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PubMed2006

Neoadjuvant and adjuvant therapy for rectal cancer.

The currently available evidence from randomized clinical trials clearly supports the use of adjuvant therapy in general and preoperative combined modality therapy in particular as effective means of decreasing the rates of local recurrence, improving sphincter preservation rates, and probably im-proving overall survival when managing patients with locally advanced adenocarcinomas of the lower two thirds of the rectum. A radical surgical approach with adequately performed, sharp TME remains the standard of care for those patients. There is clearly a need to develop and validate surrogate biomarkers for the identification of patients who respond favorably to preoperative treatment. There is still a significant fraction of rectal cancer patients who ultimately die from their disease. The armamentarium of avail-able therapies is evolving rapidly, and hopefully local control rates and overall survival of rectal cancer patients will continue to improve in the near future.

Adenocarcinoma↗
PubMed2000

Relationship of plasma bone cytokines with hypercalcemia in cancer patients.

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. This syndrome appears to be a consequence of the tumor production of humoral factors, mainly parathyroid hormone related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy have features suggesting that factors other than PTHrP might play a role in this syndrome. We performed a case-control study in cancer patients with and without hypercalcemia. A total of 105 patients with a variety of tumors, 60 of them with hypercalcemia (corrected serum calcium over 2.6 mmol/l), and 45 without hypercalcemia. In a previous study, we demonstrated that plasma PTHrP was highly associated with hypercalcemia in these patients. In the present study, we measured the plasma levels of various bone cytokines: interleukin-1beta (IL-1beta), interleukin-6 (IL-6), transforming growth factor (TGF) alpha, and tumor necrosis factor (TNF) alpha, in these cancer patients. We also determined C-terminal type I procollagen (PICP) and C-terminal telopeptide of type I collagen (ICTP), bone formation and bone resorption markers, respectively, in serum in these patients. We found that these osteolytic cytokines do not increase in plasma by the presence of hypercalcemia. In fact, using a logistic regression analysis, a significant (P<0.02) association was found between the low plasma levels of IL-1beta and TGFalpha and hypercalcemia, independent of plasma PTHrP and the presence of bone metastasis, in these patients. No significant association between the plasma levels of IL-6 or TNFalpha and hypercalcemia was found in these cancer patients. Serum ICTP correlated (r=0.35; P=0.008) with hypercalcemia in these patients, but none of the cytokines studied in plasma correlated with either ICTP or PICP in these hypercalcemic patients. Our data indicate that the circulating levels of several bone cytokines are not enhanced by PTHrP in hypercalcemic cancer patients. The mechanism responsible for the association between the low plasma levels of some of these cytokines and hypercalcemia in these patients remains obscure. However, this finding does not rule out the possible local bone effects of these cytokines, contributing to hypercalcemia in cancer patients.

Adult↗
PubMed2000

Urinary excretion of deoxypyridinoline in 24-hour and first-void samples in healthy Turkish children.

OBJECTIVES: Collagen cross-links are formed during the maturation process of bone matrix. They have been considered as valuable markers in some metabolic, endocrinologic, and neoplastic bone disorders. As an advantage, it can be measured in urine as well as in serum samples. However, the excretion characteristics remains controversial. DESIGN AND METHODS: We investigated urinary free deoxypyridinoline (f-Dpd) excretion in first-void urine samples and in 24-hour collections in healthy Turkish children. We also evaluated the possible correlations and gender-related differences in Dpd excretion between these sampling methods. Both urine samples of 62 subjects (aged from 31 to 120 months) were analyzed by Immulite chemiluminescent technique. RESULTS: There were no remarkable differences in f-Dpd excretion between first-void and 24-hour urine samples, although f-Dpd values of the first-void samples were slightly higher (Dpd: creatinine, mean +/- SD, 20.5 +/- 5.8 nmol/mmol vs. 19.6 +/- 5.6 nmol/mmol, respectively, p > 0.05). A strong linear correlation was found between 24-hour and first-void urine f-Dpd excretions (r = 0.77, p < 0.05). In addition, f-Dpd showed no gender-related differences between boys and girls in either 24-hour or first-void urine samples (p > 0.05). CONCLUSIONS: Because of difficulties in long-time urine collection in infants and young children, f-Dpd assessment in first-void single urine samples is an easy, safe, and non-invasive method.

Amino Acids↗
PubMed2002

The effect of smoking on bone metabolism: maternal and cord blood bone marker levels.

BACKGROUND: To clarify the effect of smoking on bone metabolism in the fetus, we measured osteocalcin (OC), bone isoenzyme of alkaline phosphatase (BALP), procollagen type 1 C-terminal propeptide (PICP) in maternal serum and umbilical cord blood. METHODS: 15 active smoker, 14 passive smoker, 15 nonsmoker women and their newborn were included in this study. OC, BALP, PICP were determined by enzyme immunoassay. RESULTS: Of the bone markers tested only OC was different in the serum of the three groups of women. Infants of smoker women have significantly lower umbilical cord blood OC levels than those of infants from both passive smoker and nonsmoker women.(25.6 +/- 6.6, 35.8 +/- 10.4, 37.2 +/- 16.1 ng/mL respectively, p < 0.05). Infants of smoker women have significantly lower umbilical cord blood BALP levels than those of infants from nonsmoker women. (46 +/- 12, 57 +/- 15 U/L p < 0.05). All bone markers except total ALP were significantly higher in umbilical cord blood as compared to maternal blood levels (p < 0.001 for all). CONCLUSION: High umbilical cord blood bone marker levels may reflect the altered bone metabolism of fetus. Moreover, chronic hypoxia due to smoking may cause the suppression of bone matrix synthesis or placental synthesis as reflected by low OC and BALP levels in umbilical cord blood of infants from smoker women.

Alkaline Phosphatase↗
PubMed2001

Vitamin E and genome stability.

Free radicals and reactive oxygen species (ROS) which are generated continuously cause mutagenic alterations resulting in cancer, aging and abnormalities in the nervous system. Accumulating evidence indicates that Vitamin E, the most potent lipid peroxyl radical scavenger, may reduce free radical induced chromosomal damages through inhibition of free radical formation, and activation of endonuclease that can be triggered by intracellular oxidative stress, and by increasing the rate of removal of damaged DNA. Although some studies suggest a potential usefulness of Vitamin E in the prevention of mutagenic effects caused by genotoxic free radicals, other studies report no effects. Thus the data are not conclusive enough to be used as a basis to change the current recommended dietary allowances (RDA). Future research should address molecular mechanisms underlying the protective effects of Vitamin E and develop appropriate biologically relevant biomarkers of DNA damage to further help in determining the dietary levels of Vitamin E needed to protect the genetic pool from internally and externally induced DNA damages.

Animals↗
PubMed1996

Measurement of bone specific alkaline phosphatase in the horse: a comparison of two techniques.

For many years total alkaline phosphatase (AP) activity in serum has been used to monitor bone metabolism in different species. However, total AP lacks bone specificity because the total activity in serum is made up of several isoenzymes, of which the liver and bone isoforms predominate. The aim of the present study was to evaluate an immunoradiometric assay for measuring bone specific alkaline phosphatase (BAP) in horses. BAP, a specific marker of bone formation, was measured in sera from thoroughbred horses by using a previously characterised wheat germ lectin (WGL) precipitation assay and an immunoradiometric assay. The levels of immunoreactive BAP (iBAP) and WGL precipitated BAP (wBAP) were related to the serum levels of total AP and another marker of bone formation, the carboxy-terminal propeptide of type 1 collagen (PICP). In horses over one year old, iBAP correlated at least as strongly with total AP as with wBAP, which suggests that the immunoradiometric assay may partially cross-react with liver alkaline phosphatase in horse serum. This possibility was supported by the observation that there was a weaker correlation between iBAP and PICP than between wBAP and PICP. These data indicate that WGL precipitation is currently the most specific method for measuring bone specific alkaline phosphatase in horses.

Aging↗
PubMed2003

Osteoprotegerin and its correlations with new markers of bone formation and bone resorption in kidney transplant recipients.

Osteoprotegerin (OPG), a natural decoy receptor for osteoclast differentiation factor, is produced by osteoblasts in response to PTH. OPG and its ligand RANKL constitute a complex mediator system involved in the regulation of bone resorption, probably playing an important role in the homeostasis of bone turnover. At present, little is known about the effects of OPG on uremic bone. Successful kidney transplantation reverses many abnormalities of bone metabolism; however, the improvement is often incomplete. The aim of the study was to assess OPG and RANKL concentrations in long-term kidney allograft recipients and their correlations with biochemical markers of bone resorption and formation. The present studies on 48 kidney transplant recipients and 25 healthy volunteers included concentrations of parathormone, osteocalcin, bone-specific alkaline phosphatase, serum CrossLaps, calcidiol, calcitriol, ICTP, PICP, tartrate-resistant acid phosphatase, beta2 microglobulin, IGF-1, IFGBP-1, IGFBP-3, OPG, and RANKL using commercially available kits for measurements. Among kidney transplant recipients OPG and RANKL did not differ between transplant patients and healthy volunteers, whereas other markers of bone formation and resorption were significantly higher in the former group. OPD was related to age, time on dialysis prior transplantation, urea, platelet count, CSA dose, azathioprine dose, 25(OH)D(3), TRAP, IGF-1, IGFBP-3, whereas RANKL was related to leukocyte count, CSA concentration and dose, urine DPD, and beta2 microglobulin content. In healthy volunteers OPG correlated only with CrossLaps, whereas RANKL correlated only with osteocalcin and TRAP. Correlations between OPG, IGF system components, and some markers of bone metabolism may indicate the role of OPG/RANKL system in the pathogenesis of bone metabolism disturbances following renal transplantation.

Adult↗
PubMedDate not supplied

Methods of in vitro toxicology.

In vitro methods are common and widely used for screening and ranking chemicals, and have also been taken into account sporadically for risk assessment purposes in the case of food additives. However, the range of food-associated compounds amenable to in vitro toxicology is considered much broader, comprising not only natural ingredients, including those from food preparation, but also compounds formed endogenously after exposure, permissible/authorised chemicals including additives, residues, supplements, chemicals from processing and packaging and contaminants. A major promise of in vitro systems is to obtain mechanism-derived information that is considered pivotal for adequate risk assessment. This paper critically reviews the entire process of risk assessment by in vitro toxicology, encompassing ongoing and future developments, with major emphasis on cytotoxicity, cellular responses, toxicokinetics, modelling, metabolism, cancer-related endpoints, developmental toxicity, prediction of allergenicity, and finally, development and application of biomarkers. It describes in depth the use of in vitro methods in strategies for characterising and predicting hazards to the human. Major weaknesses and strengths of these assay systems are addressed, together with some key issues concerning major research priorities to improve hazard identification and characterisation of food-associated chemicals.

Animal Testing Alternatives↗
PubMed2001

From carcinogenesis to clinical interventions for cancer prevention.

During the last three decades, the scientific community has made immense progress in acquiring the knowledge needed to prevent cancer. Pioneering research helped to identify potential causes of cancer, particularly environmental factors such as diet, and provided insight regarding their mechanisms-of-action. Concurrently, promising inhibitors of cancer that appeared able to either arrest or reverse cancer development by interfering with one or more steps in the process of carcinogenesis were identified and systematically evaluated for their potential as chemopreventive agents. Numerous agents determined to be safe and effective in preclinical trials have been and continue to be tested in Phase I,II, and III clinical interventions for cancers at various sites, including breast, colon, prostate, esophagus, mouth, lung, cervix, endometrium, ovary, liver, bladder, and skin. The development of valid intermediate biomarkers that can serve as surrogate endpoints for clinical disease is urgently needed to accelerate advances in clinical trials for cancer prevention.

Anticarcinogenic Agents↗
PubMed1997

Pathogenesis of vitamin (A and D)-induced premature growth-plate closure in calves.

The pathogenesis of vitamin A-induced premature growth-plate closure was investigated in calves. A progressive increase in the severity of growth-plate lesions with time and a progressive increase in the extent of growth-plate involvement was observed. There was initial loss of metachromasia from the growth plate in a region that formed a narrow horizontal band of cartilage composed of the epiphyseal growth zone and a strip of reserve-zone cartilage. Immunostaining revealed there was loss of aggrecan, decorin, and biglycan from this region; however, it was doubtful that the regional loss of proteoglycan was a major contributing factor in the pathogenesis of premature growth-plate closure. This is because this region was the vestige of cartilage that remained when growth-plate closure was almost complete. The major alteration was premature mineralization of columnar cartilage and subsequent endochondral ossification. This caused the depth of the columnar zone to be reduced. Columnar-zone cartilage cells appeared immature where the matrix became mineralized and lacked the morphology of hypertrophic chondrocytes. The depth of the reserve-cartilage zone also was reduced as matrix mineralization of the columnar zone progressed, and further reduction in columnar cartilage depth occurred. Eventually, there was matrix mineralization within the adjacent reserve cartilage. The distribution of reaction product after immunostaining with antibodies to the following proteins was described during normal endochondral ossification: aggrecan, decorin, biglycan, versican, type I collagen propeptide, type I collagen, type II collagen, osteopontin, osteocalcin, osteonectin, bone sialoprotein, and alkaline phosphatase. Biglycan, type I collagen propeptide, type I collagen, osteopontin, osteocalcin, osteonectin, bone sialoprotein, and alkaline phosphatase were localized within the cytoplasm or surrounding matrix of hypertrophic chondrocytes. In vitamin-treated calves, these same proteins were found in regions undergoing premature matrix mineralization even though the chondrocytes did not have a hypertrophic morphology. Therefore, vitamin treatment did not cause just a selective expression, but it caused expression of a large number of matrix proteins normally associated with the hypertrophic chondrocyte phenotype. Finally, completely mineralized columnar and reserve cartilage were removed by a modeling/remodeling process similar to that seen in the metaphysis.

Aggrecans↗
PubMed1999

Biochemical markers of bone turnover after surgical menopause and hormone replacement therapy.

The objective of this study was to evaluate the effect of surgical menopause and hormone replacement therapy (HRT) on the new biochemical markers of bone turnover. Fourteen women who had undergone surgical menopause and began HRT 3 months after surgery were recruited for a 1-year study. Results were compared with a control group of 31 healthy premenopausal women of similar age. Serum samples were obtained to determine total alkaline phosphatase, bone alkaline phosphatase, propeptides carboxy- and amino-terminal of type I procollagen (PICP, PINP), osteocalcin, tartrate-resistant acid phosphatase, and carboxy-terminal telopeptides of type I collagen (ICTP and serum CTX). Urine samples were analyzed for hydroxyproline, pyridinoline, deoxypyridinoline, alpha- and beta-carboxy-terminal telopeptides of type I collagen (alpha-CTX and beta-CTX), and amino-terminal telopeptide of type I collagen (NTX). Determinations were performed after 3 months of surgical menopause and after 3 and 9 months of HRT. All biochemical markers increased after menopause, and most of them normalized after 9 months of HRT. Serum PINP showed the highest proportion of increased values after surgery among bone formation markers (62%), as well as the highest mean percent increase (101%). Among bone resorption markers in postmenopausal women, urinary beta-CTX, alpha-CTX, NTX, and serum CTX showed the highest proportion of increased values (100%, 67%, 58%, 58%, respectively) as well as the greatest mean percent increase. They were also the markers with the most marked response to HRT. In conclusion, serum PINP is the most sensitive marker of bone formation, whereas beta-CTX is the most sensitive marker of bone resorption after surgical menopause. In addition, both markers showed the highest response after HRT.

Acid Phosphatase↗
PubMed2005

Isolation of the retinoblastoma cDNA from the marine flatfish dab (Limanda limanda) and evidence of mutational alterations in liver tumors.

We have isolated a dab (Limanda limanda) homologue of the human retinoblastoma (Rb) tumor suppressor gene. The L. limanda partial Rb cDNA encodes a partial predicted protein of 753 amino acids. DNA sequence analysis with other vertebrate Rb sequences demonstrates that the L. limanda Rb cDNA is highly conserved in regions of functional importance. The sequence reported herein, combined with the high degree of conservation observed in critical domains, has also facilitated an investigation of the molecular etiology of environmentally induced liver tumor samples in a feral fish species. Mutational alterations were detected in liver adenoma samples, also in apparently "normal" regions of liver samples dissected from fish displaying adenoma, but not in normal liver samples from otherwise healthy feral fish. These results are the first reporting the appearance of Rb mutations in wild-caught fish and suggest that the molecular etiology of fish cancer appears to involve Rb-implicated tumorigenesis. The ecotoxicological relevance of the Rb mutations in feral fish liver tumors, in terms of future genome instability and possible development of a genotoxicity biomarker, is discussed.

Animals↗
PubMed1999

Molecular dosimetry of N-7 guanine adduct formation in mice and rats exposed to 1,3-butadiene.

1,3-Butadiene (BD) is a high-volume chemical used in the production of rubber and plastic. BD is a potent carcinogen in mice and a much weaker carcinogen in rats, and has been classified as a probable human carcinogen. Upon metabolic activation in vivo, it forms DNA-reactive metabolites, 1,2-epoxy-3-butene (EB), 1,2:3, 4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBD). The molecular dosimetry of N-7 guanine adduct formation by these metabolites of BD in liver, lung, and kidney of B6C3F1 mice and F344 rats exposed to 0, 20, 62.5, or 625 ppm BD was studied. The adducts, racemic and meso forms of N-7-(2,3,4-trihydroxybut-1-yl)guanine (THB-Gua), N-7-(2-hydroxy-3-buten-1-yl)guanine (EB-Gua I), and N-7-(1-hydroxy-3-buten-2-yl)guanine (EB-Gua II), were isolated from DNA by neutral thermal hydrolysis, desalted on solid-phase extraction cartridges, and quantitated by LC/ESI(+)/MS/MS. The number of adducts per 10(6) normal guanine bases for a given adduct was higher in mice than rats exposed to 625 ppm BD, but generally similar at lower levels of exposure. The THB-Gua adducts were the most abundant (6-27 times higher than EB-Gua) and exhibited a nonlinear exposure-response relationship. In rats, the exposure-response curves for the formation of THB-Gua adducts reached a plateau after 62.5 ppm, suggesting saturation of metabolic activation. The number of THB-Gua adducts continued to increase in mice between 62.5 and 625 ppm BD. In contrast, the less common EB-Gua adducts had a linear exposure-response relationship in both species. Combining the information from this study with previous data on BD metabolism, we were able to estimate the number of THB-Gua that resulted from DEB and EBD, and conclude that most of the THB-Gua is formed from EBD. We hypothesize that most of the EBD arises from the immediate conversion of DEB to EBD within the endoplasmic reticulum. This study highlights the need for measurements of the levels of EBD in tissues of rats and mice and for the development of a unique biomarker for DEB that is available for binding to DNA.

Administration, Inhalation↗
PubMedDate not supplied

Neurotoxic pesticides and behavioural effects upon birds.

Organochlorine, organophosphorus, carbamate, pyrethroid and neonicotinoid insecticides and organomercury fungicides are all neurotoxic and therefore have the potential to cause behavioural disturbances in birds. A number of studies have described behavioural effects caused to captive birds by neurotoxic pesticides, but it is very difficult to measure such effects in the field, which is a serous limitation given their potential to cause adverse effects at the population level. The mode of action, and the neurotoxic and behavioural effects of these compounds are briefly reviewed before considering evidence for their effects in the laboratory and field. Behavioural effects may cause adverse changes at the population level either directly or indirectly. Direct effects upon avian populations may be due to disturbances of reproduction, feeding, or avoidance of predation. Indirect effects on predators may be the consequence of direct action upon the prey population leading to either (1) reduction of numbers of the prey population, or (2) selective predation by the predator upon the most contaminated individuals within the prey population. Attention is given to the historic evidence for neurotoxic and behavioural effects of persistent organochlorine insecticides, raising the question of retrospective analysis of existing data for this once important and intensively studied class of compounds. Less persistent pesticides currently in use may also have neurotoxic effects upon birds in the field. Sometimes, as with some OPs, their effects may outlast the persistence of their residues, and the ecotoxicity and persistence of some may be affected by interactions with other environmental chemicals. The development of new mechanistic biomarker assays could improve understanding of behavioural effects and possible associated effects at the population level caused by such compounds in the field.

Animals↗
PubMed1996

Metabolic effects of pamidronate in patients with metastatic bone disease.

We have evaluated the value of specific bone resorption markers in monitoring metastatic bone disease to define the duration of action of a single high-dose pamidronate infusion. Twenty patients received a single infusion of pamidronate 120 mg for painful bone metastases. Ten out of these 20 patients also received a second infusion. They were evaluated at baseline, 2, 4 and 8 weeks after each infusion. A composite pain questionnaire, serum and urine tests were carried out at these time points. Bone resorption markers measured included urinary calcium, hydroxyproline and two new markers: pyridinoline and deoxypyridinoline. Reference values were defined by 20 healthy controls matched by age and sex. Pamidronate induced a profound fall in bone resorption with a maximal effect within the first month after therapy. Changes in urinary calcium levels were confounded by a rise of 100% in the parathyroid hormone levels. Before treatment, pyridinoline and deoxypyridinoline were increased in 70% of patients, while urinary calcium was increased in only 40% of them. Thirteen patients had a > or = 50% fall in deoxypyridinoline levels and were considered as biochemical responders. These patients had a mean reduction in pain score of about 30% of baseline levels, which was significantly higher than the seven non-biochemical responders. In conclusion, urinary calcium is not a precise marker of bone resorption. Deoxypyridinoline seems to be the most specific bone resorption marker in cancer patients. Biochemical responders have the most benefit from pamidronate in terms of pain relief. This suggests that patients may benefit from more potent or repeated infusions of bisphosphonates.

Aged↗
PubMed1997

Dissociation of bone formation markers in bone metastasis of prostate cancer.

To clarify the meaning and clinical value of bone formation markers in bone metastasis from prostate cancer, we investigated the bone formation markers carboxy-terminal propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BA1-p) and osteocalcin, so-called bone gla protein (BGP) in 43 prostate cancer patients with and 46 patients without overt bone metastasis. Patients with bone metastasis were evaluated repeatedly by bone scan at intervals of 3-6 months. The expression patterns of bone formation markers in patients with progression of bone metastasis became dissociated; BA1-p and PICP were elevated in patients with progression of bone metastasis but BGP was not. Instead, BGP showed slight elevation in patients with improvement and complete remission of bone metastasis. PICP, BA1-p and BGP are all bone formation markers, but each marker appears in a different phase of bone formation: PICP appears in proliferation phase, BA1-p appears in matrix maturation phase and BGP appears in late bone formation phase. Our findings that BGP was not elevated in progression of bone metastasis and that it increased slightly with improvement and complete remission of bone metastasis may imply that the bone formation that occurs in blastic bone metastasis is different from normal bone formation.

Aged↗
PubMed1998

The effect of rectally administered steroids on bone turnover: a comparative study.

BACKGROUND: Oral glucocorticoids contribute significantly to the risk of osteoporosis in patients with inflammatory bowel disease. Less well established are the effects of rectally administered steroids on bone metabolism. AIM: To investigate the effects of two widely used rectal foam preparations (prednisolone metasulphobenzoate and hydrocortisone acetate) on biochemical markers of bone turnover. METHODS: Twenty-four patients with active inflammatory bowel disease randomly received a standard course of either prednisolone metasulphobenzoate or hydrocortisone acetate for 2 weeks. Biochemical markers of bone turnover were measured before, during and after treatment. Bone formation markers measured were serum osteocalcin (BGP) and bone-specific alkaline phosphatase (BALP). Urinary deoxypyridinoline (DPD) was measured to assess bone resorption. RESULTS: Disease activity scores improved during treatment (difference in mean Powell-Tuck score = 3.4, 95% CI: 2.0-4.8, P < 0.0001) and were similar in both hydrocortisone and prednisolone-treated groups. There was no significant reduction in BALP or BGP during treatment with either steroid preparation, and urinary DPD did not change significantly during treatment. CONCLUSIONS: During a 2-week course of rectal hydrocortisone acetate or prednisolone metasulphobenzoate, there was no significant change in biochemical markers of bone formation or resorption. These results suggest that pharmacological doses of rectal steroid foam preparations do not significantly impair bone turnover in patients with inflammatory bowel disease.

Administration, Rectal↗