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J A Ross

Publications and source records attributed to J A Ross.

At least 37 records · Page 2Linked to original sources
PubMed2001

Glutathione S-transferase polymorphisms and outcome of chemotherapy in childhood acute myeloid leukemia.

PURPOSE: Glutathione S-transferase theta (GSTT1) and mu (GSTM1) genes are polymorphic, the genes being absent in approximately 15% and 50% of the population, respectively. Because glutathione S-transferases may be involved in the metabolism of chemotherapy drugs, we hypothesized that presence or absence of the genes may influence the outcome of treatment for childhood acute myeloid leukemia (AML). PATIENTS AND METHODS: We genotyped GSTT1 and GSTM1 in 306 children with AML receiving chemotherapy on Children's Cancer Group therapeutic studies. Outcomes were compared in those with and without GSTT1 and GSTM1 genes. RESULTS: Patients with the GSTT1-negative genotype had reduced survival compared with those with at least one GSTT1 allele (GSTT1 positive) (52% v 40% at 5 years; log-rank P =.05). A multivariate model of survival adjusted for age group, sex, WBC count, chloroma, CNS involvement, and French-American-British group confirmed the increased risk of death in the GSTT1-null cases (relative risk, AQ 1.6; P =.02). The frequency of death in remission was increased in GSTT1-negative cases compared with GSTT1-positive cases (24% v 12%, log-rank P =.05). The frequency of relapse from end of induction was similar in GSTT1-negative and GSTT1-positive cases (38% v 35%, log-rank P =.5). CONCLUSION: Children who lacked GSTT1 had greater toxicity and reduced survival after chemotherapy for AML compared with children with at least one GSTT1 allele. If confirmed in further studies, GSTT1 genotype might be useful in selecting appropriate chemotherapy regimens for children with AML.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Proteolysis-inducing factor regulates hepatic gene expression via the transcription factors NF-(kappa)B and STAT3.

A novel protein, proteolysis-inducing factor (PIF), has been isolated from the urine of patients with pancreatic cancer and is capable of inducing muscle proteolysis in vitro. Only adult skeletal muscle and liver exhibit substantial binding of PIF. We have investigated the effect of PIF on hepatic gene expression. Primary cultures of human hepatocytes and the human cell line HepG2 were incubated in the presence of PIF to assess its effects on hepatic transcription factors, proinflammatory cytokine production, and acute phase proteins. PIF activates both the transcription factors NF-kB and STAT3, which result in the increased production of IL-8, IL-6, and C-reactive protein and the decreased production of transferrin. The function of PIF, beyond muscle degradation, is unknown but here we show that it is involved in hepatic gene expression, and is thus likely to be involved in the proinflammatory response observed in cachexia. These results may also suggest a potential role for PIF during embryonic development. The expression of PIF peaks during the embryonic period E8 to E9, a stage that is crucial in the development of skeletal muscle and liver and during which both NF-kB and STAT3 activation can also be observed.

Blood Proteins↗
PubMed2001

Nutritional assessment of pregnant women enrolled in the Special Supplemental Program for Women, Infants, and Children (WIC).

OBJECTIVE: To evaluate nutrient intake from dietary sources for 95 pregnant women enrolled in the Special Supplemental Program for Women, Infants, and Children (WIC). SUBJECTS/SETTING: Women were recruited from Minneapolis and St Paul area WIC clinics between January and June 1999. Based on estimates from the WIC clinics, the study was described to 159 (63%) of the 251 potentially eligible women. Of these 159 women, 107 (67%) completed the in-person interview. Ninety-five (89%) were included in the nutrition analysis. METHODS: Each woman completed a 1-hour in-person interview that included a questionnaire, anthropometric measurements, and a venous blood sample. A shortened Block 98 food frequency questionnaire was used to assess dietary intake. Serum ferritin was measured for 86 women. Means, medians, and standard deviations of dietary intake were explored as well as body mass index distributions. Additionally, the percentage of women consuming less than two thirds of the recommended dietary allowance (RDA) for certain nutrients was calculated. RESULTS: Overall, the women reported consuming only 85% of the RDA for energy. The average percentage of energy from fat was higher than recommended (37% vs 30%). The most notable nutrient shortfall was iron; 90% of the women reported consuming less than 2/3 of the RDA. Additionally, serum ferritin analysis classified 22% of the women with iron-deficiency anemia (<12 mg/L). CONCLUSIONS: Interventions should be designed to decrease fat consumption and increase iron intake among pregnant WIC participants to meet dietary recommendations.

Adult↗
PubMed2001

The measurement of fetal liver T(*)(2) in utero before and after maternal oxygen breathing: progress towards a non-invasive measurement of fetal oxygenation and placental function.

Utero-placental insufficiency is thought to be a major cause of growth retardation in utero and an important risk factor in the perinatal period. The purpose of this study was to investigate whether MRI could detect changes of fetal oxygenation, based on the blood oxygenation level dependence (BOLD) of the MRI tissue signal. Nine third trimester women (34-38 weeks) with normal pregnancies underwent abdominal MRI examinations. Following localization of the fetal liver using T(2)-weighted single-shot HASTE scans, up to 7 breath-held transaxial single-slice gradient-echo image sets were obtained through the fetal liver. The mother then commenced oxygen breathing with the imaging procedure repeated after 20 minutes of O(2) breathing. For each image set, T(*)(2) values are calculated using linear regression of log (signal) versus TE for a region of interest within the fetal liver selected by the attending radiologist. Fetal liver T(*)(2) values were calculated before and after O(2) breathing for each multi-echo image acquisition set. A signed rank test was used to test for a significant change in fetal liver T(*)(2) between the pre-O(2) and post-O(2) image sets. A significant increase in T*(2) (alpha < 0.05) was seen in 5 of the 9 fetal livers, a smaller increase (of borderline statistical significance, alpha = 0.057) in 2 livers, and no significant change (alpha > 0.05) in 2 livers. Our study indicates that T(*)(2) measurement of the fetal liver may detect alteration in fetal oxygen level following maternal oxygenation using the BOLD effect. This technique may potentially be applied to the identification and understanding of placental dysfunction in intra-uterine growth retardation.

Adolescent↗
PubMed2001

An evaluation of the mutagenicity, metabolism, and DNA adduct formation of 5-nitrobenzo[b]naphtho[2,1-d]thiophene.

Thioarenes, sulfur-containing polycyclic aromatic compounds, are environmental contaminants suspected of posing human health risks. In this study, 5-nitrobenzo[b]naphtho[2,1-d]thiophene (5-nitro-BNT), a nitrated-thioarene, was examined for its mutagenicity, metabolism and subsequent formation of DNA adducts. 5-Nitro-BNT was weakly mutagenic in Salmonella typhimurium strains TA98 and TA100 without Aroclor-1254-induced rat liver S9 (S9), and its activity was increased in the presence of S9. Anaerobic metabolism of 5-nitro-BNT by S9 or xanthine oxidase (XO) produced one major metabolite, identified as 5-amino-BNT by NMR, MS, and UV spectroscopy and by comparison with an authentic standard. Aerobic S9 metabolism of 5-nitro-BNT produced a major metabolite, identified as trans-9,10-dihydroxy-9,10-dihydro-5-nitro-BNT (5-nitro-BNT-9,10-diol). Also present was a minor amount of 5-amino-BNT and trans-9,10-dihydroxy-9,10-dihydro-5-amino-BNT (5-amino-BNT-9,10-diol). DNA adduct analyses were performed using the (32)P-postlabeling assay and reversed-phase HPLC. Three major XO-derived calf thymus DNA adducts were detected. On the basis of their chromatographic mobilities, two adducts were identified as reaction products of 5-nitro-BNT with 2'-deoxyguanosine and one adduct with 2'-deoxyadenosine. Incorporation of allopurinol (a specific XO inhibitor) in the incubation mixture resulted in loss of all three adducts, confirming enzymatic mediation by XO. Aerobic S9 activation of 5-nitro-BNT with calf thymus DNA produced three adducts. On the basis of their chromatographic mobilities, two were identified as reaction products of 5-nitro-BNT with 2'-deoxyguanosine and one with 2'-deoxyadenosine. Incorporation of 1-aminobenzotriazole (a P450 inhibitor) in the incubation mixture resulted in a loss of these adducts, confirming enzymatic mediation by P450. Aerobic S9-catalyzed metabolism of 5-nitro-BNT-9,10-diol produced the same DNA adducts as observed with 5-nitro-BNT. Aerobic S9-catalyzed metabolism of 5-amino-BNT-9,10-diol produced the same deoxyadenosine-derived DNA adducts as observed with 5-nitro-BNT and 5-nitro-BNT-9,10-diol. These results provide additional information that both ring oxidation and nitroreduction are involved in the metabolism, DNA adduct formation and mutagenicity of 5-nitro-BNT.

Animals↗
PubMed2001

Pet ownership and childhood acute leukemia (USA and Canada).

OBJECTIVES: For more than three decades there has been speculation regarding a possible role of zoonotic diseases in the development of human leukemia. This study investigated the potential relationship between exposure to pets and the development of childhood leukemia. METHODS: Data from 2359 cases of acute leukemia from two large case-control studies were analyzed. Cases were individually matched to population controls on telephone exchange, age, and race. Conditional logistic regression was used to estimate odds ratios (OR) associated with pet ownership. RESULTS: Overall, there was no association between pet ownership (either "any pet", dog, or cat) and childhood acute leukemia (OR(any pet:) = 1.01, 95% CI 0.89-1.2). Additionally, no relationship was found between exposure to an ill pet and childhood leukemia. CONCLUSION: The results of this analysis suggest that pet ownership (healthy or sick) is unrelated to an increased risk of childhood leukemia.

Adolescent↗
PubMed2001

Leptin and its relation to weight loss, ob gene expression and the acute-phase response in surgical patients.

BACKGROUND: Patients with cachexia suffer from anorexia, weight loss and hypermetabolism. This study examined the relationship between plasma leptin concentration, leptin gene expression, weight loss and the acute-phase response in a group of surgical patients. METHODS: Body composition, plasma leptin, interleukin (IL) 6, soluble tumour necrosis factor receptor (sTNF-R) 55, sTNF-R75 and C-reactive protein were analysed in a cohort of 28 patients undergoing elective surgery. Subcutaneous and omental leptin messenger RNA (mRNA) was analysed in a subgroup of 14 patients. RESULTS: After adjustment for fat mass (FM), a significant partial correlation coefficient was found between plasma leptin and serum IL-6 concentration (P = 0.037). A positive correlation was found only between plasma leptin and omental leptin mRNA (P = 0.009). Patients with an acute-phase response had a significantly higher level of plasma leptin per unit FM (P = 0.049). Stepwise multiple regression showed that FM (P < 0.0005) and serum IL-6 (P = 0.018) were independent predictors of plasma leptin level. CONCLUSION: Plasma leptin levels appear to be influenced by proinflammatory cytokines. Omental fat may have more influence on plasma leptin than subcutaneous fat. Accelerated weight loss in patients with cancer with an ongoing inflammatory response could be mediated in part by inappropriately high plasma levels of leptin.

Acute-Phase Reaction↗
PubMed2001

The Maternal and Neonatal Programme Effort Index (MNPI).

A new index is presented that measures the effort levels of national programmes to reduce maternal and neonatal mortality. These indices come from a questionnaire instrument composed of 14 major headings and 81 items. Forty-nine countries including most of the population in each geographical region are covered. Data were collected from 10 to 25 raters in each country, who rated the 81 items for both the current year and 3 years ago, using a 0-5 scale running from no adequacy to full adequacy. The raters were drawn from a variety of positions and backgrounds, and were identified by a consultant retained in each country for that purpose. On average, country programmes score at about half of the maximum score, but this varies considerably across the 14 components of effort, from very low scores for access to treatment by rural women, to high scores for neonatal care. Regional averages are not far apart for the overall score, although South Asia scores are especially low and East Asia's are especially high. To a considerable extent regions agree in the relative stress they give to each of the 14 components. Over the 3-year period, average scores rose by about 10%. When countries are divided into three groups by their maternal mortality levels, most of the 14 components distinguish the high from the medium mortality countries; and about half of the components distinguish the medium from the low mortality countries. This new Maternal and Neonatal Programme Effort Index (MNPI) appears to yield useful measures for various dimensions of programme effort, and it relates sensibly to the output measure of maternal mortality, at least as it is currently measured.

Developing Countries↗
PubMed2001

Evidence against a role for polymorphisms at tumor necrosis factor, interleukin-1 and interleukin-1 receptor antagonist gene loci in the regulation of disease severity in acute pancreatitis.

BACKGROUND: Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) and their endogenous antagonists such as IL-1 receptor antagonist (IL-1RA) are important mediators of disease severity in acute pancreatitis. Because the level of secretion of these cytokines is determined in part by genetic factors, the aim of this study was to examine the influence of genetically determined cytokine secretion upon disease severity in acute pancreatitis. METHODS: TNF (TNF-308, TNFB), IL-1beta, and IL-1 receptor antagonist (IL-1RA) genotypes were determined for 190 patients with acute pancreatitis and 102 healthy volunteers. To further assess the influence of genetic factors, the cytokine phenotype for TNF-alpha, IL-1beta, and IL-1RA was determined by using a whole blood culture technique in 51 patients after recovery. RESULTS: The distributions of TNF-308, TNFB, IL-1beta, and IL-1RA gene polymorphisms were similar in patients with mild or severe acute pancreatitis. Further, no difference in gene polymorphism frequencies was observed between patients with acute pancreatitis and healthy controls. With respect to phenotype, the secretion of TNF-alpha was similar in patients with previous mild and severe acute pancreatitis; however, the IL-1beta: IL-1RA ratio was significantly lower in patients with previous severe acute pancreatitis than in those with mild disease. CONCLUSIONS: Our observations suggest that genetic factors are not important in determining TNF-alpha secretion in patients with acute pancreatitis. However, a predetermined imbalance between IL-1beta and its antagonist IL-1RA would appear to exist in patients with severe acute pancreatitis, although the genetic basis for this altered relationship could not be determined.

Acute Disease↗
PubMed2001

Endothelial-derived selectins in the development of organ dysfunction in acute pancreatitis.

OBJECTIVE: The development of organ dysfunction is the principal determinant of outcome in acute pancreatitis and is mediated through a systemic inflammatory response characterized by leukocyte and endothelial cell activation. Up-regulation of the endothelial cell adhesion molecules, E-selectin and P-selectin, is important for endothelial/leukocyte interactions. Levels of serum-soluble E-selectin and P-selectin have been suggested as markers of endothelial activation. This study examines the kinetics of serum-soluble selectins in patients with acute pancreatitis complicated by organ dysfunction. DESIGN: Prospective observational study. SETTING: University teaching hospital with a specialist hepato-pancreatico-biliary service. PATIENTS: Eighteen patients with acute pancreatitis were studied, nine of whom had organ dysfunction. MEASUREMENTS AND MAIN RESULTS: Serial venous blood samples were collected on the first 3 days after admission for measurement of soluble E-selectin and P-selectin by enzyme-linked immunosorbent assay. In all patients, soluble P-selectin concentrations decreased significantly during the study period. Nonsurvivors had significantly higher levels of soluble P-selectin than survivors. In contrast, soluble E-selectin increased significantly during the study period in patients with organ dysfunction, whereas it remained constant in patients without evidence of organ dysfunction. CONCLUSIONS: These results suggest a role for endothelial-derived selectins in the development of organ dysfunction in patients with acute pancreatitis. The observed temporal differences in serum selectin concentrations is in keeping with in vitro observations of endothelial selectin expression.

APACHE↗
PubMed2001

Dual Y-chromosome painting and immunofluorescence staining of archival human liver transplant biopsies.

Combining fluorescence in situ hybridization (FISH) and indirect immunofluorescence staining of protein markers provides a highly specific method for identifying chromosomes in phenotypically defined cells and tissues. We developed a technique enabling dual chromosome painting and immunofluorescence staining of archival formalin-fixed, paraffin-embedded material, and used this to phenotype chimeric cells in female-to-male human liver transplants.

Chromosome Painting↗
PubMed2001

Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia.

Weight loss in advanced cancer patients is refractory to conventional nutritional support. This may be due to metabolic changes mediated by proinflammatory cytokines, hormones, and tumor-derived products. We previously showed that a nutritional supplement enriched with fish oil will reverse weight loss in patients with pancreatic cancer cachexia. The present study examines the effect of this supplement on a number of mediators thought to play a role in cancer cachexia. Twenty weight-losing patients with pancreatic cancer were asked to consume a nutritional supplement providing 600 kcal and 2 g of eicosapentaenoic acid per day. At baseline and after 3 wk, patients were weighed and samples were collected to measure serum concentrations of interleukin (IL)-6 and its soluble receptor tumor necrosis factor receptors I and II, cortisol, insulin, and leptin, peripheral blood mononuclear cell production of IL-1 beta, IL-6, and tumor necrosis factor, and urinary excretion of proteolysis inducing factor. After 3 wk of consumption of the fish oil-enriched nutritional supplement, there was a significant fall in production of IL-6 (from median 16.5 to 13.7 ng/ml, P = 0.015), a rise in serum insulin concentration (from 3.3 to 5.0 mU/l, P = 0.0064), a fall in the cortisol-to-insulin ratio (P = 0.0084), and a fall in the proportion of patients excreting proteolysis inducing factor (from 88% to 40%, P = 0.008). These changes occurred in association with weight gain (median 1 kg, P = 0.024). Various mediators of catabolism in cachexia are modulated by administration of a fish oil-enriched nutritional supplement in pancreatic cancer patients. This may account for the reversal of weight loss in patients consuming this supplement.

Adolescent↗
PubMed2001

Endogenous production of IL-8 by human colorectal cancer cells and its regulation by cytokines.

This study investigated the endogenous production of the pro-inflammatory and angiogenic cytokine IL-8 by human colorectal cancer cells. We describe substantial (>0.5 ng/ml) constitutive production of IL-8 by certain human colorectal cancer cell lines without the requirement for exogenous stimulation. Tumour cell-derived IL-8 production was upregulated by the addition of the pro-inflammatory type 1 cytokines TNF alpha, IL-1 beta and IFN gamma. Addition of the regulatory type 2 cytokines IL-4 and IL-10 produced paradoxical stimulation of IL-8 production in certain cell lines and downregulation of IL-8 production in others. These results suggest that tumour-derived cytokine production may have an important role in patients with colorectal cancer. Furthermore, they demonstrate the complexity of tumour cell cytokine production and highlight the difficulties in developing effective therapeutic biological response strategies.

Colorectal Neoplasms↗
PubMed2000

Triptolide and chemotherapy cooperate in tumor cell apoptosis. A role for the p53 pathway.

Triptolide (PG490), a diterpene triepoxide, is a potent immunosuppressive agent extracted from the Chinese herb Tripterygium wilfordii. We have previously shown that triptolide blocks NF-kappaB activation and sensitizes tumor necrosis factor (TNF-alpha)-resistant tumor cell lines to TNF-alpha-induced apoptosis. We show here that triptolide enhances chemotherapy-induced apoptosis. In triptolide-treated cells, the expression of p53 increased but the transcriptional function of p53 was inhibited, and we observed a down-regulation of p21(waf1/cip1), a p53-responsive gene. The increase in levels of the p53 protein was mediated by enhanced translation of the p53 protein. Additionally, triptolide induced accumulation of cells in S phase and blocked doxorubicin-mediated accumulation of cells in G(2)/M and doxorubicin-mediated induction of p21. Our data suggest that triptolide, by blocking p21-mediated growth arrest, enhances apoptosis in tumor cells.

Animals↗
PubMed2000

Persistent depletion of I kappa B alpha and interleukin-8 expression in human pulmonary epithelial cells exposed to quartz particles.

Chronic inflammation and fibrosis following quartz inhalation has been associated with persistent up-regulation of several "pro-inflammatory" genes, which are commonly regulated by nuclear factor kappa-B (NF-kappaB). Transcription of the NF-kappaB-inhibitor IkappaBalpha is also under NF-kappaB control, and its de novo synthesis is considered to comprise a negative feedback loop in transient inflammation. To investigate this mechanism in particle inflammation, we have studied IkappaBalpha degradation in A549 cells exposed to DQ12-quartz or TiO(2), in relation to the expression of IL-8. Although both quartz and TiO(2) were found to cause IkappaBalpha degradation, only quartz elicited a mild IkappaBalpha depletion, first appearing at 4 h. TiO(2) was found to cause a higher short-term increase in IkappaBalpha mRNA-expression compared to quartz, whereas the early enhancement of IL-8 expression and release was similar for both particles. Up-regulation of IL-8 expression was found to persist with quartz only. Cotreatment with PDTC and curcumin reduced particle-elicited IL-8 response, whereas cycloheximide caused enhancement of IL-8 mRNA expression in both the quartz- and TiO(2)-treated cells. Our results demonstrate that mineral dusts cause IkappaBalpha degradation, a transient increase in de novo synthesis of IkappaBalpha, and enhanced IL-8 expression in human pulmonary epithelial cells. While IkappaBalpha degradation and early IL-8 expression seem to be general particle phenomena, particle-specific characteristics impact on activation of IkappaBalpha gene transcription, apparently accounting for the different proinflammatory IL-8 responses seen with quartz and TiO(2) in the longer term. These observations may provide an explanation for the transient versus the persistent pulmonary inflammatory status and subsequent differences in pathogenic potency of TiO(2) and quartz.

Blotting, Western↗