leading to its late recognition and undertreatment. We present the case of a young woman whose first lupus manifestations included acute perimyocarditis, among other symptoms and signs that provided clues to the diagnosis of SLE. Transthoracic and speckle tracking echocardiography were helpful in detecting early abnormalities in myocardial wall thickness and contractility while waiting for cardiac magnetic resonance (CMR). Since the patient presented with acute decompensated heart failure (HF), HF treatment was promptly started in parallel with immunosuppressive therapy, with a good response. In the treatment of myocarditis with heart failure, we were guided by the echocardiographic findings, biomarkers for myocardial injury N-terminal pro b-type natriuretic peptide (NT-proBNP) and hs-troponin I, biomarkers for systemic inflammation erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and biomarkers for SLE disease activity (Complement C)3, C4, and anti-dsDNA levels.

Gastric Cancer (GC) is the fifth most frequently diagnosed malignant tumor and the third cause of cancer mortality worldwide. For advanced GC, a large number of novel drugs and combinations have been tested, but results are still disappointing and the disease incurable in the majority of cases. In this regard, it is critical to investigate the molecular mechanisms underlying GC development. Angiogenesis is one of the hallmarks of cancer with a fundamental role in GC growth and progression and ramucirumab, a monoclonal antibody binding to vascular endothelial growth factor-2 (VEGFR-2) is approved in the treatment of advanced and pretreated GC. However, no predictive biomarkers for ramucirumab have been identified so far. MicroRNAs (miRNAs) are a class of evolutionally conserved single-stranded noncoding RNAs playing an important role, via post-transcriptional regulation, in essentially all biologic processes such as cell proliferation, differentiation, apoptosis, survival, invasion, and migration. Notably, in our review, we focused on miRNAs involved in angiogenic pathways in GC. Moreover, we evaluated the possible prognostic and predictive role of angiogenesis-related miRNAs as novel biomarkers of GC.

Oxidative stress appears to be associated with more severe disease in WNV infected patients. Our preliminary findings warrant prospective studies to investigate the correlation of oxidative stress with clinical outcomes and severity of WNV infection.

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.

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

Viral infections cause metabolic dysregulation in the infected organism. The present study used metabolomics techniques and machine learning algorithms to retrospectively analyze the alter-ations of a broad panel of metabolites in the serum and urine of a cohort of 126 patients hospi-talized with COVID-19. Results were compared with those of 50 healthy subjects and 45 COVID-19 negative patients but with bacterial infectious diseases. Metabolites were analyzed by gas chro-matography coupled to quadrupole time-of-flight mass spectrometry. The main metabolites al-tered in the sera of COVID-19 patients were those of pentose glucuronate interconversion, ascorbate and fructose metabolism, nucleotide sugars, and nucleotide and amino acid metabolism. Alterations in serum maltose, mannonic acid, xylitol, or glyceric acid metabolites segregated positive patients from the control group with high diagnostic accuracy, while succinic acid seg-regated positive patients from those with other disparate infectious diseases. Increased lauric acid concentrations were associated with severity of infection and death. Urine analyses could not discriminate between groups. Targeted metabolomics and machine learning algorithms facilitated the exploration of the metabolic alterations underlying COVID-19 infection, and to identify po-tential biomarkers for the diagnosis and prognosis of the disease.

Endurance triathlons impose substantial physiological stress, yet effects of short-course formats remain relatively unexplored. In this preliminary study, we assessed proteinuria and hydration levels in 27 well-trained triathletes (41.9 [7.4] years) who completed a sprint triathlon consisting of a 1500-m swim, 26-km cycle, and 8-km run. Urine samples were collected before and after the race. The results showed an increase in cases of post-race proteinuria from four to nine (p=0.03). Also, one case of urobilinuria and ketoacidosis was observed after the race. Pre-race glucosuria, which was present in nine cases, decreased to three cases post-race. Although hematuria cases decreased from six to two (p=0.13), pre-race leukocyturia (found in two cases) resolved post-race. There was a significant increase in urine specific gravity (from 1.018 to 1.023, p=0.03), indicating dehydration. In conclusion, short-course triathlons were found to induce post-race proteinuria, urobilinuria, and dehydration without exacerbating pre-race glucosuria, hematuria, or leukocyturia. These preliminary findings contribute to our understanding of medical guidelines for sprint triathlons, an area of endurance sports that has received limited research attention. Further investigation, both mechanistic and longitudinal, is warranted in this regard.

The SARS coronavirus 2 (SARS-CoV-2) is the causative agent of the 2019 coronavirus disease (COVID-19) pandemic that has executed 6.9 million people and infected over 765 million. It’s become a major worldwide health alarm and is also known to cause abnormalities in various systems, including the hematologic system. COVID-19 infection primarily affects the lower res-piratory tract and can lead to a cascade of events, including a cytokine storm, intravascular thrombosis, and subsequent complications such as arterial and venous thromboses. COVID-19 can cause thrombocytopenia, lymphopenia, and neutrophilia, which are associated with worse out-comes. Prophylactic anticoagulation is essential to prevent complication and death rate associated with the virus's effect on the coagulation system. It is crucial to recognize these complications early and promptly start therapeutic anticoagulation to improve patient outcomes. While rare, COVID-19-induced disseminated intravascular coagulation exhibits some similarities to DIC induced by sepsis. LDH, D-dimer, ferritin, and CRP biomarker are often increase in serious COVID-19 cases and poor prognosis. Understanding the pathophysiology of the disease and identifying risk factors for adverse outcomes is critical for effective management of COVID-19.

The impact of metals bioaccumulation on marine organisms is under investigation. This study was designed to determine the association of oxidative stress in mussels Mytilus galloprovincialis induced by seawater enriched with trace metals with protein synthesis. Mussels were exposed to 40 μg/L Cu, 30 μg/L Hg, or 100 μg/L Cd for 5 and 15 days, and the pollution effect was evaluated by measuring established oxidative biomarkers. The results showed damage on the protein synthesis machine integrity and specifically, on translation factors and ribosomal proteins expression and modifications. Exposure of mussels to all metals caused oxidative damage that was milder in the cases of Cu and Hg, and more pronounced for Cd. However, after prolonged exposure of mussels to Cd (15 days), the effects receded. These changes that perturb protein biosynthesis can serve as a great tool for elucidating the mechanisms of toxicity and could be integrated in biomonitoring programs.

The tryptophan catabolite (TRYCAT) pathway is implicated in the pathophysiology of schizophrenia (SCZ) since the rate-limiting enzyme indoleamine-dioxygenase (IDO) may be induced by inflammatory and oxidative stress mediators. This systematic review searched PubMed, Web of Science, and Google Scholar for papers published from inception until August 2021 and meta-analyzed the association between SCZ and TRYCATs in the central nervous system (CNS) and peripheral blood. We included 61 studies comprising 2813 patients and 2948 healthy controls. In the CNS we found a significant (p<0.001) increase in the kynurenine/tryptophan (KYN/TRP) (standardized mean difference, SMD=0.769, 95% confidence interval, CI: 0.456; 1.082) and kynurenic acid (KA)/KYN+TRP (SMD=0.697, CI:0.478-0.917) ratios, KA (SMD=0.646, CI: 0.422; 0.909) and KYN (SMD=1.238; CI: 0.590; 1.886), while the 3OH-kynurenine (3HK) + KYN-3-monooxygenase (KMO)/KYN ratio was significantly reduced (SMD=-1.089, CI: -1.682; -0.496). There were significant differences between KYN/TRP, (KYN+KA)/TRP, (3HK+KMO)/KYN, KA, and KYN levels among the CNS and peripheral blood, and among serum and plasma KYN. The only useful peripheral marker of CNS TRYCATs findings was the increased KYN/TRP ratio in serum (SMD=0.211, CI: 0.056; 0.366, p=0.007), but not in plasma. There was no significant increase in a neurotoxic composite score based on KYN, 3HK, and picolinic, xanthurenic, and quinolinic acid. SCZ is accompanied by increased IDO activity in the CNS and serum, and reduced KMO activity and a shift towards KA production in the CNS. This CNS TRYCATs profile indicates neuroprotective, negative immunoregulatory and anti-inflammatory effects. Peripheral blood levels of TRYCATs are dissociated from CNS findings except for a modest increase in serum IDO activity.

Zinc (Zn) is a trace element crucial for oxidative stress, apoptosis, the immune response, and more globally for various processes involved in cellular homeostasis. In some cancers, Zn homeostasis is dysregulated. In this review, the role of Zn in cancer and all the components associated to Zn, the use of Zn and Zn -related proteins as biomarkers and Zn-based strategies for the treatment of tumors will be described. ZIP and ZnT are proteins related to Zn metabolism in normal conditions. In cancer, the level of expression of Zn related proteins is abnormal. These Zn proteins may act as prognostic or diagnostic biomarkers, and may be helpful for detecting early-stage cancers or monitoring the course of the disease. Additionally, Zn and its pathways may also be targeted to treat cancers. Indeed, the use of metals for binding Zn cations allows to regulate the biodistribution of Zn within cells, and will control several downstream signaling pathways. Zinc may also be directly used as a therapeutic substance to improve the prognosis of cancer patients, especially with the supplementation of zinc or the use of Zn oxide nanoparticles.

Many assets of clinical medicine, such as clinical chemistry and diagnostic imaging, make clinical diagnosis outstanding compared to postmortem diagnosis. An assessment of functional status certainly has priority over the postmortem, cross-sectional use of diagnostic tests and laboratory equipment. In addition, the cost of these tools is sometimes steep, and their use does not always fit into a reasonable cost–benefit ratio. However, sometimes postmortem observations, such as inflammation, pulmonary edema, or infiltration and cerebral swelling, cannot be explained without implementing immunohistochemical markers for postmortem diagnosis. Introducing blood-based biomarkers in postmortem care could significantly reduce the rates of inconclusive postmortems and discrepancies in autopsy findings and clinical diagnoses. This is particularly relevant in the scope of vascular pathology, considering the great burden of vascular diseases in overall mortality. Expanding traditional autopsy with blood-based (circulating) biomarkers to avoid invasive postmortem examination would have cultural, religious, and potential economic advantages. All of the target molecules are discussed in the context of the process they up-regulate or down-regulate and which turns out to be the final cause of death. Ultimately, it is evident that further studies are needed to provide concrete validation for a combination of markers on a specific case order to reach a postmortem diagnosis with or without clinical records.

Suicide is defined as the action of harming oneself with the intention of dying. It is estimated that worldwide one suicide occurs every 40 seconds, making it a major health problem. Studies in families have suggested that suicide has a genetic component, around the world studies have been carried out in search of genetic variants associated with suicidal behavior, these variants could be useful as potential biomarkers to identify people at risk of suicide. In this area in Mexico, some studies of variants in genes related to neurotransmission and other important pathways have been carried out and a possible association of variants located in genes has been suggested: SLC6A4, SAT-1, TPH-2, ANKK1, GSHR, SCARA50, RGS10, STK33, COMT, and FKBP5. This systematic review shows the genetic studies on the Mexican population. This article contributes by compiling the existing information on genetic variants and genes associated with suicidal behavior, said variants in the future could be used as potential biomarkers to identify people at risk of suicide.

The identification of biomarkers is crucial for cancer diagnosis, understanding the underlying biological mechanisms, and developing targeted therapies. In this study we propose a machine learning approach to predict the outcome and platinum resistance status of ovarian cancer patients using public available gene expression data. Six classical machine learning algorithms are compared on their predictive performance. Those with the highest score are analyzed by their feature importance using the SHAP algorithm. We were able to select multiple genes that were correlating with the outcome and platinum resistance status of the patients and validated those using Kaplan-Meier plots. In comparison to similar approaches the performance of the models were higher and different genes using feature importance analysis were identified. The most promising identified genes that could be used as biomarkers are: TMEFF2, ACSM3, SLC4A1 and ALDH4A1.

Cellular senescence is characterized by permanent proliferation and migration arrest, senescence-associated secretory phenotype (SASP), and oxidative stress. Senescent vascular smooth muscle cells (VSMCs) contribute to cardiovascular diseases and atherosclerotic plaque instability. To establish and characterize a model of replicative senescence (RS), human aortic VSMCs were serially passaged to represent different stages of RS such as young proliferating cells and old/senescent non-proliferating cells. More than 50% of old cells stained positive for the senescence-associated β-galactosidase compared to 20% of young cells. Old cells have a slower proliferation rate, a migratory activity reduced by 50%, but increased levels of TP53 and of cell cycle inhibitors p21/p16 expression, and accumulate in the G1 phase. Old cells showed a flattened appearance and enlarged and regular nuclei, and downregulation of the expression of LMNB1 and HMGB1. Old cells showed also an increased expression of SASP molecules (IL1β, IL6, IL8, and MMP3). Moreover, among a set of 12 manually selected long non-coding RNAs (lncRNAs), we detected significant upregulation of PURPL and NEAT1. We observed also increased levels of RRAD mRNA. The detection of novel molecular markers of senescence, such as RRAD, PURPL, and NEAT1, could be helpful for future studies on potential anti-aging factors.

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.

We aimed to determine if infection-associated urine biomarkers can differentiate true urinary tract infection (UTI) from non-UTI controls. Midstream clean-catch urine samples were collected from asymptomatic volunteers and symptomatic subjects > 60 years old diagnosed with presumptive UTI in a specialty setting. Microbial identification and density were assessed using multiplex PCR/pooled antibiotic susceptibility test (M-PCR/P-AST) and standard urine culture (SUC). Three biomarkers (NGAL, IL-8, and IL-1β) were measured in the same urine specimens. Definitive UTI cases were symptomatic and had positive microorganism detection by SUC and M-PCR, while definitive non-UTI cases were asymptomatic volunteers regardless of microbial detection. We observed a strong positive correlation (R2 ≈ 1) between microbial density and the biomarkers NGAL, IL-8, and IL-1β. Biomarker consensus criteria of two or more positive biomarkers had sensitivity 90.2%, specificity 91.2%, positive predictive value (PPV) 91.7%, negative predictive value (NPV) 89.7%, accuracy 90.7%, positive likelihood ratio of 10.28, and negative likelihood ratio of 0.11 in differentiating definitive UTI from non-UTI cases, regardless of microbial density. NGAL, IL-8, and IL-1β showed a significant elevation in symptomatic cases with positive microbe identification compared to asymptomatic cases with or without microbe identification. Biomarker consensus exhibited high accuracy in distinguishing UTI from non-UTI cases.

Documenting prehistoric and historical hemp retting for fiber extraction is important in the study of human uses of this iconic plant and its cultural implications. In paleoecology, hemp retting is usually inferred from indirect proxies, notably anomalously high percentages of Cannabis pollen in lake sediments, but some recent studies have also used specific molecular biomarkers (cannabinol, Cannabis DNA) as a more straightforward evidence. Here we provide direct evidence of hemp retting by identifying phylogenetic signatures (16S rRNA genes) from pectinolytic bacteria actually responsible for the fermentation process that separates the fiber from the stalk, namely Bacillus, Clostridium, Escherichia, Massilia, Methylobacterium, Pseusomonas, Rhizobium and Rhodobacter. These analyses have been performed in the sediments from an Iberian lake previously considered as an important hemp retting site during the last five centuries, on the basis of Cannabis pollen abundances. The good match between biomarker and pollen evidence, in the context of the recent historical development of hemp industry in Spain, can be useful to interpret paleoecological records from other similar lakes in the way toward a more regional view on the introduction, spreading, uses and associated cultural connotations of Cannabis in the Iberian Peninsula within European and Mediterranean contexts.

Demonstrating biosimilarity entails comprehensive analytical evaluations, clinical pharmacolo-gy profiling, and efficacy testing for at least one medical indication in patients. These require-ments are stipulated by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The costliest element—efficacy testing—can be waived if other compliance benchmarks are satisfied, including comparing functional pharmacodynamic (PD) biomarkers, even when they do not di-rectly correlate with clinical outcomes. Most biological drugs, such as monoclonal antibodies (mAbs), lack identifiable PD biomarkers. The FDA has employed various 'omics' technologies to identify potential PD biomarkers, including proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. Although these efforts provide a robust scientific basis for estab-lishing biosimilarity, they are neither practical nor necessarily superior to existing functional biomarkers, such as receptor binding and mode-of-action outcomes. As we report for the first time, these functional biomarkers can effectively serve as PD indicators for all FDA-licensed bio-logical drugs. We recommend that the FDA consider officially listing these functional biomarkers to expedite and reduce the cost of biosimilar development, thereby increasing the accessibility of biological drugs. PD surrogates, like the receptor binding and pharmacokinetic profiles, are more robust and offer a rational solution to finding PD markers to compare for establishing biosimi-larity.

Tryptophan is an essential nutrient required to produce niacin (vitamin B3), which is needed for energy metabolism and DNA production. Alterations in tryptophan metabolism could have significant effects on aging and musculoskeletal health. The kynurenine pathway, the main catabolic route of tryptophan, is modulated by inflammatory factors, which are increased in older persons, a process known as inflammaging. Osteoporosis, sarcopenia, osteosarcopenia and frailty have also been linked with chronic increased levels of inflammatory factors. Due to the disruption of the kynurenine pathway by chronic inflammation and/or changes in the gut microbiota, serum levels of toxic kynurenines are increased and have been associated with osteoporosis, sarcopenia and frailty. In contrast, anabolic end products of this pathway, such as picolinic acid, have demonstrated a beneficial effect on bone and muscle. In addition, recent studies have shown that physical activity can modulate this pathway by promoting the secretion of anabolic kynurenines. According to the evidence collected, kynurenines could have a promising role as biomarkers for osteoporosis sarcopenia, osteosarcopenia and frailty in older persons. In addition, some of these metabolites could become important targets for developing new pharmacological treatments for these conditions.

We hypothesized that reticuloruminal temperature and pH, as well as cow activity, can be used as biomarkers for the early diagnosis of clinical mastitis in dairy cows. Therefore, we aimed to detect the relationship between reticuloruminal temperature and pH, cow activity, and clinical mastitis in dairy cows. We randomly selected cows with clinical mastitis and clinical healthy cows (HG) out of 600 milking cows. We recorded the following parameters during the experiment: reticulorumen tem-perature (RR temp.), reticulorumen pH (RR pH), and cow activity. We used smaXtec boluses (smaXtec animal care technology®, Graz, Austria). In this investigation, reticulorumen data ob-tained seven days before diagnosis were compared to HG data from the same time period. CM cows were observed on the same days as the healthy cows. The healthy group’s RR pH was 7.32% higher than that of cows with CM. Reticulorumen temperature was also 1.25% higher in the CM group than in the control group. The healthy group had a higher average value for walking activity and was 17.37% higher than the CM group. The data of reticulorumen pH changes during 24 h showed that during the day, the pH changed from 5.53 to 5.83 in the CM group. By contrast, pH changed from 6.05 to 6.31 in the control group. The lowest reticulorumen pH in the CM group was detected on the third day before diagnosis. It was 15.76% lower than the highest reticulorumen pH detected on the sixth day before diagnosis. The lowest reticulorumen pH in CM cows was detected at 0 and 1 days before diagnosis. It was 1.45% lower than the highest reticulorumen pH detected on the second day before diagnosis. The lowest walking activity in the CM group was detected 0 days before diagnosis, 50.60% lower than on the fifth day before diagnosis. The lowest walking activity was detected 0 days before diagnosis, 39.57% lower than on the seventh day before diagnosis. In this study, we found that reticuloruminal temperature, reticuloruminal pH, and cow ac-tivity could be used as biomarkers for the early diagnosis of clinical mastitis in dairy cows.

The lethal combination involving TB and HIV, known as 'syndemic’ diseases synergistically act upon one another to magnify the disease burden. Individuals on ART are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). The underlying inflammatory complication includes the rapid restoration of immune responses following ART eventually leading to exaggerated inflammatory responses to MTB antigens. TB-IRIS continues to be a cause of morbidity and mortality among HIV/TB coinfected patients initiating ART, and although significant quantum of knowledge has been acquired on the pathogenesis of IRIS, the underlying pathomechanisms and identification of a sensitive and specific diagnostic markers still remain a grey area of investigation. Here, we reviewed the latest research developments in IRIS immunopathogenesis, and outlined the modalities to prevent and manage strategies for better clinical and diagnostic outcomes for IRIS.

Lead (Pb) is a non-essential, highly toxic, and persistent element widely recognised as one of the most concerning pollutants, and it is listed in the Priority List of Hazardous Substances. Widespread environmental contamination from Pb is a serious issue for human health and wildlife. The liver, a key compartment for metal detoxification and excretion, is also the organ in which Pb mainly accumulates in fish. Herein, we investigated for the first time the morphological and functional injuries induced in zebrafish (Danio rerio) liver by two very low and environmentally relevant concentrations of Pb (2.5 and 5 μg/L) after 48, 96, and 192 hours of exposure. We showed significant histological alterations in all the exposed samples, also demonstrating that the extent of injuries increased with dose and exposure time. The most common modifications observed were congestion of blood vessels and sinusoids, cytoplasmic vacuolizations, parenchyma dyschromia, and macrophage proliferation. Pb administration also resulted in a significant increase in lipid content and the upregulation of key genes involved in metal detoxification (mtf1) and the defensive response against oxidative stress (sod1 and cat). We showed that even very low doses of Pb can disrupt liver morphology and function.

Genome-based testing in oncology is a rapidly expanding area of health care which is the basis of the emerging area of precision medicine. Efficient and considered adoption of novel genomic medicine testing is hampered in Canada by the fragmented nature of health care oversight as well as by lack of clear and transparent processes to support rapid evaluation, assessment and implementation of genomic tests. This article provides an overview of some key barriers and proposes approaches to addressing these challenges as a potential pathway to developing a national approach to genomic medicine in oncology.

The SARS-CoV-2 infection is a cause of hypoxemic acute respiratory failure, leading to frequent intensive care unit (ICU) admission. Due to invasive organ support and immunosuppressive therapies, these patients are prone to nosocomial infections. Our aim was to assess the value of daily measurements of C-reactive protein (CRP) and Procalcitonin (PCT) in the early identification of ICU-acquired infections in COVID-19 patients Methods: We undertook a prospective observational cohort study (12 months). All adult me-chanically-ventilated patients admitted for ≥ 72 hours to the ICU with COVID-19 pneumonia were divided into an infected group (n=35) and a non-infected group (n=83). Day 0 was considered as the day of the diagnosis of infection (infected group) and day 10 of ICU stay (non-infected group). The kinetics of CRP and PCT were assessed from day -10 to day 10 and evaluated using a general linear model, univariate, repeated-measures analysis. Results: 118 patients (mean age 63 years, 74% males) were eligible for the analysis. The groups did not differ in patients' age, gender, CRP, and PCT serum levels at ICU admission. However, the infected group encompassed patients with a higher severity (SOFA score at ICU admission, p=0.009) and a higher 28-day mortality (p<0.001). Before D0, CRP kinetics showed a significant increase in infected patients, whereas in noninfected it remained almost unchanged (p<0.001), while PCT kinetics did not appear to retain diagnostic value to predict superinfection in COVID-19 patients (p=0.593). Conclusion: COVID-19 patients who develop ICU-acquired infections exhibited different biomarker kinetics before the diagnosis of those infections. Daily CRP monitoring and the recognition of the CRP kinetics could be useful in the prediction of ICU-acquired infections.

Hepatocellular carcinoma (HCC) is one of the most frequent cancers in humans, characterised by high resistance to conventional chemotherapy, late diagnosis, and high mortality rate. It is necessary to elucidate the molecular mechanisms involved in hepatocarcinogenesis to improve diagnosis and treatment outcomes. The Runt-related (RUNX) family of transcription factors (RUNX1, RUNX2, and RUNX3) participates in cardinal biological processes and play paramount roles in the pathogenesis of numerous human malignancies. Their role is often controversial as they can act as oncogenes or tumour suppressors, dependent on cellular context. Evidence shows that deregulated RUNX genes may be involved in hepatocarcinogenesis from the earliest to the latest stages. In this review, we summarise the topical evidence on the roles of RUNX gene family members in HCC. We discuss their possible application as non-invasive molecular markers for early diagnosis, prognosis, and development of novel treatment strategies in HCC patients.

The concept and policies of multiple early cancer detection (MCED) have gained significant attention from governments worldwide in recent years. In the era of burgeoning artificial intelligence (AI) technology, the integration of MCED with AI has become a prevailing trend, giving rise to a plethora of MCED AI products. However, due to the heterogeneity of both the detection targets and the AI technologies, the overall diversity of MCED AI products remains considerable. The types of detection targets encompass protein biomarkers, cell-free DNA, or combinations of these biomarkers. In the development of AI models, different model training approaches are employed, including datasets of case-control researches or real-world cancer screening datasets. Various validation techniques, such as cross-validation, location-wise validation, and time-wise validation are used. All of the factors show significant impacts on the predictive efficacy of MCED AIs. After the completion of AI model development, deploying the MCED AIs in clinical practice presents numerous challenges, including presenting the predictive reports, identifying the potential locations and types of tumor, and addressing cancer-related information such as clinical follow-up and treatment. This study reviews several mature MCED AI products currently available in the market, detecting their composing factors from serum biomarkers detection, MCED AIs training/validation, and the clinical application. The review illuminates the challenges encountered by existing MCED AI products across these stages, offering insights into the continued development and obstacles within the field of MCED AI.

Background: Micro-RNAs (miRNA) are emerging as biomarkers in the detection and prognosis of cancers due to their inherent stability and resilience. Methods: To summarize evidence regarding urinary miRNA (umiRNAs) role in the detection, prognosis and therapeutic management of urological cancers, we performed a systematic review of the most important scientific databases using the following keywords: (urinary mir-na)AND(prostate cancer); (urinary mirna)AND(bladder cancer); (urinary mirna)AND(renal cancer); (urinary mirna)AND(testicular cancer); (urinary mirna)AND(urothelial cancer). Results: Of all, 1364 articles were initially selected. Only original studies in the English language on human specimens were considered for inclusion in our systematic review. Thus, a convenient sample of 60 original articles was identified. Urinary miRNA (UmiRNAs) are downregulated in prostate cancers and may serve as potential non-invasive molecular biomarkers. Several umiR-NAs have been identified as diagnostic biomarkers of urothelial carcinoma and bladder cancer (BCa), allowing to discriminate malignant from non-malignant forms of haematuria. UmiRNAs could serve as therapeutic targets or recurrence markers of non-muscle invasive BCa and could predict the aggressivity and prognosis of muscle-invasive BCa. In renal cell carcinoma, miRNAs have been identified as predictors of tumour detection, aggressiveness, and progression to metastasis. Conclusion: umiRNAs could play an important role in the diagnosis, prognosis, and therapy of urological cancers.

The FDA has concluded that a biosimilar candidate capable of demonstrating pharmacodynamic biomarkers in a healthy subject need not be tested for clinical efficacy in patients, regardless of if the biomarker correlates with clinical response. Since monoclonal antibodies (mAbs) do not trig-ger pharmacodynamic response, they can be substituted with robust functional disqualifying them for this waiver that can be overcome by allowing comparison of functional properties that eventually result in clinical response. This suggestion is based on the FDA's preference for more sensitive testing methods. However, clinical efficacy testing in patients is the least sensitive method, as confirmed by statistical modeling, a fact that regulatory agencies need to admit. In this paper, I present a logical and rational argument to establish the biosimilarity of products that do not have pharmacodynamic biomarkers based on their orthogonally proven functional bio-similarity. This understanding will significantly lower the development cost of biosimilars, a goal that the FDA outlined in all its guidance. Keywords: biosimilarity 1; biosimilars 2; pharmacodynamic biomarkers 3; monoclonal antibodies 4; FDA 5; clinical efficacy testing in healthy subjects 6; clinical efficacy testing in patients 7; functional assays 8; receptor binding 9.

The following narrative review embarks on a comprehensive exploration of the pivotal role played by the gut microbiome within the Diet-Microbiota-Immunity (DMI) tripartite, aiming to enhance anti-cancer immunotherapy efficacy. While revolutionizing cancer treatment, resistance to immunotherapy and immune-related adverse events (irAEs) remain challenges. The tumor microenvironment (TME), shaped by cancer cells, influences immunotherapy resistance. The gut microbiome, influenced by genetics, environment, diet, and interventions, emerges as a critical player in TME reshaping, thereby modulating immune responses and treatment outcomes. Dietary patterns like the Mediterranean diet, caloric restriction modifications, and specific nutritional components show promise in influencing the tumor microenvironment and gut microbiome for better treatment outcomes. Antibiotics, disrupting gut microbiota diversity, may compromise immunotherapy efficacy. This review emphasizes the need for tailored nutritional strategies to manipulate microbial communities, enhance immune regulation, and improve immunotherapy accessibility while minimizing side effects. Ongoing studies investigate the impact of dietary interventions on cancer immunotherapy, pointing towards promising developments in personalized cancer care. This narrative review synthesizes existing knowledge and charts a course for future investigations, presenting a holistic perspective on the dynamic interplay between dietary interventions, the gut microbiome, and cancer immunotherapy within the DMI tripartite.

Abstract: Sarcopenia poses a significant challenge to public health and can severely impact the quality of life of aging populations. Despite extensive efforts to study muscle degeneration using traditional animal models, there is still a lack of effective diagnostic tools, precise biomarkers, and treatments for sarcopenia. Zebrafish models have emerged as powerful tools in biomedical research, providing unique insights into age-related muscle disorders like sarcopenia. The advantages of using zebrafish models include their rapid growth outside of the embryo, optical transparency during early developmental stages, high reproductive potential, ease of husbandry, compact size, and genetic tractability. By deepening our understanding of the molecular processes underlying sarcopenia, we may develop novel diagnostic tools and effective treatments that can improve the lives of aging individuals affected by this condition. This review aims to explore the unique advantages of zebrafish as a model for sarcopenia research, highlight recent breakthroughs, outline potential avenues for future investigations, and emphasize the distinctive contributions that zebrafish models offer. Our research endeavors to contribute significantly to addressing the urgent need for practical solutions to the impact of sarcopenia on aging populations, ultimately striving to enhance the quality of life for individuals affected by this condition.

The age-related loss of muscle mass and strength is referred to as “sarcopenia”. The combined effect of sarcopenia and osteoporosis is a devastating threat to the old adult, accounting for reduced mobility, risk for falls and subsequent fractures. In previous studies, we observed a high degree of inter-individual variability of paraspinal muscle fatty infiltration, one most relevant index of muscle wasting. This aspect solicited us to develop a computerized method to quantitatively characterize muscle fatty infiltration in aging and diseases. Magnetic resonance images of paraspinal muscles from 58 women of different age (age range 23-85 years) and physio-pathological status (healthy young, pre-menopause, post-menopause, and os-teoporosis), were used to set up the method. It is based on fractal analysis of lean muscle area (contractile muscle) to estimate muscle fatty infiltration. In particular, lacunarity was computed by parameter β from our hyperbola model function, used to fit the GBA (gliding box algorithm) curvilinear plot. Succolarity was estimated by parameter µ, for the four main directions, through an algorithm implemented on purpose. Results show that fractal lacunarity, by quantifying muscle fatty infiltration, can discriminate be-tween osteoporosis and healthy aging while succolarity can separate the other three groups showing similar lacunarity. Therefore, fractal features of contractile muscle, by measuring fatty infiltration, can represent good indices of sarcopenia in aging and disease.

Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease, char-acterized by the progressive death of motor neurons, leading to paralysis and death. It is a rare disease distinguished by high patient-to-patient heterogeneity, making its study arduous and complex. Extracellular vesicles (EVs) emerged as an important player in ALS development. Thus, ALS phenotype-expressing cells can spread their abnormal bioactive cargos through the secretion of EVs, even at far distant tissues. Importantly, due to their nature and composition, EVs’ formation and cargo can be exploited for the better comprehension of this elusive disease and identification of novel biomarkers, as well as for potential therapeutic applications, such as those based on stem cell-derived exosomes. This review highlights the recent advances in the identification of the role of EVs in ALS etiopathology and how EVs can be promising new approaches for therapeutic strategies.

Introduction: Periodontitis is a severe oral infection that can contribute to systemic inflammation. A large body of evidence suggests a role for systemic inflammation in the initiation of neurodegenerative disease. This systematic review synthesized data from observational studies to investigate the association between periodontitis and neuroinflammation in adults. Methods and materials: A systematic literature search of PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) was performed for studies published from the date of inception up to September 2021. Search terms for the exposure “oral disease” and outcome “dementia”, “neuroinflammation” and “cognitive decline” were used. Study selection and data extraction were independently undertaken by two reviewers. The final eligible articles were included only if the exposure is periodontitis and the outcome is cognitive impairment or dementia or a topic related to this condition, and if the study was conducted in an adult population. The quality and risk of bias were assessed by Newcastle Ottawa Scale (NOS). Qualitative synthesis was used to narratively synthesize the results. Six cohort studies, three cross-sectional studies, and two case-control studies met the inclusion criteria. These eleven studies were only narratively synthesized. Meta-analysis was not performed due to the methodological heterogeneity of the studies. Results: All the included studies show evidence of an association between periodontitis and cognitive im-pairment or dementia and Alzheimer’s disease pathology. Conclusion: Nonetheless, the mechanisms responsible for the association between periodontitis and dementia are still unclear.

Major depressive disorder (MDD) is a highly prevalent, debilitating disorder with a high rate of treatment resistance. One strategy to improve treatment outcomes is to identify patient-specific, pre-intervention factors that can predict treatment success. Neurophysiological measures such as electroencephalography (EEG), which measures the brain’s electrical activity from sensors on the scalp, offer one promising approach for predicting treatment response for psychiatric illnesses, including MDD. In this study, a secondary data analysis was conducted on the publicly available Two Decades-Brainclinics Research Archive for Insights in Neurophysiology (TDBRAIN) database. Specifically, hierarchical regression modeling was used to predict treatment response from baseline demographics, symptom severity, and resting-state EEG features in 119 MDD patients receiving repetitive transcranial magnetic stimulation (rTMS). Across models, both age and baseline symptom severity, assessed by the Beck’s Depression Inventory, were significant predictors of rTMS treatment response, with older individuals and more severe depression scores associated with decreased odds of a positive treatment response. EEG measures contributed predictive power to these models; however, these improvements in outcome predictability only trended towards statistical significance (p~0.07 in multiple models). These findings provide confirmation of previous demographic and clinical predictors, while pointing to EEG metrics that may provide predictive information in future studies.

Transfer RNA fragments (tRFs) have gene silencing effects similarly to miRNAs, can be sorted into extracellular vesicles (EVs) and are emerging as potential circulating biomarkers for cancer diagnosis. We aimed at analyzing the expression of tRFs in gastric cancer (GC) and understanding their potential as biomarkers. We explored miRNA datasets from gastric tumors and normal adjacent tissues (NAT) from TCGA repository, and proprietary 3D-cultured GC cell lines and corresponding EVs, in order to identify differentially represented tRFs using MINTmap and R/Bioconductor packages. Selected tRFs were validated in patient-derived EVs. We found 613 Differentially Expressed (DE)-tRFs in the TCGA dataset, of which 19 were concomitantly upregulated in TCGA gastric tumors and present in 3D-cells and EVs, but barely expressed in NAT. Moreover, 20 tRFs were expressed in 3D-cells and EVs and downregulated in TCGA gastric tumors. Of these 39 DE-tRFs, 9 tRFs were also detected in patient-derived EVs. Interestingly, the targets of these 9 tRFs affect neutrophil activation and degranulation, cadherin binding, focal adhesion and cell-substrate junction, highlighting these pathways as major targets of EV-mediated crosstalk with the tumor microenvironment. Furthermore, as they are present in four distinct GC datasets and can be detected even in low quality patient-EV derived samples, they hold promise as GC biomarkers. By repurposing already available NGS data, we could identify and cross-validate a set of tRFs holding potential as GC diagnosis biomarkers.

Extracellular vesicles (EVs), a diverse group of cell-derived exocytosed particles, are pivotal in mediating intercellular communication due to their ability to selectively transfer biomolecules to specific cell types. EVs, composed of proteins, nucleic acids, and lipids, are taken up by cells to affect a variety of signaling cascades. Research in the field has primarily focused on stem-cell derived EVs, with a particular focus on mesenchymal stem cells, for their potential therapeutic benefits. Recently, tissue specific EVs or cell type specific extracellular vesicles (CTS-EVs), have garnered attention for their unique biogenesis and molecular composition because they enable highly targeted cell-specific communication. Various studies have outlined the roles that CTS-EVs play in signaling for physiological function and maintenance of homeostasis, including immune modulation, tissue regeneration, and organ development. These properties are also exploited for disease propagation, such as in cancer, neurological disorders, infectious diseases, autoimmune conditions, and more. The insights gained from analyzing CTS-EVs in different biological roles not only enhance our understanding of intercellular signaling and disease pathogenesis, but also open new avenues for innovative diagnostic biomarkers and therapeutic targets for a wide spectrum of medical conditions. This review comprehensively outlines current understanding of CTS-EV origins, function within normal physiology, and implications in diseased states.

Through the ACE2, a main enzyme of the renin-angiotensin system (RAS), the SARS-CoV2 gains access into the cell, resulting in different complications which may extend beyond the RAS and impact the Arachidonic Acid (ArA) pathway. The contribution of the RAS through ArA pathways metabolites in the pathogenesis of COVID-19 is unknown. We investigated whether RAS components and ArA metabolites can be considered biomarkers of COVID-19. We measured the plasma levels of RAS and ArA metabolites using an LC-MS/MS. Results indicate that Ang1-7 levels were significantly lower, whereas Ang II levels were higher in the COVID-19 patients than healthy control individuals. The ratio of Ang1-7/Ang II as an indicator of the RAS classical and protective arms balance was dramatically lower in COVID-19 patients. There was no significant increase in inflammatory 19-HETE and 20-HETE lev-els. The concentration of EETs was significantly increased in COVID-19 patients, whereas the DHETs concentration was repressed. Their plasma levels were correlated with Ang II concentration in COVID-19 patients. In conclusion, evaluating the RAS and ArA pathway biomarkers could provide helpful information for the early detection of high-risk groups, avoid delayed medical attention, facilitate resource allocation and improve patient clinical outcomes to prevent long COVID incidence.

Births occurring before thirty-seven weeks of gestation are referred to as preterm births (PTBs), which is the primary cause of neonatal mortality and long-term disabilities. The unknown mechanism behind PTB makes diagnosis difficult, yet early detection is necessary for controlling and averting related consequences. The primary focus of this work is to provide an overview of the known risk factors associated with preterm labor and the conventional and advanced procedures for early detection of PTB, including multi-omics and artificial intelligence (AI)/machine learning (ML)-based approaches. It also discusses the principles of detecting various proteomic biomarkers based on lateral flow immunoassay and microfluidic chips, along with the commercially available point-of-care testing (POCT) devices and associated challenges. After briefing the therapeutic and preventive measures of PTB, the review summarizes with an outlook.

The COVID-19 pandemic has brought marked changes worldwide to the management of airborne infectious diseases. It sparked the development of the SARS-CoV-2 vaccine and pharmacotherapeutics to prevent infection and increase the survival rate during the acute viral phase and the comorbidities associated with COVID-19. Periodontal disease may increase the morbidity and perhaps the mortality of a COVID-19 infection. However, the molecular interaction between periodontitis and COVID-19 infection remains undetermined. A potential pathogenic co-morbidity may involve periodontal pathogenic release of destructive cytokines in the highly inflamed connective tissue and risk for COVID-19. Additional biomarkers such as C-reactive proteins appear to play a role for risk and pathogenesis of COVID-19. The potential of herpesviruses, especially as it is related to aggressive periodontitis may also be a comorbidity for COVID-19. This paper reviews available evidence on the bidirectional association between periodontitis and COVID-19.

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).

All severe cases of SARS-CoV-2 infections are characterized by a high risk of disease progression towards ARDS, leading to bad outcome. Respiratory symptoms in COVID-19 patients often do not correspond to disease’s worsening. A dysregulated host response to the large viral load could play a key role in the disease progression. In our sample median age was 74 years (72-75) and 54% were men. Median period of hospitalization was 9 days. Firstly, we observed an asynchronous trend of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) in 764 selected among 963 patients who were consecutively recruited in two hospitals (Cannizzaro, S. Marco) in Catania, Italy. NLR values in deceased patients showed an increase from baseline over time. By contrast, CRP tended to fall from baseline to median day of hospitalization in all four subgroups, but steeply increased at the end of hospitalization only in ICU-admitted patients. Then we evaluated the relationships between NLR and CRP as continuous variables with PaO2/FiO2 ratio (P/F). Finally, we made mediation and moderation analyses to determine the link between inflammation (CRP), immune system (neutrophils and lymphocytes) and respiratory failure (P/F). CRP, neutrophils and P/F are linked in the same pathogenetic chain leading to respiratory failure.

The ITALUNG trial started in 2004 and compared lung cancer (LC) and other-causes mortality in 55-69 years-aged smokers and ex-smokers who were randomized to four annual chest low-dose CT (LDCT) or usual care. ITALUNG showed a lower LC and cardiovascular mortality in the screened subjects after 13 years of follow-up, especially in women, and produced many ancillary studies. They included recruitment results of a population-based mimicking approach, development of software for computer aided diagnosis (CAD) and lung nodules volumetry, LDCT assessment of pulmonary emphysema and coronary artery calcifications (CAC) and their relevance to long-term mortality, results of a smoking-cessation intervention, assessment of the radiations dose associated with screening LDCT, and the results of biomarkers assays. Moreover ITALUNG data indicated that screen-detected LCs are mostly already present at baseline LDCT, can present as Lung Cancer associated with Cystic Airspaces, and can be multiple. However, several issues of LC screening are still unaddressed. They include the annual vs biennial pace of LDCT, choice between opportunistic or population-based recruitment and between uni or multi-center screening, implementation of CAD-assisted reading, containment of false positive and negative LDCT results, incorporation of emphysema and CAC quantification in models of personalized LC and mortality risk, validation of ultra-LDCT acquisitions, optimization of the smoking-cessation intervention and prospective validation of the biomarkers.

Background: Macrophage inflammatory protein-1 alpha (MIP-1α) and C-reactive protein (CRP) are pro-inflammatory biomarkers that quantify clinical and subclinical inflammation in cardiac ischemia in cardiac inflammation and disease. Adiponectin is an anti-inflammatory marker associated with good health. The susceptibility of periodontitis patients to cardiovascular events needs to be evaluated. Objective: This study aims to assess the levels of biomarkers in periodontitis patients with and without acute myocardial infarction (AMI) compared to controls. Material and methods: Pro-inflammatory and anti-inflammatory analytes were examined by collecting unstimulated saliva from three groups (n = 20/each): healthy individuals, individuals with stage III periodontitis, and post-myocardial infarction patients with stage III periodontitis. The samples were collected within 48 hours of AMI. Results: Adiponectin levels were significantly lower in patients with periodontitis with and without AMI compared to controls, while CRP and MIP-1α were significantly higher in patients with periodontitis with and without AMI compared to controls. The highest titers for MIP-1α and CRP were detected among patients with periodontitis with and AMI. Conclusion: Our study provides evidence of the association between periodontitis and salivary analytes that occur in tandem with cardiovascular disease. The lower levels of Adiponectin and higher levels of CRP and MIP-1α in patients with periodontitis indicate that this condition is a potential risk factor for cardiovascular disease. The findings emphasize the importance of early detection and intervention for periodontitis patients to prevent cardiovascular events.

Contrast-Induced Acute Kidney Injury (CI-AKI) remains a frequent iatrogenic condition since radiological procedures using intra-vascular iodinated contrast media (CM) are being widely administered for diagnostic and therapeutic purposes. Despite the improvement of the medical healthcare system worldwide, CI-AKI is still associated with direct short-term and indirect long-term outcomes including increased morbidity and mortality, specially, in patients under-lying pre-existing renal function impairment, cardiovascular disease or diabetes that could rap-idly progress into Chronic Kidney Disease. Although the RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease), AKIN (Acute Kidney Injury Network) and KDIGO (Kidney Disease Improving Global Outcomes) clinical criteria and recommendation guidelines are based on tra-ditional “gold standard” biomarkers known as serum creatinine, glomerular filtration rate and urinary output, new reliable serum and urinary biomarkers are still needed for an effective uni-fied diagnostic strategy for AKI. Starting from previous and recent publications on the benefits and limitations of validated biomarkers responding to kidney injury, glomerular filtration and inflammation among others, this review unravels the role of new emerging biomarkers used alone or in combination, as reliable tools for early diagnosis and prognosis of CI-AKI, taking into account patients and procedures-risk factors towards a new clinical perspective.

(1) Background : Low dietary intake of calcium, vitamin D, vitamin C and magnesium has been associated with increased risk of osteoposrosis. The purpose was to evaluate changes in biomarkers of bone metabolism, and cardiometabolic health in postmenopausal women, with high risk of osteoporosis, followed by a nutritional intervention program. (2) Method: It was a prospective randomized controlled trial. A sample of 115 apparently healthy postmenopausal women(45 -75 years of age) randomized into four groups: (I) nutritional intervention group(n=40) received daily 1000mg vitamin C, 500mg vitamin D3, 500mg calcium(Ca) and 300mg magnesium (Mg); (II) control group(n=42) received daily 500mg vitamin D3, 500mg Ca and 300mg Mg; (III) nutritional intervention group (n=18) received daily 150mg bisphosphonates, 500mg vitamin D3, 500mg Ca and 300mg Mg; and (IV) nutritional intervention group (n=15) received daily about 364 mg polyphenols via an innovative functional food (50g olive paste enriched with mountain tea extract) along with 500mg vitamin D3, 500mg Ca and 300mg Mg. Groups I -III received supplementation for a year whereas group IV for 5 months. Changes in calciregulatory hormone parathormone (PTH) were evaluated at the beginning of the study as well as at 5 and 12 months intervals. Blood levels of vitamin D, vitamin C, Ca, Mg and the lipid profile were assessed at the beginning and at the end of the study. Anthropometric indices (weight, body fat(Kg), Body Mass Index(BMI) and bone mineral density(BMD) were evaluated at the beginning and at the end of the study. Statistical analysis was performed with IBM-SPSS Statistics-21. The level of statistical significance was set at p<0.05. (3) Results: 25(OH)D3 levels were improved, in groups II, III and IV (+3,71% and +1.45% and +5.62% respectively). PTH levels were increased at the end of the intervention period, for groups I and IV. Significant positive changes recorded, in total BMD, in all four study groups. Significant beneficial changes for total cholesterol was observed in group IV (-2.07%, P<0.05) and positive changes in group I for HDL biomarker (+61.62%, P<0.05) (4) Conclusions:. Additional larger-scale clinical trials and intervention studies are considered essential, in order to fully investigate and elucidate associations between dietary components and biochemical indices of bone metabolism.

Aims: To date, precision medicine plays a pivotal role in the clinical administration of solid tumor patients. In this scenario, a rapidly increasing number of predictive biomarkers have been approved in diagnostic practice or are currently investigated in clinical trials. A pitfall in the molecular tests is the diagnostic routine sample available to analyze predictive biomarkers; scant tissue sample often represents the only diagnostical source of nucleic acids to assess molecular analysis. At the sight of these critical issues, Next Generation Sequencing (NGS) platforms emerged as referral testing strategy for molecular analysis of predictive biomarkers in routine practice but high-skilled personnel, extensive working-time drastically impact on the widespread diffusion of this technology in diagnostic setting. Here, we technically validate a fully integrated NGS platform on diagnostic routine tissue samples previously tested with NGS based diagnostic workflow by a referral institution. Methods: A retrospective series of n=64 samples (n=32 DNA, n=32 RNA samples), previously tested using a customized NGS assay (SiRe™ and SiRe fusion) were retrieved from internal archive of University of Naples Federico II. Each sample was tested by adopting Oncomine Precision Assay (OPA), able to detect 2769 molecular actionable alterations [hot spot mutations, copy number variations (CNV) and gene fusions on fully integrated NGS platform (Genexus, Thermofisher Scientifics. (26,27) Concordance rate between these technical approaches was carried out. Results: Genexus system successfully carried out molecular analysis in all instances. A concordance rate of 96.9% (31 out of 32) was observed between OPA and SiRe™ panel both for DNA and RNA based analysis. A negative predictive value of 100% and a positive predictive value of 96.9% (62 out of 64) was assessed. Conclusions: Fully automatized Genexus system combined with OPA (Thermofisher Scientifics) may be considered a technically valuable, saving time sequencing platform to test predictive biomarkers in diagnostic routine practice.

The study of the human microbiome is a multidisciplinary area that affects from the field of technology to that of personalized medicine. The possibility of using microbiota biomarkers for the improvement in the diagnosis and monitoring of diseases (e.g. cancer), health conditions (e.g. obesity) or clinical parameters (e.g. ageing) has aroused great expectations, also in the scope of bio-electroanalytical chemistry. The well-known advantages of electrochemical transduction: high sensitivity, rapid response and possibility of miniaturization, together with the potential of new nanomaterials to improve both the design of electrode platforms and the performance of the resulting electrochemical biosensors make presumably a huge development in the next few years providing a better understanding of human microbiome entities. In this review article, the recent applications of electrochemical (bio)sensors for monitoring microbial metabolites and biomarkers of diseases related to different types of the human microbiome, with a special focus on the gastrointestinal microbiome, are reviewed. Examples of electrochemical devices applied to real samples are critically discussed as well as the challenges and prospects to be faced.

Exosomes are small subtypes of extracellular vesicles (EVs) naturally released by different types of cells into their environment. Their physiological roles appear to be multiple, and many aspects of their biological activities remain to be understood. These vesicles can transport and deliver a variety of cargoes, including proteins, metabolites, nucleic acids, and lipids. Consequently, it is argued that exosomes may serve as unconventional secretory vesicles, playing a crucial role as important vectors for intercellular communication and the maintenance of homeostasis. Exosome production and content can vary under several stresses or modifications in the cell microenvironment, influencing cellular responses both qualitatively and quantitatively. Thus, the analysis of EVs from multiple biofluids, due to its ease of implementation, has become a booming tool for monitoring various pathologies, particularly cancer, as we shall outline further on. During infectious processes, exosomes are described as double-edged swords, displaying both beneficial and detrimental effects. Indeed, during a viral infection, the production of EVs and circulating exosomes is often enhanced to signal danger, stimulate immunity, and possibly serve as pathological biomarkers. Conversely, viruses can disrupt or hijack the exosome content and production. In this review, we discuss the particular and ambiguous functions of exosomes in infectious contexts. Furthermore, we explore the vectoring capacity of exosomes in light of the extensive literature examining their function in mounting adaptive immune responses. Exosomes provide an interesting platform for antigen presentation and could therefore serve as novel therapeutic targets or be used in vaccine strategies.

Background: Aging rate is affected by genetic changes, epigenetic modifications, oxidative stress, inflammation, lifestyle and environmental factors. In accelerated aging (AA), biological age exceeds the chronological one. Objective: To undertake a critical reappraisal of the AA concept and to reveal its weaknesses and limitations. Methods: We reviewed over 300 recent articles dealing with physiology of brain aging and pathophysiology of neurodegeneration. Results: (1) Organ systems age at different rates, which interferes with application of the AA concept to individual organs. (2) Aging rate can be decelerated due to individual structure–functional reserves built with cognitive, physical training or pharmacological interventions. (3) The AA concept lacks standardised terminology and methodology. (4) Specific molecular biomarkers (MBM) reflect aging. To consolidate the AA theory, researchers should validate numerous MBM candidates. (5) Aging factors, mechanisms and the exact nature of their biological outcomes are not well understood. Conclusion: Although considered as a perspective theory, the AA concept has serious limitations and it requires an update.

Chronic Kidney Disease (CKD) is a major public health concern with an increasing proportion of sufferers progressing to renal replacement therapy (RRT). Early identification of those at risk of disease progression could be key in improving outcomes. We hypothesise that urinary liver-type fatty acid binding protein (uL-FABP) may be a suitable biomarker for CKD progression and can add value to currently established biomarkers such as urinary protein to creatinine ratio (uPCR) 583 participants with CKD 1-5 (not receiving renal replacement therapy) entered a 2-yr prospective longitudinal study. UPCR and uL-FABP were measured at baseline and CKD progression was defined as either i) a decline in eGFR of >5ml/min/1.73m2 or an increase in serum creatinine by 10% at 1-yr or ii) a decline in eGFR of >6 ml/min/1.73m2, or an increase in serum creatinine by 20% at 2-yrs or iii) the initiation of RRT. A combined outcome of initiating RRT or death was also included. Approximately 40% of participants showed CKD progression. UL-FABP predicted CKD progression at both years 1 and 2 (OR 1.01, p<0.01). Sensitivity and specificity were comparable to those of uPCR (AUC 0.623 v 0.706) and heat map analysis suggested that uL-FABP in the absence of significant proteinuria can predict an increase in serum creatinine of 10% at 1yr and 20% at 2yr. The risk of the combined outcome of initiating RRT or death was 23% higher in those with high uL-FABP (p<0.01) independent of uPCR. UL-FABP appears to be a highly sensitive and specific biomarker of CKD progression. The use of this biomarker could enhance the risk stratification of CKD and its progression and should be assessed further.

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.

Congestion not only represents a cardinal sign of heart failure but is also now recognized as the primary cause for hospital admissions, rehospitalizations, and mortality among patients with acute heart failure. Congestion can manifest through various heart failure phenotypes in acute settings: volume overload, volume redistribution, or both. Recognizing the congestion phenotype is paramount, as it implies different therapeutic strategies for decongestion. Complete decongestion is hardly achieved among patients with acute heart failure, as more than half still have residual congestion at discharge. Residual congestion is one of the strongest predictors of future cardiovascular events and poor outcomes. Through this review, we try to provide a better understanding of the congestion phenomenon among patients with acute heart failure by highlighting insights into the pathophysiology mechanisms behind congestion and new diagnostic and management tools to achieve and maintain efficient decongestion.

Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare autosomal recessive lysosomal storage disease (LSD) caused by deficiency of a hydrolase enzyme, N-acetylgalactosamine-6-sulfate sulfatase, and characterized clinically by mainly musculoskeletal manifestations. The mechanisms underlying bone involvement in humans are typically explored using invasive techniques such as bone biopsy, which complicates analysis in humans. We compared bone proteomes using DDA and SWATH-MS in wild-type and MPS IVA knockout mice to obtain mechanistic information about the disease. Our findings reveal over 1000 dysregulated proteins in knockout mice, including those implicated in oxidative phosphorylation, oxidative stress (reactive oxygen species), DNA damage, and iron transport, and suggest that lactate dehydrogenase may constitute a useful prognostic and follow-up biomarker. Identifying biomarkers that reflect MPS IVA clinical course, severity, and progression have important implications for disease management.

The study explored the correlation between serum biomarkers and hepatocellular carcinoma detection in various fishing groups, utilizing a descriptive and experimental approach in Bangladesh. The study identified fishers often consume tobacco, polluted drinking water, and lack sufficient sunlight, all of which are extremely detrimental to their health. Fishermen who mostly fish at night and spend little time on the water during the daytime hours do not get enough sunlight, nor do they get enough vitamin D. An increased risk of liver cancer was found to be directly and strongly correlated with insufficient serum levels of vitamin D. In addition, a negligent lifestyle, a lack of awareness about hepatitis, and inadequate nutritional assistance have significantly increased their risk. Our results contribute to the information on HCC assessment and evaluation by clarifying the relevance of serum vitamin D, alpha-fetoprotein (AFP), creatinine (Cr), and hemoglobin A1C (HbA1c) in distinguishing between categories and sexes. According to the study, the combination of AFP, Vitamin-D, and Cr (AFP+Vit-D+Cr) has a high predictive value, which improves diagnosis and offers a reliable instrument for identifying liver cancer.

Atrial fibrillation (AF), a complex cardiac arrhythmia, necessitates a shift in management paradigms, emphasizing an integrative approach that incorporates lifestyle modifications. Investigations into the role of interleukins and inflammatory mediators are underway, exploring their potential as diagnostic markers and predictors of cardiovascular events in AF. Despite the identification of biomarkers related to cardiac remodeling, their predictive ability for post-cardioversion outcomes remains controversial. Computational models are being developed to understand proarrhythmic contributions and identify anti-AF targets. Addressing the rising global incidence of AF, linked to stroke and heart failure, presents a critical health challenge. As risk factors like obesity prevail, AF becomes a pervasive public health concern, expected to double in prevalence over the next 50 years. The impact on mortality and morbidity, especially through hospitalizations, underscores the need for early detection and effective clinical management. Identifying individuals at increased AF risk becomes crucial for screening and prevention strategies. Lifestyle modifications, including weight management and physical activity, emerge as influential factors in AF management, offering the potential to alleviate symptoms and modify disease progression. The paper concludes by emphasizing the need for safer antiarrhythmic therapies based on AF mechanisms, promising improvement in global AF management. The multifaceted nature of AF etiology requires a broader perspective beyond traditional medical interventions, acknowledging the importance of integrated care to address this significant public health challenge.

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.

Early diagnosis and appropriate treatments are crucial to reducing mortality risk in septic patients. Low SOFA scores and current biomarkers may not discern adequately patients that could develop severe organ dysfunction or have an elevated mortality risk. The aim of this prospective observational study is to evaluate the predictive value of the biomarkers midregional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-Reactive Protein (CRP), and lactate for 28-day mortality in patients with sepsis and a SOFA score ≤ 6. 284 patients were included, with a 28-day all-cause mortality of 8.45 % (N=24). Non-survivors were older (p=0.003), required mechanical ventilation (p=0.04) and were ventilated for longer (p=0.02), had a higher APACHE II (p=0.015) and SOFA (p=0.027) scores. Lactate showed the highest predictive ability for all-cause 28-day mortality with an area under the receiver-operating characteristic curve (AUROC) of 0.67 (0.55–0.79). The AUROC for all-cause 28-day mortality in patients with community-acquired infection was 0.69 (0.57–0.84) for SOFA, and 0.70 (0.58–0.82) for MR-proADM. A 2.1 nmol/L cut-off point for this biomarker in this subgroup of patients discerned with 100% sensibility survivors from non-survivors at 28 days. In patients with community acquired sepsis and initial SOFA score ≤ 6, MR-proADM could help identify patients at risk of 28-day mortality.

In tropical areas, simultaneous transmission of several vector-borne diseases is common due to ecological factors that are shared by arthropod vectors. Malaria and dengue virus, transmitted by Anopheles and Aedes mosquitoes, respectively, are among the top vector-borne diseases that cause significant morbidity and mortality in endemic areas. Notably, tropical areas often have suitable conditions for the co-existence of these mosquito species, highlighting the importance of identifying markers that accurately indicate the risk of acquiring each specific disease entity. Aedes are daytime-biting mosquitoes, while Anopheles preferentially bite during the night. These biting patterns raises the possibility of concurrent exposure to bites from both species. This pattern is important since mosquito saliva, deposited in the skin during blood feeding, induces immune responses that modulate pathogen establishment and infection. Previous studies have focused on characterizing such effects on the vector-pathogen interface for an individual pathogen and its mosquito vector. In this study, we evaluated associations between immune responses to salivary proteins from non-dengue and non-malaria vector mosquito species with clinical characteristics of malaria and dengue, respectively. Surprisingly, antibody responses against Anopheles antigens in dengue patients correlated with red blood cell count and hematocrit, while antibody responses against Aedes proteins were associated with platelet count in malaria patients. Our data indicate that concurrent exposure to multiple disease-carrying mosquito vectors and their salivary proteins with differing immunomodulatory properties could influence the transmission, pathogenesis, and clinical presentation of malaria, dengue fever, and other vector-borne illnesses.

Bone metabolism is a complex process which is influenced by the activity of bone cells (e.g., osteocytes, osteoblasts, osteoclasts), the effect of some specific biomarkers (e.g., parathyroid hormone, vitamin D, alkaline phosphatase, osteocalcin, osteopontin, osteoportegerin, osterix, RANKL, Runx2) and the characteristic signaling pathways (e.g., RANKL/RANK, Wnt/β, Notch, BMP, SMAD). Some phytochemical compounds such as flavonoids, tannins, polyphenols, anthocyanins, terpenoids, polysaccharides, alkaloids and others presented a beneficial and stimulating effect in the bone regeneration process due to pro-estrogenic activity, antioxidant and anti-inflammatory effects and modulation of bone signaling pathways. Lately, nanomedicine has emerged as an innovative concept for new treatments in bone related pathologies envisaged by incorporation of medicinal substances in nanometric systems for oral or local administration, as well as in nanostructured scaffolds with huge potential in bone tissue engineering.

Abstract Aim: The study aimed to evaluate the clinical laboratory features of moderate and severe COVID-19 patients among a cohort of the Egyptian population. The study also aimed to assess the accuracy—sensitivity, specificity, and area under the curve (AUC) of various detected parameters in predicting the severity of COVID-19 infection. Patients and methods: One hundred diagnosed COVID-19 patients and fifty healthy participants in total were involved in current study. COVID-19 patients were categorized based on how severe their symptoms into two groups. Estimates were made for serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, lactate dehydrogenase (LDH) and C-reactive protein (CRP) as well as white blood cells (WBCs) count, lymphocytes count, and hemoglobin content (Hb) content. Results: COVID-19 patients displayed increased serum levels of liver enzymes and CRP as well as WBCs count when compared to healthy individuals. On the other hand, Hb content, lymphocytes count, and albumin level fell in all COVID-19 patients. The severe group showed a statistically significant rise in liver enzymes, WBCs, and CRP levels, compared with moderate group. WBCs and lymphocytes counts were closely correlated with age, ALT, LDH, and CRP in all cases. WBCs and lymphocytes counts also had a negative correlation with albumin Level. Additionally, WBCs count, lymphocytes count, LDH activity and CRP level have higher AUC in severe than in moderate cases. WBCs count, LDH activity and CRP level have AUC above 0.80 in the severe group. Conclusion: The current investigation found a significant correlation between WBCs count, lymphocytes count, CRP level and liver injury in COVID-19 patients. WBCs count, lymphocytes count, LDH activity and CRP level were effective indicators for determining the severity of COVID-19.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder that can diminish the quality of life of both children and adults in academic, occupational, and social contexts. The kynurenine pathway (KP) contains a set of enzymatic reactions involved in tryptophan (TRP) degradation. It is known to be associated with the risk of developing ADHD. This review will address the KP and underlying mechanism of inflammation in ADHD. Potential inflammatory biomarkers reported in the most recent studies are summarized. Although a strong neuroimmunological basis has been established due to advances of recent neurobiological research, the pathophysiology of ADHD remains unclear.

Surgeons are increasingly faced with a challenging, ageing and frail patient population. A significant absence of biomarkers to stratify outcomes of patients undergoing emergency laparotomy exists. Inflammageing describes a state of chronic inflammation associated with ageing and frailty and may predict worse outcomes. This retrospective observational study evaluated pre-morbid inflammatory markers in the prognostication of elderly patients undergoing emergency laparotomy. Patients aged ≥65 years undergoing surgery between 01/04/2017 – 01/04/2022 were identified. Pre-admission and acute C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), total white cell count (WCC), neutrophil count (NC) and lymphocyte count (LC) data points were captured. Pre-operative risk stratification scores and postoperative outcomes were recorded using the National Emergency Laparotomy Audit (NELA) database. A cohort of 196 patients was included: 57.7% were female, median age of 74.5 years. High-risk (NELA risk of mortality ≥5%) and frail (clinical frailty scale ≥4) patients experienced a significantly longer hospital and critical care stay (p<0.05). Pre-admission ESR ≥16 and LC ≥4.1 were significantly associated with a longer critical care stay (p<0.05), however, no statistical significance was observed with CRP, WCC and NC in predicting adverse outcomes. We found an elevated pre-morbid ESR and LC identifies a potential inflammageing cohort that demonstrate worse outcomes following emergency laparotomy. The prognostication of elderly surgical patients remains a challenge and represents an area of research deserving of future attention.

Since first described by Dr. Tomisaku Kawasaki in 1967, the clinical diagnosis of Kawasaki disease (KD) has remained relatively unchanged. However, studies since then have suggested that diagnoses using only that original clinical criteria may lead to underdiagnosis. In this review, updated KD diagnostic methods, diagnostic methods for “atypical” KD, diagnostic pitfalls, and other differential diagnoses are discussed. Peripheral blood eosinophil showed important in distinguishing KD from febrile children. We review herein the current literature regarding new biomarkers, scoring systems, and microRNA panels that may aid in the diagnosis of KD, the importance of eosinophil and treatment updates.

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

The aim of our study was to assess the relationship between the concentration/activity of salivary stress biomarkers (cortisol, α-amylase) and the psychological profile of patients with oral lichen planus (OLP) and primary burning mouth syndrome (BMS). A total of 160 subjects participated in this cross-sectional study: 60 patients with OLP; 60 patients with primary BMS; 40 control subjects. Unstimulated whole saliva (UWS) was collected between 9 and 10 am. Salivary biomarkers were analyzed by enzyme-linked immunosorbent assay (ELISA). Psychological assessment was evaluated with the Depression, Anxiety, and Stress Scale (DASS-21). Patients with primary BMS had higher salivary cortisol concentrations and α-amylase activity (0.52 vs. 0.44 µg/dl; 160531 vs. 145804 U/L) compared with patients with OLP. Patients with primary BMS had statistically significantly higher scores for depression, anxiety, and stress compared with patients with OLP and control subjects (p <0.001, Kruskal-Wallis test). There was a strong positive correlation between anxiety and depression, stress and depression, stress and anxiety in patients with OLP and BMS (p <0.001 and p <0.001, respectively). There was a good positive correlation between symptom intensity (pain/burning) and psychological profile (depression, anxiety, stress) in patients with primary BMS (r=0.373, p=0.003; r=0.515, p <0.001; r=0.365, p= 0.004, respectively). Patients with BMS show a stronger association with mental disorders compared to patients with OLP. However, an interdisciplinary psychoneuroimmunological approach is equally important in both patient groups (OLP and BMS), regardless of whether mental disorders are the cause or the consequence.