Markers Of Disease Progression Research Articles

Insights into the Natural and Treatment Courses of Hepatitis B in Children: A Retrospective Study.

Chronic Hepatitis B virus (HBV) infection in children remains a significant public health challenge. The natural history and treatment outcomes of HBV can vary widely, influencing management strategies. This retrospective study was conducted in Northeast Romania and involved a cohort of 148 pediatric patients diagnosed with chronic viral Hepatitis B. Of these, 59 children underwent antiviral treatment while 89 were not treated. One of the main objectives was the rate of HBeAg (Hepatitis B-e antigen) seroconversion, a marker of disease progression and response to therapy. Among the treated group, 26 children (44%) achieved HBeAg seroconversion following therapy. In contrast, 44 of the untreated children (49%) experienced spontaneous HBeAg seroconversion, indicating a substantial rate of natural resolution within this population subset. The findings highlight a significant proportion of spontaneous seroconversion in untreated pediatric patients, suggesting a potential re-evaluation of treatment criteria and timing for children with chronic HBV infection. The comparable rates of seroconversion between treated and untreated cohorts underscore the need for individualized treatment approaches based on a combination of virological, biochemical, and clinical parameters. Further studies are required to refine management strategies to optimize long-term outcomes in pediatric HBV infections.

Diffusion Tensor Imaging-Along the Perivascular-Space Index Is Associated with Disease Progression in Parkinson's Disease.

The glymphatic clearance pathway is a waste clearance system that allows for removal of soluble proteins such as amyloid β (Aβ) from the brain. Higher Aβ levels are associated with cognitive dysfunction in Parkinson's disease (PD). Diffusion tensor imaging-along the perivascular space (DTI-ALPS) is an imaging measure proposed to indirectly measure glymphatic function. Evaluate differences in DTI-ALPS-index between PD and healthy controls (HC) and characterize relationships between this proposed measure of glymphatic clearance, cognition, and disease severity in PD. PD (n = 32) and HC (n = 23) participants underwent brain imaging to assess DTI-ALPS. PD participants were classified as PD-normal cognition (PD-NC; n = 20) or PD-mild cognitive impairment (PD-MCI; n = 12) based on a Level II comprehensive cognitive assessment. A subgroup of PD participants (n = 21) returned for annual assessments for up to 4 years after baseline. Longitudinal outcomes included changes in performance on the comprehensive cognitive assessment and changes in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). PD participants had lower DTI-ALPS-index compared to HC. PD participants classified as PD-MCI had significantly lower DTI-ALPS-index compared to PD-NC. Lower DTI-ALPS-index at baseline was associated with longitudinal cognitive decline and worse longitudinal disease severity. Glymphatic clearance, as measured with DTI-ALPS, has potential to serve as a marker of longitudinal disease progression. Interventions targeting glymphatic function should be explored for potential to slow cognitive decline in PD. © 2024 International Parkinson and Movement Disorder Society.

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case–Control Study

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients’ blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case-Control Study.

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients' blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

Role of Vascular Endothelial Growth Factor A in Pediatric Hemophilic Arthropathy

Abstract Background Hemophilia A is a hereditary bleeding disorder caused by the lack of blood clotting factor VIII. The incidence is about 1 in 5000. Although some progresses have been made in the treatment of the disease, arthropathy caused by joint bleeding is still a challenge to prevent and treat, which often results in joint deformity and disability, Biomarkers may give us the chance to early predict the joint arthropathy. Objective assess the level of serum VEGF-A as a vascular biomarker in children with hemophilia A to identify its possible role in hemophilic arthropathy and its severity. Methods This study included thirty child patients with clinical evidence of hemophilic arthropathy and thirty healthy matched age and sex as controls. All underwent history taking, clinical examination, Laboratory investigations including Vascular endothelial growth factor A. Results serum VEGF-A levels were significantly higher in patients than control group (p > 0,001) with sensitivity of 83.33% and specificity of 70.0%.it showed significant positive correlation with hemophilia severity (r=-0.734)(p < 0.001). Conclusion serum VEGF-A level was higher in Hemophilic patients which serve as a diagnostic marker for HA, also its significant correlation with severity may serve as a marker for disease progression and severity.

A prognostic impact of interleukin 32 (IL-32) as an immune marker in patients with bladder cancer

Background. Urinary bladder cancer is a prevalent global health concern. IL-32 is a cytokine that promotes inflammation and has been shown in multiple studies to suppress the development of cancer cells and trigger cell death in different types of cancer cells. Materials and methods. Expression of 32 interleukins was determined using an immunohistochemistry technique, which uses analysis of the exact concentrations and locations of specific compounds in tissues. This is done by using antibodies (antibodies) that react with the target protein (in this case IL-32), then identifying the sites where the active protein is located. The study included 114 diagnosed bladder cancer samples and 10 healthy controls. Results. By analyzing the expression of IL-32 using IHC technology on both bladder tissue from cancer patients and healthy bladder tissue that was considered a control, the results of evaluating IL-32 levels in bladder tissue from cancer patients showed a high level. Conclusion. High levels of IL-32 indicate disease progression or a poor outcome, while low levels can indicate an improvement or a good outcome. This is consistent with the fundamental aim of this study: the possibility of using IL-32 as a diagnostic or prognostic marker for disease progression and outcome prediction in cancer patients.

CCL17 and CCL19 are markers of disease progression in alveolar echinococcosis

ObjectivesAlveolar echinococcosis (AE) represents one of the deadliest helminthic infections, characterized by an insidious onset and high lethality. MethodsThis study utilized the Gene Expression Omnibus (GEO) database, applied Weighted Correlation Network Analysis (WGCNA) and Differential Expression Analysis (DEA), and employed the Matthews Correlation Coefficient (MCC) to identify CCL17 and CCL19 as key genes in AE. Immunohistochemistry and immunofluorescence co-localization techniques were used to examine the expression of CCL17 and CCL19 in liver tissue lesions of AE patients. Additionally, a mouse model of multilocular echinococcus larvae infection was developed to study the temporal expression patterns of these genes, along with liver fibrosis and inflammatory responses. ResultsThe in vitro model simulating echinococcal larva infection mirrored the hepatic microenvironment post-infection with multilocular echinococcal tapeworms. Quantitative RT-PCR analysis showed that liver fibrosis occurred in AE patients, with proximal activation and increased expression of CCL17 and CCL19 over time post-infection. Notably, expression peaked during the late stages of infection. Similarly, F4/80, a macrophage marker, exhibited corresponding trends in expression. Upon stimulation of normal hepatocytes by vesicular larvae in cellular experiments, there was a significant increase in CCL17 and CCL19 expression at 12 h post-infection, mirroring the upregulation observed with F4/80. ConclusionCCL17 and CCL19 facilitate macrophage aggregation via the chemokine pathway and their increased expression correlates with the progression of infection, suggesting their potential as biomarkers for AE progression.

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

#395 Gut dysbiosis in ADPKD patients: a controlled pilot study

Abstract Background and Aims Gut dysbiosis has been associated with chronic kidney disease (CKD) and nephrolithiasis and may thus be a factor explaining variability of outcome in autosomal dominant polycystic kidney disease (ADPKD). However, beside a single pilot study the gut microbiome has not been studied in ADPKD. Due to the implications of microbiota in inflammation and crystal formation, we hypothesized that gut dysbiosis could also negatively affect PKD. For this reason, we aimed to characterize the intestinal microbiome in a controlled pilot study of PKD patients and explore the potential impact of dysbiosis on PKD disease progression. Method This study was designed as an observational, cross-sectional controlled pilot study. 25 ADPKD patients were recruited from the AD(H)PKD patient cohort. 12 healthy control subjects were age- and sex matched. Patients with chronic bowel disease were excluded. Serum parameters including eGFR were analyzed around the timepoint of stool collection. The gut microbiome was analyzed by 16S rRNA gene profiling of stool samples. The sequencing data was processed using the DADA2 pipeline and QIIME version 2. Differentially abundant features were identified using linear discriminant analysis (LDA) effect size (LEfSe) analysis. Bacteria-derived serum uremic toxins (total and free Trimethylaminoxid, Indoxylsulfate, p-Cresyl-Sulfate) were measured using liquid chromatography coupled to tandem mass spectrometry (LC- MS/MS). Microbiome data was then correlated with age, kidney function, and markers of PKD disease progression like Mayo classification and early onset of arterial hypertension or urologic complications (<35 years of age). Results Healthy control subjects revealed a significantly higher abundance Actinobacteria (LEfSe LDA score = 3.9, p = 0.025) including probiotic Bifidobacteriaceae (LEfSe LDA score = 3.9, p = 0.021). ADPKD patients displayed a significantly increased abundance of potentially dysbiotic Enterobacteriaceae (LEfSe LDA score = 3.6, p = 0.009). Those findings were independent of kidney function. Most notably, the abundance of Streptococcaceae were significantly overrepresented in PKD patients with Mayo Classes 1D and 1E compared to 1A-1C (p = 0.011). Additionally, early onset of hypertension (< 35 years of age) was associated with an increased abundance of potentially dysbiotic Proteobacteria and a decreased abundance of potentially probiotic Tannerelleaceae. Furthermore, ADPKD patients revealed increased abundance of Peptococcaceae with increasing age and declining kidney function. Finally, serum uremic toxins were significantly increased in ADPKD patients and highly correlated with eGFR. Serum uremic toxins revealed a tendency of positive correlation with the abundance of Peptococcaceae which did not reach statistical significance. Conclusion This controlled pilot study confirms alterations of specific OTUs in PKD patients showing an increase of Enterobacteriaceae and decrease of probiotic Bifidobacteriaceae upon PKD. This suggests a potential shift towards gut dysbiosis. Most notably, the abundance of specific OTUs were observed to be associated with markers of rapid disease progression like Mayo classification 1D and 1E, as well as early onset of arterial hypertension. This suggests for the first time, that gut dysbiosis could affect PKD disease progression. However, it still remains unknown whether gut dysbiosis is caused by ADPKD itself or is a consequence of secondary circumstances such as antibiotic treatment which is common in ADPKD due to frequent urinary tract or cyst infections. Thus, further investigation in larger cohorts is warranted to elucidate the impact of gut microbiota on ADPKD.

#2160 Ketosis moderates the effect on kidney volume in dietary interventions for ADPKD—more insights on the KETO ADPKD trial

Abstract Background and Aims Autosomal-dominant polycystic kidney disease (ADPKD) is the most common monogenic disease leading to kidney failure. Tolvaptan, the only approved targeted treatment strategy, comes with adverse events such as hepatotoxicity and massive polyuria, limiting its use. Novel treatment strategies are urgently needed. Cyst-lining epithelial cells are glucose-dependent and metabolically inflexible. Evidence from polycystic kidney disease (PKD) animal models show that ketogenic dietary interventions (KDI) can ameliorate cyst growth and loss of kidney function. To enable clinical translation of these findings, our group set up a series of trials—from small cohorts and proof of principle studies to our most recent trial KETO-ADPKD, showing that KDIs are feasible and can work as a treatment for ADPKD [1]. This has received a lot of attention. With this post-hoc analyses, we aim to share further in-depth analyses of the factors moderating the effects we see on ADPKD. Method KETO-ADPKD is an exploratory randomized and controlled clinical trial (NCT04680780). Sixty-six patients were randomized to 3 months dietary intervention (ketogenic diet [KD] or water fasting [WF]) or the control group. Here, we explore correlations between biochemical readout parameters of ketosis and markers of disease progression. Results The KD group shows a promising, yet statistically not significant decline in height-adjusted total kidney volume (htTKV). Patients reaching high biochemical thresholds of ketosis however significantly reduced their htTKV in comparison with the control group (KD −16.3 ml/m, CG + 14.8 ml/m, p-value 0.049). This becomes even clearer when higher thresholds for adherence are administered: In a smaller group requiring not only beta-hydroxybutyrate (BHB) levels ≥0.5 mmol/l but breath acetone ≥5 ppm on 75% of daily measurements, htTKV could be reduced by −17.6 ml/m (KD) vs +14.8 ml/m (CG), p-value 0.026. The significant reduction of liver volume upon KD is not influenced by the level of ketosis. Beneficial effects on estimated glomerular filtration rate (eGFR) can be equally observed in all subsets. Weight loss ≥5% was nor associated with a more significant loss of kidney nor liver volume. Conclusion Subgroup analyses of the KETO-ADPKD trial show stronger impact of the dietary intervention with higher ketone body levels. In particular, ketogenesis as a marker of metabolic reprogramming strongly moderates the effects we see on kidney volume. The assessment of renal cyst fractions could further enlighten the effects on cyst burden. This is in line with preclinical data showing that ketosis rather than caloric intake is responsible for the amelioration of disease progression [2].

An interpretable data-driven prediction model to anticipate scoliosis in spinal muscular atrophy in the era of (gene-) therapies

5q-spinal muscular atrophy (SMA) is a neuromuscular disorder (NMD) that has become one of the first 5% treatable rare diseases. The efficacy of new SMA therapies is creating a dynamic SMA patient landscape, where disease progression and scoliosis development play a central role, however, remain difficult to anticipate. New approaches to anticipate disease progression and associated sequelae will be needed to continuously provide these patients the best standard of care. Here we developed an interpretable machine learning (ML) model that can function as an assistive tool in the anticipation of SMA-associated scoliosis based on disease progression markers. We collected longitudinal data from 86 genetically confirmed SMA patients. We selected six features routinely assessed over time to train a random forest classifier. The model achieved a mean accuracy of 0.77 (SD 0.2) and an average ROC AUC of 0.85 (SD 0.17). For class 1 ‘scoliosis’ the average precision was 0.84 (SD 0.11), recall 0.89 (SD 0.22), F1-score of 0.85 (SD 0.17), respectively. Our trained model could predict scoliosis using selected disease progression markers and was consistent with the radiological measurements. During post validation, the model could predict scoliosis in patients who were unseen during training. We also demonstrate that rare disease data sets can be wrangled to build predictive ML models. Interpretable ML models can function as assistive tools in a changing disease landscape and have the potential to democratize expertise that is otherwise clustered at specialized centers.

#755 Endotrophin as an early marker of kidney outcomes in persons with type 2 diabetes: findings from the PROVALID study

Abstract Background and Aims Diabetic kidney disease (DKD) is driven by a set of pathophysiological processes, including fibrosis. Endotrophin (ETP), a pro-fibrotic fragment generated during collagen type VI formation, has previously been shown to be a biomarker of DKD progression. The aim of this study was to investigate, for the first time, circulating ETP as a risk marker for kidney outcomes in persons with type 2 diabetes (T2D) being taken care of at the primary level of healthcare. Method Levels of ETP were measured using the nordicPRO-C6TM ELISA in plasma at baseline from 3226 persons with T2D enrolled in the Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers (PROVALID). Outcomes included a composite kidney endpoint defined as a sustained 40% decline in estimated glomerular filtration rate (eGFR) < an eGFR of 60 ml/min/173 m2, sustained 30% increase in albuminuria including a transition in albuminuria stage, or kidney failure with replacement therapy or kidney death. A decline in eGFR and an increase in albuminuria were considered sustained if they persisted over at least two consecutive measurements. Crude and adjusted Cox proportional hazards regression models were applied to investigate the potential of ETP as a risk marker of the kidney endpoint. Levels of ETP were log-transformed before analysis. The Kaplan–Meier estimator was used to compare the risks of experiencing the kidney endpoint according to ETP levels split by the median in persons with baseline eGFR > 90 ml/min/1.73 m2 (n = 976). Results The cohort consisted of 57% males; median age was 64 (58-70) years, and mean eGFR was 79 ± 24 ml/min/1.73 m2. Median follow-up was 3.9 years. Higher levels of ETP were associated with a higher risk of developing the kidney endpoint, with a hazard ratio (HR) of 1.63 (p = 0.0012; n = 293/3226). After adjustment for the refined variables: age, diabetes duration, HbA1c, atherosclerotic cardiovascular disease, blood pressure, duration of hypertension, BMI, LDL-cholesterol, HDL-cholesterol, and eGFR, the HR was 1.55 (p = 0.012). In persons with an eGFR > 90 ml/min/1.73 m2, higher ETP was also associated with an increased risk of developing the kidney endpoint (p = 0.03; n = 69/976). Conclusion Plasma ETP was an independent risk marker for kidney outcomes in persons with T2D with early kidney disease. Higher levels of plasma ETP were associated with a significantly increased risk of developing the kidney endpoint in persons with eGFR > 90 ml/min/1.73 m2. These findings demonstrate that biomarkers of fibrosis, such as ETP, may serve as early markers for kidney disease progression or kidney failure in persons with T2D and apparently normal kidney function.

Cardiovascular autonomic failure in hereditary transthyretin amyloidosis and TTR carriers is an early and progressive disease marker.

The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69years (mean ± SD)]. Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.

Eosinophilic Dermatosis of Hematologic Malignancy: Emerging Evidence for the Role of Insect Bites-A Retrospective Clinico-Pathological Study of 35 Cases.

Background/Objectives: Eosinophilic dermatosis of hematologic malignancy (EDHM) is a rare cutaneous disorder associated with various hematologic malignancies, most commonly chronic lymphocytic leukemia. Detailed clinicopathologic studies of EDHM are lacking and the pathogenesis remains enigmatic. Initially thought to be a hypersensitivity reaction to insect stings, subsequent reports have challenged this understanding. The prognostic implications of EDHM remain unclear. Methods: A retrospective clinicopathologic study was performed on patients diagnosed with EDHM. Hematologic and dermatologic data were reviewed. Histologic specimens were re-evaluated and lesions were classified into acute/subacute, fully developed, and chronic/regressing. Results: The study included 35 patients. In 80% of these patients, EDHM was diagnosed after the hematologic disorder. Approximately 45% of the cohort experienced hematologic disease progression or relapse, while 65% required therapeutic intervention during the course of their hematologic disease. In total, 15/19 CLL patients had non-mutated IgHV, a marker of a more aggressive hematologic disease course. Dermatologic lesion morphology was heterogeneous, with most lesions occurring on exposed areas, and a significant 94% of patients demonstrated lesion seasonality. Histopathologic findings were consistent with features typically associated with insect bites. In addition, examination of lesions at different chronological stages revealed substantial similarities with Wells syndrome. Conclusions: Our findings support the potential role of insect bites in triggering EDHM in the context of adaptive immune dysfunction. EDHM may be associated with a more aggressive disease course or may be a marker of disease progression. The observed co-occurrence of features typical of Wells syndrome in EDHM patients suggests that these conditions are part of a spectrum of disorders that vary in clinical expression.

Human T-cell lymphotropic virus type 1 (HTLV-1) grip on T-cells: investigating the viral tapestry of activation

IntroductionHuman T-cell Lymphotropic virus type 1 (HTLV-1) belongs to retroviridae which is connected to two major diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and Adult T-cell leukemia/lymphoma (ATLL). This study aims to investigate the mRNA expressions of key proteins correlated to T-cell activation in asymptomatic carriers (ACs) HTLV-1 infected patients, shedding light on early molecular events and T-cell activation following HTLV-1 infection.Material and MethodsThe study involved 40 participants, including 20 ACs and 20 healthy subjects. Blood samples were collected, ELISA assessment for screening and confirmation with PCR for Trans-activating transcriptional regulatory protein (Tax) and HTLV-1 basic leucine zipper factor (HBZ) of the HTLV-1 were done. mRNA expressions of C-terminal Src kinase (CSK), Glycogen Synthase Kinase-3 Beta (GSK3β), Mitogen-Activated Protein Kinase 14 (MAP3K14 or NIK), Phospholipase C Gamma-1 (PLCG1), Protein Tyrosine Phosphatase non-Receptor Type 6 (PTPN6) and Mitogen-Activated Protein Kinase Kinase Kinase-7 (SLP-76) and Mitogen-Activated Protein Kinase14 (MAP3K7 or TAK1) were assayed using RT-qPCR. Statistical analyses were performed using PRISM and SPSS software.ResultsWhile there were no significant upregulation in CSK and PTPN6 in ACs compared to healthy individuals, expression levels of GSK3β, MAP3K14, PLCG1, SLP-76, and TAK1 were significantly higher in ACs compared to healthy subjects which directly contributes to T-cell activation in the HTLV-1 ACs.ConclusionHTLV-1 infection induces differential mRNA expressions in key proteins associated with T-cell activation. mRNAs related to T-cell activation showed significant upregulation compared to PTPN6 and CSK which contributed to T-cell regulation. Understanding these early molecular events in ACs may provide potential markers for disease progression and identify therapeutic targets for controlling viral replication and mitigating associated diseases. The study contributes novel insights to the limited literature on T-cell activation and HTLV-1 pathogenesis.

Mineralocorticoid receptor antagonists and reno-protection: What's the evidence & where do they fit? A guide for non-specialists.

The role of aldosterone has yet to be well appreciated in chronic kidney disease (CKD). Two variables define CKD: an estimated glomerular filtration rate of <60 ml/min/1.73 m2 and a spot urine albumin-creatinine ratio of >30 mg/g. Both are needed for an accurate diagnosis. The presence of CKD at this level is associated with an elevated risk of cardiovascular death and a greater risk of CKD progression to kidney failure and subsequent dialysis. This paper presents an overview of aldosterone's importance in CKD and its contribution to the inflammatory processes involved in CKD development. Data on outcomes, both surrogate and hard, related to outcomes on CKD progression will also be discussed in the context of mineralocorticoid blockade. Based on recent epidemiological data as well as data examining markers of diabetic kidney disease progression, it is clear that use of both renin-angiotensin system inhibitors and aldosterone receptor antagonists have a significant role in altering the natural history of kidney disease progression itself, as well as reducing the risk of cardiovascular events that generally accompany long-standing kidney disease. This paper will discuss these issues and the management of consequent hyperkalaemia when both steroidal and non-steroidal mineralocorticoid receptor antagonists are used in detail.

Frontal QRST Angle as a Marker of Arrhythmogenesis and Disease Progression in Dogs with Myxomatous Mitral Valve Disease

Frontal QRST Angle as a Marker of Arrhythmogenesis and Disease Progression in Dogs with Myxomatous Mitral Valve Disease

Caspases compromise SLU7 and UPF1 stability and NMD activity during hepatocarcinogenesis

Background & AimsThe homeostasis of the cellular transcriptome depends on transcription and splicing mechanisms. Moreover, the fidelity of gene expression, essential to preserve cellular identity and function is secured by different quality control mechanisms including nonsense-mediated RNA decay (NMD). In this context, alternative splicing is coupled to NMD, and several alterations in these mechanisms leading to the accumulation of aberrant gene isoforms have been involved in human disease including cancer. MethodsRNAseq, Westen blot, qPCR, co-IP in multiple silenced culture cell lines (replicates n≥4), primary hepatocytes and samples of animal models (Jo2, APAP, Mdr2-/- mice, n≥3). ResultsHere we describe that in animal models of liver injury and in human HCC (TCGA, NT =50 vs HCC =374), the process of NMD is inhibited. Moreover, we demonstrate that the splicing factor SLU7 interacts with and preserves the levels of the NMD effector UPF1, and that SLU7 is required for a correct NMD. Our previous findings demonstrated that SLU7 expression is reduced in the diseased liver, contributing to hepatocellular de-differentiation and genome instability during disease progression. However, little was known about the mechanisms underlying SLU7 downregulation. Here we provide evidence showing that caspases activated during liver damage would be responsible of the cleavage and degradation of SLU7. ConclusionsHere we identify the downregulation of UPF1 and the inhibition of NMD as a new molecular pathway contributing to the malignant reshaping of the liver transcriptome. Moreover, and importantly, we uncover caspases activation as the mechanism responsible for the downregulation of SLU7 expression during liver disease progression, which is a new link between apoptosis an hepatocarcinogenesis. Impact and implicationsThe mechanisms involved in the reshaping of hepatocellular transcriptome driving the progressive loss of cell identity and function in liver disease are not completely understood. In this context, we provide evidence on the impairment of a key mRNA surveillance mechanism known as nonsense-mediated mRNA decay (NMD). Mechanistically, we uncover a novel role for the splicing factor SLU7 in the regulation of NMD, including its ability to interact and preserve the levels the key NMD factor UPF1. Moreover, we demonstrate that the activation of caspases during liver damage mediates SLU7 and UPF1 proteins degradation and NMD inhibition. Our findings identify potential new markers of liver disease progression, and SLU7 as a novel therapeutic target to prevent the functional decay of the chronically injured organ.

Elevated Exposure to Air Pollutants Accelerates Primary Glomerular Disease Progression

IntroductionEnvironmental contributors to kidney disease progression remain elusive. We explored how residential air pollution impacts disease progression in patients with primary glomerulopathies. MethodsNephrotic Syndrome Study Network (NEPTUNE) and CureGlomerulonephropathy (CureGN) participants with residential census tract data and ≥2 years of follow-up were included. Using Cox proportional hazards models, the associations per doubling in annual average baseline concentrations of total particulate matter with diameter ≤ 2.5 μm (PM2.5) and its components, black carbon, and sulfate, with time to ≥40% decline in estimated glomerular filtration rate (eGFR) or kidney failure were estimated. Serum tumor necrosis factor levels and kidney tissue transcriptomic inflammatory pathway activation scores were used as molecular markers of disease progression. ResultsPM2.5, black carbon, and sulfate exposures were comparable in NEPTUNE (n=228) and CureGN (n=697). In both cohorts, participants from areas with higher levels of pollutants had lower eGFR, were older and more likely self-reported racial and ethnic minorities. In a fully adjusted model combining both cohorts, kidney disease progression was associated with PM2.5 (adjusted HR 1.55 [95% CI:1.00, 2.38], p=0.0489) and black carbon (adjusted HR 1.43 [95% CI:0.98, 2.07], p=0.0608) exposure. Sulfate and PM2.5 exposure were positively correlated with serum tumor necrosis factor (TNF) (p=0.003) and interleukin-1β levels (p=0.03), respectively. Sulfate exposure was also directly associated with transcriptional activation of the TNF and JAK-STAT signaling pathways in kidneys (r=0.55-0.67, p-value <0.01). ConclusionElevated exposure to select air pollutants is associated with increased risk of disease progression and systemic inflammation in patients with primary glomerulopathies (word count: 248).

Bioactive adrenomedullin as a marker of congestion and disease progression in patients with a systemic right ventricle

BackgroundAdults with a systemic right ventricle (sRV) are at a high risk for heart failure (HF) hospitalization and mortality. Bioactive adrenomedullin (bio-ADM) has been proposed as a marker of congestion and prognosis in patients with cardiovascular disease. We aimed to evaluate the association between bio-ADM and mortality and HF events in sRV patients. MethodsPlasma bio-ADM was measured by a novel immunoassay in plasma of 85 sRV patients. A composite endpoint of all-cause mortality and HF events was used as outcome. HF events were defined as onset or progression of HF signs or symptoms requiring hospitalization, initiation or intensification of therapy. Multivariable Cox regression analyses were performed to evaluate the association between bio-ADM and outcome. ResultsThe mean age of the patients was 37 ± 9 years and 65% were male. Patients with higher plasma bio-ADM concentrations were more often treated with diuretics (p = 0.007), possibly because of signs and/or symptoms of congestion. During a median follow-up of 10.2 years, 33.7% of the patients reached the endpoint. After adjustment for age and N-terminal pro B-type natriuretic peptide (NT-pro BNP), higher bio-ADM levels were associated with a higher risk of the composite endpoint (hazard ratio: 2.09 [95%-confidence interval: 1.15–3.78]). Bio-ADM improved risk prediction when added to NT-proBNP and age (C-statistic improved from 0.748 to 0.776 [p = 0.03]). ConclusionsBio-ADM can be considered as a marker of congestion and independent predictor of death and HF events in adult patients with a sRV. Moreover, in terms of risk prediction, it has added value to NT-proBNP.