-
JPMA. the Journal of the Pakistan... Jun 2024Liquid biopsy has multiple benefits and is used extensively in other fields of oncology, but its role in neuro-oncology has been limited so far. Multiple tumour-derived... (Review)
Review
Liquid biopsy has multiple benefits and is used extensively in other fields of oncology, but its role in neuro-oncology has been limited so far. Multiple tumour-derived materials like circulating tumour cells (CTCs), tumour-educated platelets (TEPs), cell-free DNA (cfDNA), circulating tumour DNA (ctDNA), and miRNA are studied in CSF, blood (plasma, serum) or urine. Large and complex amounts of data from liquid biopsy can be simplified by machine learning using various algorithms. By using this technique, we can diagnose brain tumours and differentiate low versus highgrade glioma and true progression from pseudo-progression. The potential of liquid biopsy in brain tumours has not been extensively studied, but it has a bright future in the coming years. Here, we present a literature review on the role of machine learning in liquid biopsy of brain tumours.
Topics: Humans; Liquid Biopsy; Machine Learning; Brain Neoplasms; Neoplastic Cells, Circulating; Circulating Tumor DNA; Glioma; Biomarkers, Tumor; MicroRNAs
PubMed: 38949002
DOI: 10.47391/JPMA.24-46 -
JPMA. the Journal of the Pakistan... Jun 2024To compare the efficacy of tocotrienol and tocopherol in the management of patients with atherosclerotic cardiovascular diseases. (Comparative Study)
Comparative Study
OBJECTIVE
To compare the efficacy of tocotrienol and tocopherol in the management of patients with atherosclerotic cardiovascular diseases.
METHODS
The systematic review was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines 2020, and comprised literature search from 2002 till January 5, 2023, on PubMed, Google Scholar, Cochrane Library, Google, Wiley-Inter Science Library, Medline, SpringerLink, Taylor and Francis databases. The search was conducted using key words, such as: "tocopherol", "tocotrienol", "vitamin E", "dyslipidaemia", "cardiovascular diseases" "cardioprotective", "hypercholesterolemia" and "atherosclerosis" along with Boolean operators. Human clinical studies regarding the use of tocotrienol or tocopherol or comparison of its efficacy in patients having atherosclerosis, dyslipidaemia leading to cardiovascular diseases, and studies including details of efficacy of any of the four alpha, beta, gamma, delta isomers of tocopherol or tocotrienol were included. Pertinent data from the eligible studies was retrieved and reviewed.
RESULTS
Of the 516 articles identified, 26 (5%) articles met eligibility criteria. Of them 5(19%) were subjected to detailed analysis. Tocotrienol showed significant anti-oxidant efficacy at (250 mg/d) by decreasing cholesterol and serum inflammatory biomarkers i.e C-reactive protein (40%), malondialdehyde (34%), gamma-glutamyl transferase (22%) (p<0.001). Total anti-oxidant status (TAS) levels raised 22% (p<0.001) and Inflammatory cytokines i.e resistin, interleukin (IL)-1, IL-12, Interferon-gamma were decreased 15-17% (p<0.05-0.01) respectively by tocotrienol. Several microRNA (miRNA-133a, miRNA-223, miRNA-214, miRNA-155) were modulated by δ-tocotrienol. Whereas, tocopherol showed heterogeneity of results by either decreasing or increasing the risk of mortality in atherosclerotic cardiovascular diseases.
CONCLUSION
Compared to tocopherol, tocotrienol was found to be safe and potential candidate for improving cardiovascular health in the management of atherosclerotic cardiovascular diseases.
Topics: Humans; Tocotrienols; Atherosclerosis; Tocopherols; Antioxidants; Cardiovascular Diseases; Dyslipidemias; Cholesterol
PubMed: 38948984
DOI: 10.47391/JPMA.9227 -
HemaSphere Jul 2024Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk...
Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk subgroup in pediatric T-LBL, yet these high-risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high-risk T-LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T-LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high-risk biological subgroup of children with T-LBL. This subgroup is characterized by gene fusions, found in 21% of our T-LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C-C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T-cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy-related acute myeloid leukemia during maintenance therapy. These data indicate that T-LBL patients with a fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.
PubMed: 38948925
DOI: 10.1002/hem3.117 -
International Journal of Chronic... 2024Vitamin D deficiency (VDD, 25-hydroxyvitamin D < 20 ng/mL) has been reported associated with exacerbation of chronic obstructive pulmonary disease (COPD) but sometimes... (Observational Study)
Observational Study
PURPOSE
Vitamin D deficiency (VDD, 25-hydroxyvitamin D < 20 ng/mL) has been reported associated with exacerbation of chronic obstructive pulmonary disease (COPD) but sometimes controversial. Research on severe vitamin D deficiency (SVDD, 25-hydroxyvitamin D < 10 ng/mL) in exacerbation of COPD is limited.
PATIENTS AND METHODS
We performed a retrospective observational study in 134 hospitalized exacerbated COPD patients. 25-hydroxyvitamin D was modeled as a continuous or dichotomized (cutoff value: 10 or 20 ng/mL) variable to evaluate the association of SVDD with hospitalization in the previous year. Receiver operator characteristic (ROC) analysis was performed to find the optimal cut-off value of 25-hydroxyvitamin D.
RESULTS
In total 23% of the patients had SVDD. SVDD was more prevalent in women, and SVDD group tended to have lower blood eosinophils counts. 25-hydroxyvitamin D level was significantly lower in patients who were hospitalized in the previous year (13.6 vs 16.7 ng/mL, = 0.044), and the prevalence of SVDD was higher (38.0% vs 14.3%, = 0.002). SVDD was independently associated with hospitalization in the previous year [odds ratio (OR) 4.34, 95% CI 1.61-11.72, = 0.004] in hospitalized exacerbated COPD patients, whereas continuous 25-hydroxyvitamin D and VDD were not ( = 0.1, = 0.9, separately). The ROC curve yielded an area under the curve of 0.60 (95% CI 0.50-0.71) with an optimal 25-hydroxyvitamin D cutoff of 10.4 ng/mL.
CONCLUSION
SVDD probably showed a more stable association with hospitalization in the previous year in hospitalized exacerbated COPD patients. Reasons for lower eosinophil counts in SVDD group needed further exploration.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Vitamin D Deficiency; Female; Male; Retrospective Studies; Vitamin D; Aged; Prevalence; Disease Progression; Risk Factors; Middle Aged; Severity of Illness Index; Biomarkers; ROC Curve; Hospitalization; Time Factors; Odds Ratio; Aged, 80 and over; Area Under Curve; Logistic Models; Chi-Square Distribution; Patient Admission; Multivariate Analysis
PubMed: 38948911
DOI: 10.2147/COPD.S461029 -
International Journal of Chronic... 2024To determine the association of urinary phthalate metabolites with chronic obstructive pulmonary disease (COPD), airflow obstruction, lung function and respiratory...
OBJECTIVE
To determine the association of urinary phthalate metabolites with chronic obstructive pulmonary disease (COPD), airflow obstruction, lung function and respiratory symptoms.
METHODS
Our study included a total of 2023 individuals aged ≥ 40 years old in the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression was conducted to explore the correlation of eleven urinary phthalate metabolites (MCNP, MCOP, MECPP, MnBP, MCPP, MEP, MEHHP, MEHP, MiBP, MEOHP, and MBzP) with COPD, airflow obstruction and respiratory symptoms. Linear regression analyses were used to evaluate the relationship between urinary phthalate metabolites and lung function.
RESULTS
When compared to the first tertile, the third tertile of MEHHP was associated with the risk of COPD [OR: 2.779; 95% confidence interval (CI): 1.129-6.840; 0.026]. Stratified analysis showed that MEHHP increased the risk of COPD by 7.080 times in male participants. Both MCPP and MBzP were positively correlated with the risk of airflow obstruction. The third tertile of MBzP increased the risk of cough by 1.545 (95% CI: 1.030-2.317; 0.035) times. Both FEV1 and FVC were negatively associated with MEHHP, MECPP, MnBP, MEP, MiBP and MEOHP.
CONCLUSION
Higher levels of MEHHP are associated with increased risk of COPD, and lower measures of FEV1 and FVC. MBzP is positively related to airflow obstruction and cough.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Male; Cross-Sectional Studies; Female; Middle Aged; Risk Factors; Lung; Nutrition Surveys; Forced Expiratory Volume; Phthalic Acids; Adult; Biomarkers; United States; Vital Capacity; Aged; Multivariate Analysis; Odds Ratio; Linear Models; Logistic Models; Cough
PubMed: 38948906
DOI: 10.2147/COPD.S459435 -
BioRxiv : the Preprint Server For... Jun 2024Kidney disease is highly heritable; however, the causal genetic variants, the cell types in which these variants function, and the molecular mechanisms underlying kidney...
Kidney disease is highly heritable; however, the causal genetic variants, the cell types in which these variants function, and the molecular mechanisms underlying kidney disease remain largely unknown. To identify genetic loci affecting kidney function, we performed a GWAS using multiple kidney function biomarkers and identified 462 loci. To begin to investigate how these loci affect kidney function, we generated single-cell chromatin accessibility (scATAC-seq) maps of the human kidney and identified candidate -regulatory elements (cCREs) for kidney podocytes, tubule epithelial cells, and kidney endothelial, stromal, and immune cells. Kidney tubule epithelial cCREs explained 58% of kidney function SNP-heritability and kidney podocyte cCREs explained an additional 6.5% of SNP-heritability. In contrast, little kidney function heritability was explained by kidney endothelial, stromal, or immune cell-specific cCREs. Through functionally informed fine-mapping, we identified putative causal kidney function variants and their corresponding cCREs. Using kidney scATAC-seq data, we created a deep learning model (which we named ChromKid) to predict kidney cell type-specific chromatin accessibility from sequence. ChromKid and allele specific kidney scATAC-seq revealed that many fine-mapped kidney function variants locally change chromatin accessibility in tubule epithelial cells. Enhancer assays confirmed that fine-mapped kidney function variants alter tubule epithelial regulatory element function. To map the genes which these regulatory elements control, we used CRISPR interference (CRISPRi) to target these regulatory elements in tubule epithelial cells and assessed changes in gene expression. CRISPRi of enhancers harboring kidney function variants regulated and expression. Thus, inherited differences in tubule epithelial and expression may predispose to kidney disease in humans. We conclude that genetic variants affecting tubule epithelial regulatory element function account for most SNP-heritability of human kidney function. This work provides an experimental approach to identify the variants, regulatory elements, and genes involved in polygenic disease.
PubMed: 38948875
DOI: 10.1101/2024.06.18.599625 -
BioRxiv : the Preprint Server For... Jun 2024A single arm trial (NCT007773097) and a double-blind, placebo controlled randomized trial ( NCT02134925 ) were conducted in individuals with a history of advanced...
A single arm trial (NCT007773097) and a double-blind, placebo controlled randomized trial ( NCT02134925 ) were conducted in individuals with a history of advanced colonic adenoma to test the safety and immunogenicity of the MUC1 tumor antigen vaccine and its potential to prevent new adenomas. These were the first two trials of a non-viral cancer vaccine administered in the absence of cancer. The vaccine was safe and strongly immunogenic in 43% (NCT007773097) and 25% ( NCT02134925 ) of participants. The lack of response in a significant number of participants suggested, for the first time, that even in a premalignant setting, the immune system may have already been exposed to some level of suppression previously reported only in cancer. Single-cell RNA-sequencing (scRNA-seq) on banked pre-vaccination peripheral blood mononuclear cells (PBMCs) from 16 immune responders and 16 non-responders identified specific cell types, genes, and pathways of a productive vaccine response. Responders had a significantly higher percentage of CD4+ naive T cells pre-vaccination, but a significantly lower percentage of CD8+ T effector memory (TEM) cells and CD16+ monocytes. Differential gene expression (DGE) and transcription factor inference analysis showed a higher level of expression of T cell activation genes, such as Fos and Jun, in CD4+ naive T cells, and pathway analysis showed enriched signaling activity in responders. Furthermore, Bayesian network analysis suggested that these genes were mechanistically connected to response. Our analyses identified several immune mechanisms and candidate biomarkers to be further validated as predictors of immune responses to a preventative cancer vaccine that could facilitate selection of individuals likely to benefit from a vaccine or be used to improve vaccine responses.
PubMed: 38948837
DOI: 10.1101/2024.06.14.598031 -
BioRxiv : the Preprint Server For... Jun 2024Cirrhosis, advanced liver disease, affects 2-5 million Americans. While most patients have compensated cirrhosis and may be fairly asymptomatic, many decompensate and...
UNLABELLED
Cirrhosis, advanced liver disease, affects 2-5 million Americans. While most patients have compensated cirrhosis and may be fairly asymptomatic, many decompensate and experience life-threatening complications such as gastrointestinal bleeding, confusion (hepatic encephalopathy), and ascites, reducing life expectancy from 12 to less than 2 years. Among patients with compensated cirrhosis, identifying patients at high risk of decompensation is critical to optimize care and reduce morbidity and mortality. Therefore, it is important to preferentially direct them towards specialty care which cannot be provided to all patients with cirrhosis. We used discovery Top-down Proteomics (TDP) to identify differentially expressed proteoforms (DEPs) in the plasma of patients with progressive stages of liver cirrhosis with the ultimate goal to identify candidate biomarkers of disease progression. In this pilot study, we identified 209 DEPs across three stages of cirrhosis (compensated, compensated with portal hypertension, and decompensated), of which 115 derived from proteins enriched in the liver at a transcriptional level and discriminated the three stages of cirrhosis. Enrichment analyses demonstrated DEPs are involved in several metabolic and immunological processes known to be impacted by cirrhosis progression. We have preliminarily defined the plasma proteoform signatures of cirrhosis patients, setting the stage for ongoing discovery and validation of biomarkers for early diagnosis, risk stratification, and disease monitoring.
HIGHLIGHTS
Performed a pilot top-down LC-MS/MS analysis to identify proteoforms (PFRs) in the plasma of patients with 3 progressive stages of liver cirrhosis.Identified 2867 proteoforms (PFRs) and 209 differentially regulated proteoforms (DRPs) in the different stages of the disease.Identified DRP profiles able to potentially distinguish early from late stages of the disease, including 115 liver-derived DRPs.Fibrinogen alpha chain, haptoglobin, and Apo A-I are the proteins with the highest number of DRPs and represent potential candidate biomarkers of liver cirrhosis progression.
PubMed: 38948836
DOI: 10.1101/2024.06.19.599662 -
BioRxiv : the Preprint Server For... Jun 2024HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a...
HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a preponderance of data indicate that gut barrier disruption and microbial translocation are drivers of chronic immune activation, the molecular mechanisms of this persistent inflammatory state remain poorly understood. Here, utilizing the nonhuman primate model of HIV infection with suppressive antiretroviral therapy (ART), we investigated activation of inflammasome pathways and their association with intestinal epithelial barrier disruption and CVD pathogenesis. Longitudinal blood samples obtained from rhesus macaques with chronic SIV infection and long-term suppressive ART were evaluated for biomarkers of intestinal epithelial barrier disruption (IEBD), inflammasome activation (IL-1β and IL-18), inflammatory cytokines, and triglyceride (TG) levels. Activated monocyte subpopulations and glycolytic potential were investigated in peripheral blood mononuclear cells (PBMCs). Higher plasma levels of IL-1β and IL-18 were observed following the hallmark increase in IEBD biomarkers, intestinal fatty acid-binding protein (IFABP) and LPS-binding protein (LBP), during the chronic phase of treated SIV infection. Further, significant correlations of plasma IFABP levels with IL-1β and IL-18 were observed between 10-12 months of ART. Higher levels of sCD14, IL-6, and GM-CSF, among other inflammatory mediators, were also observed only during the long-term SIV+ART phase along with a trend of increase in frequencies of activated CD14 CD16 intermediate monocyte subpopulations. Lastly, we found elevated levels of blood TG and higher glycolytic capacity in PBMCs of chronic SIV-infected macaques with long-term ART. The increase in circulating IL-18 and IL-1β following IEBD and their significant positive correlation with IFABP suggest a connection between gut barrier disruption and inflammasome activation during chronic SIV infection, despite viral suppression with ART. Additionally, the increase in markers of monocyte activation, along with elevated TG and enhanced glycolytic pathway activity, indicates metabolic remodeling that could accelerate CVD pathogenesis. Further research is needed to understand mechanisms by which gut dysfunction and inflammasome activation contribute to HIV-associated CVD and metabolic complications, enabling targeted interventions in people with HIV.
PubMed: 38948748
DOI: 10.1101/2024.06.14.599106 -
BioRxiv : the Preprint Server For... Jun 2024Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale...
UNLABELLED
Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinson's Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominal < 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genes , , and . Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction.
SIGNIFICANCE STATEMENT
Early and accurate diagnosis of Parkinson's disease (PD) is urgently needed. However, biomarkers for early detection of PD are still lacking. Also, the limit of sample size remains one of the main pitfalls of current PD biomarker studies. We employed an analysis of large-scale whole-blood RNA-seq data. By identifying 1,111 significant marker RNAs, we establish a robust foundation for early PD detection, which implicated in neutrophil activation, degranulation, and TNF-alpha signaling, offer unprecedented insights into PD pathogenesis. Our multi-omics machine learning model, boasting an AUC of 0.89, outperforms previous studies, promising a transformative tool for precise PD diagnosis in clinical settings. This study marks a pivotal step toward enhanced biomarker development and early disease prediction.
PubMed: 38948706
DOI: 10.1101/2024.06.18.599639