Biomarkers Of Disease Severity Research Articles

Clinical significance of serum lncRNA H19, GAS5, HAR1B and linc01783 levels in Parkinson's disease.

<p>Long noncoding RNAs (lncRNAs) are highly expressed in the brain and alterations in their levels have been shown in many neurodegenerative disorders. Evidence has shown that lncRNAs play role in the onset and progression of Parkinson&rsquo;s disease (PD) and it can be used as a potential therapeutic target. Our purpose was to detect whether the serum levels of four candidate lncRNAs H19, GAS5, HAR1B and LINC01783 are related with the clinical findings and treatment of PD or not.&nbsp;</p>. <p>83 patients and 50 healthy controls were included in this study. We assessed how severe the disease is, by using Hoehn Yahr (HY) staging and Unified PD rating scale (UPDRS). Venous blood samples were taken from the participants. Serum samples were centrifuged and stored at -80&deg;C until analysis. Expression levels of these lncRNAs were analyzed by a real-time PCR instrument after RNA isolation and complementary DNA synthesis in the laboratory.</p>. <p>There was no significant difference between PD patients and healthy controls in these lncRNAs&rsquo; serum levels. Just as sociodemographic characteristics, also onset type and right or left predominance of the disease, its duration and treatment did not differ in lncRNA levels. Solely, there was a significant negative correlation between GAS5 and HY and UPDRS scores. Patients with family history of PD had significantly higher levels of LINC01783.</p>. <p>Serum lncRNA GAS5 level may be a possible biomarker for disease severity in PD patients.&nbsp;</p>.

EVALUATION OF D-DIMER LEVEL AS A BIOMARKER OF DISEASE SEVERITY AND MORTALITY IN PATIENTS WITH COVID-19.

The aim: To examine risk factors and evaluate the use of D-dimer as a biomarker of disease severity and mortality in patients with COVID-19. Materials and methods: Data from a large NYU Langone Health system were analyzed to examine the prevalence of elevated D-dimer levels at first detection and the trend. A retrospective cohort study of 2,377 patients (NYU Langone Health) with severe COVID-19. Also we conducted a retrospective study based on the mortality database of 247 patients from COVID-19 at the Chernivtsi Regional Clinical Hospital. Results: Patients with elevated baseline D-dimer were more likely to have critical illness than patients with normal D-dimer (43.9% vs. 18.5%). The frequency of adverse events increased with increasing D-dimer levels. Individuals with D-dimer >2000 ng/mL had the highest risk of critical illness (66.0%). Conclusions: Thus, the level of D-dimer can be considered an important prognostic factor in COVID-19, as its level is elevated in the vast majority of patients with COVID-19 and correlates with a severe course and high mortality.

Nonalcoholic Fatty Liver Disease and MicroRNAs: A Weighty Consideration

MicroRNAs (miRNAs) are small endogenous, noncoding RNA molecules that regulate the expression of their target genes. The biological functions of miRNAs have been explored considerably. Numerous studies have demonstrated that extracellular miRNA could be implemented as a biomarker for several diseases. Nonalcoholic fatty liver disease (NAFLD) has become one of the leading causes of chronic liver disease worldwide. NAFLD embodies an array of defects extending from elementary steatosis to nonalcoholic steatohepatitis, which might advance to fibrosis, cirrhosis, and even hepatocellular carcinoma, which are closely linked to increased activity hepatic morbidity and mortality. Liver biopsy is acknowledged as the most precise practice for diagnosis and staging of NAFLD. Invasive drawbacks have prompted the likelihood of introducing an alternative noninvasive approach for consideration. Several lines of evidence have revealed that miRNAs are emerging as a potentially useful noninvasive marker for the development and progression of NAFLD. In addition, recent studies have identified that miRNAs take part in lipid metabolism linked to NAFLD and its advancement to severity. This article reviews the contemporary corroboration associating miRNAs and NAFLD and emphasizes the potential role of miRNA as a circulatory biomarker that could alert the growing prevalence of NAFLD. Furthermore, it acknowledges the valuable compendium of information regarding biogenesis and the role of circulating miRNA in lipid metabolism, which is intimately linked to NAFLD.

Extracellular Vesicles and Cellular Ageing.

Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies. Current animal studies and clinical trials are being performed to assess the safety and beneficial effects of stem cell engraftments for regenerative medicine in ageing and age-related diseases.Since alterations in cell-cell communication have been associated with the development of pathophysiological processes, new research is focusing on the modulation of the microenvironment. Recent research has highlighted the important role of some microenvironment components that modulate cell-cell communication, thus spreading signals from damaged ageing cells to neighbor healthy cells, thereby promoting systemic ageing. Extracellular vesicles (EVs) are small-rounded vesicles released by almost every cell type. EVs cargo includes several bioactive molecules, such as lipids, proteins, and genetic material. Once internalized by target cells, their specific cargo can induce epigenetic modifications and alter the fate of the recipient cells. Also, EV's content is dependent on the releasing cells, thus, EVs can be used as biomarkers for several diseases. Moreover, EVs have been proposed to be used as cell-free therapies that focus on their administration to slow or even reverse some hallmarks of physiological ageing. It is not surprising that EVs are also under study as next-generation therapies for age-related diseases.

Standardized airway wall thickness Pi10 from routine CT scans of COPD patients as imaging biomarker for disease severity, lung function decline, and mortality.

Chest computed tomography (CT) is increasingly used for phenotyping and monitoring of patients with COPD. The aim of this work was to evaluate the association of Pi10 as a measure of standardized airway wall thickness on CT with exacerbations, mortality, and response to triple therapy. Patients of GOLD grades 1-4 of the COSYCONET cohort with prospective CT scans were included. Pi10 was automatically computed and analyzed for its relationship to COPD severity, comorbidities, lung function, respiratory therapy, and mortality over a 6-year period, using univariate and multivariate comparisons. We included n = 433 patients (61%male). Pi10 was dependent on both GOLD grades 1-4 (p = 0.009) and GOLD groups A-D (p = 0.008); it was particularly elevated in group D, and ROC analysis yielded a cut-off of 0.26 cm. Higher Pi10 was associated to lower FEV1 % predicted and higher RV/TLC, moreover the annual changes of lung function parameters (p < 0.05), as well as to an airway-dominated phenotype and a history of myocardial infarction (p = 0.001). These associations were confirmed in multivariate analyses. Pi10 was lower in patients receiving triple therapy, in particular in patients of GOLD groups C and D. Pi10 was also a significant predictor for mortality (p = 0.006), even after including multiple other predictors. In summary, Pi10 was found to be predictive for the course of the disease in COPD, in particular mortality. The fact that Pi10 was lower in patients with severe COPD receiving triple therapy might hint toward additional effects of this functional therapy on airway remodeling. ClinicalTrials.gov, Identifier: NCT01245933.

Modulation of Indoleamine 2,3-Dioxygenase 1 During Inflammatory Bowel Disease Activity in Humans and Mice.

Indoleamine 2,3 dioxygenase-1 (IDO1), a key enzyme in tryptophan metabolism, is strongly up-regulated both in human inflammatory bowel disease (IBD) and animal models of colitis, however its role in the pathogenesis is still controversial. In this study, we investigated IDO1 expression and activity in a mouse model of DSS-induced chronic colitis as well as in colon biopsies and sera from IBD patients. Chronic colitis was induced in mice through the oral administration of dextran sodium sulfate (DSS), and IDO1 activity was induced by i.p. treatment with N-acetyl serotonin (NAS). IDO1 expression and catalytic activity (measured as Kyn/Trp ratio) was evaluated in sera and tissue samples collected from mice and 93 IBD patients under immunotherapy with Vedolizumab (VDZ) or Ustekinumab (UST). Strong up-regulation of IDO1 was found in colons of mice with acute colitis, which follows disease activity. Enhanced IDO1 activity by NAS treatment protects the intestinal mucosa during the recovery phase of chronic colitis. In IBD patients, IDO1 expression and activity correlate with the severity of mucosal inflammation with inflamed regions showing higher IDO1 expression compared to non-inflamed regions within the same patient. Endoscopic response to VDZ/UST treatment is associated with decreased expression of IDO1. This is the first study demonstrating immunomodulatory activity of IDO1 in a chronic mouse model of DSS-induced colitis. As its expression and catalytic activity correlate with the grade of mucosal inflammation and treatment response, IDO1 could represent a promising biomarker for disease severity and treatment monitoring in IBD.

Immunothrombosis and Complement Activation Contribute to Disease Severity and Adverse Outcome in COVID-19

Severe COVID-19 is characterized by systemic inflammation and multiple organ dysfunction syndrome (MODS). Arterial and venous thrombosis are involved in the pathogenesis of MODS and fatality in COVID-19. There is evidence that complement and neutrophil activation in the form of neutrophil extracellular traps are main drivers for development of microvascular complications in COVID-19. Plasma and serum samples were collected from 83 patients infected by SARS-CoV-2 during the two first waves of COVID-19, before the availability of SARS-CoV-2 vaccination. Samples were collected at enrollment, day 11, and day 28; and patients had differing severity of disease. In this comprehensive study, we measured cell-free DNA, neutrophil activation, deoxyribonuclease I activity, complement activation, and D-dimers in longitudinal samples of COVID-19 patients. We show that all the above markers, except deoxyribonuclease I activity, increased with disease severity. Moreover, we provide evidence that in severe disease there is continued neutrophil and complement activation, as well as D-dimer formation and nucleosome release, whereas in mild and moderate disease all these markers decrease over time. These findings suggest that neutrophil and complement activation are important drivers of microvascular complications and that they reflect immunothrombosis in these patients. Neutrophil activation, complement activation, cell-free DNA, and D-dimer levels have the potential to serve as reliable biomarkers for disease severity and fatality in COVID-19. They might also serve as suitable markers with which to monitor the efficacy of therapeutic interventions in COVID-19.

Critical and non-critical coronavirus disease 2019 patients: which is the most predictive biomarker for disease severity and outcome?

BACKGROUND Severe acute respiratory syndrome-coronavirus-2 in coronavirus disease 2019 (COVID-19) patients leads to a wide range of clinical manifestations. The evaluation of mid-regional pro-adrenomedullin (MR-proADM) as a prognostic biomarker in noncritical wards (NON-ICU) and intensive care units (ICU), may have a potential in predicting disease severity and outcomes. OBJECTIVE To assess the difference in the prognostic power of MR-proADM in NON-ICU wards and in ICUs in a prospective multicentre cohort study. DESIGN From January to July 2021, all adult COVID-19 patients requiring admission for more than 48 h. SETTING One primary centre and two secondary centre hospitals. PATIENTS One hundred and twenty-three ICU and 77 NON-ICU patients. INTERVENTION MR-proADM, lymphocyte subpopulations and immunoglobulins were measured within 48 h and on days 3 and 7. A Log-rank test was used to compare survival curves, using a MR-proADM cut-off value of 1.5 nmol l−1. The predictive ability for mortality was compared using the area under the curve and 95% confidence interval (CI) of different receiver-operating characteristic curves. MAIN OUTCOME MEASURES The first 48 h MR-proADM values were significantly higher in the ICU group (median value 1.10 [IQR, 0.80 to 1.73] pg ml−1 vs. 0.90 [0.70 to 1.20] pg ml−1, P = 0.020), and statistically significant changes were observed over time for MR-proADM, CD3+, CD4+ and CD56+. In univariate analysis, MR-proADM was the only biomarker that significantly predicted mortality (P = 0.006). The logistic regression model showed an odds ratio for mortality equal to 1.83 (95% CI, 1.08 to 3.37) P = 0.035 for MR-proADM, 1.37 (1.15 to 1.68) P = 0.001 for MuLBSTA and 1.11 (1.05 to 1.18) P less than 0.001 for SAPS II. CONCLUSION MR-proADM admission values and trends over time appear to be a suitable marker of illness severity and a patient's risk of mortality in both ICU and NON-ICU settings. Lymphocyte subpopulation dysfunction seems to play a role in defining the severity of COVID-19 but is limited to ICU setting. TRIAL REGISTRATION on clinicaltrials.gov, NCT04873388 registered on March 2020.

Analysis of differential gene expression of pro-inflammatory cytokines in the nasopharyngeal milieu of mild & severe COVID-19 cases.

A subset of individuals with COVID-19 can suffer from a severe form of the disease requiring breathing support for respiratory failure and even death due to disease complications. COVID-19 disease severity can be attributed to numerous factors, where several studies have associated changes in the expression of serum pro-inflammatory cytokines with disease severity. However, very few studies have associated the changes in expression of pro-inflammatory changes in the nasopharyngeal milieu with disease severity. Therefore, in the current study, we performed differential gene expression analysis of various pro-inflammatory cytokines in the nasopharyngeal milieu of mild & severe COVID-19 cases. For this retrospective, cross-sectional study, a total of 118 nasopharyngeal swab samples, previously collected from mild and severe (based on the WHO criteria) COVID-19 patients were used. A real-time qPCR was performed to determine the viral loads and also evaluate the mRNA expression of eight cytokines (IL-1, IL-2, IL-4, IL-6, IL-10, IFN-γ, TGF-β1, and TNF-α). Subsequently, an unpaired T-test was applied to compare the statistical difference in mean expression of viral loads and each cytokine between the mild and severe groups, while the Pearson correlation test was applied to establish a correlation between disease severity, viral load, and cytokines expression. Similarly, a multivariable logistic regression analysis was performed to assess the relationship between different variables from the data and disease severity. Out of 118 samples, 71 were mild, while 47 were severe. The mean viral load between the mild and severe groups was comparable (mild group: 27.07± 5.22; severe group: 26.37 ±7.89). The mRNA expression of cytokines IL-2, IL-6, IFN- γ, and TNF-α was significantly different in the two groups (p<0.05), where the Log2 normalized expression of IL-2, IL-6, IFN- γ, and TNF-α was found to be 2.2-, 16-, 2.3-, and 1.73-fold less in the severe group as compared to the mild group. Furthermore, we also observed a significant positive correlation between all the cytokines in the severe group. The multivariate analysis showed a significant relationship between age, IL-6, and disease severity. This decreased expression of certain cytokines (IL-2, IL-6, TNF-α, and IFN-γ) in the nasopharyngeal milieu may be considered early biomarkers for disease severity in COVID-19 patients.

The role of the immune system in the formation and development of diseases of the oral cavity

Aims: the goals were to clarify immune mechanisms involved in the pathogenesis of oral diseases, as well as to identify biomarkers of disease severity, to assess the impacts of environmental factors on immune responses, and to explore immune-modulating therapeutic interventions. Study design: a narrative literature review. Place and Duration of Study: from 2019 to 2022. Methodology: a narrative review using the keywords "Immune System AND Oral Cavity" identified 15,438 studies on PubMed. Refinement excluded articles published before 2019 or after 2022, and those that were not trials or studies, resulting in a total of 41 articles. Following assessment, 15 only highly relevant articles were included into the review. Results: This narrative review has explored the involvement of the immune system in the development and progression of oral diseases. The key lessons were shown through the underlying mechanisms consisting of inflammatory mediators in the cases of oral graft-versus-host disease and oral lichen planus and the progression of oral cells cancer. The research uncovered the impact of the immune system on conditions such as periodontitis, highlighting the potential predictive utility of oral biomarkers in diagnosing disease progression and metastasis. Also, the modulation of the immune response was shown to be another possible approach for patient management in oral health field, thereby, facilitating new strategies. As a whole, these findings shed light on the massive body of targeted research into the specific immune pathways. This underscored the necessity for developing interventions that navigate the intricate interplay between the immune system and oral diseases. Conclusion: The narrative review illustrated that the immune system is dual faced in the oral cavity, being a factor that influences the final outcome without excluding the significance of other factors. It was established that distinct immunological profiles exist for numerous oral disorders, where the factors like IFN-γ and TNF can be taken as biomarkers for diagnosis and therapy.

The role of the immune system in the formation and development of diseases of the oral cavity

Aims: the goals were to clarify immune mechanisms involved in the pathogenesis of oral diseases, as well as to identify biomarkers of disease severity, to assess the impacts of environmental factors on immune responses, and to explore immune-modulating therapeutic interventions. Study design: a narrative literature review. Place and Duration of Study: from 2019 to 2022. Methodology: a narrative review using the keywords "Immune System AND Oral Cavity" identified 15,438 studies on PubMed. Refinement excluded articles published before 2019 or after 2022, and those that were not trials or studies, resulting in a total of 41 articles. Following assessment, 15 only highly relevant articles were included into the review. Results: This narrative review has explored the involvement of the immune system in the development and progression of oral diseases. The key lessons were shown through the underlying mechanisms consisting of inflammatory mediators in the cases of oral graft-versus-host disease and oral lichen planus and the progression of oral cells cancer. The research uncovered the impact of the immune system on conditions such as periodontitis, highlighting the potential predictive utility of oral biomarkers in diagnosing disease progression and metastasis. Also, the modulation of the immune response was shown to be another possible approach for patient management in oral health field, thereby, facilitating new strategies. As a whole, these findings shed light on the massive body of targeted research into the specific immune pathways. This underscored the necessity for developing interventions that navigate the intricate interplay between the immune system and oral diseases. Conclusion: The narrative review illustrated that the immune system is dual faced in the oral cavity, being a factor that influences the final outcome without excluding the significance of other factors. It was established that distinct immunological profiles exist for numerous oral disorders, where the factors like IFN-γ and TNF can be taken as biomarkers for diagnosis and therapy.

Baseline electrolyte disorders predict disease severity and mortality in patients with COVID-19

Distinguishing critical laboratory biomarkers for disease severity at the time of hospital presentation is important for early identification of patients who are most likely to have poor outcomes and effective use of health resources. This study aimed to evaluate whether electrolyte imbalances on hospital admission predict severe disease and mortality in patients with coronavirus disease 2019 (COVID-19). We retrospectively collected data on the blood electrolyte concentrations of 286 COVID-19 patients at admission. The correlations between electrolyte imbalances, inflammation, and thrombosis markers in COVID-19 patients were also evaluated. We assessed the predictive performance of baseline blood electrolyte concentrations for severe disease and death using receiver operating characteristic curve analysis and multivariate logistic regression methods. Abnormalities in serum sodium, calcium, and potassium levels at admission were found at 20.6%, 14%, and 4.2%, respectively in this study. In the receiver operating characteristic curve analyses, hypocalcemia and hyponatremia effectively predicted disease progression to hospitalization (area under the curve 0.82, P < .001 and 0.81, P < .001, respectively) and 30-day mortality (area under the curve 0.85, P < .001 and 0.91, P < .001, respectively). In the multivariate logistic regression analysis, baseline hypocalcemia was identified as an independent risk factor associated with the risk of hospitalization (β = 2.019, P = .01; odds ratio: 7.53). Baseline hypocalcemia and hyponatremia effectively predicted disease progression toward hospitalization and 30-day mortality in patients with COVID-19. Clinicians should closely follow up or reevaluate COVID-19 patients with baseline electrolyte disorders.

538. Human neutrophil gelatinase-associated protein (N-gal) and proinflammatory cytokines as biomarkers of disease severity in children with Hemolyitic Uremic Syndrom (HUS) and Shigatoxin-producing E.coli (STEC) infection.

Abstract Background Hemolytic Uremic Syndrome (HUS) is a complication of Shigatoxin-producing E.coli (STEC) infection which presents a characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Preliminary in vitro and experimental animal studies demonstrated that Shigatoxins (STXs) induce the secretion of proinflammatory cytokines. Human neutrophil gelatinase-associated protein (N-gal) has been reported as a marker of acute kidney injury. Dosing serum levels of IL-8, TNF-α, IL-6, IL-1β and N-gal in children with STEC-associated infection and HUS would allow to establish the role of these cytokines as biomarkers of renal injury and severity Methods Prospective study during 2017 – 2020 was performed; three groups of patients &amp;lt; 18 years were included: bloody diarrhea (BD), HUS requiring dialysis (HUSD) and HUS and no dialysis requirement (HUSND), all of them with presence of STX in stool. Blood samples were collected at diagnosis (t1) and at 7 days (t2). An immunoassay was used for detection of TNF-α, IL-1β, IL-6, and IL-8 (Bio-Plex Pro Human®, BioRad). An immunoassay (Anti-Lipocalin-2) was used for N-gal detection Results Forty-nine children were admitted; 22 (49%) were male. Median age was 24 (IQR 13-36) months. Fourteen patients with BD, 24 patients with HUS: 12 HUSD and 12 HUSND. Eleven healthy children (HC) were included. At diagnosis, higher IL-8 values were found in HUSD vs. BD (p=0.0004), HUSND (0.003) and HC (p= 0.0043). Higher TNF-α values were detected in HUSD vs. BD (P= 0.0001), HUSND (p= 0.0011) and HC (p= 0.0002). Higher TNF-α values were found in patients with BD vs HC (p= 0.0055). HUSD exhibited higher IL-6 values as compared with BD (p= 0.0145) and HC (0.0106). N-gal concentrations were higher in HUSD vs. BD (P= 0.0120), HUSND (P= 0.0166) and HC (p= 0.0049). A decrease in IL-8 was observed in HUSD between t1 and t2 (p=0.0357). (Figure 1) Conclusion Interleukin 8, IL-6, and N-gal may be considered as potential serological markers of renal damage and dialysis requirement. TNF-α concentrations are already increased in BD without HUS complications Disclosures All Authors: No reported disclosures.

Sex difference in circulating soluble form of ACE2 protein in moderate and severe COVID-19 and healthy controls.

Membrane-bound angiotensin-converting enzyme-2 (ACE2) in epithelial cells is the main receptor for SARS-CoV-2. The extracellular portion of ACE2 may be shedded to plasma in which process ADAM17 (a disintegrin and metalloproteinase 17) is important. Results on the relationship between circulating levels of the soluble form of ACE2 (sACE2) and disease severity are inconclusive. This study investigates if sACE2 concentration correlates with COVID-19 severity, and whether this is affected by sex. Soluble form of ACE2 was analyzed in three groups: 104 patients (23 women and 81 men) with severe COVID-19 admitted to an intensive care unit (ICU), patients with moderate COVID-19 who required hospital care (n = 19, 4 women and 15 men), and age and sex matched healthy controls (n = 20, 4 women and 16 men). Blood samples were collected at hospital admission between 18 March 2020, and 3 May 2021, and at follow-up between 27 October 2020, and 19 October 2021. Circulating sACE2 (μg/L) was measured in EDTA plasma with a sensitive enzyme-linked immunosorbent assay. Additionally, CRP, ferritin, and lymphocyte count were analyzed during hospital stay. In total, 23 patients (22%) died in the ICU. When comparing healthy controls [mean age 58.1 (SD 11.4) years] and patients with moderate COVID-19 [mean age 61.0 (SD 13.2) years] with patients in the ICU [mean age 63.6 (SD 11.6) years], we found that sACE2 concentration decreased (70% reduction) with disease severity in men (p = 0.002) but increased 3.7-fold with severity in women (p = 0.043), suggesting a sex-related difference in how COVID-19 severity is related to sACE2 concentration. Moreover, we identified a relationship between inflammatory biomarkers and sACE2 concentration during the intensive care treatment, such that higher CRP and higher ferritin concentration correlated with lower sACE2 concentration in men. The decrease in sACE2 concentration, selectively in men, in severe COVID-19 is of pathophysiological interest since men are affected more severely by the disease compared to women. Additionally, the inflammatory biomarkers, CRP and ferritin, correlated inversely with sACE2 concentration, suggesting a role in severe disease. Our findings imply that sACE2 is a possible biomarker of disease severity in a sex-specific manner.

Altered brain white matter structural motor network in spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 is a disorder within the brain network. However, the relationship between the brain network and disease severity is still unclear. This study aims to investigate changes in the white matter (WM) structural motor network, both in preclinical and ataxic stages, and its relationship with disease severity. For this study, 20 ataxic, 20 preclinical SCA3 patients, and 20 healthy controls were recruited and received MRI scans. Disease severity was quantified using the SARA and ICARS scores. The WM motor structural network was created using probabilistic fiber tracking and was analyzed using graph theory and network-based statistics at global, nodal, and edge levels. In addition, the correlations between network topological measures and disease duration or clinical scores were analyzed. Preclinical patients showed increasing assortativity of the motor network, altered subnetwork including 12 edges of 11 nodes, and 5 brain regions presenting reduced nodal strength. In ataxic patients assortativity of the motor network also increased, but global efficiency, global strength, and transitivity decreased. Ataxic patients showed a wider altered subnetwork and a higher number of reduced nodal strengths. A negative correlation between the transitivity of the motor network and SARA and ICARS scores was observed in ataxic patients. Changes to the WM motor network in SCA3 start before ataxia onset, and WM motor network involvement increases with disease progression. Global network topological measures of the WM motor network appear to be a promising image biomarker for disease severity. This study provides new insights into the pathophysiology of disease in SCA3/MJD.

A virological view of tenascin-C in infection.

Tenascin-C is a large extracellular matrix glycoprotein with complex, not yet fully unveiled roles. Its context- and structure-dependent modus operandi renders tenascin-C a puzzling protein. Since its discovery ∼40 years ago, research into tenascin-C biology continues to reveal novel functions, the most recent of all being its immunomodulatory activity, especially its role in infection, which is just now beginning to emerge. Here, we explore the role of tenascin-C in the immune response to viruses, including SARS-CoV-2 and HIV-1. Recently, tenascin-C has emerged as a biomarker of disease severity during COVID-19 and other viral infections, and we highlight relevant RNA sequencing and proteomic analyses that suggest a correlation between tenascin-C levels and disease severity. Finally, we ask what the function of this protein during viral replication is and propose tenascin-C as an intercellular signal of inflammation shuttled to distal sites via exosomes, a player in the repair and remodeling of infected and damaged tissues during severe infectious disease, as well as a ligand for specific pathogens with distinct implications for the host.

The association of serum total bile acid with new-onset hypertension during pregnancy

BackgroundThere has been considerable interest in the interrelationship between the liver and hypertension. The relationship between serum total bile acid (TBA) and hypertension has been reported. Moreover, intrahepatic cholestasis of pregnancy was correlated to gestation hypertension. However, the association between maternal serum TBA level in the normal range and new-onset hypertension disorders during pregnancy remains unclear. The present study aimed to evaluate the relationship between maternal serum TBA level in the normal range and the risk, disease severity and adverse pregnancy outcomes of new-onset hypertension during pregnancy.MethodUsing the electronic medical records on all pregnant women from the Department of Obstetrics and Gynecology, Third Affiliated Hospital of Guangzhou Medical University, between 2014 and 2020, we conducted a retrospective cohort study of 2581 singleton pregnant women with maternal serum TBA levels in the normal range. Patients were grouped into the non-hypertension during pregnancy (1071), gestational hypertension (480) and preeclampsia (1030) groups.ResultWe found that maternal serum TBA levels were significantly higher in the preeclampsia and gestational hypertension groups than in the non-hypertension group (p < 0.01). Multiple logistic regression analysis showed that TBA level was independently and significantly associated with preeclampsia and gestational hypertension (odds ratio: 1.37, 95% confidence interval [CI]: 1.27–1.48, p = 0.001, odds ratio: 1.34, 95% confidence interval [CI]: 1.24–1.46, p = 0.005, respectively). Moreover, elevated TBA level was positively associated with the risk of severe PE and negatively with mild PE (p < 0.01). In addition, maternal serum TBA levels were negatively related to birth weight (p < 0.001).ConclusionsThese results suggest that maternal serum TBA in the normal range also might be a valuable biomarker for disease severity in preeclampsia and gestational hypertension. Additionally, our results also indicate associations of serum total bile acid levels in the normal range with an increased risk of fetal growth restriction and low birth weight among offspring. These results suggest that TBA could serve as a prognostic biomarker for new-onset hypertension during pregnancy.

Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis

BackgroundThe increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients.MethodsTreatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed.ResultsFingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment.ConclusionOur data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.

Differentially Expressed Proteins in Transfusion-Dependent Thalassemia (TDT) and Their Role in Tdt Disease Severity

Introduction: The management of transfusion-dependent thalassemia (TDT) has seen essential improvements; however, still several challenges to controlling the incidence worldwide. Limitations of available current treatment modalities in resource-limited countries are the driving force to investigate the novel diagnostic and therapeutic options for better clinical management of these patients. Proteomics may be a potential technique to identify novel biomarkers of disease severity and understand the pathophysiological mechanisms of TDT, as proven in many other diseases. Understanding the inter-relationships of proteins affected by the disease process, such as oxidative stress in TDT patients, can help to elucidate the mechanisms involved in the disease pathophysiology. However, plasma proteome profile studies in TDT are limited. This study aimed to investigate the differentially expressed proteins (novel proteins) in serum from TDT to understand the pathophysiology of TDT and determine their role in TDT severity by performing quantitative serum proteomics profiling. Methods: The sample size was calculated based on the sensitivity and specificity of the protein biomarkers identified in the pilot study. A total of 64 patients were included in this study. A serum sample was collected from 32 TDT patients and 32 non-thalassemia controls. Before the serum samples could be processed for label-free quantification using the liquid chromatography-mass spectrometry/mass spectrometry (LCMS/MS) approach, high abundance proteins such as serum albumin and immunoglobulins were depleted using Pierce™ Albumin/IgG Removal Kit (Thermo Fisher Scientific, USA.) according to the manufacturer's protocols. The protein content in samples after depletion of high abundance proteins was determined using the Bradford assay using the protocol recommended by the manufacturer protocol (BioRad, USA). Each protein sample was prepared for LC-MS/MS analysis using EasyPep™ Mini MS Sample Prep Kit (Thermo Fisher Scientific, USA). Analysis of sera was performed on the Agilent 6560C ion mobility Q-TOF LC/MS system (Agilent, USA). To validate the LCMS/MS results, ELISA was done. Differentially regulated proteins with p-value <0.05 were identified from the dataset and uploaded to online databases PANTHER to classify and identify the proteins' functions. The functional gene ontology (GO) annotation of the identified protein in terms of molecular function, biological process, and cellular component was evaluated using this curated biological database. The statistically significant expressed proteins were submitted to STRING, and a combined score of >0.4 (medium confidence) was considered experimentally validated and statistically significant interactions between proteins. The cluster with the largest number of proteins with strong connections was identified for the pathway enrichment analysis. The identified protein cluster from the STRING database was uploaded to the KEGG online database to acquire the enriched pathway. Results: 51 dysregulated proteins were found between cases and controls (Table). However, only 13 showed statistically significant differential expression (p <0.05) with a fold change >1, and mostly were downregulated. Gene ontology functional annotation analysis showed these proteins were involved in molecular functions, mainly catalytic activities (37%), followed by molecular function regulation (15%). The biological processes primarily involved the cellular (35.5%) and metabolic processes (32.3%). The pathway analysis showed that these proteins were involved mainly in hemostasis. In KEGG pathway analysis, the proteins were involved primarily in fat digestion and absorption and vitamin digestion & absorption. Conclusion: We elucidated the possible biological processes modulated by oxidative stress using the differentially expressed novel proteins and the associated pathways using comprehensive molecular and biocomputational analysis. Interestingly, most of the differentially expressed proteins in this study have not been yet reported in previous studies to be modulated by oxidative stress in TDT patients. Therefore, the identified dysregulated proteins can serve as a potential biomarker to monitor a patient's condition, determine the effect, need for blood transfusion, and help develop novel prognostic and diagnostic methods. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Neutrophil to Lymphocyte Ratio (NLR) at Diagnosis Is a Predictor of Venous Thrombosis and Poor Outcome in Patients with Prefibrotic Primary Myelofibrosis

Background Thrombosis is a common complication in patients (pts) with myeloproliferative disease: it represents the product of a dysfunctional interaction between erythrocytes, platelets, leukocytes and endothelium. A pro-inflammatory microenvironment appears to be associated with an increased thrombotic risk. Neutrophil-to-lymphocyte ratio (NLR) reflects the balance between systemic inflammation and immunity and is emerging as a prognostic biomarker in several diseases, including hematological ones. Recently Carobbio et al. [BCJ, 2022] described NLR as a predictor of venous thrombosis in Polycythemia Vera. No score was specifically developed to assess thrombotic risk in myelofibrosis (MF), and even less is known in the setting of prefibrotic primary myelofibrosis (pre-MF). Aims In a multicenter cohort of pre-MF pts, we retrospectively investigated the relationship between NLR values at diagnosis and the risk of: 1) thrombosis 2) disease progression into overt-MF, accelerated (AP) or blast phase (BP); 3) overall survival (OS). Methods We collected clinical, histopathological and hematological data of 176 pts with a diagnosis of pre-MF, revised according to 2016 World Health Organization criteria, followed at 4 Hematological Centers between 2002 and 2022. NLR values were calculated using data obtained from the complete blood count at diagnosis, as the ratio between absolute neutrophilic count (ANC) and absolute lymphocyte (ALP) count. Pts were dichotomized using the best threshold identified by ROC analysis. Thrombotic complications included arterial (ischemic stroke, myocardial infarction, peripheral arterial disease) and venous (deep vein thrombosis, pulmonary embolism, cerebral and splanchnic vein thrombosis) events. Thrombosis-free survival (TFS) and OS were determined from pre-PMF diagnosis to the first thrombotic event and to death or last contact, respectively. TFS/OS were estimated by Kaplan-Meier analysis; the log-rank test was used to compare TFS/OS differences between risk stratified groups. Results Overall, 176 pts were included in this study. Median age was 63.6 (range 25-80) years; 88 (50%) were male. Majority of pts were JAK2V617F mutated (76,1%). Median NLR value at diagnosis was 3 (range 0,64-41,5). By ROC analysis, 6 was identified as the best cut-off value to dichotomize pts based on NLR; 23 pts (13%) presented NLR >6 at diagnosis. A major thrombotic event occurred before or at diagnosis in 53 pts (30,1%): 29 arterial and 25 venous (one patient had both a venous and arterial event). During the follow-up (FU), 30 pts (17%) developed a thrombosis, for a total of 38 thrombotic events (20 venous and 18 arterial events, accounting for an incidence rate of 1,67 and 1,50 per 100 pts-year, respectively). In statistical analysis, factors significantly associated to thrombosis during the FU were previous thrombosis (p=0.05) and JAK2 V617F mutation (p=0.03). Total leucocyte and platelets count, as well as age, sex and IPSET thrombosis score did not correlate with thrombotic events. Pts with ANC > 9 x10^9/L or ALP count < 1,5x10^9/L at diagnosis showed a trend towards a greater incidence of thrombosis in FU (p=0.06 and p=0.07, respectively). Pts with NLR value > 6 at diagnosis had a significantly higher incidence of venous thrombotic events (p=0.03) and a shorter venous TFS (p=0.004, Figure 1) compared to patients with NLR <6. The NLR value was not predictive of arterial thrombotic risk. After a median FU of 6.14 years (range 0,5-27,96) years, 32 pts (18,2%) died; 22 pts (12,5%) had disease progression: of them, 13 (7,4%) experienced overt MF and 9 (5,1%) evolved into an AP or BP. Pts with NLR value > 6 at diagnosis had a significant shorter OS compared to the group with NLR <6 (median OS 4,93 vs 6,22 months respectively, p=0.02). Conclusions This multicenter study investigated for the first time whether the NLR value at diagnosis could be a predictive marker of thrombotic risk and poor outcome in pre-PMF setting. Previous thrombosis and JAK2V617F mutation are confirmed to be risk factors for thrombotic events also in pre-MF setting. Notably, NLR > 6 at diagnosis emerged as a simple marker to identify pts at higher risk of thrombosis and poor outcome in the pre-PMF setting: pts with a NLR value > 6 have a significantly higher venous thrombotic risk and a shorter venous TFS. Furthermore, NLR group > 6 appears to have a shorter OS. These data are promising but require to be confirmed on a larger scale. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal