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Biomedical subjects

J A Ross

Publications and source records attributed to J A Ross.

At least 19 recordsLinked to original sources
PubMed2006

Elevated tumour interleukin-1beta is associated with systemic inflammation: A marker of reduced survival in gastro-oesophageal cancer.

Systemic inflammation is associated with adverse prognosis cancer but its aetiology remains unclear. We investigated the expression of proinflammatory cytokines within normal mucosa from healthy controls and tumour tissue in cancer patients and related these levels with markers of systemic inflammation and with the presence of a tumour inflammatory infiltrate. Tissue was collected from 56 patients with gastro-oesophageal cancer and from 12 healthy controls. Tissue cytokine mRNA concentrations were measured by real-time PCR and tissue protein concentrations by cytometric bead array. The degree of chronic inflammatory cell infiltrate was recorded. Serum cytokine and acute phase protein concentrations (including C-reactive protein (CRP)) were measured by enzyme-linked immunosorbent assay. Proinflammatory cytokines were significantly overexpressed (interleukin (IL)-1beta, IL-6, IL-8 and tumour necrosis factor-alpha) both at mRNA and protein levels in the cancer specimens compared with mucosa from controls. Interleukin-1beta was expressed in greatest (10-100-fold) concentration and protein levels correlated significantly with systemic inflammation (CRP) (P = 0.05, r = 0.31). A chronic inflammatory infiltrate was observed in 75% of the cancer specimens and was associated with systemic inflammation (CRP: P = 0.01). However, the presence of chronic inflammation per se was not associated with altered cytokine expression within the tumour. Both a chronic inflammatory infiltrate and systemic inflammation (CRP) were associated with reduced survival (P = 0.05 and P = 0.03, respectively). Tumour chronic inflammatory infiltrate and tumour tissue IL-1beta overexpression are potential independent factors influencing systemic inflammation in oesophagogastric cancer patients.

Acute-Phase Proteins↗
PubMed2006

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues.

Proteolysis-inducing factor, a cachexia-inducing tumour product, is an N-glycosylated peptide with homology to the unglycosylated neuronal survival peptide Y-P30 and a predicted product of the dermcidin gene, a pro-survival oncogene in breast cancer. We aimed to investigate whether dermcidin is pro-survival in liver cells, in which proteolysis-inducing factor induces catabolism, and to determine the role of potentially glycosylated asparagine residues in this function. Reverse cloning of proteolysis-inducing factor demonstrated approximately 100% homology with the dermcidin cDNA. This cDNA was cloned into pcDNA3.1+ and both asparagine residues removed using site-directed mutagenesis. In vitro translation demonstrated signal peptide production, but no difference in molecular weight between the products of native and mutant vectors. Immunocytochemistry of HuH7 cells transiently transfected with V5-His-tagged dermcidin confirmed targeting to the secretory pathway. Stable transfection conferred protection against oxidative stress. This was abrogated by mutation of both asparagines in combination, but not by mutation of either asparagine alone. These findings suggest that dermcidin may function as an oncogene in hepatic as well as breast cells. Glycosylation does not appear to be required, but the importance of asparagine residues suggests a role for the proteolysis-inducing factor core peptide domain.

Asparagine↗
PubMed2006

Expression of the proteolysis-inducing factor core peptide mRNA is upregulated in both tumour and adjacent normal tissue in gastro-oesophageal malignancy.

Gastro-oesophageal cancer is associated with a high incidence of cachexia. Proteolysis-inducing factor (PIF) has been identified as a possible cachectic factor and studies suggest that PIF is produced exclusively by tumour cells. We investigated PIF core peptide (PIF-CP) mRNA expression in tumour and benign tissue from patients with gastro-oesophageal cancer and in gastro-oesophageal biopsies for healthy volunteers. Tumour tissue and adjacent benign tissue were collected from patients with gastric and oesophageal cancer (n=46) and from benign tissue only in healthy controls (n=11). Expression of PIF-CP mRNA was quantified by real-time PCR. Clinical and pathological information along with nutritional status was collected prospectively. In the cancer patients, PIF-CP mRNA was detected in 27 (59%) tumour samples and 31 (67%) adjacent benign tissue samples. Four (36%) gastro-oesophageal biopsies from healthy controls also expressed PIF-CP mRNA. Expression was higher in tumour tissue (P=0.031) and benign tissue (P=0.022) from cancer patients compared with healthy controls. In the cancer patients, tumour and adjacent benign tissue PIF-CP mRNA concentrations were correlated with each other (P<0.0001, r=0.73) but did not correlate with weight loss or prognosis. Although PIF-CP mRNA expression is upregulated in both tumour and adjacent normal tissue in gastro-oesophageal malignancy, expression does not relate to prognosis or cachexia. Post-translational modification of PIF may be a key step in determining the biological role of PIF in the patient with advanced cancer and cachexia.

Aged↗
PubMed2006

Manufacture and acoustical characterisation of a high-frequency contrast agent for targeting applications.

The aim of this study was to develop and acoustically to optimise an ultrasonic contrast agent for research imaging applications at 40 MHz. A range of liposomal dispersions were manufactured and the mean backscatter power was measured using a Boston Scientific ClearView Ultra intravascular scanner with a 40 MHz, 2.5 Fr Atlantis SR Plus catheter. The scanner had been modified to allow access to the unprocessed ultrasound data, which were digitised, and the mean backscatter power was calculated over a region-of-interest centred at 2 mm from the transducer. Mean backscatter power was normalised to the data collected from a water-air interface. The effects of sonication and rapid shaking on six liposomal samples were also studied and this indicated that both techniques significantly reduced the size of the liposomes within the dispersions. Maximum mean backscatter power was measured for sonicated liposomal dispersions with 60% by weight of phosphatidylethanolamine. Moreover, this dispersion had greater mean backscatter power than sheep blood at 40 MHz.

Contrast Media↗
PubMed2006

The molecular mechanisms of skeletal muscle wasting: implications for therapy.

Skeletal muscle wasting is an important systemic manifestation of a wide range of diseases, including trauma, sepsis and cancer. The clinical consequences of muscle wasting undoubtedly include significant patient morbidity and worsened survival. Recently, there has been important progress in our understanding of the molecular mechanisms behind muscle wasting. In this review, the common systemic mediators, intracellular signalling pathways and effector mechanisms of skeletal muscle wasting are discussed with particular reference to different models of wasting and the development of novel therapeutic strategies.

Animals↗
PubMed2005

Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver.

The largest single underlying cause of hepatocellular carcinoma (HCC) worldwide is hepatitis B virus (HBV) infection. Hepatitis B virus increases cellular oxidative stress and the development of HCC occurs after a long latency period. The study was carried out to determine whether mitochondrial DNA abnormalities were associated with HCC in individuals with HBV. The frequency of mutation and deletion of specific areas of the mitochondrial genome in tumour and matched normal tissue of patients with HBV infection was investigated in the current study. The percentage of control subjects harbouring D-loop mutations was 11%, which was significantly lower than that observed in both the noncancerous (49%, P=0.033) and tumour tissue (59%, P=0.014) of patients with HCC. In contrast, the number of cases in which the common 4977 bp deletion of the mitochondrial genome was detected was significantly greater in control liver and noncancerous liver tissue of subjects with HCC (100 and 95%, respectively) than in cancerous liver tissue (28%, P<0.001). These observations suggest that the inflammatory process contributes to the rate of mitochondrial mutations. However, the lower frequency of the large deletion in cancerous tissue suggests that there is selection against either mitochondria, which harbour large deletions, or against cells that contain these mitochondria during hepatocarcinogenesis.

Adult↗
PubMed2005

Eicosapentaenoic acid modulates the immune response but has no effect on a mimic of antigen-specific responses.

OBJECTIVE: It has been suggested that the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has immunosuppressive effects and that these may be detrimental in some circumstances. Many studies have used high-fat diets or have concentrated on one aspect of immune function, such as mitogen-induced proliferation. In the present study we assessed the effect of high-purity EPA provided as a novel diester with propane-1,3-diol, which was delivered orally within the normal dietary fat content. METHODS: Mitogen-induced proliferation and a mimic of antigen-specific splenocyte proliferation were examined. Proinflammatory cytokine production in response to lipopolysaccharide ex vivo was also measured. Balb/c mice were fed a fat-free diet to which was added oil to make up 5% of the final diet weight by using corn oil or 95% pure EPA as a diester with propane-1,3-diol (4%, plus 1% corn oil). RESULTS: There was no difference in food consumption or weight gain between mice fed the control and EPA-enriched diets for 10 or 24 d. There was a significant decrease in the splenocyte proliferation index in animals fed the EPA-enriched diet after 10 and 24 d when stimulated by concanavalin A (P<0.05), but no difference when cells were stimulated with anti-CD3 and interleukin-2. There was a significant increase in the production of tumor necrosis factor by splenocytes of mice fed the EPA-enriched diet when stimulated by lipopolysaccharide (P<0.0005). However, there was no difference in ex vivo lipopolysaccharide-stimulated production of interleukin-6 between the two diets at either time point (P>0.05). CONCLUSIONS: The present study found that, rather than producing a generalized immunosuppression, the administration of approximately 10 g of EPA/kg of body weight has more subtle effects in modulating the immune system. The observed effects of EPA may explain some of its reported beneficial effects in inflammatory conditions without producing detrimental effects on antigen-specific immunosurveillance.

Animals↗
PubMed2004

Childhood and maternal infections and risk of acute leukaemia in children with Down syndrome: a report from the Children's Oncology Group.

Children with Down syndrome (DS) are highly susceptible to acute leukaemia. Given the potential role of infections in the aetiology of leukaemia in children without DS, we investigated whether there was an association between early-life infections and acute leukaemia in children with DS. Maternal infections during pregnancy were also examined. We enrolled 158 incident cases of acute leukaemia in children with DS (97 acute lymphoblastic leukaemia (ALL) and 61 acute myeloid leukaemia (AML)) diagnosed at Children's Oncology Group institutions between 1997 and 2002. DS controls (N=173) were selected from the cases' primary care clinics and frequency matched on age at leukaemia diagnosis. Data were collected on demographics, child's medical history, mother's medical history, and other factors by maternal interview. Analyses were conducted using unconditional logistic regression adjusted for potential confounders. A significant negative association was observed between acute leukaemia and any infection in the first 2 years of life (adjusted odds ratio (OR)=0.55, 95% confidence interval (CI) (0.33-0.92); OR=0.53, 95% CI (0.29-0.97); and OR=0.59, 95% CI (0.28-1.25) for acute leukaemia combined, ALL, and AML respectively). The association between acute leukaemia and maternal infections during pregnancy was in the same direction but not significant. This study offers support for the hypothesis that early-life infections may play a protective role in the aetiology of acute leukaemia in children with DS.

Acute Disease↗
PubMed2004

Latent effects of fibronectin, alpha5beta1 integrin, alphaVbeta5 integrin and the cytoskeleton regulate pancreatic carcinoma cell IL-8 secretion.

Interactions between tumour cells and the microenvironment are increasingly recognised to have an influence on cancer progression. In pancreatic carcinoma, a highly desmoplastic stroma with abnormal extracellular matrix (ECM) protein and interleukin-8 (IL-8) expression is seen. To investigate whether the ECM may further contribute to abnormalities in the microenvironment by influencing IL-8 secretion, we cultured the Mia PaCa2 pancreatic carcinoma cell line on fibronectin. This resulted in a dose-dependent increase in IL-8 secretion, which was RGD dependent and accompanied by cell spreading and proliferation. The role of spreading was assessed by disruption of the cytoskeleton with cytochalasin D, resulting in a large increase in IL-8 secretion, which was reduced from 31- to 24-fold by fibronectin. This remarkable response was associated with inhibition of spreading and proliferation and represents a novel cytoskeletal function. To investigate whether it could be accounted for by the loss of integrin-mediated signalling, the expressed alpha5beta1, alphaVbeta5 and alpha3beta1 integrins were inhibited. alpha5beta1 inhibition prevented spreading and proliferation but produced a much smaller rise in IL-8 secretion than cytochalasin D. alphaVbeta5 inhibition alone had only minor effects but when inhibited in combination with alpha5beta1 completely abolished the response to fibronectin. These results reveal latent stimulatory effects of the alphaVbeta5 integrin on IL-8 secretion and suggest that integrin crosstalk may limit the induction of IL-8 secretion by fibronectin. However, the magnitude of IL-8 secretion induced by cytochalasin cannot be accounted for by integrin signalling and may reflect the influence of another signalling pathway or a novel, intrinsic cytoskeletal function.

Carcinoma↗
PubMed2004

The response of leptin, interleukin-6 and fat oxidation to feeding in weight-losing patients with pancreatic cancer.

At baseline, weight-losing pancreatic cancer patients (n=7) had lower leptin (P<0.05) but higher cortisol, interleukin-6, resting energy expenditure and fat oxidation than healthy subjects (n=6, P<0.05). Over a 4 h feeding period, the areas under the curve for glucose, cortisol and interleukin-6 were greater (P<0.05), but less for leptin in the cancer group (P<0.05). Therefore, it would appear that low leptin concentrations, increased fat oxidation and insulin resistance are associated with increased concentrations of cortisol and interleukin-6 in weight-losing patients with pancreatic cancer.

Blood Glucose↗
PubMed2004

Interferon-gamma polymorphisms correlate with duration of survival in pancreatic cancer.

Despite progress in diagnosis and staging, pancreatic cancer still has a poor prognosis and it remains difficult to predict duration of survival in advanced pancreatic cancer. Nutritional decline, or cachexia, is a contributory factor to decreased survival in advanced pancreatic carcinoma, and it has been demonstrated that proinflammatory cytokines give rise to cachexia. Interferon (IFN)-gamma is a proinflammatory cytokine whose administration increases survival outcomes in a variety of cancers. The human IFN-gamma gene has a variable length CA-repeat sequence, the length that has been shown to influence IFN-gamma production. The current study was performed to ascertain whether polymorphisms of the IFN-gamma gene would influence survival of individuals with advanced pancreatic cancer. The study demonstrated that the presence of allele 2 (12 CA repeats) was consistently associated with increased duration of survival after confirmation of nonresectable pancreatic carcinoma. We therefore propose that the presence of allele 2 may be a useful marker for patient outcome.

Adult↗
PubMed2002

Effect of interleukin-2 on peripheral blood mononuclear cell cytokine production and the hepatic acute phase protein response.

This study investigated the ability of recombinant interleukin-2 (IL-2) to modulate the ability of peripheral blood mononuclear cells (PBMCs) to stimulate an acute phase protein response in isolated human hepatocytes. The effect of IL-2 on the production of tumour necrosis factor-alpha (TNF) and interleukin-6 (IL-6) by PBMCs isolated from patients with gastrointestinal cancer, multiple organ failure, and healthy controls was also studied. The ability of supernatants from IL-2-treated PBMCs to elicit an acute phase response in hepatocytes was then investigated. IL-2 had no effect on IL-6 or TNF production by PBMCs isolated from any group in the presence or absence of bacterial lipopolysaccharide (LPS). Despite this, preincubation of PBMCs with IL-2 significantly reduced the potential of LPS-stimulated PBMC supernatants to stimulate production of alpha1 antichymotrypsin, alpha1-acid glycoprotein, and C-reactive protein by hepatocytes. These observations were not due to a direct effect of IL-2 on hepatocyte acute phase protein production. These findings suggest that in this model IL-2 may modulate PBMC-induced acute phase protein production through an IL-6 and TNF-independent pathway.

Acute-Phase Proteins↗
PubMed2002

Simulated use of premixed 0.25% isoflurane in 50% nitrous oxide and 50% oxygen.

BACKGROUND: Isoflurane (0.25%) in premixed nitrous oxide and oxygen, 50/50, v/v (IN(2)O), has been suggested for pain relief in labour. Possible phase separation of the mixture was studied during simulated administration. METHODS: A sinusoidal pump set at stroke volume of 2 litres and a rate of 20-22 bpm and cycling for 1 min in three was used to simulate breathing during the painful contractions of labour. RESULTS: The temperature inside a 10-litre capacity cylinder did not drecrease sufficiently to cause separation of the gas mixture. Temperature in the demand valve decreased to -15.5 degrees C and this caused a small amount of liquid formation within the valve. Accordingly, the inspired concentration during the first breath of mixture in a cycle could be transiently as high as 0.55%. The concentration observed at the patient connection after the first breath varied between 0.17 and 0.28%. CONCLUSIONS: The system delivered a clinically acceptable performance although further development to avoid liquid condensation is needed.

Anesthesiology↗
PubMed2002

Phase behaviour of premixed 0.25% isoflurane in 50% nitrous oxide and 50% oxygen.

BACKGROUND: Isoflurane (0.25%) in premixed nitrous oxide and oxygen 50/50, v/v, (IN(2)O), has been suggested for pain relief in labour. METHODS: Possible phase separation of this mixture was studied by analysis of samples from pre-filled cylinders as they were cooled. RESULTS: Condensation of isoflurane was found at 3.1 degrees C in a cylinder, which held 8.7 MPa at 15 degrees C. In a cylinder holding 13.8 MPa, which is the standard filling pressure stipulated by the National Health Service, the condensation temperature was -2.3 degrees C. At the highest cylinder filling pressure investigated (14.15 MPa) the separation temperature was even less, -3.0 degrees C. After exposure of cylinders to -40 degrees C and complete phase separation of the mixture, complete mixing was achieved by 24 h storage in the horizontal position at room temperature and, either three complete inversions of the cylinder or mechanical rolling at 30 r.p.m. CONCLUSIONS: These findings should assist the use and storage of IN(2)O.

Anesthesiology↗
PubMed2002

Proteolysis-inducing factor differentially influences transcriptional regulation in endothelial subtypes.

Proteolysis-inducing factor (PIF) is a novel sulfated glycoprotein initially identified as a protein capable of triggering muscle proteolysis during the process of cancer cachexia. Only skeletal muscle and liver exhibit substantial binding of PIF in adult tissue. Here, we demonstrate that PIF induces transcriptional regulation in both the liver endothelial cell line SK-HEP-1 and in human umbilical vein endothelial cells (HUVECs) but not in pulmonary artery endothelial cells. PIF differentially induces activation of nuclear factor-kappaB, resulting in the induction of proinflammatory cytokines [interleukin (IL)-8 and IL-6] and increased expression of the cell surface proteins intercellular adhesion molecule-1 and vascular cell adhesion molecule in SK-HEP-1 and HUVECs only. In addition, PIF induces the shedding of syndecans from the cell surface. Syndecans are involved in wound repair, metastasis of cancers, and embryonic development. These results suggest that PIF may play additional roles in the proinflammatory response observed in cancer cachexia but may also have a role without the cachectic process.

Blood Proteins↗
PubMed2002

Cytokine regulation of constitutive production of interleukin-8 and -6 by human pancreatic cancer cell lines and serum cytokine concentrations in patients with pancreatic cancer.

Patients with pancreatic cancer frequently demonstrate symptoms such as weight-loss and muscle wasting and have clinical evidence of a systemic inflammatory response. Such effects may be mediated by pro-inflammatory cytokines derived from tumor cells. The production of interleukin-6 and -8 by pancreatic cancer cell lines and the influence of other cytokines on this production was studied. IL-8 was produced by all cell lines and production was increased following exposure to IL-1 and TNF. Cytokine-stimulated, but not basal IL-8 production was reduced by co-incubation with IL-4 in the MIA PaCa-2 and PANC-1 cell lines. The CFPAC cell line produced IL-6, but this production was not altered by IL-1, TNF or IL-4. In the PANC-1 cell line IL-8 and IL-8 receptors were only detected by PCR in cells which had been stimulated with TNF or IL-1. Serum concentrations of IL-6 and IL-8 were elevated in patients with pancreatic cancer compared with controls. In conclusion, human pancreatic cancer cell lines elaborate pro-inflammatory cytokines which have the potential to mediate elements of the systemic inflammatory response.

Aged↗