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C Sweeney

Publications and source records attributed to C Sweeney.

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

Rapid diagnosis of leishmaniasis by fluorogenic polymerase chain reaction.

A fluorescent DNA probe (LEIS.P1) specific for a conserved region of the small-subunit ribosomal RNA gene of Leishmania and a pair of flanking primers (LEIS.U1 and LEIS.L1) were designed for use in a fluorogenic polymerase chain reaction. Optimal assay conditions with zero background were established to detect low levels of Leishmania from clinical samples. By use of this assay, we amplified DNA from 27 strains of cultured Leishmania (both Old and New World strains) and selectively amplified Leishmania DNA from 12 paraffin-embedded human biopsy samples and 3 fresh human skin biopsy specimens. For the fresh human tissue biopsies, the turnaround time from biopsy to test result was < 24 hr. No amplification was detected in negative control samples (including the kinetoplastid protozoa Trypanosoma rangelli and Crithidia fasiculata). This assay provides a specific and rapid diagnostic modality to detect infection with Leishmania.

DNA, Protozoan↗
PubMed2001

Research opportunities in palliative medicine.

Patients who require palliative care have many physical and psychosocial needs. Their families also require care and advice. Despite recent advances in assessment and management, major issues relating to palliative care for patients and their families remain unanswered. Several challenges face researchers in this area. We discuss administrative issues, including historical development, funding, academic recognition, integration of services, and cooperation among different centers. Methodological challenges in patient issues and trial design are outlined, and areas for future research are proposed.

Humans↗
PubMed2001

History of testicular cancer chemotherapy: maximizing efficacy, minimizing toxicity.

All patients presenting with metastatic testis cancer should be treated with the goal of cure. However, all physicians treating patients with germ cell tumors need to be aware of the toxicities of chemotherapy. Because many patients are cured of their disease, both short-term and long-term toxicities have been identified. The short-term toxicities are myelosuppression, nausea and vomiting, pulmonary toxicity, nephropathy, and neuropathy. The longer term toxicities often discussed are ototoxicity, impairment of fertility, persistent neuropathy or ototoxicity, cardiovascular diseases, and secondary malignancies, which are all described in this review.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Effects of the reactive oxygen species hydrogen peroxide and hypochlorite on endothelial nitric oxide production.

Reactive oxygen species (ROS) hydrogen peroxide (H(2)O(2)) and hypochlorite (HOCl) participate in the pathogenesis of ischemia/reperfusion injury, inflammation, and atherosclerosis. Both NO and ROS are important modulators of vascular tone and architecture and of adhesive interactions between leukocytes, platelets, and vascular endothelium. We studied the effect of H(2)O(2) and HOCl on receptor-dependent (bradykinin [10(-6) mol/L] and ADP [10(-4) mol/L]) and receptor-independent mechanisms (calcium ionophore A23187 [10(-6) mol/L]) of NO production by porcine aortic endothelial cells (ECs). Changes in the level of EC cGMP (the second messenger of NO) were used as a surrogate of NO production. EC cGMP increased 300% in response to bradykinin and A23187 and 200% in response to ADP. Exposure of ECs to H(2)O(2) (50 micromol/L) for 30 minutes significantly impaired cGMP levels in response to ADP, bradykinin, and the receptor-independent NO agonist A23187. In contrast, preincubation with HOCl (50 micromol/L) impaired cGMP production only in response to ADP and bradykinin but not A23187. These concentrations of H(2)O(2) and HOCl did not result in increased EC lethality as assessed by lactate dehydrogenase release. Neither H(2)O(2) nor HOCl affected EC cGMP production in response to NO donor sodium nitroprusside, which suggests that guanylate cyclase is resistant to these oxidants. We also demonstrated that neither H(2)O(2) nor HOCl affects endothelial NO synthase (eNOS) catalytic activity as measured by conversion of L-arginine to L-citrulline in EC homogenates supplemented with eNOS cofactors. The present studies show that H(2)O(2) impairs NO production in response to both receptor-dependent and receptor-independent agonists and that these effects are due, at least in part, to inactivation of eNOS cofactors, whereas HOCl inhibits NO production by interfering with receptor-operated mechanisms at the level of the cell membrane. Concentrations of H(2)O(2) and HOCl used in the present studies have been shown to be generated in vivo during inflammation and ischemia/reperfusion. Therefore, we infer that these effects of H(2)O(2) and HOCl on EC NO production may contribute to disregulated vascular tone and altered leukocyte-EC interactions that occur in vascular injury as a result of those causes in which ROS generation is involved.

Adenosine Diphosphate↗
PubMed2000

Ligand discrimination by ErbB receptors: differential signaling through differential phosphorylation site usage.

The four members of the ErbB family of receptor tyrosine kinases (RTKs) mediate a variety of cellular responses to epidermal growth factor (EGF)-like growth factors, and serve as a model for the generation of both diversity and specificity in RTK signaling. Previous studies indicate that receptor-receptor interactions figure prominently in signaling through ErbB receptors. In addition to a role in receptor kinase activation, ligand-induced ErbB receptor homo- and heterodimerization is thought to account for the diversity of biological responses stimulated by EGF-like growth factors. Since each receptor has the potential to couple to different complements of signaling pathways, EGF-like ligands specify cellular response by dictating which pairs of receptors become activated. More recently evidence has been uncovered for ligand discrimination by individual ErbB receptor dimers; receptors appear to realize which ligand is binding and differentially respond through autophosphorylation site usage. These observations indicate that ligand stimulation of RTKs is not generic, and point to another layer in the ErbB signal diversification mechanism. The mechanistic implications of ligand discrimination are discussed.

Animals↗
PubMed2000

Association between survival after treatment for breast cancer and glutathione S-transferase P1 Ile105Val polymorphism.

A glutathione S-transferase (GST) P1 polymorphism results in an amino acid substitution, Ile105Val; the Val-containing enzyme has reduced activity toward alkylating agents. Cancer patients with the variant enzyme may differ in removal of treatment agents and in outcomes of therapy. We evaluated survival according to GSTP1 genotype among women (n = 240) treated for breast cancer. Women with the low-activity Val/Val genotype had better survival. Compared with Ile/Ile, hazard ratios for overall survival were 0.8 (95% confidence interval, 0.5-1.3) for Ile/Val and 0.3 (95% confidence interval, 0.1-1.0) for Val/Val (P for trend = 0.04). Inherited metabolic variability may influence treatment outcomes.

Adult↗
PubMed2000

Ligand discrimination in signaling through an ErbB4 receptor homodimer.

The epidermal growth factor (EGF)-like family of growth factors elicits cellular responses by stimulating the dimerization, autophosphorylation, and tyrosine kinase activities of the ErbB family of receptor tyrosine kinases. Although several different EGF-like ligands are capable of binding to a single ErbB family member, it is generally thought that the biological and biochemical responses of a single receptor dimer to different ligands are indistinguishable. To test whether an ErbB receptor dimer is capable of discriminating among ligands we have examined the effect of four EGF-like growth factors on signaling through the ErbB4 receptor homodimer in CEM/HER4 cells, a transfected human T cell line ectopically expressing ErbB4 in an ErbB-null background. Despite stimulating similar levels of gross receptor tyrosine phosphorylation, the EGF-like growth factors betacellulin, neuregulin-1beta, neuregulin-2beta, and neuregulin-3 exhibited different biological potencies in a cellular growth assay. Moreover, the different ligands induced different patterns of recruitment of intracellular signaling proteins to the activated receptor and induced differential usage of intracellular kinase signaling cascades. Finally, two-dimensional phosphopeptide mapping of ligand-stimulated ErbB4 revealed that the different growth factors induce different patterns of receptor tyrosine phosphorylation. These results indicate that ErbB4 activation by growth factors is not generic and suggest that individual ErbB receptors can discriminate between different EGF-like ligands within the context of a single receptor dimer. More generally, our observations significantly modify our understanding of signaling through receptor tyrosine kinases and point to a number of possible models for ligand-mediated signal diversification.

Cell Division↗
PubMed2000

Cachexia and asthenia in cancer patients.

Over the past 10 years, there have been major advances in the understanding of cancer cachexia and asthenia. These common complications of cancer are now thought to be the consequences of complex interactions between host, tumour, and psychosocial factors. Cachexia and asthenia commonly coexist, but they can occur independently of each other. Recently identified tumour-derived factors cause lipolysis and protein catabolism. Cytokines produced by the host in response to tumour presence cause metabolic abnormalities, which result in decreased protein and lipid synthesis, increased lipolysis, and anorexia. Many other factors contribute to asthenia, such as anaemia, autonomic failure, and muscular abnormalities. Future research should clarify optimum management. The way forward seems to lie in a multidimensional approach with combined therapy to manage both cancer cachexia and asthenia.

Asthenia↗
PubMed2000

Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer.

OBJECTIVE: The incidence of esophageal adenocarcinoma has risen rapidly in the past two decades, for unknown reasons. The goal of this analysis was to determine whether gastroesophageal reflux disease (GERD) or the medications used to treat it are associated with an increased risk of esophageal or gastric cancer, using data from a large population-based case-control study. METHODS: Cases were aged 30-79 years, newly diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or non-cardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were chosen by random digit dialing and from Health Care Financing Administration rosters. Data were collected using an in-person structured interview. RESULTS: History of gastric ulcer was associated with an increased risk of non-cardia gastric adenocarcinoma (OR 2.1, 95% CI 1.4-3.2). Risk of esophageal adenocarcinoma increased with frequency of GERD symptoms; the odds ratio in those reporting daily symptoms was 5.5 (95% CI 3.2-9.3). Ever having used H2 blockers was unassociated with esophageal adenocarcinoma risk (OR 0.9, 95% CI 0.5-1.5). The odds ratio was 1.3 (95% CI 0.6-2.8) in long-term (4 or more years) users, but increased to 2.1 (95% CI 0.8-5.6) when use in the 5 years prior to the interview was disregarded. Risk was also modestly increased among users of antacids. Neither GERD symptoms nor use of H2 blockers or antacids was associated with risk of the other three tumor types. CONCLUSIONS: Individuals with long-standing GERD are at increased risk of esophageal adenocarcinoma, whether or not the symptoms are treated with H2 blockers or antacids.

Adenocarcinoma↗
PubMed2000

Differential survival related to smoking among patients with renal cell carcinoma.

We examined the relation between tobacco smoking and survival among renal cell carcinoma cases, using information from a population-based cancer registry. Current smokers were at increased risk of death compared with non-smokers (hazard ratio (HR) 1.7, 95% CI = 1.2-2.5). The association was strongest within 6 months of diagnosis (HR 2.5, 95% CI = 1.5-4.3). Most of the association was explained by stage at diagnosis, with current smokers more likely (OR 2.2, 95% CI = 1.4-3.5) to have distant disease. Case-control studies may be biased if cases who do not participate owing to short survival have different smoking histories than participating cases.

Adult↗
PubMed2000

Glutathione S-transferase M1, T1, and P1 polymorphisms as risk factors for renal cell carcinoma: a case-control study.

Renal cell carcinoma (RCC) has known environmental risk factors, notably smoking, and enzymes that biotransform carcinogens have high levels of activity in the kidney. However, a possible role of polymorphisms in these enzymes in RCC etiology has received little study. We investigated glutathione S-transferase (GST) polymorphisms in a population-based case-control study of RCC. Subjects completed a structured interview, and DNA was isolated from pathological material or buccal cells for 130 cases, and from blood for 505 controls. Genotypes for GSTM1 and GSTT1 were determined by multiplex PCR, and for GSTP1 by oligonucleotide ligation assay. The frequency of GSTM1 null genotype was 50.0% in cases and 50.5% in controls, with an adjusted odds ratio (OR) of 1.0 [95% confidence interval (CI), 0.6-1.6]. For GSTP1, the frequencies of genotypes AA, AG, and GG representing the Ile104Val variant were: cases, 44.6%, 43.1%, and 12.3%; controls, 43.4%, 44.0%, and 12.6%; OR for AG and GG, 1.0 (95% CI, 0.6-1.6). An excess of the GSTT1 null genotype was observed in cases compared with controls, 28.6% versus 18.5% (OR, 1.9; 95% CI, 1.1-3.4). The association with GSTT1 was present among both smokers and nonsmokers, but was modified by body mass index, a recognized risk factor for RCC; among subjects in the lowest tertile of body mass index, the OR for GSTT1 null was 4.8 (95% CI, 1.8-13.0). The association between GSTT1 null and increased RCC risk in this population-based study suggests that activity of the GSTT1 enzyme protects against RCC. This contrasts with a recent report of reduced risk of RCC associated with GSTT1 null in a cohort of trichloroethene-exposed workers and suggests that specific chemical exposures alter the effect of GSTT1 on cancer risk.

Adult↗
PubMed1997

Delayed early embryonic lethality following disruption of the murine cyclin A2 gene.

In higher eukaryotes, cell cycle progression is controlled by cyclin dependent kinases (Cdks) complexed with cyclins. A-type cyclins are involved at both G1/S and G2/M transitions of the cell cycle. Cyclin A2 activates cdc2 (Cdk1) on passage into mitosis and Cdk2 at the G1/S transition. Antisense constructs, or antibodies directed against cyclin A2 block cultured mammalian cells at both of these transitions. In contrast, overexpression of cyclin A2 appears to advance S phase entry and confer anchorage-independent growth, and can lead to apoptosis. A second A-type cyclin, cyclin A1 has been described recently which, in the mouse, is expressed in germ cells but not somatic tissues. To address the possible redundancy between different cyclins in vivo and also the control of early embryonic cell cycles, we undertook the targeted deletion of the murine cyclin A2 gene. The homozygous null mutant is embryonically lethal, demonstrating that the cyclin A2 gene is essential. Surprisingly, homozygous null mutant embryos develop normally until post-implantation, around day 5.5 p.c. This observation may be explained by the persistence of a maternal pool of cyclin A2 protein until at least the blastocyst stage, or an unexpected role for cyclin A1 during early embryo development.

Animals↗
PubMed1996

IgA multiple myeloma presenting as Henoch-Schönlein purpura/polyarteritis nodosa overlap syndrome.

We report the unusual case of a man with a 5-year history of relapsing Henoch-Schonlein purpura (HSP) and macroscopic polyarteritis nodosa (PAN) as early manifestations of IgA kappa multiple myeloma. The glomeruli contained monoclonal IgA kappa deposits, without other immunoglobulins or lambda light chains. Glomerular deposits lacked the usual electron density but could be demonstrated by immunoelectron microscopy. Multisystem large vessel vasculitis (antineutrophil cytoplasmic antibody negative) produced aneurysms of renal and hepatic arteries, whereas small vessel vasculitis affected the skin and glomeruli, producing a symptom complex of HSP with dermal and glomerular deposits of IgA. We conclude that HSP/overlap syndrome may be the initial manifestation of IgA myeloma and should be considered within the spectrum of monoclonal IgA deposition disease.

Humans↗
PubMed1996

A distinct cyclin A is expressed in germ cells in the mouse.

In this paper, the existence of two A-type cyclins in the mouse is demonstrated. In the adult mouse, the expression of cyclin A1, which has greatest sequence identity with Xenopus cyclin A1, is restricted to germ cells. In contrast cyclin A2, which has greatest sequence identity with human cyclin A and Xenopus cyclin A2, is expressed in all tissues analysed. In order to explore the function of cyclin A1 in germ cells, its expression during the meiotic cell cycle and its associated kinase subunits have been characterised in the testis. The levels of cyclin A1 mRNA rise dramatically in late pachytene spermatocytes and become undetectable soon after completion of the meiotic divisions; thus its expression is cell cycle regulated. In lysates of germ cells from adult testes, cyclin A1 is present in p13suc1 precipitates, and cyclin A1 immunoprecipitates possess histone H1 kinase activity. Three kinase partners of cyclin A1 were identified: p34cdc2, a polypeptide of 39 x 10(3) M(r) that is related to p33cdk2 and, in lesser quantities, p33cdk2. Cyclin A1 was also detected in oocytes; in metaphase I and metaphase II oocytes, a proportion of the cyclin A1 colocalises with the spindle, possibly suggestive of a functional interaction. These data indicate that mammalian germ cells contain cyclin A1-dependent kinases that either act as a substitute for, or in addition to, the cyclin A2-dependent kinases characterised in somatic tissues.

Amino Acid Sequence↗