Metastatic bone disease and the role of biochemical markers of bone metabolism in benign and malignant diseases.
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Biomarkers↗
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Bone markers in the management of metastatic bone disease.
Newer markers of bone formation and bone resorption are now available. Alone these new markers do not appear to be useful to diagnose metastatic bone disease. Several markers appear to be of prognostic importance and correlate with the extent of tumour in the skeleton. Serial monitoring of bone markers may be useful to monitor the efficacy of bisphosphonate and/or systemic therapy of both lytic and blastic bone metastases.
Biomarkers↗
The effect of bovine whey protein on ectopic bone formation in young growing rats.
The beneficial effect of bovine whey protein (WP) on bone metabolism has been shown in adult human subjects and ovariectomised rats. However, its effect on bone formation in earlier life, particularly during periods of bone mineral accrual, has not been investigated. Twenty-one male rats (4 weeks old, Wistar strain) were randomised by weight into three groups of seven rats each and fed ad libitum on a semi-purified low-Ca diet (3.0 g Ca/kg diet) containing 0 (control), 10 (diet WP1) or 20 (diet WP2) g bovine WP/kg for 47 d. On day 34 of the dietary intervention, all rats had two gelatine capsules containing demineralised bone powder implanted subcutaneously in the thorax region (a well-established in vivo model of ectopic bone formation). At 14 d after implantation, alkaline phosphatase activity (reflective of bone formation) in the bone implants from animals fed WP1 and -2 diets was almost 2-fold (P<0.01) that of control animals. Insulin-like growth factor (IGF)-I mRNA levels were about 3-fold (P<0.05) higher in implants from animals fed the WP diets compared with those from control animals. Serum- and urine-based biomarkers of bone metabolism and bone mineral composition in intact femora were unaffected by WP supplementation. In conclusion, the present findings suggest that bovine WP can enhance the rate of ectopic bone formation in young growing rats fed a Ca-restricted diet. This effect may be mediated by an increased synthesis of IGF-I in growing bone. The effect of WP on bone formation warrants further investigation.
Acid Phosphatase↗
Dietary aflatoxin exposure and chemoprevention of cancer: a clinical review.
Exposure to dietary aflatoxins is considered to be an important risk factor for the development of hepatocellular carcinoma in certain regions of the world. Significant advances have recently been made in understanding the clinical toxicology of aflatoxins. These include the development and validation of biomarkers of exposure and genotoxic effect. These biomarkers are currently being utilized to explore the potential that pharmaceutical interventions may have in modifying the toxicokinetics of dietary aflatoxin exposure. Preliminary results of clinical trials with the drug oltipraz suggest that it may modify the genotoxic effects of aflatoxin B1 by inhibiting bioactivation pathways and stimulating detoxification pathways. More recent results of a clinical trial with chlorophyllin suggest that this drug may have a role in preventing dietary exposure to aflatoxin B1 by reducing its oral bioavailability. The preliminary results of these chemoprevention studies may ultimately have implications for cancer prevention in high-risk populations in the future.
Aflatoxins↗
Chemoprevention of lung cancer--from biology to clinical reality.
Lung cancer is the commonest cause of cancer death in developed countries and throughout the world. Cigarette smoking is the main risk factor for lung cancer and ex-smokers today comprise approximately 50% of all new lung cancer cases. Chemoprevention builds on the concepts of field of cancerization and multistep carcinogenesis and can be defined as the use of natural or chemical compounds to prevent, inhibit or reverse the process of carcinogenesis. So far, chemoprevention studies in lung cancer have failed to reduce lung cancer mortality. New developments in biotechnology have made it possible to define more accurately high-risk populations, make earlier diagnosis possible, and allow more specific targeted therapies to be developed. Both the development and validation of biomarkers, for the selection of high-risk study populations and for response evaluation in chemoprevention studies, are important for the faster turnover of studies evaluating new agents. This article reviews the current status and describes the perspectives for new approaches in the chemoprevention of lung cancer.
Anticarcinogenic Agents↗
Suppression of cell proliferation and telomerase activity in 4-(hydroxyphenyl)retinamide-treated mammary tumors.
The detection of telomerase activity has been proposed as a biomarker of breast cancer development and progression. In this study, we used cell proliferation and telomerase in MNU (N-methyl-N-nitrosourea)-induced mammary carcinomas as targets for assessing the response of tumor cells to 4-(hydroxyphenyl)retinamide (4-HPR), a known inhibitor of mammary carcinogenesis in animal models and premenopausal women. In mammary tumors of rats treated for 1, 2, 4 or 6 weeks with 4-HPR, we observed that telomerase activity decreased progressively with the extension of 4-HPR administration. A marked reduction in telomerase activity was already observed by 2 weeks after treatment and the lowest level was found at 6 weeks after initiation of 4-HPR treatment. The changes in telomerase activity were preceded and accompanied by a significant decrease in the percentage of proliferating cells as evaluated by 5-bromodeoxyuridine (BrdU)-labeling. However, when the values of telomerase activity in the individual tumors were compared with the percentage of proliferating cells, no significant correlation was found. These data suggest that the decreased telomerase activity in the animals treated with 4-HPR is not a simple consequence of the changes in cell proliferation, but a more complex phenomenon involving different cellular mechanisms and pathways. The time-dependent and consistent decrease of telomerase activity in the tumors treated with 4-HPR suggests that, in addition to the percentage of proliferating cells, telomerase activity could also be used as an endpoint in breast cancer chemotherapy studies.
Animals↗
Insulin and IGF-I as determinants of low "Western" cancer rates in the rural third world.
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Biomarkers, Tumor↗
Biochemical markers of bone turnover in the diagnosis of renal osteodystrophy: what do we have, what do we need?
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Alkaline Phosphatase↗
Nonlethal development, validation, and application of cytochrome P4501A1 (CYP1A1) as a biomarker for contaminant exposure.
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Animals↗
Screening of the key single nucleotide polymorphisms in type 2 diabetes mellitus complicated with lower extremity arterial disease by machine learning.
OBJECTIVES: Diabetic lower extremity arterial disease (LEAD) is a manifestation of diabetic lower extremity vascular complications. This study aimed to screen the key single nucleotide polymorphism (SNP) gene signature in patients with type 2 diabetes mellitus (T2DM) and LEAD. METHODS: A total of 147 patients with T2DM complicated by LEAD and 144 patients with T2DM without LEAD were enrolled for transcriptome sequencing. The Plink software was used to preprocess the data. Five machine learning methods were adopted to build the SNP diagnosis models. The receiver operating characteristic (ROC) curve was used to quantify the predicted probabilities of the model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the cluster Profiler package. Finally, regression statistical analysis was used to correlate the key SNPs with clinical information and biochemical indicators. RESULTS: A total of 24 SNPs were retained and 10 SNPs were risk allele genes. Nine SNPs (rs7412, rs1800629, rs699947, rs3918242, rs668, rs1800470, rs1800449, rs1800469, and rs1024611) were identified as the key SNPs sites. GO and KEGG pathway analyses revealed that these genes are mainly enriched in fluid shear stress and atherosclerosis. Finally, rs1800449 was associated with low-density lipoprotein cholesterol (LDL-C). With high density lipoprotein cholesterol (HDL-C), related site was rs1024611. The sites associated with total cholesterol (CHOL) were rs1800449 and rs7412.The site associated with apolipoprotein B (APOB) and apolipoprotein A1 (APOA1) were rs1800470 and rs1800469. CONCLUSION: This study authenticated nine SNPs for the diagnosis of T2DM patients with LEAD, which will be of great significance in the development of diagnostic molecular biomarkers for T2DM patients.
Humans↗
Classification of a large microarray data set: algorithm comparison and analysis of drug signatures.
A large gene expression database has been produced that characterizes the gene expression and physiological effects of hundreds of approved and withdrawn drugs, toxicants, and biochemical standards in various organs of live rats. In order to derive useful biological knowledge from this large database, a variety of supervised classification algorithms were compared using a 597-microarray subset of the data. Our studies show that several types of linear classifiers based on Support Vector Machines (SVMs) and Logistic Regression can be used to derive readily interpretable drug signatures with high classification performance. Both methods can be tuned to produce classifiers of drug treatments in the form of short, weighted gene lists which upon analysis reveal that some of the signature genes have a positive contribution (act as "rewards" for the class-of-interest) while others have a negative contribution (act as "penalties") to the classification decision. The combination of reward and penalty genes enhances performance by keeping the number of false positive treatments low. The results of these algorithms are combined with feature selection techniques that further reduce the length of the drug signatures, an important step towards the development of useful diagnostic biomarkers and low-cost assays. Multiple signatures with no genes in common can be generated for the same classification end-point. Comparison of these gene lists identifies biological processes characteristic of a given class.
Algorithms↗
Prospects for urinary proteomics: exosomes as a source of urinary biomarkers.
Recent progress in biotechnology offers the promise of better medical care at lower costs. Among the techniques that show the greatest promise is mass spectrometry of proteins, which can identify proteins present in body fluids and tissue specimens at a large scale. Because urine can be collected in large amounts in a non-invasive fashion, the potential exists to use mass spectrometry to discover urinary biomarkers that are early predictors of renal disease, or useful in making therapeutic choices. Recently, the authors demonstrated that both membrane proteins and cytosolic proteins from renal epithelia are highly enriched in low-density urinary structures identified as exosomes. Exosomes were found to contain many disease-associated proteins including aquaporin-2, polycystin-1, podocin, non-muscle myosin II, angiotensin-converting enzyme, Na+ K+ 2Cl- cotransporter (NKCC2), thiazide-sensitive Na-Cl cotransporter (NCC), and epithelial sodium channel (ENaC). Potentially, other disease biomarkers could be discovered by mass spectrometry-based proteomic studies in well-defined patient populations. Herein is described the advantages of using urinary exosomes as a starting material for biomarker discovery. In addition, the purpose of this review is to present an overall strategy for biomarker discovery in urine using exosomes and for developing cost-effective clinical assays for these biomarkers, which can potentially be used for early detection of disease, as a means of differential diagnosis, or as a means of guiding therapy. Finally, potential barriers that need to be overcome before urinary proteomics can be applied clinically, are emphasized.
Biomarkers↗
Influence of osteoarthritis on serum marker levels of bone formation and resorption in patients with benign prostatic hypertrophy.
BACKGROUND: The aim of this study was to investigate the influence of osteoarthritis of lumbar vertebrae on serum bone formation and resorption marker levels of patients with benign prostatic hypertrophy (BPH). METHODS: Serum levels of carboxyterminal propeptide of type I procollagen (PICP), alkaline phosphatase (ALP), carboxyterminal telopeptide of type I collagen (ICTP), and prostate-specific antigen (PSA) were examined in 40 patients with BPH, and the presence of osteoarthritis at the lumbar vertebrae of the patients was evaluated by plain x-ray-p. RESULTS: Findings of osteoarthritis were observed in 23 of the 40 patients (58%), and 10 of the patients had severe osteoarthritis (involving at least 2 lumbar vertebral bodies). The serum levels of PICP, ALP, ICTP, and PSA of the patients without osteoarthritis findings were not different from those of the patients with osteoarthritis or severe osteoarthritis. CONCLUSION: The influence of osteoarthritis on serum bone formation and resorption marker levels of patients with BPH appears to be rather slight, if there is any influence at all.
Aged↗
Assessment of anaerobic benzene degradation potential using 16S rRNA gene-targeted real-time PCR.
Benzene is a common groundwater pollutant that is often recalcitrant under the anaerobic conditions that prevail at hydrocarbon-contaminated aquifers. Thus, determining the potential for anaerobic benzene degradation is important to assess the feasibility of intrinsic bioremediation. In this work we developed a 16S rRNA biomarker to estimate the concentration of putative benzene degraders in a methanogenic consortium that has been enriched on benzene for several years. Primers were designed based on phylogenetic information from this consortium. The primers and probe were obtained by sequencing the dominant denaturing gradient gel electrophoresis band of this consortium, which corresponded to Desulfobacterium sp. clone OR-M2. No hybridization was observed with DNA samples from negative controls (i.e. toluene-degrading and dehalorespiring methanogenic consortia that do not degrade benzene). Samples from an anaerobic aquifer column that was bioaugmented with this benzene-degrading consortium showed a strong correlation between benzene degradation activity and the concentration of the target organism. Although our data do not prove that Desulfobacterium sp. is a benzene degrader, its enrichment as a result of benzene consumption and its correlation to anaerobic benzene degradation activity suggest that it either initiates benzene degradation or is a critical (commensal) partner. Therefore, the utility of this primers and probe set to assess anaerobic benzene degradation potential was demonstrated. This is the first report of the use of real-time quantitative PCR for forensic analysis of anaerobic benzene degradation. Whether this biomarker will be adequately selective and broadly applicable to assess benzene degradation potential under strongly anaerobic (sulfate reducing and methanogenic) conditions will require further research.
Bacteria, Anaerobic↗
Association between HLA-DQB1 and cervical dysplasia in Vietnamese women.
Host genetic background seems to play a key role in cervical carcinogenesis as only a small subset of women infected with high-risk human papillomaviruses (HPVs) develop cervical cancer. The rate of cervical cancer in Vietnamese women is notably high. To explore the association of human leukocyte antigen (HLA)-DQB1 alleles, HPV infection, and cervical dysplasia in this population, cervical smears were obtained from 101 women attending the obstetrics and gynecology clinic of Da Nang General Hospital in Vietnam. Besides the Papanicolaou test, HPV and HLA-DQB1 genotyping were performed using cervical smear DNA. Additionally, a subset of 30 blood samples was used as the gold standard for HLA genotyping. HLA-DQB1 alleles showed no association with HPV infection status. However, a positive association with cervical dysplasia was found for HLA-DQB1*0302 (P= 0.0229, relative risk (RR) = 4.737) and HLA-DQB1*0601 (P= 0.0370, RR = 4.038), whereas HLA-DQB1*0301 (P= 0.0152, RR = 0.221) was found negatively associated. The low diversity of HLA-DQB1 alleles, wide spectrum of HPV genotypes, and high prevalence of HPV 16 and HPV 18 observed in the study population suggest a permissive/susceptible genetic background that deserves further research. Total concordance of HLA-DQB1 genotyping results between blood and cervical cells confirms the potential value of cervical smears as an effective tool for the development of cervical cancer biomarkers.
Adult↗
Developing and delivering new medical technologies: issues beyond access.
The articles in this issue illuminate psychosocial issues raised by the development and delivery of new medical technologies. Five kinds of questions surface repeatedly: questions about a technology's purpose(s), the value judgments it presumes, the locus of its control, the external forces that drive it, and its long-term social risks. These questions take the discussion of new technologies beyond the challenge of improving access to their benefits. They also raise issues that will become increasingly important as the capabilities of medical technology expand. For example, they suggest research questions for three other emerging medical technologies: use of biosynthetic growth hormone to treat short stature in hormonally normal children, genetic tests on fetal cells from the circulating maternal blood, and development of clinically reliable biomarkers of the aging process. Part Three of this issue provides a theoretical basis for encouraging psychosocial perspectives in this area, by illustrating the central role that "robust," multifaceted analysis has come to play within the methods of bioethics.
Aging↗
Changes in markers of bone metabolism during dexamethasone treatment for chronic lung disease in preterm infants.
AIM: To characterise the change in serum and urinary bone markers in the early postnatal period, and to assess the effect of systemic corticosteroid on bone metabolism in preterm infants. METHODS: Bone formation was quantified by measurement of serum concentrations of bone specific alkaline phosphatase (BALP) and osteocalcin. Bone resorption was measured by monitoring creatinine adjusted urinary deoxypyridinoline (Dpd) concentration. Blood and urinary samples were collected from corticosteroid treated infants (n = 19) immediately before the start (T(d-pre)), three weeks after the start (T(d-end)), and two (T(d-post2)) and four weeks (T(d-post4)) after the end of the dexamethasone course. Untreated patients (n = 30) had specimens taken at week 3 (T(wk-3)), 6 (T(wk-6)), 8 (T(wk-8)), and 10 (T(wk-10)) of postnatal age. RESULTS: Serum concentrations of BALP and osteocalcin at T(d-end) were significantly lower than pretreatment levels and the levels at the corresponding time point (T(wk-6)) of the non-treatment group. In contrast, urinary Dpd concentration at T(d-end) was not significantly decreased compared with the pretreatment level. However, it was significantly lower than the urinary Dpd concentration at T(wk-6) of the non-treatment group. The rate of increase in lower leg length was significantly higher in the non-treatment group between weeks 3 and 6 than in the corresponding period during dexamethasone treatment in the corticosteroid group. CONCLUSION: Systemic corticosteroid causes appreciable suppression of serum BALP and osteocalcin and, to a lesser extent, urinary Dpd. The results suggest that corticosteroid inhibits bone growth mainly by decreasing bone formation.
Alkaline Phosphatase↗
Medical staff in emergency situations: severity of patient status predicts stress hormone reactivity and recovery.
BACKGROUND: Although repetitive exposure to stressful situations is thought to habituate the physical stress responses, work stress is experienced by medical personnel in emergency and intensive care units; performance should, however, remain stable over time. AIMS: To investigate the neuroendocrine reactions (reactivity during and recovery after work) in experienced emergency caregivers during emergency situations. METHODS: A within subjects pre-post design was studied in the natural work environment of 20 municipal Dutch emergency caregivers. A stress protocol was developed in which the biomarker cortisol was measured in saliva at baseline, during the emergency period, and during recovery. Four scenarios were tested between subjects in which the severity of the emergency situation and the time of day were taken into account. RESULTS: Greater endocrine reactions were shown during and after the handling of patients in direct life threatening situations during morning hours compared to the handling of patients who were not in direct life threatening situations.
Adult↗