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PubMedDate not supplied

Development of a population-based questionnaire to explore psychosocial determinants of screening for memory loss and Alzheimer Disease.

Alzheimer disease research has focused on detecting the earliest signs of cognitive decline and efforts are ongoing to develop biomarkers and cognitive measures that reliably distinguish between nondemented and demented individuals. However, little is known about factors that may directly or indirectly influence screening behavior of older community-dwelling adults. We describe an iterative process for the development and formative evaluation of a questionnaire about dementia knowledge and screening behaviors in older adults to understand the psychosocial factors underlying intention to obtain dementia screening to profile individuals manifesting intention to undergo dementia screening compared to those who will not. The Behavioral Model of Health Services Use was used as a conceptual framework for a questionnaire with constructs from the Health Belief Model, Theory of Reasoned Action and Self-Efficacy. After pretesting, we used a random dialing strategy to test our questionnaire on a final sample of 1024 older Missourians. Internal consistency and construct validity were examined. Pretesting identified several potential problems that were improved with rewording. Cronbach alpha was greater than 0.6 (range 0.62 to 0.92) in all but one construct testing dementia knowledge, suggesting good to excellent internal consistency. Convergent (construct) validity was assessed using confirmatory factor analysis. All constructs but 3 demonstrated good validity. Addressing these issues will allow researchers to identify unique characteristics based on age, race, sex, socioeconomic differences and geographic location, and characterize barriers to screening programs to more effectively develop targeted community-based interventions.

Aged↗
PubMed1998

Biomarkers of leukemia risk: benzene as a model.

Although relatively rare, leukemias place a considerable financial burden on society and cause psychologic trauma to many families. Leukemia is the most common cancer in children. The causes of leukemia in adults and children are largely unknown, but occupational and environmental factors are strongly suspected. Genetic predisposition may also play a major role. Our aim is to use molecular epidemiology and toxicology to find the cause of leukemia and develop biomarkers of leukemia risk. We have studied benzene as a model chemical leukemogen, and we have identified risk factors for susceptibility to benzene toxicity. Numerous studies have associated exposure to benzene with increased levels of chromosome aberrations in circulating lymphocytes of exposed workers. Increased levels of chromosome aberrations have, in turn, been correlated with a heightened risk of cancer, especially for hematologic malignancy, in two recent cohort studies in Europe. Conventional chromosome analysis is laborious, however, and requires highly trained personnel. Further, it lacks statistical power, as only a small number of cells can be examined. The recently developed fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR)-based technologies have allowed the detection of specific chromosome aberrations. These techniques are far less time consuming and are more sensitive than classical chromosomal analysis. Because leukemias commonly show a variety of specific chromosome aberrations, detection of these aberrations by FISH and PCR in peripheral blood may provide improved biomarkers of leukemia risk.

Adult↗
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↗
PubMed2000

Induction of replicative senescence biomarkers by sublethal oxidative stresses in normal human fibroblast.

We tested the long-term effects of sublethal oxidative stresses on replicative senescence. WI-38 human diploid fibroblasts (HDFs) at early cumulative population doublings (CPDs) were exposed to five stresses with 30 microM tert-butylhydroperoxide (t-BHP). After at least 2 d of recovery, the cells developed biomarkers of replicative senescence: loss of replicative potential, increase in senescence-associated beta-galactosidase activity, overexpression of p21(Waf-1/SDI-1/Cip1), and inability to hyperphosphorylate pRb. The level of mRNAs overexpressed in senescent WI-38 or IMR-90 HDFs increased after five stresses with 30 microM t-BHP or a single stress under 450 microM H(2)O(2). These corresponding genes include fibronectin, osteonectin, alpha1(I)-procollagen, apolipoprotein J, SM22, SS9, and GTP-alpha binding protein. The common 4977 bp mitochondrial DNA deletion was detected in WI-38 HDFs at late CPDs and at early CPDs after t-BHP stresses. In conclusion, sublethal oxidative stresses lead HDFs to a state close to replicative senescence.

Biomarkers↗
PubMed2026

Novel immunotherapeutic strategies for colorectal cancer treatment: Advances, challenges, and future directions.

Immunotherapy has reshaped the treatment landscape of colorectal cancer (CRC), with the clearest and most durable benefit established in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) disease. However, framing CRC immunotherapy simply as "MSI-H responsive versus microsatellite stable (MSS) resistant" is no longer sufficient. Recent studies indicate that a subset of proficient mismatch repair (pMMR) colon cancers, particularly in the neoadjuvant setting, can mount clinically meaningful responses to immune checkpoint blockade, suggesting that disease stage, local immune organization, and treatment timing critically influence immunotherapy sensitivity. In parallel, emerging evidence has expanded the relevant immune landscape beyond the tumor bed itself, showing that spatially organized stromal and adipose niches can actively divert tumor-reactive lymphocytes and promote immune escape. These advances shift the central challenge in CRC immunotherapy from simply identifying new agents to defining when and in whom immune resistance is reversible, and which biological bottlenecks-such as vascular dysfunction, myeloid suppression, and spatial immune exclusion-must be overcome. In this context, alternative checkpoint inhibitors, bispecific antibodies, cellular therapies, vaccines, nanotechnology-enabled platforms, and microbiome-targeted approaches remain important, but their translational maturity and evidentiary support differ substantially. Biomarker development is likewise evolving from static genomic classification toward dynamic and mechanism-informed stratification incorporating circulating tumor DNA (ctDNA), chromosomal instability, immune architecture, and treatment-induced response trajectories. This review synthesizes recent advances in CRC immunotherapy while emphasizing evidence hierarchy, biomarker-guided patient selection, and the mechanistic basis of combination strategies. We argue that the next phase of CRC immunotherapy will depend less on the indiscriminate addition of novel agents and more on the rational deployment of immunotherapy across molecularly, spatially, and temporally defined disease states.

Humans↗
PubMed2004

Biomarkers for assessing reproductive development and health: Part 1--Pubertal development.

The proposed National Children's Study has helped raise awareness of the issues related to children's health and the importance of monitoring the growth and development of children from preconception through adulthood. Many genetic predispositions can adversely impact the normal development process, and various environmental exposures have been linked to adverse reproductive health in rodent models and a small number of accidental human exposures. To monitor reproductive health and identify adverse effects at the earliest possible juncture, investigators must develop a network of biomarkers covering all stages and aspects of reproductive development and function. Biomarkers are biological indicators that can be measured repeatedly and are informative on one or more aspects of biological development or function. They can range from the anatomical level down to the molecular level and may provide information on the nature of an exposure, the effect of an exposure, or the susceptibility of individuals or populations to the toxic effects of an exposure. In theory, biomarkers can be used to monitor a wide variety of conditions and responses ranging from abnormal development to early indicators of late-onset disease. The main stumbling block with this theory has been finding appropriate biomarkers for particular conditions and exposures. Such biomarkers must be easily accessible, robust, and sensitive. Ideally, they will be expressed across a large section of the population, and can be monitored quickly, easily, conveniently, and with minimal cost. In this review, we discuss some of the current and emerging biomarkers of human pubertal development.

Adolescent↗
PubMed2004

Improved small volume lung cancer detection with computer-aided detection: database characteristics and imaging of response to breast cancer risk reduction strategies.

Computer-aided detection (CAD) and diagnosis (CADx) of in vivo imaging studies are important tools based on bioinformatics. Currently, there are two diseases for which the United States Food and Drug Administration (FDA) has given premarket approval (PMA): the detection of signs consistent with lung cancer on chest radiographs and breast cancer on mammograms. There are systems for other diseases and other types of images under development; however, this process depends on the availability of an accurate database. The author helped in the development of the databases for such systems and management of the clinical trial that resulted in the FDA-PMA of the system that detects findings consistent with lung cancer. The characteristics of the database used will be described. Further, a woman's risk of developing breast cancer differs from those of other women. Risk can be high, average, or low. There are now pharmaceuticals that decrease the risk that women, as a group, will develop breast cancer and it has been suggested that dietary changes could have similar effects. The pharmaceutical agents, though, have some associated side effects, and it is clinically important to determine whether these agents have decreased an individual woman's risk of breast cancer. In vivo imaging biomarkers of risk and successful risk reduction are therefore sought, but the information on possible in vivo imaging biomarkers is less mature than activities in CAD. Bioinformatics will be an important contributor to this in vivo imaging biomarker development.

Breast Neoplasms↗
PubMed2006

Autoantibody biomarkers in the detection of cancer.

By definition, tumor biomarkers are selective molecules that can distinguish between patients with cancer and controls. Serum tumor markers have been the most widely used approach for cancer detection. However, the limitations of these markers, which are based on the measurement of tumor antigens, preclude their general use in cancer screening and diagnosis. Here we give an overview of recent cancer biomarker developments based on the detection of autoantibodies produced against tumor antigens in patients' sera. This new detection method can measure the autoantibodies for a spectrum of tumor antigens in a single assay, with sensitivity and specificity exceeding those obtained using the conventional antigen determination method. Autoantibodies against serum cancer biomarkers offer a novel technology for cancer detection.

Animals↗
PubMed2004

Sensitive genetic biomarkers for determining apoptosis in the brown bullhead (Ameiurus nebulosus).

Biomarkers are necessary for monitoring environmentally induced alterations at the molecular level in order to assess the impact of xenobiotic compounds on organism health. Apoptosis is a highly regulated cellular process that controls programmed cell death and is involved in tumor formation. Apoptosis thus may provide the basis for developing biomarkers for use in the field of ecotoxicology to monitor non-lethal levels of xenobiotic induced cellular stress and toxicity. This study shows that a brown bullhead (Ameiurus nebulosus) fibroblast cell line (BB-2) responds to known apoptotic inducers (staurosporine, cycloheximide, and tumor necrosis factor alpha (TNF-alpha)), as characterized by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP digoxigenin nick end-labelling (TUNEL). Furthermore, we characterized the apoptotic process using a series of newly identified bullhead genetic markers. Exposure to protein kinase C inhibitors altered the transcription of TF-cell apoptosis-related protein (TFAR)-15 and p23 with no effect on p53, inhibitor of apoptosis protein (IAP), or PNAS-2. Inhibition of protein synthesis caused a consistent reduction in the transcription of p53 and PNAS-2. This study demonstrates that our novel transcriptional markers are sensitive biomarkers for the study of the effects of xenobiotic chemicals on apoptosis in the brown bullhead.

Animals↗
PubMed2005

Cancer biomarkers: knowing the present and predicting the future.

In recent years the discovery of cancer biomarkers has become a major focus of cancer research. The widespread use of prostate-specific antigen in prostate cancer screening has motivated researchers to identify suitable markers for screening different types of cancer. Biomarkers are also useful for diagnosis, monitoring disease progression, predicting disease recurrence and therapeutic treatment efficacy. With the advent of new and improved genomic and proteomic technologies such as DNA and tissue microarray, two-dimensional gel eletrophoresis, mass spectrometry and protein assays coupled with advanced bioinformatic tools, it is possible to develop biomarkers that are able to reliably and accurately predict outcomes during cancer management and treatment. In years to come, a serum or urine test for every phase of cancer may drive clinical decision making, supplementing or replacing currently existing invasive techniques.

Animals↗
PubMed2005

Development of medications for alcohol use disorders: recent advances and ongoing challenges.

During the past decade, efforts to develop medications for alcoholism have burgeoned. Three agents, disulfiram, naltrexone and acamprosate, are now approved in a large number of countries. Although many patients have benefited from existing medications, their effects are moderate, and some alcoholics fail to respond to them. A host of new agents are currently under active investigation. Critical barriers must be overcome to ensure that future efforts in the development of medications for alcohol use disorders reach full fruition. These challenges include: establishing key targets for drug discovery; validating animal and human screening models; and developing biomarkers to help predict treatment success. In addition, it is important to formulate methodological and statistical strategies to efficiently conduct alcohol pharmacotherapy trials; to specify genetic and phenotypic patient characteristics associated with efficacy and safety for lead compounds; to forge productive alliances among governmental agencies, the pharmaceutical industry and academic researchers to further drug development; and, ultimately and perhaps most difficult, to engage the practitioner community to incorporate medications into the alcohol treatment process.

Alcohol-Related Disorders↗
PubMed2005

Glomerular disease workshop.

Recent observations regarding intrinsic glomerular cell biology, particularly in the podocyte, have provided exciting new insights into potential pathogenic mechanisms of human glomerular disease. Although both immune and nonimmune mechanisms of glomerular injury have been studied previously, experimental models of disease and recent techniques that provide tools for molecular profiling show great promise for identifying glomerular disease biomarkers. Despite these recent advances, additional work in both basic and clinical studies of glomerular disease is needed to advance the field. Standardization of animal models of distinct forms of glomerular disease would likely facilitate the search for biomarkers. Several factors limit current efforts to implement clinical trials of glomerular disease. Identification of disease biomarkers, development of disease-specific end points, and organization of collaborative clinical groups are critical for ultimately designing and implementing appropriately powered trials of glomerular disease.

Animals↗
PubMed1993

The Malmö biological bank.

Currently there are no available biological markers that have been satisfactorily validated clinically as 'intermediate end-points' for evaluation of the impact of diet on cancer. Therefore, there is high scientific value in banking biological specimens for future use in the Malmö Diet and Cancer Study. The banking procedures we have developed are adequate for assessing factors that estimate dietary intake (e.g. vitamins, lipids or micronutrients) as well as non-dietary variables (e.g. immunologic and ecogenetic factors of biologically effective doses of xenobiotic exposures) that may regulate the biological expression of dietary variables. This approach is further justified by state-of-the-art technology that includes assessment of the concept of gene-environment interactions. Purified viable mononuclear leucocytes, granulocytes, erythrocytes, plasma and serum are being stored from each individual entering the study under the guidelines of a strict quality control programme. Storage of tumour/normal tissues from incident cancer cases are also being stored and quality controlled. It is hoped that these banking procedures will encourage a high activity in biomarker development in the future.

Algorithms↗
PubMedDate not supplied

Urinary bladder tumor markers.

Bladder cancer is amenable to biomarker development because many tumor-associated molecules are secreted in urine. Tumor cells are shed in urine, and, therefore, tests that detect tumor cell-surface markers have also been developed to diagnose bladder cancer and monitor its recurrence. Several bladder tumor markers show higher sensitivity than cytology, but most have lower specificity. In addition to markers that use conventional technologies such as enzyme-linked immunosorbent assay, point-of-care devices, reverse transcriptase polymerase chain reaction, fluorescent in situ hybridization, and immunocytochemistry, proteomic and gene profiling approaches are being used to find new biomarkers to assist in the molecular profiling of bladder cancer. This review describes both new and well-studied bladder tumor markers.

Biomarkers, Tumor↗
PubMed2005

Gene methylation data--a new challenge for bioinformaticians?

OBJECTIVES: Changes in the status of DNA methylation, known as epigenetic alterations, are among the most common molecular alterations in human neoplasia. For the first time, we reported on the analysis of fecal DNA from patients with CRC to determine the feasibility, sensitivity and specificity of this approach. We want to present basic information about DNA methylation analysis in the context of bioinformatics, the study design and several statistical experiences with gene methylation data. Additionally we outline chances and new research questions in the field of DNA methylation. METHODS: We present current approaches to DNA methylation analysis based on one reference study. Its study design and the statistical analysis is reflected in the context of biomarker development. Finally we outline perspectives and research questions for statisticians and bioinformaticians. RESULTS: Identification of at least three genes as potential DNA methylation-based tumor marker genes (SFRP2, SFRP5, PGR). CONCLUSIONS: DNA methylation analysis is a rising topic in molecular genetics. Gene methylation will push the extension of biobanks to include new types of genetic data. Study design and statistical methods for the detection of methylation biomarkers must be improved. For the purpose of establishing methylation analysis as a new diagnostic/prognostic tool the adaptation of several approaches has become a challenging field of research activity.

Biomarkers, Tumor↗
PubMed2005

The future of post-genomic biology at the proteomic level: an outlook.

Drug discovery and early-stage drugs and biomarkers development is a continuous adaptation and maturation process. The cycle of changes based on new findings is coupled with shifts in research priorities and make this part of pharmaceutical research a challenging endeavour. Over the last years, the emphasis on genomics has shifted to proteomics, the science of understanding how proteins translate gene information into function, and metabonomics, the science of small metabolites that are further apart from genomic projects. Proteomics describes the analysis of the protein complement of a biological sample with respect to temporal and spatial resolution. This technology is based on separation of complex protein mixtures by 2D gel-electrophoresis, in gel digest and mass spectrometric analysis of the protein fragments. Proteomics has been recently flanked by peptidomics, a new research direction aimed at the comprehensive analysis of small (1-20 kDa) polypeptides, thus covering the gap between proteomics and metabonomics. The refinement of peptidomics is based on an essential paradigm related to modularity and diversity. Peptides are a paramount example of how one single gene can release multiple functionalities. We can expect fast progress in understanding protein and peptide networks from a systems biology approach ending in the discovery of new peptide targets. However, the way from a complex sample to potential diagnostic and therapeutic targets will depend on technological developments and from the ability to discriminate true disease-related signals from false positive and negative signals, and the way from target discovery to target validation will not be short.

Aged↗
PubMed2006

Novel approaches to the diagnosis of fetal alcohol spectrum disorder.

The diagnosis of fetal alcohol spectrum disorder is a difficult task, especially in cases where clear, physical markers of in utero alcohol exposure are not apparent. Reviewed in the following paper are some older tools for screening alcohol use in pregnancy and present novel approaches to the diagnosis of FASD, including ethanol biomarker development to behavioural phenotyping. Improving current FASD diagnostic methodology through more novel approaches may provide the possibility of earlier and wider diagnosis, allowing intervention and treatment at stages where the advanced effects of alcohol can still be mitigated.

Alcohols↗
PubMed1999

Reactive nitrogen species in colon carcinogenesis.

The role of reactive nitrogen species (RNS) in colon carcinogenesis is multifactorial and affects diverse processes, such as proliferation, apoptosis, differentiation, tumorigenesis, and metastases. This review describes the stages in colon carcinogenesis where nitric oxide (NO) and inducible NO synthase (NOS2) may influence the progression of a normal mucosa to overt metastatic cancer. Overexpression of NOS2 and an increase in the generation of NO and other RNS may lead to apoptosis resistance, DNA damage, mutation, up-regulation of COX-2, increased proliferation, an increase in oxidative stress and an increase in tumor vascularity and metastatic potential. Therefore, future goals are to establish mechanistically based biomarkers to assess individuals at risk for colon cancer and to implement chemopreventive and dietary strategies that reduce colon cancer risk. An understanding of NO signaling pathways in colon epithelial cells should provide the basis for novel biomarker development. Colon cancer prevention may be achieved effectively by chemically interfering with key components of the NO signaling pathways, changing dietary habits to reduce fat and increase antioxidant-containing vegetables, and dietary supplementation to increase DNA repair.

Animals↗