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PubMed2002

Clinical trial end points: on the road to nowhere?

Over the past decade, there have been an increasing number of therapeutic clinical trials of PD. Despite many of these trials showing a positive treatment effect, few have resulted in clear and unambiguous recommendations regarding clinical practice, unlike trials of cerebrovascular disease. The authors hypothesize that lingering therapeutic uncertainty exists because many of the clinical trial end points have been surrogate outcome measures rather than end points with clear and convincing value to patients. The theoretical advantage of using validated surrogate outcomes in definitive trials includes smaller, faster, and less expensive studies. Consequences of using surrogate outcomes that have not been validated include ambiguous evidence and wasted resources as well as patient harm and missed opportunities. To optimize the chance that future trial results will provide clear treatment verdicts and to take full advantage of exciting developments in biomarker technology such as SPECT and PET, it is becoming progressively more urgent to understand the proper role, use, and challenges of using surrogate outcome measures in PD therapeutics.

Biomarkers↗
PubMed2000

Health effects of residence near hazardous waste landfill sites: a review of epidemiologic literature.

This review evaluates current epidemiologic literature on health effects in relation to residence near landfill sites. Increases in risk of adverse health effects (low birth weight, birth defects, certain types of cancers) have been reported near individual landfill sites and in some multisite studies, and although biases and confounding factors cannot be excluded as explanations for these findings, they may indicate real risks associated with residence near certain landfill sites. A general weakness in the reviewed studies is the lack of direct exposure measurement. An increased prevalence of self-reported health symptoms such as fatigue, sleepiness, and headaches among residents near waste sites has consistently been reported in more than 10 of the reviewed papers. It is difficult to conclude whether these symptoms are an effect of direct toxicologic action of chemicals present in waste sites, an effect of stress and fears related to the waste site, or an effect of reporting bias. Although a substantial number of studies have been conducted, risks to health from landfill sites are hard to quantify. There is insufficient exposure information and effects of low-level environmental exposure in the general population are by their nature difficult to establish. More interdisciplinary research can improve levels of knowledge on risks to human health of waste disposal in landfill sites. Research needs include epidemiologic and toxicologic studies on individual chemicals and chemical mixtures, well-designed single- and multisite landfill studies, development of biomarkers, and research on risk perception and sociologic determinants of ill health.

Environmental Health↗
PubMed2007

Depletion of high-abundance proteins in plasma by immunoaffinity subtraction for two-dimensional difference gel electrophoresis analysis.

Blood plasma is believed the most complex human-derived proteome, containing other tissue proteome subsets. Almost all body cells communicate with the plasma, either directly or through tissues or biological fluids, and many of these cells release at least a part of their content into the plasma upon damage or death. A comprehensive, systematic characterization of the plasma proteome in the healthy and diseased states will greatly facilitate the development of biomarkers for early disease detection, clinical diagnosis, and therapy. However, the characterization of human plasma proteome is a very complicated task, owing to the wide dynamic range of concentration that separates the most abundant proteins and the less common ones (10-12 orders of magnitude). The removal of its predominant proteins by affinity chromatography using an FPLC system improves the presence of low-abundance proteins in two-dimensional gel electrophoresis (2DE). The "Multiple Affinity Removal System" (Agilent Technologies) retains albumin, IgG, IgA, haptoglobin, transferrin, and antitrypsin with high specificity and reproducibility. After depletion, we have independently analyzed the flow-through (low-abundance proteins), and the retained fractions, by 2DE (4.0-7.0 pH range). Image analysis of the stained gels revealed that more than 300 spots appeared in the retained fraction and about 1800 spots appeared in the nonretained fraction. This methodology is a valuable tool for clinical proteomics, because its reproducibility allows comparative studies and quantitative analysis by 2DE or two-dimensional differential gel electrophoresis of plasma or sera samples from subjects with different pathological or physiological conditions. In addition, the method allows the comparison of experimental results from different laboratories.

Biomarkers↗
PubMed2006

Chronic obstructive pulmonary disease: linking outcomes and pathobiology of disease modification.

Recent guidelines define chronic obstructive pulmonary disease (COPD) as a preventable and treatable disease characterized by airflow limitation and systemic consequences. Airflow limitation in COPD worsens over years as assessed by the forced expiratory volume in one second (FEV(1)). Regardless, while it is likely that cardiovascular and other systemic components also worsen as COPD progresses, there are no accepted or validated outcomes to measure such pathophysiologic changes as they relate to COPD disease progression. It is clear that health status in COPD is more closely related to levels of patients' physical functional capacity than it is to changes in FEV(1). Furthermore, the relative contributions of pathoanatomic changes such as small airways fibrosis and pulmonary emphysema to declining airflow remain unknown. These features may even progress at different rates in the same individuals. Although stopping smoking is the only intervention shown to alter the relentless progression of COPD, the resultant slowing of FEV(1) decline takes several years to evince and requires at least 1,000 subjects to demonstrate annual therapeutic benefits of as little as 20 ml. The FEV(1) cannot distinguish between peribronchiolar fibrosis and emphysema and it is feasible that, as techniques are developed and validated, lung imaging methodologies may become important and sensitive outcomes measures of time- and age-dependent lung structural changes in COPD. The development of biomarkers of lung damage, pulmonary inflammation, and systemic disease will be essential to our further understanding of the natural history of COPD and the discovery of new, effective treatments for its progression.

Animals↗
PubMed2005

Emergence of targeted immune therapies for systemic lupus.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterised by flares of rampant inflammation that can threaten, in an unpredictable manner, almost any organ in the body. Current standard of care is largely empiric, involving the use of corticosteroids and toxic immune suppressive agents that are widely acknowledged to have unacceptable side effects for long-term use. Recently, there have been significant advances in understanding the nature of some fundamental immune imbalances underlying the complicated clinical manifestations of SLE. Nevertheless attempts to develop and test more targeted, and potentially safer immune-modulating drugs for lupus have encountered significant obstacles, due to the lack of validated biological markers for disease flare and remission, and difficulties in the clinical assessment of the heterogeneous patients. In support of renewed interest in drug development for lupus, large collaborative groups have formed, and efforts are underway to develop objective biomarkers for SLE as well as to improve the standardisation and reproducibility of clinical outcome measures in multi-centre trials.

Drug Delivery Systems↗
PubMed2002

Toxicogenomics: an opportunity to optimise drug development and safety evaluation.

'Toxicogenomics', the use of complex populations of mRNA to understand toxicity, is a relatively new field which combines the wealth of gene sequence information with advances in miniaturisation technology. In a parallel evolutionary path that the broader field of toxicology has encountered, toxicogenomics is steadily changing from descriptive to mechanistic research and will ultimately progress to a predictive science. This review focuses on the application of microarray research tools to toxicology studies in preclinical development. In particular, the 'testing funnel' approach to candidate selection in drug development is used to discuss the strategic implementation of toxicogenomics to help develop drugs that harbour less toxicity. Examples of where toxicogenomics has increased mechanistic and descriptive understanding of cellular toxicity are discussed, as are early efforts to develop molecular biomarkers that are predictive of longer-term toxicity.

Animals↗
PubMed2005

3p21.3 tumor suppressor cluster: prospects for translational applications.

Chromosomal abnormalities at the 3p21.3 region, including homozygous deletions and loss of heterozygosity and expressional deficiencies in 3p21.3 genes including transcriptional silences by promoter hypermethylation, altered mRNA splicing and aberrant transcripts, and lost or defect protein translation and post-translational modifications, are frequently found in most human cancers. Inactivation of 3p21.3 genes in primary tumors affects a wide spectrum of key biological processes such as cell proliferation, cell cycle kinetics, signaling transduction, ion exchange and transportation, apoptosis and cell death, and demonstrates the molecular signatures of carcinogenesis. Restoration of defective 3p21.3 genes with several wild-type 3p21.3 genes suppresses tumor cell growth both in vitro and in vivo. These findings suggest several 3p21.3 genes as potential tumor suppressors and implicates these 3p21.3 genes for future development as biomarkers for the early detection and diagnosis of cancer, and as prognostic and therapeutic tools for cancer prevention and molecular cancer therapy.

Animals↗
PubMed2006

Cytoreductive nephrectomy in metastatic renal cell carcinoma.

Metastatic renal cell carcinoma is associated with a poor prognosis and a median survival time of only 6-12 months. However, the emergence of immunotherapies has rekindled interest in cytoreductive nephrectomy as a therapeutic option. Phase III randomized trials have demonstrated that cytoreductive nephrectomy significantly improves overall survival in selected patients with metastatic renal cell carcinoma treated with interferon immunotherapy. While cytokine-based immunotherapy may be considered the standard systemic therapy, clinical studies are ongoing to develop molecular biomarkers and new therapies with improved efficacy and tolerability. With further advances in our understanding of the pathogenesis, behavior and molecular biology of renal cell carcinoma, cytoreductive nephrectomy, in combination with molecular targeted therapies, may become the new standard of care for patients with metastatic renal cell carcinoma.

Carcinoma, Renal Cell↗
PubMed2006

Genomic profiling of hormone-naïve lymph node metastases in patients with prostate cancer.

The progression of organ-confined prostate cancer to metastatic cancer is inevitably fatal. Consequently, identification of structural changes in the genome and associated transcriptional responses that drive this progression is critical to understanding the disease process and the development of biomarkers and therapeutic targets. In this study, whole genome copy number changes in genomes of hormone-naïve lymph node metastases were profiled using array comparative genomic hybridization, and matched primaries were included for a subset. Matched primaries and lymph node metastases showed very similar copy number profiles that are distinct from primary tumors that fail to metastasize.

Biomarkers, Tumor↗
PubMed2026

Integrated single-cell RNA sequencing and mendelian randomization analysis identifies causal immune-related driver genes in the heart failure inflammatory microenvironment.

BACKGROUND: Heart failure (HF) is a major global cause of cardiovascular death and disability. Chronic inflammation and immune dysregulation are critical in its development. The cardiac immune microenvironment, especially macrophages, drives HF progression, yet its molecular mechanisms and prognostic impact are not fully clear. This study aimed to identify causal immune-related driver genes in the HF inflammatory microenvironment. METHODS: We combined single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) to study how the inflammatory immune microenvironment affects HF risk. Using two public scRNA-seq datasets, we identified differentially expressed genes (DEGs) in HF heart tissues and selected 489 candidate genes. Causal relationships between these genes and HF were tested using expression quantitative trait loci (eQTL) data and HF genome-wide association study (GWAS) summary statistics. RESULTS: MR analysis showed that 65 genes were causally linked to HF risk. These genes were enriched in pathways related to cardiomyopathy, leukocyte migration, natural killer (NK) cell cytotoxicity, neutrophil extracellular traps, and NF-κB signaling. HF hearts displayed increased levels of macrophages, T cells, B cells, lymphoid cells, and mast cells, while neutrophils were reduced. CONCLUSIONS: Our integrated analysis reveals the central role of the cardiac inflammatory immune microenvironment in HF and identifies 65 key genes causally associated with HF susceptibility. These genes influence specific immune pathways and cell infiltration, shaping HF progression, and provide a basis for developing new biomarkers and immune-targeted therapies.

Heart failure (HF)↗
PubMed2026

Prognostic significance of DNA damage response-related markers in esophageal squamous cell carcinoma using machine learning approaches.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) lacks reliable prognostic biomarkers. Homologous recombination deficiency (HRD) has been implicated in genomic instability across multiple cancers, but its prognostic significance in ESCC remains unexplored. This study aimed to evaluate HRD score as a prognostic biomarker and develop a machine learning-based predictive model for ESCC. METHODS: Transcriptomic and clinical data from 78 ESCC patients were obtained from The Cancer Genome Atlas (TCGA) and randomly split into training (70%) and test (30%) cohorts. Prognostic models were constructed using 112 machine learning algorithm combinations based on DNA damage response (DDR)-related genes. Gene set enrichment analysis (GSEA), somatic mutation profiling, and immune cell infiltration estimation via CIBERSORT were performed to characterize HRD-associated molecular features. RESULTS: High HRD scores were significantly associated with poorer overall survival (P<0.05). Among 112 algorithm combinations, the survival support vector machine (Survival-SVM) model demonstrated optimal performance [training concordance index (C-index): 0.741; test C-index: 0.708], identifying six hub genes: PARP1, MBD4, TELO2, NSMCE3, SMUG1, and BABAM1. A nomogram incorporating risk score (RS) and clinical variables achieved strong predictive accuracy for 1- to 3-year survival [area under the curve (AUC) >0.7]. High-HRD tumors exhibited distinct mutational patterns (TP53 and TTN) and enriched glutathione metabolism and cytochrome P450 pathways. Immune infiltration analysis revealed significant differences in plasma cell and neutrophil infiltration between risk groups (P<0.05), suggesting HRD-associated immune microenvironment remodeling. CONCLUSIONS: We developed a novel HRD-based prognostic model incorporating six DDR-related genes that demonstrates robust predictive performance in ESCC. HRD score is identified as an independent prognostic factor associated with genomic instability, immune microenvironment alterations, and clinical outcomes. These findings provide a theoretical basis for personalized treatment strategies, including potential applications of PARP inhibitors and immunotherapy in ESCC.

Esophageal squamous cell carcinoma (ESCC)↗
PubMed2005

The role of transcriptome analysis in pre-clinical toxicology.

A major benefit of the genomics revolution in biomedical research has been the establishment of transcriptome analysis as an enabling technology in the drug development process. Nowhere in the realm of drug development has the expectation of the impact of transcriptome analysis been greater than in the area of pre-clinical toxicology. Transcriptome analysis, along with other new high-content data generating technologies, has the potential to radically improve the drug safety assessment process by allowing drug development teams to identify potential toxicity liabilities earlier, and thus proceed only with those molecules that have both efficacy at the target and a low potential for toxicity in the human population. In this review we will briefly describe the major ways in which transcriptome analysis is being applied in the pre-clinical safety assessment process, focusing primarily on four areas where transcriptome analysis has already begun to have impact. These include using transcriptome analysis to: 1) understand mechanisms of toxicity: 2) predict toxicity: 3) develop in vivo and in vitro surrogate models and screens; and, 4) develop toxicity biomarkers. We will close by briefly addressing future trends and needs in the application of transcriptome analysis to drug safety assessment.

Amyloid Precursor Protein Secretases↗
PubMed2026

Tissue-based genomic instability markers for predicting malignant transformation in oral leukoplakia and proliferative verrucous leukoplakia: a systematic review.

OBJECTIVES: Although several biomarkers have been described for predicting malignant transformation in oral leukoplakias (OLs) and proliferative verrucous leukoplakias (PVLs), no systematic review has comprehensively evaluated tissue-based genomic instability markers. This review aimed to evaluate the evidence for these markers and their potential role in biomarker panel development. METHODS: A systematic review across PubMed, Embase and Cochrane Library was performed to identify studies evaluating the differences in tissue-based genomic markers between OL and PVL patients with and without malignant transformation. RESULTS: 34 observational studies comprising 3,237 patients were included, and genomic aberrations were categorised into DNA-level, chromosomal, and gene-specific alterations. For studies on OLs, DNA-level and chromosomal markers for which individual studies reported associations with malignant transformation included aneuploidy, impaired DNA repair capacity, loss of heterozygosity, chromosomal instability, and copy number alterations. Multiple gene-specific alterations also showed associations (e.g., TP53, MKI67, FGFR1), but findings varied across studies. The genomic markers of PVLs differed substantially, with fewer consistent predictors found. No meta-analysis was performed as all included studies were observational. CONCLUSIONS: Genomic instability across multiple levels contributes to malignant transformation, and represents a promising biological framework for predicting malignant transformation for OLs. While no single marker reliably demonstrates sufficient predictive performance, the integration of complementary genomic alterations with clinical and histopathological risk factors may provide a basis for the development of robust multi-marker panels. Future prospective studies using standardised detection methods and multivariable prediction models are required before clinical implementation. SYSTEMATIC REVIEW REGISTRATION: identifier CRD42024585830.

carcinoma↗
PubMed2005

Evaluation of irinotecan plus paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: We conducted a phase II study to evaluate the efficacy and safety of the combination of irinotecan and paclitaxel in patients with advanced stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were eligible if they had histologically confirmed chemotherapy naïve stage IV NSCLC or stage IIIB disease that was not suitable for combined modality therapy. Patients were treated with irinotecan 50 mg/m2 and paclitaxel 75 mg/m2 on days 1 and 8 of a 21-day cycle. If the patient did not experience >grade 1 toxicity during the first cycle, the dose of irinotecan could be escalated to 60 mg/m(2). Patients were evaluated for tumor response rate, time to progression (TTP), overall survival (OS) and toxicity. RESULTS: Twenty-three eligible patients were treated. Two (9%) patients achieved a partial response. Eight patients (35%) had stable disease. The median number of cycles given per patient was four (range 1-29). The major toxicities were grade >or=3 neutropenia (26%) and grade 3 diarrhea (5%). The median time to progression was 2.8 months (range 0.5-21.8 months) for all patients and 4.3 months for the patients who had either stable disease or a partial response. The median overall survival was 9.2 months (range 0.5-40 months). The one- and two-year survival rates were 39% and 13%, respectively. CONCLUSION: The combination of irinotecan and paclitaxel is safe in advanced NSCLC and affords a survival similar to other non-platinum as well as platinum-based doublets. However, this combination does not have sufficient activity to justify further study in an unselected population. If biomarkers are developed that can guide the selection of chemotherapy in an individual patient, there may be a rationale for further evaluation of this regimen.

Aged↗
PubMed2006

Proteomics: applications to the study of rheumatoid arthritis and osteoarthritis.

The study of both DNA and protein technologies has been marked by unprecedented achievement over the last decade. The completion of the Human Genome Project in 2003 is representative of a new era in genomics; likewise, proteomics research, which has revolutionized the way we study disease, offers the potential to unlock many of the pathophysiologic mechanisms underlying the clinical problems encountered by orthopaedic surgeons. These new fields are extending our approach to and investigation of the etiology and progression of musculoskeletal disorders, notably rheumatoid arthritis and osteoarthritis. Advances in proteomics technology may lead to the development of biomarkers for both rheumatoid arthritis and osteoarthritis. Such biomarkers would improve early detection of these diseases, measure response to treatment, and expand knowledge of disease pathogenesis.

Arthritis, Rheumatoid↗
PubMed2002

The further development of ionoregulatory measures as biomarkers of sensitivity and effect in fish species.

Extensive season-by-season sampling was used to establish the normal range of whole-body Na+ and Cl- and Na+ uptake in healthy populations of two fish species, rainbow trout, Oncorhynchus mykiss, and fathead minnow, Pimephales promelas, of known differences in sensitivity to ionoregulatory toxicants (low pH, trace metals). These data together with responses of both species to six different ionoregulatory challenge tests of increasing severity (mild handling, exposure to low Ca2+ water, epinephrine injection, net-confinement stress, exposure to copper, and osmotic shock) were evaluated for their potential as biomarkers of sensitivity and of effect of ionoregulatory toxicants. There were no obvious biomarkers of sensitivity in the ion measures themselves, but four of the six challenges (exposure to low Ca2+ water, epinephrine injection, exposure to copper, and osmotic shock) produced a significantly greater effect in the more sensitive of the two species, fathead minnow. Based on the responses of both species, this article makes a number of recommendations for the application of ion measures alone and in combination with challenge tests to the assessment of chronic effects in populations experiencing sublethal ionoregulatory stress.

Animals↗
PubMed2002

Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability.

Green tea and tea polyphenols have been studied extensively as cancer chemopreventive agents in recent years. The bioavailability and metabolic fate of tea polyphenols in humans, however, are not clearly understood. In this report, the pharmacokinetic parameters of (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin (EC) were analyzed after administration of a single oral dose of green tea or decaffeinated green tea (20 mg tea solids/kg) or EGCG (2 mg/kg) to eight subjects. The plasma and urine levels of total EGCG, EGC, and EC (free plus conjugated forms) were quantified by HPLC coupled to an electrochemical detector. The plasma concentration time curves of the catechins were fitted in a one-compartment model. The maximum plasma concentrations of EGCG, EGC, and EC in the three repeated experiments with green tea were 77.9 +/- 22.2, 223.4 +/- 35.2, and 124.03 +/- 7.86 ng/ml, respectively, and the corresponding AUC values were 508.2 +/- 227, 945.4 +/- 438.4, and 529.5 +/- 244.4 ng x h x ml(-1), respectively. The time needed to reach the peak concentrations was in the range of 1.3-1.6 h. The elimination half-lives were 3.4 +/- 0.3, 1.7 +/- 0.4, and 2.0 +/- 0.4 h, respectively. Considerable interindividual differences and variations between repeated experiments in the pharmacokinetic parameters were noted. Significant differences in these pharmacokinetic parameters were not observed when EGCG was given in decaffeinated green tea or in pure form. In the plasma, EGCG was mostly present in the free form, whereas EGC and EC were mostly in the conjugated form. Over 90% of the total urinary EGC and EC, almost all in the conjugated forms, were excreted between 0 and 8 h. Substantial amounts of 4'-O-methyl EGC, at levels higher than EGC, were detected in the urine and plasma. The plasma level of 4'-O-methyl EGC peaked at 1.7 +/- 0.5 h with a half life of 4.4 +/- 1.1 h. Two ring-fission metabolites, (-)-5-(3',4',5'-trihydroxyphenyl)-gamma-valerolactone (M4) and (-)-5-(3',4'-dihydroxyphenyl)-valerolactone (M6), appeared in significant amounts after 3 h and peaked at 8-15 h in the urine as well as in the plasma. These results may be useful for designing the dose and dose frequency in intervention studies with tea and for development of biomarkers of tea consumption.

Administration, Oral↗
PubMed2002

Inhibition of mitogen-activated protein kinase activity of human lymphocytes after oral administration of Oltipraz.

Several preclinical studies indicated that Oltipraz appears to be one of the most potent cancer chemopreventive agents. Pharmacological studies in humans provided substantial amounts of information related to doses and schedules. Oltipraz has been reported to induce phase II drug-metabolizing enzymes. However, its chemopreventive activity suggests that it may also interact with cellular processes associated with cancer cell growth and proliferation. During a clinical trial designed to monitor eventual Oltipraz toxicity in high-risk population for development of lung cancer, we performed companion studies related to cell proliferation. Human lymphocytes were chosen as surrogate tissue to assess the in vivo effects of Oltipraz on cell signaling pathways involved in cell proliferation. The results of this study demonstrate that Oltipraz markedly inhibited the activation state of the extracellular signal-regulated kinases of the mitogen-activated protein kinase family of kinases in lymphocytes of subjects treated with two different doses and schedules of Oltipraz. Individual variations were observed that were not related to Oltipraz dosing or schedule of administration. The results from this study indicate that lymphocytes could be used as surrogate tissue for the development of biomarkers for studies of anticarcinogenic agents.

Administration, Oral↗