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Biomedical subjects

C Sweeney

Publications and source records attributed to C Sweeney.

At least 19 recordsLinked to original sources
PubMed2006

Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States.

BACKGROUND: An insulin-related pathway to breast cancer has been hypothesized. METHODS: We examine the 19 CA repeat of the IGF1 gene, the -202 C > A IGFBP3, the G972R IRS, and the G1057D IRS2 polymorphisms among 1,175 non-Hispanic white (NHW) and 576 Hispanic newly diagnosed breast cancer cases and 1,330 NHW and 727 Hispanic controls living in Arizona, Colorado, New Mexico, and Utah. RESULTS: Among post-menopausal women not recently exposed to hormones, not having the 19 CA repeat of IGF1 gene was associated with breast cancer among NHW women [odds ratio (OR) 2.14, 95% confidence interval (CI) 1.21-3.79] and having an R allele of G972R IRS1 increased breast cancer risk among Hispanic women (OR 2.70, 95% CI 1.13-6.46). Among post-menopausal Hispanic women recently exposed to hormones the A allele of the -202 C > A IGFBP3 polymorphism increased risk of breast cancer (OR 1.57, 95% CI 1.06-2.33). The IGF1 19 CA repeat polymorphism interacted with hormone replacement therapy (HRT) among NHW post-menopausal women; women who had the 19/19 IGF1 genotype were at reduced risk of breast cancer (OR 0.64, 95% CI 0.47-0.88) if they did not use HRT. We also observed interaction between body mass index and IGF1 19 CA repeat (p=0.06) and between weight gain and the -202 C > A IGFBP3 polymorphism (p=0.05) in NHW post-menopausal women not recently exposed to hormones. CONCLUSIONS: Our data suggest that associations between insulin-related genes and breast cancer risk among women living in the Southwestern United States may be dependent on estrogen exposure and may differ by ethnicity.

Adolescent↗
PubMed2004

CYP1A1, cigarette smoking, and colon and rectal cancer.

Cytochrome P-450 (CYP) is involved in the activation and metabolism of polycyclic aromatic hydrocarbons in tobacco products. The authors evaluated the association of two polymorphisms in the CYP1A1 gene--the noncoding Msp I polymorphism in the 3'-untranslated region and the Ile462Val polymorphism in exon 7--with colon and rectal cancer. The authors used data from two incident case-control studies of colon cancer (1,026 cases and 1,185 controls) and rectal cancer (820 cases and 1,036 controls) conducted in California and Utah (1991-2002). CYP1A1 genotype was not associated with colon or rectal cancer. Having GSTM1 present, a CYP1A1 variant allele, and the rapid-acetylator NAT2 imputed phenotype was associated with increased risk of colon cancer (odds ratio = 1.7, 95% confidence interval: 1.2, 2.3). Among men, the greatest colon cancer risk was observed for having any CYP1A1 variant allele and currently smoking (odds ratio = 2.5, 95% confidence interval: 1.3, 4.8; Wald chi(2)test: p < 0.01). Assessment of GSTM1 and CYP1A1 and rectal cancer in men showed a twofold elevation in risk for more than 20 pack-years of smoking, except among those with GSTM1 present who had a variant CYP1A1 allele. These data support the association between smoking and colon and rectal cancer. Smoking may have a greater impact on colorectal cancer risk based on CYP1A1 genotype; this might further be modified by GSTM1 for rectal cancer risk.

3' Untranslated Regions↗
PubMed2004

Negative regulation of ErbB family receptor tyrosine kinases.

Receptors of the EGF receptor or ErbB family of growth factor receptor tyrosine kinases are frequently overexpressed in a variety of solid tumours, and the aberrant activation of their tyrosine kinase activities is thought to contribute to tumour growth and progression. Much effort has been put into developing inhibitors of ErbB receptors, and both antibody and small-molecule approaches have exhibited clinical success. Recently, a number of endogenous negative regulatory proteins have been identified that suppress the signalling activity of ErbB receptors in cells. These include intracellular RING finger E3 ubiquitin ligases such as cbl and Nrdp1 that mediate ErbB receptor degradation, and may include a wide variety of secreted and transmembrane proteins that suppress receptor activation by growth factor ligands. It will be of interest to determine the extent to which tumour cells suppress these pathways to promote their progression, and whether restoration of endogenous receptor-negative regulatory pathways may be exploited for therapeutic benefit.

Disease Progression↗
PubMed2004

Hepatitis A virus and injecting drug misuse in Aberdeen, Scotland: a case-control study.

To describe an epidemiological investigation of an outbreak of hepatitis A virus (HAV) infection among injecting drug users in Aberdeen, Scotland. A case-control study to determine whether transmission was facilitated by poor personal hygiene or through sharing injecting equipment. Cases were more likely to report not washing their hands after using the toilet [odds ratio (OR) = 12.9, 95% confidence interval (CI) = 1.58-105.89] or before preparing food (OR = 4.0, 95% CI = 1.01-15.8), and less likely to have washed their hands prior to preparing drugs (OR = 10.67, 95% CI = 2.14-53.07). Cases were also more likely to report recipient sharing of needles/syringes (OR = 8.27, 95% CI = 1.68-40.57), and to have had injecting contact with someone who was jaundiced (OR = 29.4, 95% CI = 3.18-271.44). The results indicate that the lack of hygiene within the context of individuals gathering to prepare and inject drugs provides ample opportunity for the transmission of HAV. Although the promotion of good hygiene and the avoidance of sharing injecting equipment are important measures in preventing HAV transmission, they are unlikely to effect major behavioural change. Such measures should, therefore, be reinforced by routinely offering HAV vaccine to injectors.

Adolescent↗
PubMed2004

The phosphatidylinositol-3 kinase pathway regulates bladder cancer cell invasion.

OBJECTIVES: To investigate the role of the phosphatidylinositol (PI)-3 kinase pathway in the invasion of bladder cancer cell lines, and to assess the activation of this pathway in primary human bladder tumours. MATERIALS AND METHODS: Human bladder cancer cells were treated with pathway specific inhibitors or were transfected with PI-3 kinase pathway components. The invasion of cultured bladder cancer cells was analysed by an invasion assay. Bladder cancer cells lines and primary human bladder tumours were analysed for pathway activation by western blotting. RESULTS: A specific inhibitor of PI-3 kinase enzyme activity, Ly294002, potently suppressed the invasive properties of three highly invasive bladder tumour cell lines. Restoration of the PTEN gene to invasive UM-UC-3 bladder tumour cells or expression of a dominant-negative version of the PI-3 kinase target, Akt, also potently inhibited invasion, indicating a central role for the PI-3 kinase/Akt pathway in this process. In addition, 55% of primary tumours from patients with bladder cancer had markedly high levels of phosphorylated Akt. CONCLUSION: Pharmacological or biochemical inhibition of the PI-3 kinase pathway drastically reduced the invasive capacity of bladder cancer cell lines; over half of primary human bladder tumours had high Akt phosphorylation, suggesting that the aberrant activation of this pathway may contribute to the invasion of a significant subset of bladder cancers.

Cell Line, Tumor↗
PubMed2003

Expression of KIT and epidermal growth factor receptor in chemotherapy refractory non-seminomatous germ-cell tumors.

BACKGROUND: The majority of patients with germ-cell tumors (GCTs) are curable with standard therapy. The molecular differences between curable and incurable disease are unknown. We have studied the expression of KIT and the epidermal growth factor receptor (EGFR) to determine their incidence in chemorefractory disease. PATIENTS AND METHODS: We retrospectively analyzed 23 patients with chemorefractory non-seminomatous GCTs (15 late relapse and eight transformed teratomas). None of these 23 patients were cured by their initial chemotherapy and/or surgery. Immunohistochemical analysis of KIT and EGFR was performed on the most recently available specimen from a metastatic site. PCR amplimers of KIT exon 17 were screened for mutations by a combination of denaturing high-performance liquid chromatography and direct sequencing. RESULTS: KIT was expressed (>/=10% of the tumor displaying membranous or cytoplasmic staining) in 11 of 23 GCT patients [48%; 95% confidence interval (CI) 26% to 68%]. There were no activating KIT mutations in the phosphoryltransferase domain (exon 17) in 21 patients analyzed. EGFR was expressed (1+ to 3+) in 15 of 23 GCT patients (65%; 95% CI 41% to 82%). CONCLUSIONS: KIT and EGFR are expressed in a significant proportion of refractory GCTs. The significance of these findings will be determined by ongoing clinical trials.

Adolescent↗
PubMed2001

Factors affecting microbial formation of nitrate-nitrogen in soil and their effects on fertilizer nitrogen use efficiency.

Mineralization of soil organic matter is governed by predictable factors with nitrate-N as the end product. Crop production interrupts the natural balance, accelerates mineralization of N, and elevates levels of nitrate-N in soil. Six factors determine nitrate-N levels in soils: soil clay content, bulk density, organic matter content, pH, temperature, and rainfall. Maximal rates of N mineralization require an optimal level of air-filled pore space. Optimal air-filled pore space depends on soil clay content, soil organic matter content, soil bulk density, and rainfall. Pore space is partitioned into water- and air-filled space. A maximal rate of nitrate formation occurs at a pH of 6.7 and rather modest mineralization rates occur at pH 5.0 and 8.0. Predictions of the soil nitrate-N concentrations with a relative precision of 1 to 4 microg N g(-1) of soil were obtained with a computerized N fertilizer decision aid. Grain yields obtained using the N fertilizer decision aid were not measurably different from those using adjacent farmer practices, but N fertilizer use was reduced by >10%. Predicting mineralization in this manner allows optimal N applications to be determined for site-specific soil and weather conditions.

Agriculture↗
PubMed2001

The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk.

Food-derived heterocyclic amines (HCAs), particularly 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are implicated in the etiology of human colorectal cancer (CRC) via a process of N-oxidation followed by O-acetylation or O-sulfation to form electrophilic metabolites that react with DNA. Glutathione S-transferases (GSTs) detoxify activated carcinogen metabolites by catalysis of their reaction with GSH. However, among HCAs, only N-acetoxy-PhIP has been shown to be a substrate for the GSTs. By using a competitive DNA-binding assay, we confirm that hGSTA1-1 is an efficient catalyst of the detoxification of N-acetoxy-PhIP. Further, we show that hGSTs A2-2, P1-1, M1-1, T1-1 and T2-2 appear to have low activity towards N-acetoxy-PhIP, and that hGSTs A4-4, M2-2, M4-4 and Z1-1 appear to have no activity towards N-acetoxy-PhIP. A genetic polymorphism in the 5'-regulatory sequence of hGSTA1 has been shown to correlate with the relative and absolute levels of expression of GSTA1/GSTA2 in human liver. Examination of hGSTA1 allele frequency in 100 Caucasian CRC patients and 226 Caucasian controls demonstrated a significant over-representation of the homozygous hGSTA1*B genotype among cases compared to controls (24.0 and 13.7%, respectively, P=0.04). This corresponds to an odds ratio for risk of CRC of 2.0 (95% CI 1.0-3.7) when comparing homozygous hGSTA1*B individuals with all other genotypes. Thus, individuals who are homozygous hGSTA1*B, and who would be predicted to have the lowest levels of hGSTA1 expression in their livers, appear to be at risk of developing CRC, possibly as a result of inefficient hepatic detoxification of N-acetoxy-PhIP.

Adult↗
PubMed2001

Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer.

The response to treatment for breast cancer is likely predicted by a number of disease and tumor tissue characteristics, many of which are under active investigation. One area that has received little attention is that of endogenous capabilities to respond to reactive oxygen species and subsequent byproducts resulting from radiation therapy and a number of chemotherapeutic agents, preventing cytotoxicity toward tumor cells. The glutathione S-transferases are key conjugating enzymes in this response, and GSTM1 and GSTT1 have deletion polymorphisms that result in no enzyme activity. In this retrospective study, we evaluated the role of GSTM1- and GSTT1-null genotypes on disease-free and overall survival among 251 women who received treatment for incident, primary breast cancer. Women were identified through Tumor Registry records and normal archived tissue retrieved for genotyping. Adjusting for age, race, and stage at diagnosis, women with null genotypes for GSTM1 and GSTT1 had reduced hazard of death [adjusted hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.36-0.97; and HR, 0.51; CI, 0.29-0.90, respectively] in relation to those with alleles present. Furthermore, women who were null for both GSTM1 and GSTT1 had one-third the hazard of death of those with alleles for both genes present (adjusted HR, 0.28; 95% CI, 0.11-0.70). Similar relationships were noted for risk of recurrence. These data indicate that interindividual differences in activity of enzymes that prevent therapy-generated reactive oxidant damage may have an important impact on disease recurrence and overall survival.

Adult↗
PubMed2001

Patient preferences versus physician perceptions of treatment decisions in cancer care.

PURPOSE: To examine patient preferences as well as physician perceptions of these preferences for decision making and communication in palliative care. PATIENTS AND METHODS: Medical decision-making preferences (DMPs) were prospectively studied in 78 assessable cancer patients after initial assessment at a palliative care outpatient clinic. DMPs were assessed with a questionnaire using five possible choices ranging from 1 (patient prefers to make the treatment decision) to 5 (patient prefers the physician to make the decision). In addition, the physician's perception of this preference was assessed. RESULTS: Full concordance between the physician and the patient was seen in 30 (38%) of 78 cases; when the five original categories were recombined to cover active, shared, and passive decision making, there was concordance in 35 (45%) of 78 cases. The kappa coefficient for agreement between physician and patient was poor at 0.14 (95% confidence limit, -0.01 to 0.30) for simple kappa and 0.17 (95% confidence interval [CI], 0.00 to 0.34) for weighted kappa (calculated on the three regrouped categories). Active, shared, and passive DMPs were chosen by 16 (20%) of 78, 49 (63%) of 78, and 13 (17%) of 78 patients, and by 23 (29%) of 78, 30 (39%) of 78, and 25 (32%) of 78 physicians, respectively. The majority of patients (49 [63%] of 78; 95% CI, 0.51 to 0.74) preferred a shared approach with physicians. Physicians predicted that patients preferred a less shared approach than they in fact did. Patient age or sex did not significantly alter DMP. CONCLUSION: An individual approach is needed and each patient should be assessed prospectively for DMP.

Adult↗
PubMed2001

Growth factor-specific signaling pathway stimulation and gene expression mediated by ErbB receptors.

The mechanisms by which receptor tyrosine kinases (RTKs) utilize intracellular signaling pathways to direct gene expression and cellular response remain unclear. A current question is whether different RTKs within a single cell target similar or different sets of genes. In this study we have used the ErbB receptor network to explore the relationship between RTK activation and gene expression. We profiled growth factor-stimulated signaling pathway usage and broad gene expression patterns in two human mammary tumor cell lines expressing different complements of ErbB receptors. Although the growth factors epidermal growth factor (EGF) and neuregulin (NRG) 1 similarly stimulated Erk1/2 in MDA-MB-361 cells, EGF acting through an EGF receptor/ErbB2 heterodimer preferentially stimulated protein kinase C, and NRG1beta acting through an ErbB2/ErbB3 heterodimer preferentially stimulated Akt. The two growth factors regulated partially overlapping yet distinct sets of genes in these cells. In MDA-MB-453 cells, NRG1beta acting through an ErbB2/ErbB3 heterodimer stimulated prolonged signaling of all pathways examined relative to NRG2beta acting through the same heterodimeric receptor species. Surprisingly, NRG1beta and NRG2beta also regulated partially overlapping but distinct sets of genes in these cells. These results demonstrate that the activation of different RTKs, or activation of the same RTKs with different ligands, can lead to distinct profiles of gene regulation within a single cell type. Our observations also suggest that the identity and kinetics of signaling pathway usage by RTKs may play a role in the selection of regulated genes.

Animals↗
PubMed2001

Localization and modulation of ErbB receptor tyrosine kinases.

The ErbB family of receptor tyrosine kinases serves as a model for understanding the propagation of growth factor signals across the plasma membrane and the interpretation of those signals into a cellular response. Recent studies point to a critical role for the accumulation of ErbBs at specific cell-surface locations in the fidelity of ErbB signaling. The past year has witnessed significant advances in our understanding of the molecular mechanisms of ErbB localization and the role of PDZ-domain-containing proteins and cell-surface glycoproteins in directly modulating signaling through ErbBs.

Animals↗
PubMed2001

The long form of CDK2 arises via alternative splicing and forms an active protein kinase with cyclins A and E.

We have reinvestigated the long form of cyclin-dependent kinase (CDK)2 that is expressed in many rodent cells. We show that the mRNA encoding CDK2L arises by alternative splicing and that the encoded protein can bind to, and be activated by, cyclins A and E. The complex of CDK2L with cyclin A has about half the specific activity of the equivalent CDK2-cyclin A complex. Also, CDK2L--cyclin A is inhibited to the same extent and by the same concentrations of p21(CIP1) as CDK2--cyclin A. The nucleotide sequences of intron V in the human and murine CDK2 genes, where the sequences encoding the 48-residue insert in CDK2L are located, show very high conservation in the position of the alternatively spliced exon and its surroundings. Despite this, we were not able to detect significant expression of CDK2L in human cell lines, although a low level is expressed in COS-1 cells from monkeys.

Alternative Splicing↗
PubMed2001

Clinical research in palliative care: choice of trial design.

Prospective controlled clinical trials provide the highest level of evidence in palliative care. Both parallel and crossover studies have unique advantages and disadvantages. Excellent knowledge of the patient population, interventions and endpoints are useful in choosing the most appropriate trial. Open pilot studies can assist the investigator in understanding the intervention and measurement tools better before embarking in costly and lengthy controlled trials. More controlled clinical trails are need to generate the evidence that will advance patient management in palliative care.

Cross-Over Studies↗