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PubMed2025

Transcriptomic analysis at 48 h postmortem: a proof of concept for the identification of biomarkers to estimate time since death.

BACKGROUND: The postmortem interval (PMI) refers to the time elapsed between an individual's death and the examination of the body. Tissues undergo a sequence of anatomical changes following death, which are routinely used to estimate the PMI. METHODS: To determine if these anatomical changes are associated with identifiable genomic adaptations that could characterize the PMI more accurately, we analyzed the rat skeletal muscle transcriptome at 0 and 48&#xa0;h postmortem using Clariom&#x2122; S arrays. This study investigates whether specific transcriptomic changes correlate with PMI progression, offering a potential molecular tool to complement established anatomical methods. RESULTS: A total of 3,873 differentially expressed mRNAs were identified, of which 2,787 downregulated and 1,086 upregulated transcripts. The most significantly downregulated mRNA was Tnni1 (FC = -30.95, p&#x2009;=&#x2009;1&#x2009;&#xd7;&#x2009;10-3), while the most upregulated were mt-ATP6, mt-ATP8, and mt-CO3 (FC&#x2009;>&#x2009;7.78, p&#x2009;<&#x2009;1.36&#x2009;&#xd7;&#x2009;10-12). Gene ontology (GO) enrichment analyses revealed that mRNAs upregulated at 48&#xa0;h in the PMI were primarily associated with vascular and endothelial processes, including nitric oxide transport and angiogenesis. Conversely, downregulated mRNAs were linked to mitochondrial activity and cellular metabolism, reflecting both a transient vascular response and metabolic pathway shutdown in the rat skeletal muscle. CONCLUSION: Our results demonstrate significant transcriptomic changes at 48&#xa0;h postmortem, highlighting specific genes and biological pathways that may serve as candidate biomarkers for PMI estimation.

Animals↗
PubMed2004

Amyloid beta peptides in cerebrospinal fluid as profiled with surface enhanced laser desorption/ionization time-of-flight mass spectrometry: evidence of novel biomarkers in Alzheimer's disease.

BACKGROUND: The advent of new therapeutic avenues for Alzheimer's disease (AD) calls for an improved early and differential diagnosis. METHODS: With surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), cerebrospinal fluid from patients with AD (n = 10) and nondemented control subjects (n = 9) was studied. RESULTS: Molecular mass signals were observed corresponding to three novel amyloid beta (Abeta) peptides that have not previously been described, in addition to those previously known, with molecular masses of 4525.1 d, 4846.8 d, and 7755.8 d. The signal-to-noise ratios (S/NR) of Abeta(4525.1) and Abeta(7758.8+2H) were significantly decreased in AD [Abeta(4525.1): median 2.2 and 4.3 in AD and control subjects, respectively, p <.01; Abeta(7758.8+2H): median 1.0 and 14.0 in AD and control subjects, respectively, p <.01], whereas the S/NR of Abeta(4846.8) was significantly increased in AD (median 3.6 and 2.5 in AD and control subjects, respectively, p <.05). The S/NR of two known AD biomarkers, Abeta1-42 and Abeta1-40, expectedly turned out to be significantly decreased (p <.01) and unaltered in AD, respectively. A moderate and highly significant correlation was observed between S/NR of Abeta1-42 and Abeta42 concentration as measured with enzyme-linked immunosorbent assay (R =.67, p <.01). CONCLUSIONS: We report evidence of three novel amyloid beta peptides that might play an important role in the diagnosis and pathophysiology of Alzheimer's disease.

Aged↗
PubMed2006

Genomic analysis of circulating cells: a window into atherosclerosis.

Translational studies using genomic techniques in cardiovascular diseases are still in their infancy. Access to disease-associated cardiovascular tissues from patients has been a major impediment to progress in contrast to the diagnostic advances made by oncologists using gene expression on readily available tumor samples. Nonetheless, progress is being made for atherosclerosis by carefully designed experiments utilizing diseased tissue or surrogate specimens. This review details the rationale and findings of a study utilizing freshly isolated blood mononuclear cells from patients undergoing carotid endarterectomy due to atherosclerotic stenosis and from matched healthy subjects. By querying this cardiovascular tissue surrogate, the messenger RNA levels of the Finkel-Biskis-Jenkins osteosarcoma gene in circulating monocytes were found to correlate with atherosclerosis severity in patients and with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy in healthy subjects. The major finding of this investigation is discussed in relation to observations from other human atherosclerosis gene expression studies. These distinct studies converge to demonstrate the unequivocal importance of inflammation in atherosclerosis. Although the clinical utility of the specific findings remains open, the identification of similar genes by different investigations serves to validate our report. They also provide us with insights into pathogenesis that may impact future translational applications.

Atherosclerosis↗
PubMed2003

Serial analysis of gene expression provides new insights into regulatory T cells.

It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. Such peripheral tolerance is maintained by regulatory CD4+ T cells, not only in transplantation models, but also in autoimmunity. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells, aiming to reveal new insights into their mechanisms of action, and to find novel targets for therapeutic manipulation of the immune system.

Animals↗
PubMed2006

Fatty acid composition of nuts--implications for cardiovascular health.

It is well established that, due to their high content of saturated fatty acids (SFA), the intake of meat and meat products is strongly associated with elevated blood cholesterol concentrations and an increased risk of hypertension, diabetes and cardiovascular diseases. Conversely, the intake of foods rich in unsaturated fatty acids, such as those contained in most vegetable fats and oils and oily fish, is associated with improved lipid profiles, a lower potency of intermediate biomarkers of atherosclerosis and lesser incidence of cardiovascular diseases. There are persuasive evidences that dietary substitution of monounsaturated fatty acids (MUFA) or n-6 polyunsaturated fatty acids (PUFA) for SFA lowers blood cholesterol and may have beneficial effects on inflammation, thrombosis, and vascular reactivity. MUFA may have an advantage over PUFA because enrichment of lipoprotein lipids with MUFA increases their resistance to oxidation. Marine n-3 PUFA have a number of anti-atherosclerotic effects, including anti-arrhythmic properties and, at relatively high doses, reduce serum triglycerides. These effects appear to be shared in part by vegetable n-3 PUFA. Nuts are natural foods rich in unsaturated fatty acids; most nuts contain substantial amounts of MUFA, while walnuts are especially rich in both n-6 and n-3 PUFA. Healthy fats in nuts contribute to the beneficial effects of frequent nut intake observed in epidemiological studies (prevention of coronary heart disease, diabetes, and sudden death) and in short-term feeding trials (cholesterol lowering, LDL resistance to oxidation, and improved endothelial function).

Animals↗
PubMed2026

Immunoproteomic Profiling of Autoantibodies and Antibodies against Infectious Agents in Autoimmune Diseases.

Prior research investigated limited antibody sets within individual autoimmune diseases. Using the Nucleic-Acid Programmable Protein Array platform, we measured antibodies against 280 human, 40 viral, and 15 bacterial antigens in serum from 237 patients with 8 autoimmune diseases, including autoimmune gastritis (AG), autoimmune thyroiditis (AT), celiac disease (CD), idiopathic inflammatory myopathies (IIM), type 1 diabetes mellitus (T1D), rheumatoid arthritis (RA), Sj&#xf6;gren's disease (SjD), and systemic lupus erythematosus (SLE), and 112 controls. Candidate antibodies were identified by combining Firth logistic regression and machine learning. We identified disease-specific antibodies, ranging from 3 in IIM to 13 in SLE for IgG and 1 in CD to 13 in AG for IgA. Additionally, 63 IgG and 44 IgA antibodies were shared across two or more diseases. Notably, two IgG autoantibodies overlapped in up to five diseases: directed against STNM4 (SLE, SjD, T1D, CD, and RA) and TRIM21 (SLE, SjD, IIM, CD, and RA); and three IgA antibodies in up to seven diseases: directed against H1N1 Influenza A virus NP (IIM, SjD, AG, T1D, CD, RA, and AT) and Coxsackievirus B3MK012537 and Enterovirus C PVgp1 (IIM, SjD, AG, T1D, CD, SLE, and RA). These findings underscore the potential of antibody profiling in autoimmune disease characterization and biomarker discovery.

Humans↗
PubMed2006

Metabolomic study of cisplatin-induced nephrotoxicity.

We have shown that cisplatin inhibits fatty acid oxidation, and that fibrate treatment ameliorates renal function by preventing the inhibition of fatty acid oxidation and proximal tubule cell death. Urine samples of mice treated with single injection of cisplatin (20 mg/kg body weight) were collected for 3 days and analyzed by 1H-nuclear magnetic resonance (NMR) spectroscopy. In a separate group, urine samples of mice treated with peroxisome proliferator-activated receptor-alpha (PPARalpha) ligand WY were also analyzed by NMR after 2 days of cisplatin exposure. Biochemical analysis of endogenous metabolites was performed in serum, urine, and kidney tissue. Electron microscopic studies were carried out to examine the effects of PPARalpha ligand and cisplatin. Principal component analysis demonstrated the presence of glucose, amino acids, and trichloacetic acid cycle metabolites in the urine after 48 h of cisplatin administration. These metabolic alterations precede changes in serum creatinine. Biochemical studies confirmed the presence of glucosuria, but also demonstrated the accumulation of nonesterified fatty acids, and triglycerides in serum, urine, and kidney tissue, in spite of increased levels of plasma insulin. These metabolic alterations were ameliorated by the use of PPARalpha ligand. Electron microscopic analysis confirmed the protective effect of the fibrate on preventing cisplatin-mediated necrosis of the S3 segment of the proximal tubule. Our study shows that cisplatin-induces a unique NMR metabolic profile in urine of mice that developed acute renal failure, and confirms the protective effect of a fibrate class of PPARalpha ligands. We propose that the injury-induced metabolic profile may be used as a biomarker of cisplatin-induced nephrotoxicity.

Acute Kidney Injury↗
PubMed2003

CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK).

Several key growth factors, cytokines, and proto-oncogenes transduce their growth- and differentiation-promoting signals through the mitogen-activated protein kinase or extracellular signal-regulated protein kinase (ERK) cascade. Overexpression or constitutive activation of this pathway has been shown to play an important role in the pathogenesis and progression of breast and other cancers, making the components of this signaling cascade potentially important as therapeutic targets. CI-1040 (PD184352) is an orally active, highly specific, small-molecule inhibitor of one of the key components of this pathway (MEK1/MEK2), and thereby effectively blocks the phosphorylation of ERK and continued signal transduction through this pathway. Antitumor activity has been seen in preclinical models with this compound, particularly for pancreas, colon, and breast cancers, which has been shown to correlate with its inhibition of pERK. Clinically, CI-1040 has been shown to be well tolerated in phase I studies, with safety and pharmacokinetic profiles that permit continuous daily dosing. Biomarker studies have shown target inhibition in patients, and antitumor activity has also been observed with a partial response in one patient with pancreatic cancer and stable disease in approximately 25% of phase I patients. Given the central role of the ERK/mitogen-activated protein kinase pathway in mediating growth-promoting signals for a diverse group of upstream stimuli, inhibitors of MEK, as a key central mediator, could have significant clinical benefit in the treatment of breast and other cancers.

Animals↗
PubMed2004

Proteins associated with diseases show enhanced sequence correlation between charged residues.

MOTIVATION: Function of proteins or a network of interacting proteins often involves communication between residues that are well separated in sequence. The classic example is the participation of distant residues in allosteric regulation. Bioinformatic and structural analysis methods have been introduced to infer residues that are correlated. Recently, increasing attention has been paid to obtain the sequence properties that determine the tendency of disease-related proteins (Abeta peptides, prion proteins, transthyretin, etc.) to aggregate and form fibrils. Motivated in part by the need to identify sequence characteristics that indicate a tendency to aggregate, we introduce a general method that probes covariations in charged residues along the sequence in a given protein family. The method, which involves computing the sequence correlation entropy (SCE) using the quenched probability P(sk)(i,j) of finding a residue pair at a given sequence separation, sk, allows us to classify protein families in terms of their SCE. Our general approach may be a useful way in obtaining evolutionary covariations of amino acid residues on a genome wide level. RESULTS: We use a combination of SCE and clustering based on the principle component analysis to classify the protein families. From an analysis of 839 families, covering approximately 500,000 sequences, we find that proteins with relatively low values of SCE are predominantly associated with various diseases. In several families, residues that give rise to peaks in P(sk)(i,j) are clustered in the three-dimensional structure. For the class of proteins with low SCE values, there are significant numbers of mixed charged-hydrophobic (CH) and charged-polar (CP) runs. Our findings suggest that the low values of SCE and the presence of (CH) and/or (CP) may be indicative of disease association or tendency to aggregate. Our results led to the hypothesis that functions of proteins with similar SCE values may be linked. The hypothesis is validated with a few anecdotal examples. The present results also lead to the prediction that the overall charge correlations in proteins affect the kinetics of amyloid formation--a feature that is common to all proteins implicated in neurodegenerative diseases.

Algorithms↗
PubMed2005

Knowledge-based computational search for genes associated with the metabolic syndrome.

MOTIVATION: A methodology to search for genes associated with multifactorial diseases by integrating the large amount of accumulated knowledge is seriously needed. A comprehensive understanding derived from a holistic view of gene relationship structures can be gained from our proposed analysis called the cross-subspace analysis (CSA). In this analysis, gene objects are generated by machine learning using their term occurrence patterns in MEDLINE abstracts and the degree of relationship between gene objects is quantified by matching these patterns. RESULTS: Structuralization of relationships of a set of genes was performed using CSA, which were retrieved using the terms, 'obesity', 'diabetes', 'hypertriglyceridemia' and 'hypertension' that refer to diseases comprising metabolic syndrome, on a 2D plane inferring important biomedical concepts from the gene distribution. Then, we prioritized the significance of 6131 well-annotated human genes in terms of the distance on the plane from the centroid of 'metabolic syndrome'-related genes distribution. The validity was confirmed by comparing the knowledge extracted by the ordering with existing medical knowledge.

Abstracting and Indexing↗
PubMed2006

The application of microarray technology to neuropathology: cutting edge tool with clinical diagnostics potential or too much information?

Microarray technology is a tremendously powerful method for simultaneously monitoring the expression of thousands of species of nucleic acids, usually cellular mRNA, producing a high-resolution representation of the genes encoded or expressed in a cell. As such, microarray technology has great potential for impacting research and clinical approaches to treatment. However, this complex technology has been challenging to apply as a result of difficulties discerning biologic variation from technologic issues, therefore slowing the application of the technology to human diagnostics. Nevertheless, significant advances in microarray technology, improvements that avoid potential pitfalls, and a wider spectrum of application are making this technology easier to apply. Indeed, microarray technology has provided valuable insights into mechanisms involving gene regulation and expression in Alzheimer disease, and it remains a powerful tool to identify biomarkers for disease diagnosis. Ultimately, the most robust markers will enable the application of more specific treatments particular to disease stages or subcategories. Currently, no widely applicable molecular test is available to identify those at risk for developing Alzheimer disease or those who have early markers of pathology but show discernible cognitive impairment. The progression of this technology will lead to earlier detection of the disease through enhanced understanding of disease onset and progression.

Alzheimer Disease↗
PubMed2005

Expression of CTL associated transcripts precedes the development of tubulitis in T-cell mediated kidney graft rejection.

The usual phenotype of clinical kidney allograft rejection is infiltration by lymphocytes and macrophages and evolution of histologic Banff lesions, particularly tubulitis, which indicate parenchymal injury. Using Affymetrix microarrays, we evaluated the relationship between the evolution of pathologic lesions and the transcriptome. We studied CBA/J into C57Bl/6 mouse kidney allografts in which one host kidney is left in place to permit observation of lesion development. Histology was dominated by early infiltration by mononuclear cells from day 3 and slower evolution of tubulitis after day 7. We defined a set of cytotoxic T lymphocyte-associated transcripts (CATs) on the basis of expression in purified cytotoxic T lymphocytes (CTL) and in a mixed lymphocyte culture, and absence in normal kidney. CATs were detectable by day 3 and highly expressed by day 5 in rejecting kidneys, with a median signal 14% of that in CTL, compared to 4% in isografts and normal kidneys, and persisted through day 42. Lack of mature B cells had little effect on CAT expression, confirming that CATs reflect T-cell-mediated rejection. Expression of CATs was established before diagnostic lesions and remained remarkably consistent through day 42 despite massive alterations in the pathology, and probably reflects T cells recruited to the graft.

Animals↗
PubMed2001

Using Serial Analysis of Gene Expression to identify tumor markers and antigens.

Tumor markers and antigens are normally highly expressed in malignant tissue, but not in the surrounding normal tissue. Serial Analysis of Gene Expression (SAGE) is a technology that counts mRNA transcripts and can be used to find those genes most highly induced in malignant tissues. SAGE produces a comprehensive profile of gene expression and can be used to search for tumor biomarkers in a limited number of samples. Public sources of SAGE data, in particular through the Cancer Genome Anatomy Project, increase the value of this technology by making a large source of information on many tumors and normal tissues available for comparison. Although the perfect tumor-specific gene does not exist, the differences in gene expression between tumor and normal can be exploited for therapeutic or diagnostic purposes.

Antigens, Neoplasm↗
PubMed2006

CpG island methylator phenotype redefines the prognostic effect of t(12;21) in childhood acute lymphoblastic leukemia.

PURPOSE: To examine cancer genes undergoing epigenetic inactivation in a set of ETV6/RUNX1-positive acute lymphoblastic leukemias in order to define the CpG island methylator phenotype (CIMP) in the disease and evaluate its relationship with clinical features and outcome. EXPERIMENTAL DESIGN: Methylation-specific PCR was used to analyze the methylation status of 38 genes involved in cell immortalization and transformation in 54 ETV6/RUNX1-positive samples in comparison with 190 ETV6/RUNX1-negative samples. RESULTS: ETV6/RUNX1-positive samples had at least one gene methylated in 89% of the cases. According to the number of methylated genes observed in each individual sample, 20 patients (37%) were included in the CIMP- group (0-2 methylated genes) and 34 (67%) in the CIMP+ group (>2 methylated genes). Remission rate did not differ significantly among either group of patients. Estimated disease-free survival and overall survival at 9 years were 92% and 100% for the CIMP- group and 33% and 73% for the CIMP+ group (P = 0.002 and P = 0.04, respectively). Multivariate analysis showed that methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.01) and overall survival (P = 0.05). A group of four genes (DKK3, sFRP2, PTEN, and P73) showed specificity for ETV6/RUNX1-positive subset of samples. CONCLUSION: Our results suggest that methylation profile may be a potential new biomarker of risk prediction in ETV6/RUNX1-positive acute lymphoblastic leukemias.

Adolescent↗
PubMed2004

Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia.

Promoter hypermethylation plays an important role in the inactivation of cancer-related genes. This abnormality occurs early in leukemogenesis and seems to be associated with poor prognosis in acute lymphoblastic leukemia (ALL). To determine the extent of hypermethylation in ALL, we analyzed the methylation status of the CDH1, p73, p16, p15, p57, NES-1, DKK-3, CDH13, p14, TMS-1, APAF-1, DAPK, PARKIN, LATS-1, and PTEN genes in 251 consecutive ALL patients. A total of 77.3% of samples had at least 1 gene methylated, whereas 35.9% of cases had 4 or more genes methylated. Clinical features and complete remission rate did not differ among patients without methylated genes, patients with 1 to 3 methylated genes (methylated group A), or patients with more than 3 methylated genes (methylated group B). Estimated disease-free survival (DFS) and overall survival (OS) at 11 years were 75.5% and 66.1%, respectively, for the nonmethylated group; 37.2% and 45.5% for methylated group A; and 9.4% and 7.8% for methylated group B (P < .0001 and P = .0004, respectively). Multivariate analysis demonstrated that the methylation profile was an independent prognostic factor in predicting DFS (P < .0001) and OS (P = .003). Our results suggest that the methylation profile may be a potential new biomarker of risk prediction in ALL.

Adolescent↗
PubMed2025

Multi&#x2011;omics identification of a novel signature for serous ovarian carcinoma in the context of 3P medicine and based on twelve programmed cell death patterns: a multi-cohort machine learning study.

BACKGROUND: Predictive, preventive, and personalized medicine (PPPM/3PM) is a strategy aimed at improving the prognosis of cancer, and programmed cell death (PCD) is increasingly recognized as a potential target in cancer therapy and prognosis. However, a PCD-based predictive model for serous ovarian carcinoma (SOC) is lacking. In the present study, we aimed to establish a cell death index (CDI)-based model using PCD-related genes. METHODS: We included 1254 genes from 12 PCD patterns in our analysis. Differentially expressed genes (DEGs) from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) were screened. Subsequently, 14 PCD-related genes were included in the PCD-gene-based CDI model. Genomics, single-cell transcriptomes, bulk transcriptomes, spatial transcriptomes, and clinical information from TCGA-OV, GSE26193, GSE63885, and GSE140082 were collected and analyzed to verify the prediction model. RESULTS: The CDI was recognized as an independent prognostic risk factor for patients with SOC. Patients with SOC and a high CDI had lower survival rates and poorer prognoses than those with a low CDI. Specific clinical parameters and the CDI were combined to establish a nomogram that accurately assessed patient survival. We used the PCD-genes model to observe differences between high and low CDI groups. The results showed that patients with SOC and a high CDI showed immunosuppression and hardly benefited from immunotherapy; therefore, trametinib_1372 and BMS-754807 may be potential therapeutic agents for these patients. CONCLUSIONS: The CDI-based model, which was established using 14 PCD-related genes, accurately predicted the tumor microenvironment, immunotherapy response, and drug sensitivity of patients with SOC. Thus this model may help improve the diagnostic and therapeutic efficacy of PPPM.

Humans↗