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PubMedDate not supplied

Biomarkers in psychotropic drug development.

The authors review the use of biomarkers in the development of novel psychotropic agents. They briefly review clinical drug development, emphasizing the importance of incorporating biomarkers. For the development of psychotropic agents, biomarkers are particularly useful for assessing central nervous system exposure and effects and for serving as surrogate measures for safety and efficacy. Collectively, biomarkers allow for more accurate estimation of doses for clinical trials as drug development progresses. For drugs that target the pathophysiology of Alzheimer disease, several promising biomarkers are becoming available that may allow improved signal detection in clinical trials. Procedures for developing new drugs are evolving rapidly. Technical advances in the field are making it possible to shift from empirically-based methods to mechanistically-driven schemes. Biomarkers enhance the quality and safety of clinical drug development and reduce its cost and duration.

Aged↗
PubMed1992

Biomarker intermediate endpoints and cancer prevention.

Detection of cancer is the definitive endpoint in the conduct of chemoprevention trials. There are, however, several reasons why cancer as the endpoint may not be feasible or ethical: 1) the usage of patients with easily followable preneoplasias may preclude the development of cancer, and 2) the time to a cancer event may be long or the incidence uncommon, even in individuals at high risk. Two major types of biomarker intermediate endpoints should be considered: 1) those that identify individuals at high risk and 2) those that serve as a surrogate for cancer. Various epidemiologic features, including family history, have been used to estimate relative risk. This approach, however, only slightly decreases the size of populations needed for chemoprevention trials and only little addresses the question of individual risk. Advances in understanding the genetic basis for cancer will lead to the development of probes that will help assess risk for many cancers. Innumerable biomarker intermediate endpoints can be identified as associated with cancer formation, including genetic, epigenetic, and histologic features. The challenge is not in identifying potential biomarker intermediate endpoints but in showing that they are relevant. Carcinogenesis has been shown to be carcinogen, inhibitor, dose, tissue, and species specific; it is likely that relevant biomarker intermediate endpoints will need to be identified, studied, and verified in human models. The upper aerodigestive system should be a rich source for biomarker intermediate endpoint studies, as tissue is readily available, the carcinogenic process can be monitored, and there are currently available reasonable compounds to use in biomarker intermediate endpoint modulation and chemoprevention trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗
PubMed2004

Cytogenetic biomarkers.

Cytogenetic biomarkers in peripheral blood lymphocytes such as chromosomal aberrations, sister chromatid exchanges and micronuclei have long been applied in surveillance of human genotoxic exposure and early effects of genotoxic carcinogens. The use of these biomarker assays is based on the fact that most established human carcinogens are genotoxic in short-term tests and capable of inducing chromosomal damage. The relevance of chromosomal aberrations as a biomarker has been further emphasized by epidemiological studies suggesting that a high frequency of chromosomal aberrations is predictive of an increased risk of cancer. Structural and numerical chromosomal aberrations are typical of cancer cells, probably as a manifestation of genetic instability of such cells, but may also represent mechanisms leading to such instability. The frequency of all three biomarkers increases with age, and this effect is particularly clear for micronuclei in women. Tobacco smoking is known to increase the level of sister chromatid exchanges and chromosomal aberrations, but its effect on micronuclei is unclear. Several studies have recently examined the influence of genetic polymorphisms of xenobiotic metabolizing enzymes on cytogenetic biomarkers. The lack of glutathione S-transferase M1 (GSTM1 null genotype) appears to be associated with increased sensitivity to genotoxicity of tobacco smoking. N-Acetyltransferase (NAT2) slow acetylation genotypes seem to elevate baseline level of chromosomal aberrations, whereas deletion of glutathione S-transferase T1 gene (GSTT1 null genotype) has been found to yield an increase in baseline sister chromatid exchange frequency. These findings may be explained by reduced detoxification capacity rendered by the altered gene and may be linked with exposure to, for example, heterocyclic amines in the case of NAT2 and endogenously formed ethylene oxide in the case of GSTT1. Recently discovered polymorphisms affecting DNA repair may be expected to be of special importance in modulating genotoxic effects, but, as yet, there is very little information about the significance of these polymorphisms or about their impact on cytogenetic biomarkers.

Biomarkers↗
PubMed2006

A strategic view on the use of pharmacodynamic biomarkers in early clinical drug development.

Early-phase clinical trials have traditionally focused on the safety, tolerability and pharmacokinetic properties of a therapeutic candidate, while questions regarding efficacy have been left unanswered until phase II clinical development. Although an understanding of all of these parameters is unarguably essential to the successful development of a drug candidate, this information is insufficient. Biomarkers are increasingly being used in early drug development to allow for the exploration of pharmacodynamic effects of targeted therapeutics before clinical signs and symptoms are evaluated. The trend of using pharmacodynamic biomarkers will continue and, ultimately, may enable these biomarkers to be used routinely to demonstrate the impact of a compound on the treatment of a disease, and to aid in the selection of therapeutic doses and regimens based on accurate measures of human physiological responses. Biomarkers are also beginning to be used to determine those patients who are most likely to respond to a therapeutic, and thereby improve treatment outcomes while avoiding the administration of a drug to individuals who are unlikely to benefit. This article describes a strategy that is being used to achieve these aims for biomarkers, and discusses how biomarkers can be used to identify information that can be applied back into to the drug discovery process.

Biomarkers↗
PubMed1994

Surrogate endpoint biomarkers for phase II cancer chemoprevention trials.

Three critical aspects govern successful Phase II cancer chemoprevention trials--well-characterized agents, suitable cohorts, and reliable intermediate biomarkers for measuring efficacy. Requirements for the agent are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the chemopreventive activity observed. The cohort should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen. Also, many cohorts proposed for Phase II trials are patients with previous cancers or premalignant lesions. For such patients, the trials should be conducted within the context of standard treatment to avoid unusual risks. The criteria for biomarkers are that they fit expected biological mechanisms (i.e., differential expression in normal and high-risk tissue, on or closely linked to the causal pathway for the cancer, modulated by chemopreventive agents, and short latency compared with cancer), may be assayed reliably and quantitatively, measured easily, and correlate to decreased cancer incidence. They must occur in sufficient incidence to allow their biological and statistical evaluation relevant to cancer. Since carcinogenesis is a multipath process, single biomarkers are difficult to validate as surrogate endpoints, as they may appear on only one or a few of the many possible causal pathways. Panels of biomarkers, particularly those representing the range of carcinogenesis pathways, may prove more useful as surrogate endpoints. It is important to avoid relying solely on biomarkers representing isolated events that may or may not be on the causal pathway or otherwise associated with carcinogenesis. These include markers of normal cellular processes that may be increased or expressed during carcinogenesis, but are nonspecific.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticarcinogenic Agents↗
PubMed1994

Summary of recommendations for colonic biomarker studies of candidate chemopreventive compounds in phase II clinical trials.

New genetic, morphologic, proliferative and differentiation-associated biomarkers are available for study in Phase II chemoprevention clinical trials. These biomarkers have potential as surrogate intermediate endpoints for cancer incidence and eventual tumor inhibition. At this meeting, approaches to improve the standardization and quality control of biomarker assays were considered. Useful biomarkers should be amenable to quality control monitoring; sensitive, specific, and precise; sensitive to modulation by chemopreventive agents; and simple enough to be performed routinely in research or clinical laboratories. Human studies have more factors that contribute to biomarker assay variation than rodent studies. These include: (1) wider differences in genetic background of study subjects; (2) differing extent and duration of previous colonic diseases; (3) varying amounts of chronic irritation in the colonic mucosa of "normal" subjects induced by exposure to dietary and other factors; (4) differing initial levels of study nutrients ingested prior to the study; (5) administration of fluids prior to biomarker measurement which are followed by biopsies after hypermetabolic changes become quiescent; (6) failure to use strict morphologic criteria in counting fewer available human colonic crypts; (7) amplifying field variations in colonic mucosa by decreasing the number of colonic crypts counted; (8) colonoscopic miss-rate of adenomas; (9) a clinical trial window of observation of short duration which limits the stage of adenoma development that is measured; and (10) failure to measure the activity of a chemopreventive agent during the stage of adenoma development in which it is active. Some of these points are relevant to chemopreventive agents used in clinical trials involving other organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticarcinogenic Agents↗
PubMed1996

Molecular biomarkers for aflatoxins: from adducts to gene mutations to human liver cancer.

Over the past 30 years there have been extensive efforts to investigate the association between aflatoxin exposure and human liver cancer. These studies have been hindered by the lack of adequate dosimetry data on aflatoxin intake, excretion, and metabolism in people, as well as by the general poor quality of worldwide cancer morbidity and mortality statistics. These realities have spurred the efforts to develop new technologies to assess exposure status and risk for aflatoxins, and these agents are among the few environmental carcinogens for which quantitative risk assessments have been attempted. One of the goals of these risk assessments has been the development of primary and secondary preventive intervention methods to lower the human health impact from aflatoxin exposures. The long-term goal of the research described herein is the application of biomarkers to the development of preventive interventions for use in human populations at high risk for cancer. Several of the aflatoxin-specific biomarkers have been validated in epidemiologic studies and are now available for use as intermediate biomarkers in prevention trials. The development of these aflatoxin biomarkers has been based upon the knowledge of the biochemistry and toxicology of aflatoxins gleaned from both experimental and human studies. These biomarkers have been utilized subsequently in experimental models to provide data on the modulation of the markers under different situations of disease risk. This systematic approach provides encouragement for preventive interventions and should serve as a template for the development for the development and validation of other chemical-specific biomarkers and their application to cancer or other chronic diseases.

Aflatoxins↗
PubMed1997

Comparing measurements of biomarkers with other measurements of exposure.

The issue of the relative merit of biomarkers and alternative measures of exposure arises most commonly in the context of epidemiological studies aimed at hazard detection and quantification. When exposures are from biological agents, biomarkers are usually the first and often the only justifiable choice. In general, however, the relative merit of different types of exposure measurements need to be evaluated on a case-by-case basis. Biomarkers may be affected by random errors, time-related sampling errors, physiological confounding and disease-induced differential error, all of which need to be explicitly evaluated before embarking on the use of a biomarker in a full-scale epidemiological study. Random errors affecting biomarkers may be reduced by replication or combination of measurements, or both. Alternative measurements of exposure can be evaluated against a biomarker when there is adequate evidence for regarding the marker as the true measure of a biologically relevant exposure.

Biomarkers, Tumor↗
PubMed1998

Cardiac biomarkers: past, present, and future.

Accurate recognition of signs and symptoms and prompt diagnosis of myocardial infarction are essential for preserving myocardial function and saving lives. However, measurements of cardiac enzymes such as creatine kinase, lactate dehydrogenase, and their isoenzymes do not always provide accurate clinical diagnosis, particularly in patients with other concomitant diseases. Recently, alternative biomarkers of cardiac disease have been described: creatine kinase mass, cardiac troponins, and myoglobin. All cardiac biomarkers have some clinical usefulness in diagnosing acute coronary syndrome and acute myocardial infarction. Indications for use vary for each biomarker, and each has advantages and disadvantages and can be used at various times. However, the following must be considered: (1) Serial testing is essential with any biomarker. (2) None of the current biomarkers can be used to detect myocardial ischemia. (3) The decision of which biomarker to use should be based on the capabilities of the healthcare facility and the signs and symptoms of the patient.

Biomarkers↗
PubMed2004

Differential sensitivity of three marine invertebrates to copper assessed using multiple biomarkers.

Understanding how biomarkers relate to each other on exposure to particular contaminants in different species is key to their widespread application in environmental management. However, few studies have systematically used multiple biomarkers in more than a single species to determine the variability of sublethal effects of a particular contaminant. In this study, three marine invertebrates, the shore crab Carcinus maenas, the common limpet Patella vulgata and the blue mussel Mytilus edulis, were exposed over 7 days in the laboratory to environmentally realistic concentrations of the priority pollutant copper. A combination of molecular, cellular and physiological biomarkers was measured in each organism to detect the toxic effects of copper. Biomarkers included lysosomal stability (neutral red retention), neurotoxicity (acetylcholinesterase activity), metabolic impairment (total haemolymph protein), physiological status (heart rate) and induction of protective metallothionein proteins. P. vulgata was the most sensitive to copper with significant effects measured in all biomarkers at concentrations of 6.1 microg Cu l(-1). In C. maenas, cellular and neurotoxic endpoints were affected significantly only at 68.1 microg Cu l(-1). Exposure to copper also induced metallothionein production in crabs. Over a 7-day exposure period, M. edulis was the most tolerant species to copper with significant effects being observed at the cellular level only at 68.1 microg Cu l(-1) . In all three species, cellular and neurotoxic pathways were more sensitive to disruption than physiological processes (protein and heart rate). Results illustrate how a suite of biomarkers applied to different sentinel species can provide a 'diagnosis of stress', whereby, effects at the molecular level can be used to interpret the level of physiological impairment of the organism.

Acetylcholinesterase↗
PubMed2006

Biomarker-driven care in asthma: are we there?

Clinical asthma management is limited by the lack of straightforward and clinically applicable techniques to assess control and appropriately adjust therapy. The availability of biomarkers associated with airway caliber, responsiveness, or inflammation has prompted interest in the application of these measures as surrogate asthma end points in clinical trials. Use of a biomarker as a surrogate outcome in practice is most appropriate in settings in which the effects of therapy on clinical disease, as experienced by patients, are fully captured by that biomarker. Recent studies suggest that although asthma therapies can alter various biomarkers, the relationship between these biomarker changes and important clinical outcomes is inconsistent. Because symptom-driven titration of therapy is feasible and effective, additional data demonstrating clinically important benefits of biomarker-driven care in asthma are needed to justify the logistic and economic burdens associated with clinical dissemination of these techniques.

Asthma↗
PubMed2000

Enzymatic biomarker measurement and study of DNA adduct formation in benzo

The aim of this study was to improve the knowledge on the metabolic pathways involved in benzo[a]pyrene (B[a]P) activation and on the relationship between adduct levels and enzymatic biomarker activities. With this purpose, a model to assess pollutant exposure via food supply has been developed for the sentinel organism, Mytilus galloprovincialis. Mussels were fed for 4 weeks with B[a]P-contaminated feed (50 mg/kg dry weight mussel). Bioaccumulation was studied by determination of B[a]P concentration in whole mussel by GC/MS analysis. Different biomarkers of pollutant exposure were measured to assess the metabolic state of the exposed organisms. CYP1A-like immunopositive protein titration and B[a]P hydroxylase (BPH) activity were assessed as indicators of phase I biotransformation. Glutathione-S-transferase (GST) activity was measured as an indicator of the conjugation activities. Catalase (CAT) and DT-diaphorase (DTD) activities were assessed as potential biomarkers of oxidative stress, whereas acetylthiocholine esterase (AChE) activity was measured as an indication of possible neurotoxicity of B[a]P exposure. DNA adduct levels were determined in digestive gland DNA by applying the 32P-postlabeling technique with nuclease P1 enhancement. For the developed conditions of exposure, B[a]P concentration reached in whole mussel tissues was very high (>500 mg/kg d.w. mussel) and significant B[a]P-induced changes were recorded for each enzymatic biomarkers. BPH and CAT activities were significantly increased by B[a]P exposure, whereas GST in the gills, DTD and AChE were significantly depressed. On the other hand, no change in CYP1A-like immunopositive protein content was observed. Induction and increase with time of bulky B[a]P-related DNA adducts were demonstrated in the digestive gland, although at low levels (0.269+/-0.082 adduct/10e8 dNps at maximum) by the 32P-postlabeling assay. DNA adduct level was significantly correlated with whole mussel tissue B[a]P concentration, so were all the enzymatic biomarkers measured except to GST activity in both gill and digestive gland tissues. BPH, DTD, CAT and AChE displayed a strong correlation with adduct levels. These results demonstrate the neurotoxicity and the genotoxicity of B[a]P exposure in the mussel. The induction of bulky DNA adducts in mussels demonstrates the existence of activation pathways already identified in vertebrates. It validates also the suitability of this model for further studies on B[a]P metabolism in mussels. Our results support the proposal of BPH, AChE, DTD and CAT activities as suitable biomarkers of PAH exposure for these sentinel species.

Journal Article↗
PubMed2003

DNA microarrays and likelihood ratio bioinformatic methods: discovery of human melanocyte biomarkers.

In this article, some of the advantages and limitations of DNA microarray technologies for gene expression profiling are summarized. As a model experiment, DermArray DNA microarrays were utilized to identify potential biomarkers of cultured normal human melanocytes in two different experimental comparisons. In the first case, melanocyte RNA was compared with vastly dissimilar non-melanocytic RNA samples of normal skin keratinocytes and fibroblasts. In the second case, melanocyte RNA was compared with a primary cutaneous melanoma line (MS7) and a metastatic melanoma cell line (SKMel-28). The alternative approaches provide dramatically different lists of 'normal melanocyte' biomarkers. The most robust biomarkers were identified using principal component analysis bioinformatic methods related to likelihood ratios. Only three of 25 robust biomarkers in the melanocyte-proximal study (i.e. melanocytes vs. melanoma cells) were coincidentally identified in the melanocyte-distal study (i.e. melanocytes vs. non-melanocytic cells). Selected up-regulated biomarkers of melanocytes (i.e. TRP-1, melan-A/MART-1, silver/Pmel17, and nidogen-2) were validated by qRT-PCR. Some of the melanocytic biomarkers identified here may be useful in molecular diagnostics, as potential molecular targets for drug discovery, and for understanding the biochemistry of melanocytic cells.

Aged↗
PubMed2005

Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury.

Previous studies from our laboratory indicate that traumatic brain injury (TBI) in humans results in proteolysis of neuronally-localized, intracellular microtubule associated protein (MAP)-tau to produce cleaved tau (C-tau). The present study evaluated the utility of C-tau to function as a biomarker of neuronal injury and as a biomarker for evaluating neuroprotectant drug efficacy in a controlled cortical impact model of rat TBI. Brain C-tau was determined in rats subjected to controlled cortical impact-induced mild, moderate or severe levels of TBI. A significant severity-dependent increase in C-tau levels was observed in the cortex and hippocampus (1.5-8-fold) of TBI rats compared to shams 72 h after impact. C-tau rat brain and serum time course was determined by measuring levels at 0.25, 6, 24, 48, 72 and 168 h after TBI. A significant time-dependent increase in C-tau levels was observed in ipsilateral cortex (5-16-fold) and hippocampus (2-40-fold) compared to sham animals. C-tau levels increased as early as 6 h after TBI with peak C-tau levels observed 168 h after injury. Elevated brain C-tau levels were associated with TBI-induced tissue loss, which was histologically determined. The effect of cyclosporin-A (CsA), previously demonstrated to be neuroprotective in rat TBI, on brain C-tau levels was examined. CsA (20 mg/kg i.p., 15 min and 24 h after TBI) significantly attenuated the TBI-induced increase in hippocampal C-tau levels observed in vehicle-treated animals confirming CsA's neuroprotectant effect. CsA treatment also lowered ipsilateral cortical C-tau levels, although it did not reach statistical significance. CsA's neuroprotectant effect was confirmed utilizing histologic measures of TBI-induced tissue loss. In addition, serum C-tau levels were significantly increased 6 h after TBI but not at later time points. These results suggest that C-tau is a reliable, quantitative biomarker for evaluating TBI-induced neuronal injury and a potential biomarker of neuroprotectant drug efficacy in the rat TBI model. Serum data suggests that C-tau levels are dependent both on a compromised blood-brain barrier as well as release of TBI biomarkers from the brain, which has implications for the study of human serum TBI biomarkers.

Animals↗
PubMed2005

Regularized ROC method for disease classification and biomarker selection with microarray data.

MOTIVATION: An important application of microarrays is to discover genomic biomarkers, among tens of thousands of genes assayed, for disease classification. Thus there is a need for developing statistical methods that can efficiently use such high-throughput genomic data, select biomarkers with discriminant power and construct classification rules. The ROC (receiver operator characteristic) technique has been widely used in disease classification with low-dimensional biomarkers because (1) it does not assume a parametric form of the class probability as required for example in the logistic regression method; (2) it accommodates case-control designs and (3) it allows treating false positives and false negatives differently. However, due to computational difficulties, the ROC-based classification has not been used with microarray data. Moreover, the standard ROC technique does not incorporate built-in biomarker selection. RESULTS: We propose a novel method for biomarker selection and classification using the ROC technique for microarray data. The proposed method uses a sigmoid approximation to the area under the ROC curve as the objective function for classification and the threshold gradient descent regularization method for estimation and biomarker selection. Tuning parameter selection based on the V-fold cross validation and predictive performance evaluation are also investigated. The proposed approach is demonstrated with a simulation study, the Colon data and the Estrogen data. The proposed approach yields parsimonious models with excellent classification performance.

Algorithms↗
PubMed2004

Clinical utility of biomarkers in myocardial injury.

PURPOSE OF REVIEW: This review will focus on recent developments in biomarkers of myocardial injury. We will discuss the clinical utility of cardiac-specific troponin in the post-operative setting and highlight some of the most promising new biomarkers under development. RECENT FINDINGS: Troponin I and T, measured in the post-operative setting, have been recently shown to have strong short- and long-term prognostic information in cardiac and vascular surgery patients. This ability of troponins to risk stratify post-operative patients occurs independent of clinical factors and other biomarkers. Additionally, brain natriuretic peptide has garnered significant interest as a biomarker of neurohormonal activation and appears to yield independent prognostic information from troponins. Recent studies have introduced two new biomarkers, soluble CD40 ligand and ischemia-modified albumin, which may aid in both diagnostic and prognostic decision making. SUMMARY: The current data strongly supports the use of troponin I and T in post-operative non-cardiac and cardiac surgical patients to assist in identifying those patients at high risk for short- and long-term complications. Several promising new biomarkers are currently under development but further studies are warranted to define their role in the post-operative setting.

Journal Article↗
PubMed2026

Comprehensive In Silico Analysis Identifies MSTO1 and LIG1 as Candidate Biomarkers With Diagnostic and Prognostic Relevance in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and remains a major cause of cancer-related mortality worldwide. Its poor clinical outcomes are largely attributed to late-stage diagnosis and the limited accuracy of currently available diagnostic and prognostic biomarkers. Therefore, identifying novel molecular markers with improved sensitivity, specificity, and therapeutic relevance is essential for enhancing early detection and guiding personalized treatment strategies. AIMS: To identify and prioritize novel candidate HCC biomarkers with diagnostic and prognostic value and potential therapeutic vulnerability using integrated multi-omics, survival, functional dependency, and tumor microenvironment analyses. METHODS AND RESULTS: We examined the mRNA and protein expression levels of 8 DEGs in HCC tissues in the TCGA and CPTAC datasets using UALCAN, which showed that MSTO1 and LIG1 were overexpressed consistently in HCC relative to normal liver tissues. Moreover, elevated expression levels of these genes were significantly associated with higher tumor grade and advanced stage. Kaplan-Meier plotter survival data confirmed that increased expression of MSTO1 and LIG1 was associated with poorer overall survival. The DepMap CRISPR knockout data confirmed a functional dependency of both genes in HCC cell lines. CBioPortal analyses provided characterization of genomic alterations and enabled enrichment analysis of co-expressed genes, and the TCGA-UALCAN pan-cancer analyses supported the assessment of tissue specificity across tumor types. TIMER3 analyses linked candidate gene expression with immune cell infiltration patterns. Diagnostic performance by ROC analysis showed excellent discrimination for MSTO1 (AUC = 0.987) and good discrimination for LIG1 (AUC = 0.897). Multivariate Cox regression with Benjamini-Hochberg FDR correction across the eight genes supported MSTO1 as a candidate independent prognostic factor after adjustment for tumor stage, grade, etiology, age, and sex (HR = 1.29, p = 0.035), whilst LIG1 showed no independent prognostic value. Promoter methylation of MSTO1 and ADH4, assessed via UALCAN, showed that both genes were significantly differentially methylated in the promoter region of primary HCC tissues compared with normal liver tissues. Our study also confirmed the biological and clinical relevance of established HCC biomarkers: TERT, IRAK1, and ADH4. CONCLUSION: MSTO1 and LIG1 emerged as candidate diagnostic biomarkers in HCC. Additionally, MSTO1 showed a candidate prognostic association with overall survival that remained significant after adjusting for tumor stage, grade, and etiology, as well as patients' age, but not after further adjustment for AFP status. Functional data also highlighted MSTO1 as a candidate therapeutic dependency. On the other hand, LIG1 showed no independent prognostic association in either multivariate model. Their differential expression and functional essentiality in HCC cell lines highlighted their value for further experimental and independent-cohort validation before potential integration into biomarker development pipelines aimed at improving early detection and targeted therapy in HCC.

Humans↗
PubMed2006

Biomarker analysis on breast ductal lavage cells in women with and without breast cancer.

Recent studies show that morphology based analysis of ductal lavage specimens failed to detect many cancers in women with breast cancer. Such an observation raises doubts about the potential role of ductal lavage in an individual's risk assessment and early detection of breast cancer. We hypothesize that biomarker-based analysis using markers of malignancy field defects including DNA 5c exceeding rate (DNA 5cER) and G-actin might provide a more reliable test for breast cancer risk. The study was performed in 2 phases, the training and validation phase. For the training phase, 36 Chinese women were recruited (13 with breast cancer, 8 with intraductal papilloma and 15 with benign breast diseases). The validation phase included 10 women with cancer and 7 women without cancer. Ductal lavage samples were processed by the ThinPrep technique and evaluated by morphology followed by biomarker analysis using laser scan cytometry (LSC) for G-actin and DNA5cER. In the training phase, biomarker analysis was performed on the 67% (24 of 36) of samples that had over 100 epithelial cells. The sensitivity of DNA5cER was 90% with a specificity of 100%, and G-actin was 100% and 93%, respectively. By contrast, the sensitivity and specificity obtained by cytology alone were 67% and 93%, respectively. Similar results were obtained from the small validation study. Quantitative analysis of biomarkers for G-actin and DNA5cER is feasible and useful in distinguishing benign from malignant breast disease on archived ductal lavage slides. Further studies are warranted to determine the value of these biomarkers in prospective trials.

Actins↗