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[Biology and treatment options during the development of prostate cancer].

BACKGROUND: Compelling evidence indicates that environmental and life-style factors, in addition to well-known risk factors such as testosterone level and age, are important for the development of prostate cancer. METHODS: In this review we summarize up-to-date knowledge about carcinogenesis in the prostate. The review is based on our own clinical research experience in this field and relevant articles identified by a literature search in the Medline and PubMed databases. RESULTS: During carcinogenesis of the prostate, significant changes are consistently observed in several molecular pathways. These molecular pathways are possible targets for intervention directed at reversing, stopping, or delaying cancer development. Racial differences indicate that genetic factors are also important for the development of prostate cancer. Improved surrogate biomarkers are needed for appropriate initiation of therapy and in order to monitor response. INTERPRETATION: Prostate cancer might be targeted early in the course of the disease provided that suitable markers reflecting carcinogenesis are identified.

Biomarkers, Tumor↗

[Gastric cancer and eradication of H. pylori].

Diagnosis and treatment of gastric cancer has now been established, and prevention is thought to be of importance to overcome this disease. Many experimental and clinical researches have clarified the pivotal role of H. pylori infection in gastric carcinogenesis. Therefore, prevention of gastric carcinogenesis by H. pylori eradication seems to be promising, and the possibility has been suggested by experimental and clinical studies. The issues to be solved are to select the candidates for eradication and to assess the timing of eradication. Development of new diagnostic methods and biomarkers for H. pylori eradication is required.

Alkylating Agents↗

Monoclonal antibody CO17-1A and leukapheresis in immunotherapy of pancreatic cancer.

Eighteen patients with measurable or evaluable advanced (metastatic or unresectable) adenocarcinoma of the pancreas were treated with a single infusion of monoclonal antibody CO17-1A in autologous leukocytes. No toxicity was experienced with treatment. Three of seventeen patients evaluable for response demonstrated unusually stable disease and a decrease in serum CA 19-9 antigen in two patients who expressed this biomarker. Human anti-mouse antibody developed in 81% of these patients. Monoclonal antibody CO17-1A may have a cytostatic effect in a small fraction of patients. Future clinical trials will focus on enhancing this effect with other immune modulators.

Adenocarcinoma↗

Osteocalcin is not a marker of progress in multiple myeloma. Le Groupe d'Etude et de Recherche sur le Myélome (GERM).

The aim of this study was to evaluate the usefulness of serum osteocalcin (OC) levels in multiple myeloma (MM) in order to assess its significance and activity, and to predict its course. Serum OC was measurement in 117 patients with MM and 116 healthy controls matched for age and sex. Serum OC levels were weakly correlated with Karnofsky index (r=0.22; p<0.03). Lowest OC levels were observed when lytic bone lesions increased (p<0.05). There was no relationship between serum OC levels and vertebral crush fractures, serum calcium concentrations or stage of MM, neither was there any relationship between initial serum OC levels and survival. Progression of the disease was associated with a clear fall of serum OC in 61.5% of the "progressive" patients, versus 41% of the persisting "stabilized" cases. Serum OC level was strongly correlated with bone formation (p = 0.005), but not with bone resorption. Serum OC level is a sensitive marker of osteoblast activity, but a poor marker of the severity of MM. We do not consider it as a marker of MM activity or prognosis.

Aged↗

Determination of tissue polypeptide antigens (TPA) and carcinoembryonic antigen (CEA) in serum: its value in the preliminary cancer risk assessment in asbestos exposed workers.

Seeking the changes at the cellular level or at the level of cellular metabolism products, present in the biological fluids, in order to detect early stages of the carcinogenic process is an essential step in preventing cancer development among asbestos exposed workers. Carcinogenic biomarkers such as tissue polypeptide antigens (TPA) and carcinoembryonic antigen (CEA) were found very useful in this attempt. The objective of this work was to identify individuals at critical cancer risk in the population of workers exposed to asbestos and to evaluate the value of TPA and CEA determinations for this particular purpose. The study was carried out in the group of workers exposed to asbestos (n = 274). Age, exposure duration, smoking habits and the kind of job performed, were considered in the analysis of the results. To sum up, it should be concluded that in 22 persons exposed to asbestos TPA values exceeded the cut off concentrations, established on the basis of the studies performed in the control group, and CEA value accounted for 10 ng/lm. Statistically significant differences in the percentage of TPA increased values between two groups under study were indicated. Such a relationship did not apply to CEA. In the exposed group, an evident effect of the age and exposure duration on the number of persons with TPA concentrations above the cut off, was also revealed. These changes show a growing tendency and statistical significance for TPA only. Smoking had a great impact on the occurrence of TPA increased concentrations. Three kinds of jobs were considered: operation of the production line, white collar workers and miscellaneous'. The significant differences in TPA concentrations between the operators and miscellaneous, and between white collar workers and miscellaneous were found. Therefore, it may be concluded that a similar percentage of TPA increased values was observed in the group of operators and white collar workers. The study allowed to identify, among those exposed to asbestos, 22 persons who should be covered with target medical care. It also indicated that TPA determination was more useful than that of CEA in this kind of investigations.

Adult↗

Behavioral inhibition, heart period, and respiratory sinus arrhythmia in young children.

Children were selected according to criteria for high or low behavioral inhibition (BI) on the basis of both a maternal questionnaire and interviewer ratings at home. Subsequent laboratory assessments involved further BI ratings as well as heart period (HP) and respiratory sinus arrhythmia (RSA). BI, HP, and RSA were all moderately stable from 4.5 to 7 years. HP and RSA changed in meaningful ways according to the context of different laboratory episodes. No significant relations emerged between BI and HP or RSA over the whole sample. However, HP predicted which of the children in the high inhibition group would remain inhibited at 7 years: HP at 4.5 years was significantly lower for children with high BI ratings at 4.5 who remained high at 7 years compared with children with high BI at 4.5 years who were less inhibited at 7 years.

Age Factors↗

Quantification of urinary N-acetyl-S- (propionamide)cysteine using an on-line clean-up system coupled with liquid chromatography/tandem mass spectrometry.

Acrylamide has been reported to be present in high-temperature processed foods and normal processed food intake could lead to significant acrylamide exposure. Acrylamide in vivo can be conjugated with glutathione in the presence of glutathione transferase. This conjugation product is further metabolized and excreted as N-acetyl-S-(propionamide)cysteine (NASPC) in the urine. NASPC could be considered a biomarker for acrylamide exposure. The objective of this study was to develop a highly specific, rapid and sensitive method to quantify urinary NASPC, serving as a biomarker for acrylamide exposure assessment. Isotope-labeled [13C3]NASPC was successfully synthesized and used as an internal standard. This urine mixture was directly analyzed using a newly developed liquid chromatographic/tandem mass spectrometric method coupled with an on-line clean-up system. The detection limit for this method was estimated as < 5 microg l(-1)(0.4 pmol) on-column. The method was applied to measure the urinary level of NASPC in 70 apparently health subjects. The results showed that the NASPC urinary level was highly associated with smoking. Smokers had a significantly higher urinary NASPC level (135 +/- 88 microg g(-1) creatinine) than non-smokers (76 +/- 30 microg g(-1) creatinine). A highly sensitive and selective LC/MS/MS isotope dilution method was successfully established. With an on-line clean-up system, this system is capable of routine high-throughput analysis and accurate quantitation of NASPC in urine. This could be a useful tool for health surveillance for acrylamide exposure in a population for future study.

Acetylcysteine↗

Fluorophore-mediated, fiber-optic, multi-analyte, immunosensing system for rapid diagnosis and prognosis of cardiovascular diseases.

A prototype of a fiber-optic, multi-analyte, immunobiosensing system was developed to simultaneously quantify disease-representing biomarkers in blood plasma. This system was for simultaneous quantification of two different groups of multi-biomarkers related to cardiovascular diseases (CVD): anticoagulants (protein C, protein S, antithrombin III, and plasminogen) for deficiency diagnosis; and cardiac markers (B-type natriuretic peptide, cardiac troponin I, myoglobin, and C-reactive protein) for coronary heart disease diagnosis. As an initial effort towards the development of a disposable and easy-to-use sensing cartridge as a rapid diagnostic tool for CVD related diseases, a prototype of a flow control system was also developed to automatically perform simultaneous four-analyte quantification. Currently, the system is capable of quantifying the multiple anticoagulants in their clinically significant sensing ranges within 5 minutes, at an average signal-to-noise (S/N) ratio of 25. A simultaneous assay of the four cardiac markers can be performed within 10 min, at an average S/N ratio of 20. When this highly portable multi-analyte sensing system is completed and successfully tested for CVD patient's plasma, it can provide rapid (<10 min) and reliable diagnostic and prognostic information at a patient's bedside.

Biomarkers↗

Biomarkers in environmental and human health risk assessment.

Marine pollution is a major threat to human and environmental health. Given the complexity of function of marine and coastal ecosystems, it is unlikely that a balanced view of the nature and extent of risk will easily be achieved if human and environmental risk assessments continue to be conducted in isolation. Here, the integration of assessment protocols is advocated as a holistic means of improving risk management. Biomarkers can provide the common conceptual framework and measurable endpoints necessary for successful integration. Examples are given of the ways in which suites of biomarkers encompassing molecular change, cellular pathology and physiological impairment can be developed and adapted for human and ecological scenarios. By placing a greater emphasis on the health status of impacted biota, it is more likely that risk assessment will develop the efficiency, reliability and predictive power to adapt to the unforeseen environmental threats that are an inevitable consequence of human development and global change.

Acetylcholinesterase↗

Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus.

CONTEXT: Endothelial dysfunction occurs in diagnosed type 2 diabetes mellitus but may also precede development of diabetes. OBJECTIVE: To determine whether elevated plasma levels of biomarkers reflecting endothelial dysfunction (E-selectin; intercellular adhesion molecule 1 [ICAM-1]; and vascular cell adhesion molecule 1 [VCAM-1]) predict development of type 2 diabetes in initially nondiabetic women. DESIGN AND SETTING: Prospective, nested case-control study within the Nurses' Health Study, an ongoing US study initiated in 1976. PARTICIPANTS: Of 121 700 women initially enrolled, 32 826 provided blood samples in 1989-1990; of those free of diabetes, cardiovascular disease, or cancer at baseline, 737 developed incident diabetes by 2000. Controls (n = 785) were selected according to matched age, fasting status, and race. MAIN OUTCOME MEASURE: Risk of confirmed clinically diagnosed type 2 diabetes by baseline levels of E-selectin, ICAM-1, and VCAM-1. RESULTS: Baseline median levels of the biomarkers were significantly higher among cases than among controls (E-selectin, 61.2 vs 45.4 ng/mL; ICAM-1, 264.9 vs 247.0 ng/mL; VCAM-1, 545.4 vs 526.0 ng/mL [all P values < or =.004]). Elevated E-selectin and ICAM-1 levels predicted incident diabetes in logistic regression models conditioned on matching criteria and adjusted for body mass index (BMI), family history of diabetes, smoking, diet score, alcohol intake, activity index, and postmenopausal hormone use. The adjusted relative risks for incident diabetes in the top quintile vs the bottom quintiles were 5.43 for E-selectin (95% confidence interval [CI], 3.47-8.50), 3.56 for ICAM-1 (95% CI, 2.28-5.58), and 1.12 for VCAM-1 (95% CI, 0.76-1.66). Adjustment for waist circumference instead of BMI or further adjustment for baseline levels of C-reactive protein, fasting insulin, and hemoglobin A(1c) or exclusion of cases diagnosed during the first 4 years of follow-up did not alter these associations. CONCLUSION: Endothelial dysfunction predicts type 2 diabetes in women independent of other known risk factors, including obesity and subclinical inflammation.

Adult↗

Biological and functional definition of the older patient: the role of biomarkers of aging.

The rate of aging is not uniform among all individuals. Thus, determination of the biological age of an individual and possibly the biological age of his or her organ systems poses a special challenge to the gerontologist. This could be accomplished if specific biomarkers of aging were available, which would allow standardization of studies, help us understand the various determinants of aging, monitor the impact of various interventions on the rate of aging, and possible allow estimates of life expectancy and predictions of future morbidity. Specific criteria need to be developed for accepting a parameter as a biomarker of aging, since an age-related alteration in a biological parameter does not necessarily qualify. Potential biomarkers of human aging include in vitro proliferative capacity of fibroblasts, glycation of collagen, and DNA unwinding rate.

Aging↗

Disruption of rat forebrain development by glucocorticoids: critical perinatal periods for effects on neural cell acquisition and on cell signaling cascades mediating noradrenergic and cholinergic neurotransmitter/neurotrophic responses.

Glucocorticoids are the consensus treatment for the prevention of respiratory distress in preterm infants, but there is evidence for increased incidence of neurodevelopmental disorders as a result of their administration. We administered dexamethasone (Dex) to developing rats at doses below or within the range of those used clinically, evaluating the effects on forebrain development with exposure in three different stages: gestational days 17-19, postnatal days 1-3, or postnatal days 7-9. At 24 h after the last dose, we evaluated biomarkers of neural cell acquisition and growth, synaptic development, neurotransmitter receptor expression, and synaptic signaling mediated by adenylyl cyclase (AC). Dex impaired the acquisition of neural cells, with a peak effect when given in the immediate postnatal period. In association with this defect, Dex also elicited biphasic effects on cholinergic presynaptic development, promoting synaptic maturation at a dose (0.05 mg/kg) well below those used therapeutically, whereas the effect was diminished or lost when doses were increased to 0.2 or 0.8 mg/kg. Dex given postnatally also disrupted the expression of adrenergic receptors known to participate in neurotrophic modeling of the developing brain and evoked massive induction of AC activity. As a consequence, disparate receptor inputs all produced cyclic AMP overproduction, a likely contributor to disrupted patterns of cell replication, differentiation, and apoptosis. Superimposed on the heterologous AC induction, Dex impaired specific receptor-mediated cholinergic and adrenergic signals. These results indicate that, during a critical developmental period, Dex administration leads to widespread interference with forebrain development, likely contributing to eventual, adverse neurobehavioral outcomes.

Acetylcholine↗

Differential expression of proteins in kidney, eye, aorta, and serum of diabetic and non-diabetic rats.

Diabetes mellitus (DM) is a chronic progressive disease that often results in microvascular and macrovascular complications, yet its pathogenesis is not clear. Automated proteomic technology, coupled with powerful bioinformatics and statistical tools, can provide new insights into the molecular alterations implicated in DM. Following our previous findings of redox changes in the eye and aorta of diabetic rats, as well as the activities of different antioxidant enzymes during the development of DM, this study is further launched to find potential biomarkers by comparing the serum and tissue samples of 26 diabetic rats (8 weeks after streptozotocin [STZ] administration) with 29 normal controls using surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) technology. Eight potential biomarkers were found in the serum, one potential biomarker was found in the kidney and eye, respectively, whereas three potential biomarkers were discovered in the aorta. One of the serum biomarker candidates was found to match the C-reactive protein (CRP) in the Swiss-Prot knowledgebase. Further validation has been conducted by ELISA kit to confirm the role of CRP during the development of DM. To conclude, the increased level of CRP in diabetic serum demonstrated in this study indicates that the development of DM is associated with inflammation. This is also the first report demonstrating that some potential lysate biomarkers in the kidney, eye, and aorta may be involved in the development of diabetes and its complications. Further identification and evaluation of these potential biomarkers will help unravel the underlying mechanisms of the disease.

Animals↗

Oxygen and nitrogen are pro-carcinogens. Damage to DNA by reactive oxygen, chlorine and nitrogen species: measurement, mechanism and the effects of nutrition.

Humans are exposed to many carcinogens, but the most significant may be the reactive species derived from metabolism of oxygen and nitrogen. Nitric oxide seems unlikely to damage DNA directly, but nitrous acid produces deamination and peroxynitrite leads to both deamination and nitration. Scavenging of reactive nitrogen species generated in the stomach may be an important role of flavonoids, flavonoids and other plant-derived phenolic compounds. Different reactive oxygen species produce different patterns of damage to DNA bases, e.g., such patterns have been used to implicate hydroxyl radical as the ultimate agent in H(2)O(2)-induced DNA damage. Levels of steady-state DNA damage in vivo are consistent with the concept that such damage is a major contributor to the age-related development of cancer and so such damage can be used as a biomarker to study the effects of diet or dietary supplements on risk of cancer development, provided that reliable assays are available. Methodological questions addressed in this article include the validity of measuring 8-hydroxydeoxyguanosine (8OHdG) in cellular DNA or in urine as a biomarker of DNA damage, the extent of artifact formation during analysis of oxidative DNA damage by gas chromatography-mass spectrometry and the levels of oxidative damage in mitochondrial DNA.

Antioxidants↗

UALCAN Mobile, an app for cancer proteogenomic data analysis.

Cancer is a complex disease affecting various organs and is a major cause of death worldwide. During cancer initiation, disease progression, and tumor metastasis, various genomic and proteomic alterations are observed. Recent technological advances have led to the generation of large amounts of molecular data, including genomics and transcriptomics. These large-scale datasets can be utilized to analyze and identify sub-class-specific cancer biomarkers and targets. However, there is a need for the development of user-friendly tools for large-scale data analysis, disseminating the analyzed data in a visualizable format to cancer researchers with no programming skills. We developed UALCAN, a comprehensive platform that allows users to integrate disparate data to better understand the genes, proteins, and pathways perturbed in cancer and make discoveries of potential biomarkers and targets. In the current study, we describe the development of the UALCAN Mobile application (app) that will provide cancer transcriptomic data obtained from The Cancer Genome Atlas (TCGA) project to evaluate protein-coding gene expression based on various stratifications, including stage, grade, race, gender, and molecular-subtypes across over 30 types of cancers. In addition, the UALCAN mobile provides data analysis options for epigenetic changes due to DNA promoter methylation and Clinical Proteomic Tumor Analysis Consortium (CPTAC) cancer proteomic data. The app provides access to large cancer molecular datasets on the go. To find changes in the expression of causative genes and proteins and to identify biomarkers and therapeutic targets, UALCAN mobile app will be extremely valuable. The "UALCAN Mobile" app is free to use and can be downloaded from both the iOS/Apple and the Android Play Store and has been downloaded over 100 times in each of iOS and android app stores.

app↗

Quantitative screening of protein biomarkers of early glycation, advanced glycation, oxidation and nitrosation in cellular and extracellular proteins by tandem mass spectrometry multiple reaction monitoring.

Glycation of proteins forms fructosamines and AGEs (advanced glycation end products). Oxidative and nitrosative stress leads to the formation of oxidative and nitrosative modifications. The modified amino acid residues formed in these processes are biomarkers of protein damage: some are risk markers and some may be risk factors for disease development. We developed a method for the concurrent quantitative measurement of 16 biomarkers indicative of protein glycation, oxidation and nitrosation damage using LC-MS/MS (LC with tandem MS detection). Underivatized analytes were detected free in physiological fluids and in enzymatic hydrolysates of cellular and extracellular proteins. Hydroimidazolones were the most important glycation biomarkers, and methionine sulphoxide was the most important oxidative biomarker quantitatively; 3-nitrotyrosine was the biomarker of nitrosation. Quantitative screening showed high levels of AGEs in cellular protein and moderate levels in protein of blood plasma. Levels of 3-nitrotyrosine were typically 100-fold lower than this. The major glycation adducts in blood plasma had high renal clearances in normal healthy human subjects, whereas methionine sulphoxide and 3-nitrotyrosine had low renal clearances due to further metabolism. Physiological AGEs in blood plasma were eliminated from the circulation in the kidney and not in the liver. LC-MS/MS peptide mapping was also used to locate the protein biomarkers. These studies reveal that advanced glycation is a significant modification of cellular and extracellular protein. The enzymatic defences against glycation, antioxidants and proteasomal protein degradation inside cells are probable factors regulating biomarker levels of cellular protein.

Biomarkers↗