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At least 379 records · Page 21Linked to original sources
PubMed2005

Molecular markers in malignant cutaneous melanoma: gift horse or one-trick pony?

The management of malignant cutaneous melanoma is problematic. Current clinical prognostic factors do not adequately predict disease recurrence and overall survival in a significant subset of patients. Adjuvant therapies for melanoma are notoriously toxic and associated with significant morbidity. Furthermore, it has been difficult to predict which patients will respond best to these treatments, if at all. DNA and RNA biomarkers have been developed to help overcome these problems. Biomarkers have been shown to upstage patients with melanoma, but are the assays sensitive and specific enough for clinical use as predictors of disease outcome or treatment response? We review our experience with DNA and RNA biomarkers in terms of their prognostic and predictive capabilities in malignant melanoma and outline their likely role in the future of melanoma staging, surveillance, and treatment.

Biomarkers↗
PubMed2005

Aromatase cytochrome P450: cloning, intron variation, and ontogeny of gene expression in southern flounder (Paralichthys lethostigma).

Aromatase cytochrome P450 (P450arom) is the enzyme complex responsible for conversion of androgens to estrogens in vertebrates. Consequently, in some fishes its activity appears critical to ovarian differentiation. Southern flounder (Paralichthys lethostigma) is a commercially important flatfish in which females grow larger than males and sex determination is temperature sensitive. Through cloning of the P450arom gene in ovary and quantitative reverse transcription-polymerase chain reaction, we developed a biomarker for early female differentiation in southern flounder. The deduced amino acid sequence for southern flounder P450arom is similar to other teleosts. Comparison of P450arom intron sequences from fish of different populations revealed substantial inter-individual variation. Adult ovary and spleen exhibited high levels of P450arom mRNA, while P450arom mRNA was only weakly detected in testes. Brain, liver, intestine, kidney, gill, muscle, and heart showed little or no P450arom mRNA expression. Gonads of wild and hatchery-produced juvenile flounder of sizes spanning the period of sex differentiation initially exhibited low levels of P450arom mRNA followed by increases in some individuals and bifurcation into two clearly segregated groups (i.e., putative males and females) beginning at approximately 65 mm in total length. Gonadal histology confirmed predictions of sex based on P450arom expression in juvenile flounder, demonstrating that the patterns of P450arom expression observed relate to sex-specific differentiation. This research represents a unique approach to assessing sex differentiation in a natural population, and a powerful technique for better understanding mechanisms of flounder sex determination and rapidly defining conditions for controlling sex for aquaculture.

Amino Acid Sequence↗
PubMed2004

The Human Proteome Organization Plasma Proteome Project pilot phase: reference specimens, technology platform comparisons, and standardized data submissions and analyses.

A comprehensive, systematic characterization of cirolating proteins in health and disease will greatly facilitate development of biomarkers for prevention, diagnosis, and therapy of cancers and other diseases. The Human Proteome Organization Plasma Proteome Project pilot phase aims to (1) compare the advantages and limitations of many technology platforms; (2) contrast reference specimens of human plasma (ethylenediaminetetra acetic acid, heparin, citrate-anticoagulated) and serum, in terms of numbers of proteins identified and any interferences with various technology platforms; and (3) create a global knowledge base/data repository.

Biomarkers↗
PubMed2006

Quantitative proteomic profiling of pancreatic cancer juice.

Pancreatic juice is an exceptionally rich source of cancer-specific proteins shed from cancerous ductal cells into the pancreatic juice. Quantitative proteomic analysis of the proteins specific to pancreatic cancer juice has not previously been reported. We used isotope-code affinity tag (ICAT) technology and MS/MS to perform quantitative protein profiling of pancreatic juice from pancreatic cancer patients and normal controls. ICAT technology coupled with MS/MS allows the systematic study of the proteome and measures the protein abundance in pancreatic juice with the potential for development of biomarkers. A total of 105 proteins were identified and quantified in the pancreatic juice from a pancreatic cancer patient, of which 30 proteins showed abundance changes of at least twofold in pancreatic cancer juice compared to normal controls. Many of these proteins have been externally validated. This is the first comprehensive study of the pancreatic juice proteome by quantitative global protein profiling, and the study reveals numerous proteins that are shown for the first time to be associated with pancreatic cancer, providing candidates for diagnostic biomarkers. One of the identified proteins, insulin-like growth factor binding protein-2 was further validated by Western blotting to be elevated in pancreatic cancer juice and overexpressed in pancreatic cancer tissue.

Amino Acid Sequence↗
PubMed2003

Bone quality: where do we go from here?

As was true 10 years ago, tremendous interest surrounds the concept of "bone quality," as shown by the intense and growing research activity in the field. The urgency to advance knowledge in this area is motivated by the need to understand not only the causes of increased skeletal fragility with aging and disease, but also the mechanisms by which drugs reduce fracture risk. As reflected in the preceding articles, in the past decade collaborations between biologists, physicists, engineers and clinicians have led to new insights regarding the biological, material and structural features that contribute to skeletal fragility. Despite these new insights, important issues remain unresolved. Our challenges lie in identifying, describing and understanding the totality of features and characteristics that determine a bone's ability to resist fracture, and using this information to identify new therapeutic targets and develop better biomarkers and noninvasive imaging modalities. This summary is intended to integrate reports in the literature with presentations and discussions that occurred during the meeting, to highlight areas of consensus and those of continued controversy, and thus to identify critical areas for future research.

Biomechanical Phenomena↗
PubMed2003

Core biological marker candidates of Alzheimer's disease - perspectives for diagnosis, prediction of outcome and reflection of biological activity.

Alzheimer's disease (AD) is a complex neurodegenerative dementing illness. Over the past few years, however, remarkable advances have taken place in understanding both the genetic and molecular biology with the intracellular processing of amyloid and tau and the changes leading to the pathologic formation of extracellular amyloid plaques and the intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles. This progress in our understanding of the molecular pathology has set the stage for clinically meaningful advances in the development of biomarkers. Emerging diagnostic methods that are based on biochemical and imaging biomarkers of disease specific pathology hold the potential to provide effective measures of natural history (marker of disease that is predictive of outcome), biological activity (such as magnitude and frequency of response correlating with drug potency) and markers of surrogate endpoints (single or composite marker that accounts for clinical benefit of the therapy). Markers of biological activity should be also evaluated regarding their value to reflect disease progression, heterogeneity of the clinical population, for early decision making and characterization of new treatments. We focussed on the current status of core analytes which provide reasonable evidence for association with key mechanisms of pathogenesis or neurodegeneration in AD. In addition, feasibility was important, such as availability of a validated assay for the biological measure in question, with properties that included high precision and reliability of measurement, reagents and standards well described. On this basis we reviewed the body of literature that has examined CSF total tau (t-tau) and beta-amyloid 1-42 (Abeta(1-42)), phosphorylated tau (p-tau) and beta-amyloid-antibodies as diagnostic tests for AD versus clinically representative comparison groups. Measurement of t-tau and Abeta(1-42) in the CSF seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. First studies showed that measurement of p-tau proteins significantly improves early and differential diagnosis, as well as disease prediction in subjects at risk for AD and comes closest to fulfilling proposed criteria of a biological marker for AD. However, the nature of the majority of reported findings are still preliminary and retrospective. General issues for biomarkers have to be adequately addressed, such as sensitivity of the method, frequency of assessments, stability of the method, standardization of methods and dynamic range. There is still a partial lack of comparison patient populations that must be addressed in future studies. International dementia networks have been recently established to advance the establishment of core biomarker candidates of AD as potential surrogate endpoints for clinical trials and their clinical use for predictive and diagnostic purposes.

Alzheimer Disease↗
PubMed2006

Neuroproteomics: relevance to anxiety disorders.

Despite advances in the treatment of anxiety disorders, there is a need for medications with greater efficacy and fewer side effects. Advances in techniques to facilitate high throughput, mass analysis of proteins potentially allows for new drug targets, with a shift in focus from membrane receptor proteins and enzymes of neurotransmitter metabolism to molecules in intracellular signal transduction and other pathways. A computerized literature search was done to collect studies on recently developed proteomic techniques and their application in psychiatric research. Particular techniques, such as two-dimensional electrophoresis, two-dimensional differential gel electrophoresis, isotope-coded affinity tags, and isotope tags for relative and absolute quantification, are reviewed. In addition, a combination of these techniques with MALDI-TOF/TOF and ESI-Q-TOF mass spectrometry analysis is discussed in relation to possible novel signaling pathways relevant to anxiety disorders, and to the development of biomarkers for the evaluation of these conditions.

Animals↗
PubMed1991

Distribution of chromium within cells of the blood.

Although a number of investigators have examined the uptake of chromium in red blood cells (RBC) or whole blood, little is known about chromium uptake in white blood cells (WBC). Radiolabeled chromium (51Cr) was used to determine chromium uptake and distribution. Isolated RBC and enriched WBC populations were exposed in vitro to potassium chromate (Cr+6) and uptake was determined over a 2-hr time period. Exposure of either rat or human blood cells to 50 microM K2CrO4 for 2 hr resulted in greater accumulation of chromium within WBC than RBC. Uptake by rat WBC was significantly greater than that of human; whereas, uptake by human RBC was greater than that of the rat. Exposure of human whole blood to 50 microM K2CrO4, prior to isolation of WBC, also resulted in an increased uptake of chromium by WBC. Fisher 344 rats were exposed either orally or intravenously to a single dose of K2CrO4 and the distribution of chromium within blood cells was determined 1 hr, 24 hr, or 7 days following exposure. Regardless of the route or time following exposure, WBC chromium levels were consistently greater than those of RBC. However, the absolute levels of chromium did change with time. A comparison of chromium distribution 24 hr following a single oral exposure (1 ppm Cr+6) to the distribution 7 days following exposure demonstrated a reduction in chromium levels for RBC (10-fold) and for WBC (approximately 2.5-fold). In contrast, intravenous administration of chromate resulted in no significant decrease in RBC chromium levels when compared 1 hr, 24 hr, and 7 days following exposure. Although no difference in WBC chromium content was observed at 1 and 24 hr after exposure, an approximate 1.7-fold decrease in chromium content was detected at Day 7 for WBC. Intravenous administration of chromic chloride (Cr+3) resulted in a low level of chromium associated with RBC following 1 hr, and chromium was undetected in the WBC. These data demonstrate that WBC accumulate hexavalent chromium following both in vitro and in vivo exposure. In addition, white blood cells accumulate chromium to a greater extent than red blood cells. Since WBC accumulate chromium, their use as a target for the development of biomarkers of chromium exposure may be warranted.

Animals↗
PubMed2026

Epigenetic clues: Predicting maternal depression through DNA methylation.

Perinatal depression (PND) is a prevalent and multifactorial mood disorder affecting approximately 10-20 % of women globally, with higher burdens reported in low- and middle-income countries. Despite the availability of screening tools such as the Edinburgh Postnatal Depression Scale, these approaches primarily identify risk without elucidating underlying biological mechanisms. Emerging evidence highlights the role of epigenetic regulation particularly DNA methylation as a key mediator linking genetic susceptibility and environmental exposures during the perinatal period. This review synthesizes current knowledge on DNA methylation dynamics in maternal depression, emphasizing both candidate gene and epigenome-wide association study (EWAS) approaches. Candidate gene studies have identified differential methylation in stress-related pathways, including HPA axis genes (NR3C1, FKBP5), serotonergic signalling (SLC6A4), and oxytocin pathways (OXTR), though findings remain limited by poor reproducibility and small sample sizes. In contrast, EWAS provides a hypothesis-free framework, identifying novel differentially methylated positions and regions associated with PND, including predictive CpG panels with potential diagnostic utility. The review also highlights the importance of tissue specificity, temporal epigenetic remodeling across pregnancy, and the interplay between maternal and fetal epigenomes. Furthermore, methodological challenges such as heterogeneity in study design, lack of replication, and analytical inconsistencies remain barriers to clinical translation. Integrating genetic, epigenetic, and environmental data through multi-omics approaches may enhance predictive accuracy and improve early intervention strategies. Overall, DNA methylation represents a promising avenue for understanding the biological underpinnings of PND and developing robust biomarkers for risk prediction and personalized care.

Humans↗
PubMed2005

Tissue-specific accumulation of cadmium in subcellular compartments of eastern oysters Crassostrea virginica Gmelin (Bivalvia: Ostreidae).

Cadmium distribution was studied in different subcellular fractions of gill and hepatopancreas tissues of eastern oysters Crassostrea virginica. Oysters were exposed for up to 21 days to low sublethal Cd concentrations (25 microg L(-1)). Gill and hepatopancreas tissues were sampled and divided into organelle fractions and cytosol by differential centrifugation. Organelle content of different fractions was verified by activities of marker enzymes, citrate synthase and acid phosphatase for mitochondria and lysosomes, respectively. In both tissue types, there was a significant accumulation of cadmium in cytosol reaching 230-350 ng mg(-1) protein. Among organelles, mitochondria were the main target for Cd bioaccumulation in gills (250-300 ng mg(-1) protein), whereas in hepatopancreas tissues, the highest cadmium accumulation occurred in lysosomes (90-94 ng mg(-1) protein). Although 75-83% of total cadmium burden was associated with the cytosol reflecting high volume fraction of this compartment, Cd concentrations in organelle fractions reached levels that could cause dysfunction of mitochondria and lysosomes. Organ- and organelle-specific patterns of cadmium bioaccumulation support our previous in vivo studies, which showed adverse effects of cadmium exposures on mitochondrial oxidation in gills and on the lysosomal system of hepatopancreas. This may have important implications for the development of biomarkers of effect for heavy metals and for understanding the mechanisms of toxic effects of metals.

Acid Phosphatase↗
PubMed2005

Expression profiling in the aging brain: a perspective.

To evaluate molecular events associated with the aging process in animal models and human tissues, microarray analysis is performed at the regional and cellular levels to define transcriptional patterns or mosaics that may lead to better understanding of the mechanism(s) that drive senescence. In this review, we outline the experimental and analytical issues associated with high-throughput genomic analyses in aging brain and other tissues for a comprehensive evaluation of the current state of microarray analysis in aging paradigms. Ultimately, the goal of these studies is to apply functional genomics and proteomics approaches to aging research to develop new tools to assess age in cell- and tissue-specific manners in order to develop aging biomarkers for pharmacotherapeutic interventions and disease prevention.

Adult↗
PubMed2006

Gene expression profiling in vLINCL CLN6-deficient fibroblasts: Insights into pathobiology.

The CLN6 vLINCL is caused by molecular defects in CLN6 gene coding for an ER resident transmembrane protein whose function is unknown. In the present study gene expression profiling of CLN6-deficient fibroblasts using cDNA microarray was undertaken in order to provide novel insights into the molecular mechanisms underlying this neurodegenerative fatal disease. Data were validated by qRT-PCR. Statistically significant alterations of expression were observed for 12 transcripts. The two most overexpressed genes, versican and tissue factor pathway inhibitor 2, are related to extracellular matrix (ECM), predicting changes in ECM-related proteins in CLN6-deficient cells. Transcript profiling also suggested alterations in signal transduction pathways, apoptosis and the immune/inflammatory response. Up-regulated genes related to steroidogenesis or signalling, and the relationship between cholesterol dynamics and glycosphingolipid sorting, led to investigation of free cholesterol and gangliosides in CLN6-deficient fibroblasts. Cholesterol accumulation in lysosomes suggests a homeostasis block as a result of CLN6p deficiency. The cholesterol imbalance may affect structure/function of caveolae and lipid rafts, disrupting signalling transduction pathways and sorting cell mechanisms. Alterations in protein/lipid intracellular trafficking would affect the composition and function of endocytic compartments, including lysosomes. Dysfunctional endosomal/lysosomal vesicles may act as one of the triggers for apoptosis and cell death, and for a secondary protective inflammatory response. In conclusion, the data reported provide novel clues into molecular pathophysiological mechanisms of CLN6-deficiency, and may also help in developing disease biomarkers and therapies for this and other neurodegenerative diseases.

Cells, Cultured↗
PubMed2005

Amyloidosis.

Amyloidosis is an uncommon plasma-cell dyscrasia with an incidence of eight patients per million per year. It is often difficult to recognize because of the myriad symptoms and vague nature of the clinical presentation. Symptoms include fatigue, dyspnea, edema, paresthesias, and weight loss. Clinical syndromes at presentation include nephrotic-range proteinuria with or without renal insufficiency, cardiomyopathy, hepatomegaly, symptomatic peripheral neuropathy, and autonomic failure. Recent advances have occurred in evaluation of patients by using the free light chain assay and new prognostic assessments with cardiac biomarkers. Newly developed therapeutic strategies, involving high-dose and intermediate-dose chemotherapy, have evolved in the last 3 years. This paper reviews a diagnostic pathway clinicians can use to diagnose the disorder, assess a patient's prognosis, and logically plan a therapeutic strategy.

Amyloidosis↗
PubMed2006

The future perspectives of breast cancer therapy.

Adjuvant therapy after surgery for breast cancer has provided significant benefits to patients at risk of relapse. However, the success of therapy for each individual patient will often take years to reveal. Preoperative therapy has brought about significant advances in the treatment of breast cancer. More breast conservation therapy can be performed and it becomes clear that pathologic complete response (pCR) is a good prognostic marker. Moreover, patients can be segregated into different clinical phenotypes after preoperative therapy: the responder non-recurrent, the responder recurrent, the non-responder non-recurrent and the non-responder recurrent. While conventional therapy and surgery is adequate for the responder non-recurrent and the non-responder non-recurrent cases, modification of conventional therapy, the adoption of a new approach or the incorporation of novel therapeutics may be necessary to improve the pCR and reduce recurrence for the later two groups of patients. Preoperative therapy has also made possible the development of biomarkers to predict response and resistance to treatment. With this translational approach, the therapy for each patient can be more targeted and individualized. A higher rate of success is expected.

Antineoplastic Agents↗
PubMed2005

Use of 'Omic' technologies to study humans exposed to benzene.

'Omic' technologies include genomics, transcriptomics (gene expression profiling), proteomics and metabolomics. We are utilizing these new technologies in an effort to develop novel biomarkers of exposure, susceptibility and response to benzene. Advances in genomics allow one to study hundreds to thousands of single nucleotide polymorphisms simultaneously on small quantities of DNA using array-based technologies. We are currently utilizing these technologies to examine genetic variation in pathways relating to biotransformation, DNA repair, folate metabolism and immune response with the goal of finding biomarkers of susceptibility to benzene hematotoxicity. Transcriptomics is used to measure the full complement of activated genes, mRNAs or transcripts in a particular tissue at a particular time typically using microarray technology. We have applied microarrays to the study of global gene expression in the peripheral blood cells of benzene-exposed workers. More than 100 genes were identified as being potentially differentially expressed, with genes related to apoptosis and immune function being the most significantly affected. Initial studies employing proteomics have also shown that several proteins are altered in the serum of exposed compared to control subjects and these proteins are potential biomarkers of benzene exposure. Omic technologies therefore have significant potential in generating novel biomarkers of exposure, susceptibility and response to benzene.

Air Pollutants, Occupational↗
PubMed2006

Microarray analysis of radiation response genes in primary human fibroblasts.

PURPOSE: To identify radiation-induced early transcriptional responses in primary human fibroblasts and understand cellular pathways leading to damage correction. METHODS AND MATERIALS: Primary human fibroblast cell lines were irradiated with 2 Gy gamma-radiation and RNA isolated 2 h later. Radiation-induced transcriptional alterations were investigated with microarrays covering the entire human genome. Time- and dose dependent radiation responses were studied by quantitative real-time polymerase chain reaction (RT-PCR). RESULTS: About 200 genes responded to ionizing radiation on the transcriptional level in primary human fibroblasts. The expression profile depended on individual genetic backgrounds. Thirty genes (28 up- and 2 down-regulated) responded to radiation in identical manner in all investigated cells. Twenty of these consensus radiation response genes were functionally categorized: most of them belong to the DNA damage response (GADD45A, BTG2, PCNA, IER5), regulation of cell cycle and cell proliferation (CDKN1A, PPM1D, SERTAD1, PLK2, PLK3, CYR61), programmed cell death (BBC3, TP53INP1) and signaling (SH2D2A, SLIC1, GDF15, THSD1) pathways. Four genes (SEL10, FDXR, CYP26B1, OR11A1) were annotated to other functional groups. Many of the consensus radiation response genes are regulated by, or regulate p53. Time- and dose-dependent expression profiles of selected consensus genes (CDKN1A, GADD45A, IER5, PLK3, CYR61) were investigated by quantitative RT-PCR. Transcriptional alterations depended on the applied dose, and on the time after irradiation. CONCLUSIONS: The data presented here could help in the better understanding of early radiation responses and the development of biomarkers to identify radiation susceptible individuals.

Aged↗
PubMed2004

Differential gene expression in mummichogs (Fundulus heteroclitus) following treatment with pyrene: comparison to a creosote contaminated site.

Mummichogs, Fundulus heteroclitus, an estuarine fish with a relatively small home range found along the eastern coast of the United States are well-suited to monitoring contaminant effects, including those of polycyclic aromatic hydrocarbons (PAHs). One of the common PAHs in estuaries is pyrene. We report here on efforts to develop multiple biomarkers of pyrene exposure in this species. Adult male mummichogs were exposed in the laboratory to the weak aryl hydrocarbon receptor (AhR) agonist pyrene at 0, 30, or 50 microg/L in 7-day static renewal exposures. The RNA was extracted from livers and alterations in mRNA expression were assessed by subtractive hybridization and differential display in order to produce multiple biomarkers of pyrene exposure. Genes demonstrating differential expression were confirmed by quantitative-PCR (Q-PCR) and include cytochrome P-450 1A (CYP1A), a putative hepatocyte growth factor activator, a X-ray inducible retrotransposon, and several expressed sequenced tags (ESTs). Some of these genes represent new biomarkers of pyrene exposure and potential biomarkers of PAH exposure. Therefore, similar changes were investigated at a Superfund site in Charleston, SC. Mummichogs from a creosote contaminated site and from a reference site (North Inlet National Estuarine Research Reserve near Georgetown, SC) were trapped, RNA extracted from the livers, and Q-PCR performed. Many of the genes differentially expressed following pyrene exposure were not altered at the creosote contaminated site in comparison to the reference site. However, CYP1A and an EST were induced. CYP1A induction at Diesel Creek indicates that this population of fish does not demonstrate refractory CYP1A phenotypes observed at several sites with high levels of AhR agonists. Ultimately, we anticipate that the use of multiple biomarkers of PAH exposure will provide useful information on the potential effects of toxicants.

Amino Acid Sequence↗