SARS-CoV-2 infection triggers more potent antibody-dependent cellular cytotoxicity (ADCC) responses than mRNA-, vector-, and inactivated virus-based COVID-19 vaccines.

Neutralizing antibodies (NAbs) are elicited after infection and vaccination and have been well studied. However, their antibody-dependent cellular cytotoxicity (ADCC) functionality is still poorly characterized. Here, we investigated ADCC activity in convalescent sera from infected patients with wild-type (WT) severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or omicron variant compared with three coronavirus disease 2019 (COVID-19) vaccine platforms and postvaccination breakthrough infection (BTI). We analyzed ADCC activity targeting SARS-CoV-2 spike (S) and nucleocapsid (N) proteins in convalescent sera following WT SARS-CoV-2-infection (n = 91), including symptomatic and asymptomatic infections, omicron-infection (n = 8), COVID-19 vaccination with messenger RNA- (mRNA)- (BNT162b2 or mRNA-1273, n = 77), adenovirus vector- (n = 41), and inactivated virus- (n = 46) based vaccines, as well as post-mRNA vaccination BTI caused by omicron (n = 28). Correlations between ADCC, binding, and NAb titers were reported. ADCC was elicited within the first month postinfection and -vaccination and remained detectable for ≥3 months. WT-infected symptomatic patients had higher S-specific ADCC levels than asymptomatic and vaccinated individuals. Also, no difference in N-specific ADCC activity was seen between symptomatic and asymptomatic patients, but the levels were higher than the inactivated vaccine. Notably, omicron infection showed reduced overall ADCC activity compared to WT SARS-CoV-2 infection. Although post-mRNA vaccination BTI elicited high levels of binding and NAbs, ADCC activity was significantly reduced. Also, there was no difference in ADCC levels across the four vaccines, although NAbs and binding antibody titers were significantly higher in mRNA-vaccinated individuals. All evaluated vaccine platforms are inferior in inducing ADCC compared to natural infection with WT SARS-CoV-2. The inactivated virus-based vaccine can induce N-specific ADCC activity, but its relevance to clinical outcomes requires further investigation. Our data suggest that ADCC could be used to estimate the extra-neutralization level against COVID-19 and provides evidence that vaccination should focus on other Fc-effector functions besides NAbs. Also, the decreased susceptibility of the omicron variant to ADCC offers valuable guidance for forthcoming efforts to identify the specific targets of antibodies facilitating ADCC.

Laboratory Diagnosis of Intrathecal Synthesis of Immunoglobulins: A Review about the Contribution of OCBs and K-index.

The diagnosis of MS relies on a combination of imaging, clinical examinations, and biological analyses, including blood and cerebrospinal fluid (CSF) assessments. G-Oligoclonal bands (OCBs) are considered a "gold standard" for MS diagnosis due to their high sensitivity and specificity. Recent advancements have involved the introduced of kappa free light chain (k-FLC) assay into cerebrospinal fluid (CSF) and serum (S), along with the albumin quotient, leading to the development of a novel biomarker known as the "K-index" or "k-FLC index". The use of the K-index has been recommended to decrease costs, increase laboratory efficiency, and to skip potential subjective operator-dependent risk that could happen during the identification of OCBs profiles. This review aims to provide a comprehensive overview and analysis of recent scientific articles, focusing on updated methods for MS diagnosis with an emphasis on the utility of the K-index. Numerous studies indicate that the K-index demonstrates high sensitivity and specificity, often comparable to or surpassing the diagnostic accuracy of OCBs evaluation. The integration of the measure of the K-index with OCBs assessment emerges as a more precise method for MS diagnosis. This combined approach not only enhances diagnostic accuracy, but also offers a more efficient and cost-effective alternative.

Sex hormones differentially contribute to Parkinson disease in males: A multimodal biomarker study.

BACKGROUND AND PURPOSE: Parkinson disease (PD) presents relevant sex-related differences in epidemiology, pathophysiology, and clinical features, with males being more vulnerable to the disease. Sex hormones might have a role, as the experimental models suggest; however, human-based evidence is scarce. Here, we integrated multimodal biomarkers to investigate the relationships between circulating sex hormones and clinical-pathological features in male PD patients. METHODS: A cohort of 63 male PD patients underwent comprehensive clinical evaluation of motor and nonmotor disturbances; measurement of estradiol, testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) blood levels; and cerebrospinal fluid (CSF) assay of total α-synuclein, amyloid-ß-42, amyloid-ß-40, total tau, and phosphorylated-181 tau levels. A subgroup of 47 PD patients underwent brain volumetry by 3-T magnetic resonance imaging for further correlations. A control group of 56 age-matched individuals was enrolled for comparative analyses. RESULTS: Male PD patients had higher estradiol and testosterone levels than controls. Estradiol had independent inverse associations with Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 3 score and disease duration; it was also lower in nonfluctuating patients. Testosterone had inverse independent correlations with CSF α-synuclein and right globus pallidus volume. FSH and LH had age-dependent correlations with cognitive impairment and CSF amyloid-ß-42/amyloid-ß-40 ratio. CONCLUSIONS: The study suggested that sex hormones could differentially contribute to clinical-pathological features of PD in male patients. Whereas estradiol might have a protective role in motor impairment, testosterone might be involved in male vulnerability to PD neuropathology. Gonadotropins instead might mediate age-dependent phenomena of amyloidopathy and cognitive decline.

Partial Loss of Function ABCA12 Mutations Generate Reduced Deposition of Glucosyl-Ceramide, Leading to Patchy Ichthyosis and Erythrodermia Resembling Erythrokeratodermia Variabilis et Progressiva (EKVP).

Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.

OTX Genes in Adult Tissues.

OTX homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. Recently, their expression has also been reported in adult physiological and pathological tissues, including retina, mammary and pituitary glands, sinonasal mucosa, in several types of cancer, and in response to inflammatory, ischemic, and hypoxic stimuli. Reactivation of OTX genes in adult tissues supports the notion of the evolutionary amplification of functions of genes by varying their temporal expression, with the selection of homeobox genes from the "toolbox" to drive or contribute to different processes at different stages of life. OTX involvement in pathologies points toward these genes as potential diagnostic and/or prognostic markers as well as possible therapeutic targets.

The COVID-19 pandemic: viral variants and vaccine efficacy.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has prompted the scientific community and the pharmaceutical companies to put maximum efforts into developing vaccines to contain the spread of this disease. Presently, many vaccines have been developed and authorized for use in human beings in different countries. In particular, in Europe to date, the Pfizer-BioNTech, Moderna, AstraZeneca and Janssen COVID-19 vaccines have been authorized. All of them are based on a version of the spike (S) glycoprotein characterized at the beginning of the pandemic. However, they differ by their level of efficacy against COVID-19. SARS-COV-2, like other RNA viruses, mutates continually. Genome sequencing analysis shows a nucleotide substitution rate of about 1 × 10-3 substitutions per year that leads to the emergence of variants through point mutations, insertions, deletions and recombination. There is concern about the ability of the current vaccines to protect against emerging viral variants. Mutations in the S-glycoprotein may affect transmission dynamics and the risk of immune escape. In this review, we address the different technological platforms in use for developing COVID-19 vaccines, the impact of emerging viral variants on virus transmission, hospitalization, and response to current vaccines, as well as rare but important adverse reactions to them. Finally, different methods for measuring antibody response to the vaccines, including the importance of using the WHO International Standard to calibrate immunoassays accurately to an arbitrary unit, to reduce interlaboratory variation and to create a common language for reporting results, are reported.

Evaluation of serological anti-SARS-CoV-2 chemiluminescent immunoassays correlated to live virus neutralization test, for the detection of anti-RBD antibodies as a relevant alternative in COVID-19 large-scale neutralizing activity monitoring.

The Spike-Receptor Binding Domain (S-RBD) is considered the most antigenic protein in SARS-CoV-2 and probably the key player in SARS-CoV-2 immune response. Quantitative immunoassays may help establish an anti-RBD Abs threshold as an indication of protective immunity. Since different immunoassays are commercial, the standard reference method for the neutralizing activity is the live Virus Neutralization Test (VNT). In this study, anti-RBD IgG levels were detected with two chemiluminescent immunoassays in paucisymptomatic, symptomatic and vaccinated subjects, and their neutralizing activity was correlated to VNT titer, using SARS-CoV-2 original and British variant strains. Both immunoassays confirmed higher anti-RBD Abs levels in vaccinated subjects. Furthermore, despite different anti-RBD Abs median concentrations between the immunoassays, a strong positive correlation with VNT was observed. In conclusion, although the SARS-CoV-2 immune response heterogeneity, the use of immunoassays can help in large-scale monitoring of COVID-19 samples, becoming a valid alternative to VNT test for diagnostic routine laboratories.

Validation of a quantitative lateral flow immunoassay (LFIA)-based point-of-care (POC) rapid test for SARS-CoV-2 neutralizing antibodies.

With the widespread use of coronavirus disease 2019 (COVID-19) vaccines, a rapid and reliable method to detect SARS-CoV-2 neutralizing antibodies (NAbs) is extremely important for monitoring vaccine effectiveness and immunity in the population. The purpose of this study was to evaluate the performance of the RapiRead™ reader and the TestNOW™ COVID-19 NAb rapid point-of-care (POC) test for quantitative measurement of antibodies against the spike protein receptor-binding domain of severe respiratory syndrome coronavirus 2 (SARS-CoV-2) in different biological matrices compared to chemiluminescence immunoassay (CLIA) methods. Ninety-four samples were collected and analyzed using a RapiRead™ reader and TestNOW™ COVID-19 NAb kits for detecting neutralizing antibodies, and then using two CLIAs. The data were compared statistically using the Kruskal-Wallis test for more than two groups or the Mann-Whitney test for two groups. Specificity and sensitivity were evaluated using a receiver operating characteristic (ROC) curve. Good correlation was observed between the rapid lateral flow immunoassay (LFIA) test system and both CLIA methods. RapiRead™ reader/TestNOW™ COVID-19 NAb vs. Maglumi: correlation coefficient (r) = 0.728 for all patients; r = 0.841 for vaccinated patients. RapiRead™ reader/TestNOW™ COVID-19 NAb vs. Mindray: r = 0.6394 in all patients; r = 0.8724 in vaccinated patients. The time stability of the POC serological test was also assessed considering two times of reading, 12 and 14 minutes. The data revealed no significant differences. The use of a RapiRead™ reader and TestNOW™ COVID-19 NAb assay is a quantitative, rapid, and valid method for detecting SARS-CoV-2 neutralizing antibodies and could be a useful tool for screening studies of SARS-CoV-2 infection and assessing the efficacy of vaccines in a non-laboratory context.

Combined anti-SARS-CoV-2 IgA, IgG, and IgM Detection as a Better Strategy to Prevent Second Infection Spreading Waves.

Coronavirus disease (COVID-19) is challenging many health, economic, and social systems. RT-PCR assays are diagnosis gold standard; however, they can lead to false-negative results. Therefore, anti-SARS-CoV-2 IgG, IgM, and IgA investigation can play a complementary role in assessing the individuals immune status. Majority of serological tests focus on IgM and IgG although IgA are the main immunoglobulins involved in mucosal immunity. It has been reported that digestive symptoms may occur in the absence of any typical respiratory symptom. Thus, a complete screening, comprising IgA, IgM, and IgG detection could be more consistent and useful in patients with atypical symptoms or in paucisymptomatic cases. Current literature describes over 200 immunoassays available worldwide, pointing out a great results variability, depending on methodology or antigens' nature. In our study we evaluated anti-SARS-CoV-2 IgA, IgM, and IgG trend on a control group and on two COVID-19 patient groups (early and late infection time) with a lateral-flow combined immunoassay (LFIA) and an enzyme-linked immunosorbent assay (ELISA). Dissimilar antibodies time kinetics have been described in COVID-19 (decreasing IgM concentration with IgA/IgG persistence for a longer time; as well as persistent IgA, IgG, and IgM concentration); our results confirmed both of them depending on the methodology; therefore, it is difficult to compare different studies outcomes, suggesting the importance of a serological tests international standardization. Nevertheless, we propose a flowchart with combined anti-SARS-CoV-2 IgG/IgM/IgA detection as a screening on general population, where serological positivity should be considered as an "alert," to avoid and contain possible new outbreaks.

Performance evaluation of the new Chemiluminescence Immunoassay CL-1200i Thyroid Panel.

Aim of this work was to verify the analytical performance of thyroid panel tests measured by chemiluminescence immunoassay (CLIA) CL-1200i and to validate its efficacy as laboratory test for thyroid disorder.Serum samples were obtained by standard centrifugation, thawed and assayed in a blinded fashion, and in a single batch. This study compares the values of thyroid panel tests measured by Mindray CL-1200i chemiluminescent system to the Abbott platforms for TSH, FT3, FT4, and Beckman Coulter for Tg, TgAb, and TPOAb on patient serum samples. A total of 180 randomly selected patients including both hospitalized and ambulatory patients from the Policlinico Tor Vergata (PTV) of the University of Rome Tor Vergata were used. In all analyses performed, the thyroid panel tests of the Mindray platform showed discriminative ability to quantitatively assess the analyte involved in thyroid disease and disorder. This study verified that Mindray CL-1200i chemiluminescent system thyroid panel tests is a valid method for obtaining a quantitative analysis of thyroid disorders. It showed high diagnostic efficiency and could represent a valid tool with a potential reduction in time and workload for the diagnosis.

Post-decompression bubble and inflammation interactions: a non-extensive dynamical system model.

Inert gas bubbles in tissues and in blood have been historically considered as the only triggering factors for DCS, but now many other factors are considered to affect the final outcome of a decompression profile for a certain individual. In this sense, inflammation seems to play a relevant role, not only due to the physical damage of tissues by the bubbles, but as a potentiator of the process as a whole. The present study aims to put forward a mathematical model of bubble formation associated with an inflammatory process related to decompression. The model comprises four state-variables (inert gas pressure, inert gas bubbles, proinflammatory and inflammatory factors) in a set of non-linear differential equations. The model is non-extensive: inert gas transitions between liquid and gaseous phases do not change the concentration of the dissolved gas. The relationship between bubbles and inflammation is given through parameters that form a positive feedback loop. The results of the model were compared with the experimental results of echocardiography from volunteers in two dive/decompression profiles; the model shows a very good agreement with the empirical data and previews different inflammatory outcomes for different experimental profiles. We suggest that slight changes in the parameters' values might turn the simulations from a non-inflammatory to an inflammatory profile for a given individual. Therefore, the present model might help address the problem of DCS on a particular basis.

Clinical validation of a second generation anti-SARS-CoV-2 IgG and IgM automated chemiluminescent immunoassay.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has proven to be extremely contagious and has spread rapidly all over the world. A key aspect in limiting the virus diffusion is to ensure early and accurate diagnosis. Serological assays could be an alternative in increasing testing capabilities, particularly when used as part of an algorithmic approach combined with molecular analysis. The aim of this study was to evaluate the diagnostic accuracy of a second generation chemiluminescent automated immunoassay able to detect anti-SARS-CoV-2 immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies. Data are carried out on healthy subjects and other infectious diseases pre-pandemic sera, as controls, and on two different coronavirus disease 2019 hospitalized patient groups (early and late infection time). Data obtained have been analyzed in terms of precision, linearity, sensitivity and specificity. Specificities are: 100% for anti-SARS-CoV-2 IgG and 98% for anti-SARS-CoV-2 IgM, in all patient groups. Sensitivities are: 97%, 100%, and 98% for anti-SARS-CoV-2 IgG and 87%, 83%, and 86% for anti-SARS-CoV-2 IgM in the early infection, in the late infection and in the total patient group, respectively. The Mindray anti-SARS-CoV-2 IgG and IgM assays demonstrated higher sensitivity and specificity, indicating that IgG and IgM simultaneous detection is useful even in the early phases of infection.

Performance of a rapid antigen test in the diagnosis of SARS-CoV-2 infection.

Diagnostics is crucial for a prompt identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients, their isolation and treatment. Real-time PCR is the reference method for the diagnosis of SARS-CoV-2 infection; however, the unprecedented increase in the number of infections worldwide calls for faster and easy methods that do not require skilled personnel and special equipment. Rapid antigen tests have been developed and used as first line screening. Here, we assessed the performance of a rapid antigen test in comparison to a real-time qualitative PCR as gold standard. Fifty nasopharyngeal swabs from suspected cases of SARS-CoV-2 infection have been tested by Coris coronavirus disease 2019 Ag Respi-Strip test and Allplex 2019n-CoV assay. Of the 50 nasopharyngeal swabs tested, 11 were negative by both tests, 27 were negative by Ag test but positive by real-time PCR, and 12 were positive by both methods. PCR detected the 39 positive samples at a median cycle threshold (Ct) value of 22.78 (mean: 24.51; range: 13.59-39.6). In the 12 concordant samples, the median Ct value was 17.37. The sensitivity of the Ag test was 30.77% (95% confidence interval [CI]: 17.02%-47.57%), specificity 100% (95% CI: 71.51%-100.00%), positive predictive value 100%, negative predictive value 85.25% (95% CI: 82.42%-87.69%), and accuracy 86.15% (95% CI: 73.45%-94.28%). The level of agreement between the two tests was poor, k = 0.164. The Ag test performs well in the presence of high viral loads, whereas lower levels are missed. Considering the poor sensitivity of the method, real-time PCR remains the gold standard as front line screening for SARS-CoV-2 infection.

Evaluation of the Diesse Cube 30 touch erythrocyte sedimentation method in comparison with Alifax test 1 and the manual Westergren gold standard method.

The erythrocyte sedimentation rate (ESR) is a traditional nonspecific laboratory test used for the assessment of inflammation. Even if its usefulness is nowadays being largely debated, it is still considered a valuable laboratory test in selected clinical conditions, such as rheumatoid diseases, orthopedic infections and Hodgkin's lymphoma, and it can be used for the infectious, inflammatory, malignancies, and autoimmune diseases follow-up. The introduction of new methodologies on semi-automated and automated analyzers started about four decades ago and opened a new era of ESR analysis characterized by shorter assay time, use of (EDTA) undiluted blood, that increases sample stability and allows using a single sample for also other hematologic tests, and greater safety for laboratory personnel. In this context, the aim of this study was to evaluate the performances of new device Diesse Cube 30 touch, comparing it with Alifax Test 1 and with the gold standard Westergren method. The new Diesse Cube 30 touch for determination of the ESR shows a good correlation with the manual Westergren gold standard method in a shorter time, and in a standardized way, since all the phases of the test are automatized. The Diesse Cube 30 touch respect the manual gold standard method, displayed a small bias to confirm that the new automated test system tended to have a small bias for ESR values (mean positive bias +0.2 mm/h). The findings of the present study show that the Diesse Cube 30 touch Westergren-based method can be a valid alternative in laboratory analysis for the determination of ESR.

Post Zygotic, Somatic, Deletion in KERATIN 1 V1 Domain Generates Structural Alteration of the K1/K10 Dimer, Producing a Monolateral Palmar Epidermolytic Nevus.

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.

Anti-Inflammatory and Proliferative Properties of Luteolin-7-O-Glucoside.

Flavonoids display a broad range of structures and are responsible for the major organoleptic characteristics of plant-derived foods and beverages. Recent data showed their activity, and in particular of luteolin-7-O-glucoside (LUT-7G), in reduction of oxidative stress and inflammatory mechanisms in different physiological systems. In this paper, we tried to elucidate how LUT-7G could exert both antioxidant and anti-inflammatory effects in endothelial cells cultured in vitro. Here, we showed that LUT-7G is able to inhibit the STAT3 pathway, to have an antiproliferative action, and an important antioxidant property in HUVEC cells. These properties are exerted by the flavone in endothelial through the transcriptional repression of a number of inflammatory cytokines and their receptors, and by the inhibition of ROS generation. ROS and STAT3 activation has been correlated with the production of oxysterols and other hydroxylated fatty acids, and they have been recognized important as players of atherogenesis and cardiocirculatory system diseases. The analysis of the general production pathway of these hydroxylated species, showed a strong decrease of cholesterol hydroxylated species such as 7-alpha-hydroxicholesterol, 7-beta-hydroxicholesterol by the treatment with LUT-7G. This confirms the anti-inflammatory properties of LUT-7G also in the endothelial district, showing for the first time the molecular pathway that verify previous postulated cardiovascular benefits of this flavone.

The miR-133a, TPM4 and TAp63γ Role in Myocyte Differentiation Microfilament Remodelling and Colon Cancer Progression.

MicroRNAs (miRNAs) play an essential role in the regulation of a number of physiological functions. miR-133a and other muscular miRs (myomiRs) play a key role in muscle cell growth and in some type of cancers. Here, we show that miR133a is upregulated in individuals that undertake physical exercise. We used a skeletal muscle differentiation model to dissect miR-133a's role and to identify new targets, identifying Tropomyosin-4 (TPM4). This protein is expressed during muscle differentiation, but importantly it is an essential component of microfilament cytoskeleton and stress fibres formation. The microfilament scaffold remodelling is an essential step in cell transformation and tumour progression. Using the muscle system, we obtained valuable information about the microfilament proteins, and the knowledge on these molecular players can be transferred to the cytoskeleton rearrangement observed in cancer cells. Further investigations showed a role of TPM4 in cancer physiology, specifically, we found that miR-133a downregulation leads to TPM4 upregulation in colon carcinoma (CRC), and this correlates with a lower patient survival. At molecular level, we demonstrated in myocyte differentiation that TPM4 is positively regulated by the TA isoform of the p63 transcription factor. In muscles, miR-133a generates a myogenic stimulus, reducing the differentiation by downregulating TPM4. In this system, miR-133a counteracts the differentiative TAp63 activity. Interestingly, in CRC cell lines and in patient biopsies, miR-133a is able to regulate TPM4 activity, while TAp63 is not active. The downregulation of the miR leads to TPM4 overexpression, this modifies the architecture of the cell cytoskeleton contributing to increase the invasiveness of the tumour and associating with a poor prognosis. These results add data to the interesting question about the link between physical activity, muscle physiology and protection against colorectal cancer. The two phenomena have in common the cytoskeleton remodelling, due to the TPM4 activity, that is involved in stress fibres formation.

Biomarkers of Glyco-Metabolic Control in Hemodialysis Patients: Glycated Hemoglobin vs. Glycated Albumin.

Background and Objectives: Glycated hemoglobin (HbA1c) dosage is considered the gold standard in glycol-metabolic monitoring, but it presents limits, which can underestimate the glycemia trend. In this regard, it was introduced the glycated albumin (GA). The aim of the study is to verify the predictivity of the GA compared to HbA1c in identifying glyco-metabolic alterations in non-diabetic and diabetic hemodialysis (HD) patients. Materials and Methods: For this purpose, we conducted a multicenter study involving one analysis laboratory and six dialysis centers in the Lazio region (Rome, Italy). Both diabetic and non-diabetic HD patients represent the study population, and the protocol included five time points. Results: The analyzed data highlighted the ability of GA to predict changes in glycemic metabolism in HD patients, and GA values are not significantly influenced, like HbA1c, by dialysis therapy itself and by comorbidities of the uremic state, such as normochromic and normocytic anemia. Thus, GA seems to reflect early glyco-metabolic alterations, both in patients with a previous diagnosis of diabetes and in subjects without diabetes mellitus. As part of this study, we analyzed two HD patients (one diabetic and one non-diabetic) in which GA was more predictive of glycol-metabolic alterations compared to HbA1c. Our study confirms the need to compare classical biomarkers used for the monitoring of glyco-metabolic alterations with new ones, likely more reliable and effective in specific subgroups of patients in which the classic biomarkers can be influenced by the preexisting pathological conditions. Conclusions: In conclusion, our evidence highlights that in uremic patients, GA shows a better ability to predict glyco-metabolic alterations allowing both an earlier diagnosis of DM and a prompt modulation of the hypoglycemic therapy, thus improving the clinical management of these patients.

Clustering of recreational divers by their health conditions in a database of a citizen science project.

Divers Alert Network Europe has created a database with a large amount of dive-related data that has been collected since 1993 within the scope of the Diving Safety Laboratory citizen science project. The main objectives of this study are the grouping divers by their health information and revealing significant differences in diving parameters using data mining techniques. Due to the methodology of the project, data cleaning was performed before applying clustering methods in order to eliminate potential mistakes resulting from inaccuracies and missing information. Despite the fact that 63% of the data were lost during the cleaning phase, the remaining 1,169 "clean" diver data enabled meaningful clustering using the "two-step" method. Experienced male divers without any health problems are in Cluster 1. Male and female divers with health problems and high rates of cigarette smoking are in Cluster 2; healthy, overweight divers are in Cluster 3. There are significant differences in terms of dive parameters including pre- and post-dive conditions with respect to each group, such as: exercise level, alcohol consumption, thermal comfort, equipment malfunctions, and maximum depth. The study proves the usefulness of citizen science projects, while data collection methodologies can be improved to decrease potential mistakes resulting from inconsistencies, inaccuracies and missing information. It is hypothesized that if naturally occurring clusters of divers were identified it might be possible to identify risk factors arising from different clusters while merging the database with other dive accident databases in the future.