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Biomedical subjects

J A Ross

Publications and source records attributed to J A Ross.

At least 73 records · Page 4Linked to original sources
PubMed1999

Polycyclic aromatic hydrocarbons: correlations between DNA adducts and ras oncogene mutations.

This review describes a series of studies on the tumorigenic activities of polycyclic aromatic hydrocarbons (PAHs) in various experimental animal model systems, their abilities to form PAH-DNA adducts in target tissues, and their abilities to mutate ras oncogenes in PAH-induced tumors. The review is limited to those PAHs that do not contain nitrogen, for which ras mutations have been detected in induced tumors, and for which some information is available about the structures of the DNA adducts induced in the target tissue. In general, PAHs that form DNA adducts at deoxyadenosine induce mutations at codon 61, whereas those PAHs that form DNA adducts at deoxyguanosine primarily induce mutations at codons 12 or 13. Those PAHs that induce adducts at both bases induce both types of mutations. These correlations provide evidence for the involvement of adduct-directed mutations in ras in the etiology of these tumors. The induced mutation spectra in ras may in fact point back to the identity of the type of adduct formed.

Animals↗
PubMed1999

Epidemiologic studies of childhood leukemia: where do we go from here?

Much of our knowledge of the mechanisms of carcinogenesis has resulted from the study of rare cancers, including retinoblastoma, angiosarcoma, and vaginal clear cell carcinoma. Due to the heterogeneity of childhood leukemia, epidemiologic studies that focus on children with unique clinical and genetic manifestations of the disease could potentially lead to further understanding of leukemogenesis.

Acute Disease↗
PubMed1999

Pancreatic cancer as a model: inflammatory mediators, acute-phase response, and cancer cachexia.

Patients with pancreatic cancer frequently develop the syndrome of cancer cachexia. Pro-inflammatory cytokines have been strongly implicated in the pathogenesis of this syndrome. In patients with pancreatic cancer an acute-phase response (an index of pro-inflammatory cytokine activity) is associated with accelerated weight loss, hypermetabolism, anorexia, and a shortened duration of survival. However, little is known about the primary significance of the acute-phase response in terms of altered hepatic export protein synthesis rates and its potential impact on the body's nitrogen economy. In a recent series of studies on weight-losing pancreatic cancer patients with hypoalbuminemia we have demonstrated albumin synthesis to be unaltered whereas fibrinogen synthesis is increased two- to threefold compared with healthy controls. Because of the mismatch in amino acid composition between the body's main labile amino acid reserve (skeletal muscle) and that of acute-phase proteins, these results lend support to the concept that in pancreatic cancer the reprioritization of body protein metabolism during an acute-phase response may well be a significant factor in the loss of lean tissue in these patients.

Acute-Phase Proteins↗
PubMed1999

Cancer cachexia.

Cachexia is a common cause of morbidity and mortality in patients with advanced cancer. It is characterised by numerous metabolic abnormalities including inefficient substrate utilisation, alterations in the balance of energy intake and expenditure and the acute-phase protein response. These changes seem to be driven by pro-inflammatory cytokines, alterations of the neuro-endocrine axis and tumour-derived catabolic factors. This results in the loss of both fat and lean tissue. Trials of conventional nutritional supplements in patients with cancer cachexia have failed to show any benefit in terms of weight gain or quality of life and this may be because the ongoing metabolic abnormalities prevent the efficient use of additional calories supplied. A variety of pharmacological agents have been studied in an attempt to normalise these metabolic changes with only limited success. However, it is possible that the combination of an agent to normalise the metabolic milieu along with the provision of additional nutritional support may have the potential to reverse cachexia in advanced cancer.

Anti-Inflammatory Agents↗
PubMed1999

The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer.

Previous studies have suggested that administration of oral eicosapentaenoic acid (EPA) will stabilize weight in patients with advanced pancreatic cancer. The aim of the present study was to determine if a combination of EPA with a conventional oral nutritional supplement could produce weight gain in these patients. Twenty patients with unresectable pancreatic adenocarcinoma were asked to consume two cans of a fish oil-enriched nutritional supplement per day in addition to their normal food intake. Each can contained 310 kcal, 16.1 g protein and 1.09 g EPA. Patients were assessed for weight, body composition, dietary intake, resting energy expenditure (REE) and performance status. Patients consumed a median of 1.9 cans day(-1). All patients were losing weight at baseline at a median rate of 2.9 kg month(-1). After administration of the fish oil-enriched supplement, patients had significant weight-gain at both 3 (median 1 kg, P= 0.024) and 7 weeks (median 2 kg, P = 0.033). Dietary intake increased significantly by almost 400 kcal day(-1) (P = 0.002). REE per kg body weight and per kg lean body mass fell significantly. Performance status and appetite were significantly improved at 3 weeks. In contrast to previous studies of oral conventional nutritional supplements in weight-losing cancer patients, this study suggests that an EPA-enriched supplement may reverse cachexia in advanced pancreatic cancer.

Adenocarcinoma↗
PubMed1999

Seasonal variations in the diagnosis of childhood cancer in the United States.

Seasonal trends in month of diagnosis have been reported for childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL). This seasonal variation has been suggested to represent an underlying viral aetiology for these malignancies. Some studies have shown the highest frequency of diagnoses in the summer months, although this has been inconsistent. Data from the Children's Cancer Group and the Pediatric Oncology Group were analysed for seasonal incidence patterns. A total of 20,949 incident cancer cases diagnosed in the USA from 1 January 1989 through 31 December 1991 were available for analyses. Diagnosis-specific malignancies available for evaluation included ALL, acute myeloid leukaemia (AML), Hodgkin's disease, NHL, rhabdomyosarcoma, neuroblastoma, retinoblastoma, osteosarcoma, Wilms' tumour, retinoblastoma, Ewings' sarcoma, central nervous system (CNS) tumours and hepatoblastoma. Overall, there was no statistically significant seasonal variation in the month of diagnosis for all childhood cancers combined. For diagnosis-specific malignancies, there was a statistically significant seasonal variation for ALL (P = 0.01; peak in summer), rhabdomyosarcoma (P = 0.03; spring/summer) and hepatoblastoma (P = 0.01; summer); there was no seasonal variation in the diagnosis of NHL. When cases were restricted to latitudes greater than 40 degrees ('north'), seasonal patterns were apparent only for ALL and hepatoblastoma. Notably, 33% of hepatoblastoma cases were diagnosed in the summer months. In contrast, for latitudes less than 40 degrees ('south'), only CNS tumours demonstrated a seasonal pattern (P = 0.002; winter). Although these data provide modest support for a summer peak in the diagnosis of childhood ALL, any underlying biological mechanisms that account for these seasonal patterns are likely complex and in need of more definitive studies.

Adolescent↗
PubMed1999

The use of 0.25% isoflurane premixed in 50% nitrous oxide and oxygen for pain relief in labour.

The addition of 0.25% isoflurane to 50% nitrous oxide in oxygen provides more effective pain relief in labour than 50% nitrous oxide alone. This study was carried out to determine whether self-administration by demand valve of 0.25% isoflurane in 50% nitrous oxide in oxygen premixed in cylinders at 13.7 MPa (IN2O) was practical and safe during labour. Two hundred and twenty-one mothers used IN2O in labour after 50% nitrous oxide had become inadequate for pain relief. Data on IN2O use was recorded during labour and details of the course of labour and opioid usage were taken from the clinical notes. The duration of IN2O use was 0.1-12.35 h (median 2.3). Thirty-two mothers (14.5%) required an epidural and intolerance to IN2O was seen in a maximum of 17 cases (7.7%). One hundred and twenty-six cases were primiparous and 93 parous with 151 deliveries being spontaneous and 70 interventional, of which 12 were by Caesarean section. Maternal blood loss was 20-1500 ml (median 200 ml). Apgar scores at 1 and 5 min were unaffected by IN2O use although a positive correlation was found between the use of opioids and the number of neonates with a 1-min score below 8 and the number requiring resuscitation. Six neonates had an Apgar score below 8 at 5 min, but their condition was adequately explained by factors other than the sedative technique used. Self-administered IN2O was found to be a safe and practical technique for sedation in labour when 50% nitrous oxide alone had become inadequate.

Adolescent↗
PubMed1999

Two polymorphisms of the tumour necrosis factor gene do not influence survival in pancreatic cancer.

Polymorphisms of the tumour necrosis factor (TNF) gene have been related to TNF production and outcome in a variety of inflammatory and malignant diseases. Proinflammatory cytokines and the inflammatory state appear to affect outcome in pancreatic cancer. Thus, the present study examined the TNFB and TNF-308 polymorphisms for their relationship to the inflammatory state and survival in pancreatic cancer. Sixty-four patients with advanced pancreatic cancer and 101 healthy subjects were genotyped for each polymorphism. Serum concentrations of the two TNF receptors and C-reactive protein (CRP) were measured in 45 of the cancer patients with no evidence of infection or jaundice, 1 month after surgical intervention. There was no difference in distribution of genotypes between the patient and control groups. There was no association between any genotype and concentrations of any of the measured inflammatory mediators. While those with an elevated CRP concentration had significantly poorer survival, there was no association between either TNF genotype and survival. This study found no association between TNF genotype and the inflammatory state or survival in advanced pancreatic cancer. Other cytokines may be more important than TNF in determining the inflammatory state and disease progress in pancreatic cancer.

Adult↗
PubMed1999

The effectiveness of non-surgical management of early interstitial pregnancy: a report of ten cases and review of the literature.

OBJECTIVE: To assess the effectiveness of non-surgical management of interstitial pregnancy. DESIGN: A prospective interventional study. SUBJECTS: Eleven women with the ultrasound diagnosis of interstitial ectopic pregnancy. METHODS: Women with suspected early pregnancy complications were examined by transvaginal ultrasound. Those with the diagnosis of interstitial pregnancy were offered non-surgical treatment with methotrexate, which was administered systemically or by local injection. Follow-up with regular measurements of beta-human chorionic gonadotropin and ultrasound scans continued until the pregnancy had resolved completely. RESULTS: Ten women were managed non-surgically, and one woman opted for surgery. Five women received systemic and five local methotrexate. Local therapy was successful in all five cases (100%), whereas four out of five (80%) women receiving systemic methotrexate were cured. Significant side-effects were noted in two women following systemic therapy. In comparison, there were no side-effects in the group of women who received local therapy. There were no significant differences between the two treatment groups in the length of time taken for the pregnancy to resolve. CONCLUSIONS: Non-surgical treatment of interstitial pregnancy with methotrexate appears to be safe and effective. Local administration appears to be more successful and better tolerated by patients and may be used as the first-line therapy.

Abortifacient Agents, Nonsteroidal↗
PubMed1999

Fish oil-enriched nutritional supplement attenuates progression of the acute-phase response in weight-losing patients with advanced pancreatic cancer.

The presence of an acute-phase protein response (APPR) has been suggested to shorten survival and contribute to weight loss in patients with pancreatic cancer. Fatty acids derived from fish oil have been shown to alter proinflammatory cytokine production and acute-phase protein synthesis in vitro. The present study was designed to determine the effects of a fish oil-enriched nutritional supplement on the concentrations of a range of individual acute-phase proteins (APP) in patients with advanced pancreatic cancer. In a sequential series, 18 patients with pancreatic cancer received the supplement (providing 2 g eicosapentaenoic acid and 1 g docosahexaenoic acid/d) for 3 wk while another 18 received full supportive care alone. Six healthy subjects served as additional controls. Acute-phase proteins were measured before and after the 3-wk intervention period in cancer patients. At baseline, albumin, transferrin and pre-albumin were significantly reduced and fibrinogen, haptoglobin, alpha-1-acid glycoprotein, alpha-1-antitrypsin, ceruloplasmin and C-reactive protein (CRP) were significantly elevated in the cancer patients compared with healthy controls, reflecting their roles as negative and positive acute phase proteins, respectively. In the supplemented cancer group, the only significant change in APP concentrations over the 4-wk study period was an increase in transferrin. In the control cancer group there were further significant reductions in albumin, transferrin and pre-albumin, and a significant increase in CRP concentration. These results suggest that many positive and negative APP are altered in advanced pancreatic cancer. The APPR tends to progress in untreated patients but may be stabilized by the administration of a fish oil-enriched nutritional supplement. This may have implications for reducing wasting in such patients.

Acute-Phase Proteins↗
PubMed1999

The causes of acute leukemia.

Although impressive biologic advances have increased understanding of leukemogenesis, we know little about the causes of the acute leukemias. Epidemiologic studies have focused primarily on children. Higher birth weight is associated with an increased risk of childhood acute leukemia. Several theories have been advanced that may account for these observations, and additional biologic studies are needed. Some epidemiologic studies suggest that the acute leukemias in children may have an infectious component. Again, further work, especially in the area of specific causative agents, is necessary. Another area for future epidemiologic study includes investigation of exposure to natural and synthetic DNA topoisomerase II inhibitors. Preliminary evidence suggests that exposure to these agents, which are found in certain foods and medications, may be related to the subsequent development of acute leukemia in infants.

Acute Disease↗
PubMed1999

The anti-catabolic effects of n-3 fatty acids.

The reversal of catabolic processes remains a significant challenge, partly related to the complexity of such processes and our incomplete understanding of the mechanisms involved. The n-3 fatty acids may be able to attenuate catabolism. This review examines the potential sites of action for these fatty acids and the evidence that supports their anti-catabolic properties.

Animals↗
PubMed1999

Effect of cold exposure, exercise and high altitude on plasma endothelin-1 and endothelial cell markers in man.

The aims were to examine the effect of cold exposure, exercise and high altitude on plasma concentrations of big endothelin-1, endothelin-1, von Willebrand factor and serum e-selectin in twenty five healthy male volunteers. Clinical evaluation and venesection were performed before and after 24 hours of low altitude mountaineering, exposure to temperatures of -18 degrees C and +4 degrees C and whilst ascending from sea level to an altitude of 5000 m in the Karakoram. Plasma big endothelin-1, plasma endothelin-1 and serum soluble e-selectin concentrations were significantly elevated after two hours at -18 degrees C (p < 0.05, p < 0.05 and p < 0.01 respectively). At +4 degrees C, plasma big endothelin-1 and endothelin-1 concentrations rose significantly after 5 hours (p < 0.005 for both) but not after 2.5 hours. Low altitude mountaineering did not alter circulating marker concentrations. At high altitude, big endothelin-1 and endothelin-1 (p < 0.01 for both) rose significantly at 2500 m and initially at 5000 m but returned to sea level values after prolonged exposure to 5000 m. Serum e-selectin rose at all altitudes greater than sea level (p < 0.05). In conclusion, exposure to high altitude, moderate cold or freezing temperatures, but not exercise, selectively activates endothelial cells increasing endothelin-1 production. Cold exposure may contribute to the observed increase in plasma endothelin-1 in mountaineers at high altitude.

Adult↗
PubMed1999

Changes in nutritional, functional, and inflammatory markers in advanced pancreatic cancer.

Weight loss and the acute-phase response have been associated with poor quality of life and survival in advanced pancreatic cancer; however, little information is available on changes in these factors over time and their interrelationships. This study examined changes in weight, Karnofsky performance status, C-reactive protein (CRP), and serum albumin in 25 patients with advanced pancreatic cancer given supportive symptomatic treatment only. Patients were assessed at approximately monthly intervals on a total of 70 occasions, allowing assessment of changes over 37 intervals. Overall, patients had a median weight loss of 2.3 kg/28 days. Median CRP levels rose by 15 mg/l, and serum albumin fell by 1 g/l on average over 28 days. Karnofsky performance status fell by 4 points every 28 days. The nine patients assessed close to death were compared with the 13 assessed close to diagnosis. The increase in CRP level and fall in weight and performance status were significantly greater within eight weeks of death than within eight weeks of diagnosis. Among patients close to diagnosis, 13% had an elevated CRP compared with 100% of those close to death. In multivariate analysis, Karnofsky performance status was significantly associated with percent weight loss and CRP levels. These data further implicate the acute-phase protein response as being associated with the progressive weight loss seen in patients with advanced pancreatic cancer. Changes appear to accelerate close to death. Moreover, the development of cachexia is associated with a reduction in patients' functional capacity.

Adult↗
PubMed1999

Peripheral blood cells from weight-losing cancer patients control the hepatic acute phase response by a primarily interleukin-6 dependent mechanism.

Cancer cachexia is associated with an elevated hepatic acute phase protein response, poor outcome and elevated cytokine production from peripheral blood mononuclear cells (PBMC). This study investigates the mechanism by which PBMC can induce a hepatic acute phase response. Supernatants from the peripheral blood cells of cancer patients induced significantly higher C-reactive protein (CRP) from hepatocytes (198+/-21 ng ml-1) than did supernatants from healthy controls (64+/-20, p<0.005). CRP production in vitro correlated with IL-6 production by PBMC from patients with pancreatic cancer (r=0.76, p<0.0001). This C-reactive protein production was reduced by 84% using neutralising antibody to IL-6 (p<0.001). There was a significant negative correlation between PBMC-induced hepatocyte C-reactive protein production and survival (r=-0.45, p<0.01). PBMC from cancer patients induce the hepatic acute phase response via a primarily IL-6-dependent mechanism.

Acute-Phase Reaction↗
PubMed1999

A quantitative comparison of dibenzo[a,l]pyrene-DNA adduct formation by recombinant human cytochrome P450 microsomes.

Dibenzo[a,l]pyrene (DB[a,l]P), an extremely potent environmental carcinogen, is metabolically activated in mammalian cells and microsomes through the fjord-region dihydrodiol, trans-DB[a,l]P-11, 12-diol, to syn- and anti-DB[a,l]P-11,12-diol-13,14-epoxides (syn- and anti-DB[a,l]PDEs). The role of seven individual recombinant human cytochrome P450s (1A1, 1A2, 1B1, 2B6, 2C9, 2E1, and 3A4) in the metabolic activation of DB[a,l]P and formation of DNA adducts was examined by using (32)P postlabeling, thin-layer chromatography, and high-pressure liquid chromatography. We found that, in the presence of epoxide hydrolase, only P450 1A1 and P450 1B1 catalyzed the formation of DB[a,l]PDE-DNA adducts and several unidentified polar adducts. Human P450 1A1 catalyzed the formation of DB[a, l]PDE-DNA adducts and unidentified polar adducts at rates threefold and 17-fold greater than did human P450 1B1 (256 fmol/h/nmol P450 versus 90 fmol/h/nmol P450 and 132 fmol/h/nmol P450 versus 8 fmol/h/nmol P450, respectively). P450 1A1 DNA adducts were derived from both anti- and syn-DB[a,l]PDE at rates of 73 fmol/h/nmol P450 and 51 fmol/h/nmol P450, respectively. P450 1B1 produced adducts derived from anti-DB[a,l]PDE at a rate of 82 fmol/h/nmol, whereas only a small number of adducts were derived from syn-DB[a,l]PDE (0.4 fmol/h/nmol). These results demonstrated the potential of human P450 1A1 and P450 1B1 to contribute to the metabolic activation and carcinogenicity of DB[a,l]P and provided additional evidence that human P450 1A1 and 1B1 differ in their stereospecific activation of DB[a,l]P. Mol. Carcinog. 26:74-82, 1999. Published 1999 Wiley-Liss, Inc.

Animals↗