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Biomedical subjects

K Kelly

Publications and source records attributed to K Kelly.

At least 91 records · Page 5Linked to original sources
PubMed1998

Genetic analysis of extended life span in Drosophila melanogaster. II. Replication of the backcross test and molecular characterization of the N14 locus.

We are interested in localizing chromosomal regions that extend life span in Drosophila. Using stocks artificially selected for long life by Luckinbill and his colleagues, we have identified marker loci that are highly divergent in allelic frequencies between replicated long-lived lines and controls (Curtsinger et al., 1998). Several of the most divergent loci have been found to be associated with effects on life span in segregating backcross populations. Here we report an independent replication of the backcross test for the N14 marker locus, previously reported to extend male life spans by 12 days. The life span effect successfully replicates in males. N14 accounts for 30% of the total selection response in males. Life span extension occurs by a decrease in age-specific mortality rates at all ages, and is not attributable to modification of the slope of the age-specific mortality curve. The effect in females is small or nonexistent. Sequencing of the N14 locus shows that it is non-coding and not obviously regulatory, suggesting that the phenotypic effect arises from linkage disequilibrium with another locus or loci that directly affect life span. N14 DNA hybridizes to 63F/64A on the left arm of chromosome 3. The location is consistent with previous whole-chromosome substitution studies, and suggests new candidate genes for life span extension in Drosophila, including ras2.

Aging↗
PubMed1998

Genetic analysis of extended life span in Drosophila melanogaster. I. RAPD screen for genetic divergence between selected and control lines.

Using lines selected for long life by Luckinbil and his co-workers, we screened two selected and two control lines for allelic frequency differences at 1200 randomly chosen RAPD marker loci. Twenty-three marker loci showed frequency differences in excess of 80%, and five were greater than 90%. Age-specific effects of the five most differentiated loci were estimated by collecting complete survival data in segregating backcross populations. Alleles at four of the five marker loci were associated with significant extension of life span in males, while two marker loci had significant effects in females. Eighty percent of the total selection response in males can be explained by the identified QTL's, under the assumption of additivity. The N14+ marker allele accounted for a 12-day life span extension in males, but had little effect in females. Both sex-limited and sex-shared effects were observed. Analysis of age-specific mortality rates suggests that life span extension occurs by a combination of genetic factors that moderate both the level of mortality and the rate at which mortality increases with age.

Aging↗
PubMed1998

A role for interleukin-6 in host defense against murine Chlamydia trachomatis infection.

Interleukin-6-deficient (IL-6(-/-)) knockout mice had significantly increased Chlamydia trachomatis levels in lung tissue and increased mortality compared to B6129F2/J controls early after intranasal infection. Gamma interferon production and chlamydia-specific antibody levels were consistent with a decreased but reversible Th1-like response in IL-6(-/-) mice. IL-6 is needed for an optimal early host response to this infection.

Animals↗
PubMed1998

Neutrophil-dependent augmentation of PAF-induced vasoconstriction and albumin flux in coronary arterioles.

Platelet-activating factor (PAF) has been implicated in the pathogenesis of ischemic heart disease, reperfusion injury, and inflammatory reactions. Although neutrophils have been shown to primarily mediate PAF-induced microvascular dysfunction, the vasoactive effect of PAF and its neutrophil-dependent mechanism have not been directly and systematically studied in coronary resistance vessels. Therefore, the aim of this study was to examine the effects of PAF on coronary arteriolar function and neutrophil dynamics using an isolated and perfused microvessel preparation. Topical application of PAF to the vessels induced a dose-dependent decrease in the diameter but an increase in the apparent permeability coefficient of albumin. Disruption of the endothelium abolished the vasomotor response to PAF, and perfusion of neutrophils significantly augmented PAF-induced changes in vasomotor tone and permeability. Furthermore, the interaction between neutrophils and the endothelium was studied in the intact perfused coronary arterioles. Under control conditions, there were no adherent neutrophils observed in the vessels at varied intraluminal flow velocities. However, administration of PAF caused neutrophil adhesion to the endothelium of coronary arterioles at low flow velocities. Western blot analysis indicated that PAF upregulated the expression of intercellular adhesion molecule-1 in cultured coronary microvascular endothelial cells. Taken together, the results suggest that 1) PAF induces vasoconstriction and hyperpermeability in coronary arterioles via an endothelium-dependent and neutrophil-mediated mechanism, and 2) PAF is able to stimulate neutrophil adhesion in coronary arterioles under a condition of low flow rate.

Animals↗
PubMed1998

Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.

PURPOSE: Cisplatin has played a major role in the treatment of non-small-cell lung cancer (NSCLC). This randomized trial was performed by the Southwest Oncology Group (SWOG) to determine whether the combination of vinorelbine and cisplatin has any advantage with regard to response rate, survival, and time to treatment failure over single-agent cisplatin in the treatment of patients with advanced NSCLC. METHODS: Between October 1993 and April 1995, 432 patients with advanced stage NSCLC were randomized to receive arm I (cisplatin 100 mg/m2 every 4 weeks) or arm II (cisplatin 100 mg/m2 every 4 weeks and vinorelbine 25 mg/m2 weekly). All patients were chemotherapy-naive, had performance status (PS) 0 or 1, and had adequate hematologic, renal, and hepatic function. RESULTS: Four hundred fifteen patients were eligible and assessable. On arm I (cisplatin), there was a 12% partial response rate. Arm II (cisplatin and vinorelbine) had a 26% response rate (2% complete responses and 24% partial responses, P = .0002). There was a statistically significant advantage with regard to progression-free survival (median, 2 v 4 months; P = .0001) and overall survival (median, 6 v 8 months; P = .0018) for the cisplatin and vinorelbine arm. One-year survival was 20% for cisplatin alone and 36% for the combination arm. There was more hematologic toxicity on arm II of the study (81% grades 3 and 4 granulocytopenia v 5% on arm I). Other toxicities, such as renal insufficiency, ototoxicity, and nausea and vomiting, and neuropathy were similar. CONCLUSION: The results of this study indicate that the combination of cisplatin and vinorelbine is a superior treatment when compared with single-agent cisplatin in the treatment of advanced NSCLC. Cisplatin and vinorelbine is the new standard for SWOG against which new therapies will be evaluated.

Adult↗
PubMed1998

New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions.

In past years, there has been considerable pessimism over the role of chemotherapy in non-small cell lung cancers. The pessimism was largely derived from the fact that alkylating agent-based therapies shortened survival and produced severe side effects. This was especially important because the vast majority of patients (approximately 85%) develop metastatic disease during their course. Randomized trials from the 1980s showed that cisplatin-based chemotherapy improved patient survival, improved quality of life as assessed by the patients, and relieved symptoms in the majority of symptomatic patients. When chemotherapy was administered on an outpatient basis, it actually lowered the total patient care costs for advanced stage patients. In the 1990s, five new agents, including two taxanes (paclitaxel, docetaxel), gemcitabine, navelbine, and irinotecan, were shown to produce higher response rates and longer survival in Phase II trials compared to cisplatin or carboplatin. In randomized trials, combinations of paclitaxel, gemcitabine, and vinorelbine with cisplatin improved the survival of advanced stage patients compared to cisplatin alone or in combination with etoposide. The toxicity profile of the new agents is also favorable compared to cisplatin-based therapy. Preliminary results in earlier stages are also encouraging. Thus, currently available chemotherapy given to non-small cell lung cancer patients with good performance status can improve survival to a similar extent as other solid tumors, such as small cell lung cancer and breast cancer.

Antineoplastic Agents↗
PubMed1998

Effects of human intravenous immunoglobulin on canine monocytes and lymphocytes.

OBJECTIVE: To evaluate interactions of human intravenous immunoglobulin (IVIG) with canine lymphocytes and monocytes. SAMPLE POPULATION: Heparinized blood samples from 4 clinically normal Beagles. PROCEDURE: Binding ability of IVIG to canine lymphocytes and monocytes was measured by flow cytometry and an indirect immunofluorescent assay. Dual-staining fluorescent assays were done to determine lymphocyte subsets that bind IVIG. Competitive assays were done, using intact canine IgG and Fc fragments, and inhibition of binding was compared with that of F(ab)2 fragments. Ability of IVIG to inhibit phagocytosis of antibody-coated canine RBC also was determined, using a canine mononuclear cell phagocytic assay. RESULTS: IVIG concentrations (10, 1, 0.1, and 0.01 mg/ml) bound to (mean+/-SD) 99.6+/-0.4, 92.4+/-6.1, 20.4+/-24.6 and 2.0+/-5.1 % of canine lymphocytes, respectively, Dual staining analyses with IVIG and canine lymphocyte markers indicated that IVIG bound to CD4, CD8, and B lymphocytes. The aforementioned 4 IVIG concentrations bound to 98.0+/-2.1, 85.5+/-13.5, 64.7+/-32.8, and 26.5+/-17.1 % of monocytes, respectively. Inhibition of IVIG (0.01 mg/ml) binding to monocytes was significant (P< 0.05) in the presence of 1 and 10 mg of canine IgG/ml and 1 mg of canine Fc fragments/ml. In the presence of F(ab')2 fragments of canine IgG, inhibition was not significant, suggesting that binding is Fc mediated. Co-culturing of monocytes, opsonized RBC, and the 4 concentrations of IVIG and no IVIG resulted in 11.8+/-5.1, 27.7+/-12.3, 31.8+15.1, 53.8+/-6.7, and 45 + 12% of the monocytes containing RBC, respectively. Phagocytosis inhibition was significant (P < 0.05) at an IVIG concentration of 10 mg/ml. CONCLUSIONS: IVIG binds to canine lymphocytes and monocytes; binding to the latter is Fc mediated. IVIG also inhibits Fc-mediated phagocytosis of antibody-coated RBC. CLINICAL RELEVANCE: Owing to its ability to inhibit Fc-mediated phagocytosis of antibody-coated RBC, IVIG may be an effective short-term treatment for dogs with immune-mediated hemolytic anemia.

Animals↗
PubMed1997

A human cDNA sequence with homology to non-mammalian lysophosphatidic acid acyltransferases.

A novel human homologue of Escherichia coli, yeast and plant 1-acylglycerol-3-phosphate acyltransferase has been isolated from U937 cell cDNA. Expression of the cloned sequence in 1-acylglycerol-3-phosphate acyltransferase-deficient E. coli resulted in increased incorporation of oleic acid into cellular phospholipids. Membranes made from COS7 cells transfected with the cDNA exhibited higher acyltransferase activity towards a range of donor fatty acyl-CoAs and lysophosphatidic acid. Northern-blot analysis of the cDNA sequence indicated high levels of expression in immune cells and epithelium. Rapid amplification of cDNA ends revealed differentially expressed splice variants, which suggests regulation of the enzyme by alternative splicing. This cDNA therefore represents the first described sequence of a mammalian gene homologous to non-mammalian lysophosphatidic acid acyltransferases.

Acyltransferases↗
PubMed1997

Recruitment of p300/CBP in p53-dependent signal pathways.

The products of the p53 and CBP/p300 genes have been individually implicated in control of cell growth and regulation of transcription. p53 is known to act as a positive and negative regulator of gene expression. Here we show that p53, in both wild-type and mutant conformation, forms a specific protein complex with p300. However, in its wild-type but not mutant conformation, p53 inhibits a promoter containing the DNA-binding sequences for the transcription factor AP1, in a p300-dependent manner. p300 stimulates the transcriptional activity of p53 on p53-regulated promoters, and it enhances the responsiveness to a physiological upstream modulator of p53 function, ionizing radiation. A dominant negative form of p300 prevents transcriptional activation by p53, and it counteracts p53-mediated G1 arrest and apoptosis. The data implicate p300 as an important component of p53-signaling, thus providing new insight into the mechanisms of cellular proliferation.

Animals↗
PubMed1997

CD40-triggered protein tyrosine phosphorylation on Vav and on phosphatidylinositol 3-kinase correlates with survival of the Ramos-Burkitt lymphoma B cell line.

Signals transduced through CD40 rescue cells of the Ramos-Burkitt lymphoma (Ramos-BL) B cell line from surface immunoglobulin M (sIgM)-triggered growth arrest and apoptosis. This study investigates whether protein tyrosine kinase (PTK) activity and tyrosine phosphorylation on p95(vav) and on the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3 kinase) play a role in the regulation of Ramos-BL B cell survival. The PTK inhibitor herbimycin A (HA) triggers significant growth arrest prior to apoptosis from the G1-phase of the cell cycle, indicating that tyrosine phosphorylation of key proteins is critical for Ramos-BL cell cycle progression and survival. Indeed, signals transduced through CD40 fail to rescue Ramos-BL B cells from HA-triggered growth arrest and apoptosis. Since Vav and PI3 kinase are intimately involved in the regulation of cellular growth, their tyrosine phosphorylation status was determined in unstimulated and anti-IgM- and anti-CD40-treated Ramos-BL B cells: Vav and p85 are devoid of tyrosine-phosphorylated epitopes in control cells whereas p85, but not Vav, is significantly phosphorylated following ligation of sIgM and anti-CD40 triggers tyrosine phosphorylation on both proteins. Thus, tyrosine-phosphorylated Vav may be a critical effector of CD40-mediated survival. As tyrosine-phosphorylated PI3 kinase is common to both sIgM-triggered death and CD40-triggered survival pathways, its lipid kinase activity was correlated with tyrosine phosphorylation on p85: Ramos-BL B cells exhibit high basal levels of PI3 kinase activity, determined by immunoprecipitation with anti-p85 and 32P incorporation into phosphatidylinositol, which is not significantly affected by stimulation with anti-IgM but which is elevated by 36 +/- 2.9% following ligation of CD40. Thus, tyrosine phosphorylation on p85 correlates with the CD40-triggered increase in PI3 kinase activity but not with basal levels nor with sIgM-triggered levels of enzymatic activity: these data suggest the presence of different PI3 kinase isoforms or the existence of multiple regulatory pathways for the same PI3 kinase isotype in Ramos-BL B cells.

B-Lymphocytes↗
PubMed1997

Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative.

The extracellular signal-regulated kinase (ERK) pathway, the stress-activated protein kinase (SAPK) pathway, and the p38 pathway are three major mitogen-activated protein kinase (MAPK) cascades known to participate in the regulation of cellular responses to a variety of extracellular signals. Upstream regulatory components of these kinase cascades, the MAPK/ERK kinase kinases (MEKK), have been described in several systems. We have isolated a cDNA encoding human MEKK3. Transfected MEKK3 has the ability to activate both SAPK and ERK pathways, but does not induce p38 activity, in agreement with a previous report on murine MEKK3 (Blank, J. L., Gerwins, P., Elliott, E. M., Sather, S., and Johnson, G. L. (1996) J. Biol. Chem. 271, 5361-5368). We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK, respectively. Utilizing an estrogen ligand-activated MEKK3 derivative, we furthermore demonstrate that MEKK3 regulates the SAPK and the ERK pathway directly. Consistent with the fact that several SAPK-inducing agents activate the transcription factor NFkappaB, we now show that MEKK3 also enhances transcription from an NFkappaB-dependent reporter gene in cotransfection assays. The ability of MEKK3 to simultaneously activate the SAPK and ERK pathways is remarkable, given that they have divergent roles in cellular homeostasis.

3T3 Cells↗
PubMed1997

Assessment of hormone refractory prostate cancer.

OBJECTIVES: To define guidelines for the assessment of treatment in patients with hormone-refractory prostate cancer (HRPC). METHODS: In the light of modern research, and taking new treatment options into account, the Committee essays to specify different categories of patients entering clinical trials, and to define response criteria and those endpoints that are relevant in phase III studies and in short-term follow-up. RESULTS: HRPC comprises a range of disease states with varying responsiveness to therapy and length of survival. Patients with progression as evaluated by increasing prostate-specific antigen (PSA) values alone have a more favorable prognosis than those presenting with increasing tumor spread. In the assessment of these patients, the modes of previous therapy and the kind of tumor progression must be taken into account. The benefit of treatment of HRPC is often modest. While duration of survival remains the main and ultimate endpoint, the means of measuring short-term responsiveness to therapy are limited. A minority of patients have measurable tumor lesions. Decrease of PSA or other biochemical tumor markers may indicate depression of the tumor activity, but is not always associated with prolongation of survival. A variety of new treatments in HRPC are being investigated. They affect measurable tumor parameters in different ways. CONCLUSIONS: When a new agent is to be tested, it is important to measure all possible parameters before deciding which particular ones are appropriate for future investigations of this agent. In symptomatic patients, evaluation of subjective parameters, for example, relief of pain or improvement of performance status, is often the most reliable measure of treatment effect. However, these parameters should be clearly defined.

Antineoplastic Agents, Hormonal↗
PubMed1997

Obliterative bronchiolitis.

Obliterative bronchiolitis following lung transplantation is common and potentially devastating. Its exact cause is undefined, but multiple immune and nonimmune processes contribute to its pathogenesis. Severe acute rejection and recurrent acute rejection have been shown to confer the greatest risk for obliterative bronchiolitis, signifying the central importance of alloimmunity in the disease process. Treatment of established disease with intensification of immune suppression has been of limited benefit, so current clinical strategies include early detection and minimization of risk. As our understanding of the disease evolves, it is hoped that effective interventions targeted at specific pathogenetic steps will emerge. In the meantime, obliterative bronchiolitis remains the most important and sinister long-term complication of lung transplantation.

Acute Disease↗
PubMed1997

Humoral and cellular immunity in secondary infection due to murine Chlamydia trachomatis.

A murine model of pneumonia due to the mouse pneumonitis agent (MoPn [murine Chlamydia trachomatis]) in mice deficient in CD4+ T-cell function (major histocompatibility complex [MHC] class II function [class II-/-], CD8+ T-cell function (beta2-microglobulin deficient, MHC class I deficient [Beta2m-/-]), B-cell function (C57BL/10J-Igh(tm1Cgn) [Igh-/-]), and gamma interferon (IFN-gamma) (C57BL/6-Ifg(tm1) [Ifg-/-]) or interleukin-4 (C57BL/6J(tm1Cgn29) [IL4-/-]) production was employed to determine if each of these mechanisms was critical to resistance against reinfection by C. trachomatis or if alternate compensatory mechanisms existed in their absence which could potentially be exploited in vaccine development. Resistance to reinfection with MoPn was heavily dependent on CD4+ T cells. CD4 T-cell-deficient MHC class II-/- mice were very susceptible to reinfection with MoPn, showing the critical importance of this cell to resistance. These mice lacked antibody production but did produce IFN-gamma, apparently by mechanisms involving NK and CD8+ T cells. Neutralization of IFN-gamma in these mice led to a borderline increase in susceptibility, showing a possible role (albeit small) of this cytokine in this setting. Tumor necrosis factor alpha (TNF-alpha) was also present at increased levels in these mice. Igh-/- B-cell-deficient mice which produce no antibody to MoPn were only modestly more susceptible to reinfection than immunized B-cell-intact controls, showing that antibody, including lung immunoglobulin A, is not an absolute requirement for relatively successful host defense in this setting. Levels of lung IFN-gamma and TNF-alpha were elevated in Igh-/- mice compared to those in controls. IL-4-/- mice (deficient in Th2 function) could develop normal resistance to reinfection with MoPn. Conversely, normal mice rendered partially IFN-gamma deficient by antibody depletion were somewhat impaired in their ability to develop acquired immunity to MoPn, again indicating a role for this cytokine in host defense against rechallenge. Of most importance, however, congenitally IFN-gamma-deficient Ifg-/- mice (which have elevated levels of other cytokines, including TNF-alpha and granulocyte-macrophage colony-stimulating factor) are paradoxically more resistant to MoPn rechallenge than controls, showing that IFN-gamma is not an absolute requirement for acquired resistance and implying the presence of very effective compensatory host defense mechanism(s). In vivo depletion of TNF-alpha significantly increased MoPn levels in the lungs in these mice. Thus, resistance to reinfection in this model is flexible and multifactorial and is heavily dependent on CD4+ T cells, with a probable role for IFN-gamma and TNF-alpha and a possible modest role for Th1-dependent antibody. Since IFN-gamma was dispensable in host defense, the highly effective mechanism or mechanisms which can compensate for its absence (which include TNF-alpha) deserve further study.

Animals↗
PubMed1997

Diabetes self-management. Self-reported recommendations and patterns in a large population.

OBJECTIVE: Diabetes self-management is the cornerstone of overall diabetes management. Yet many questions concerning self-management remain unanswered. The current study was designed to examine several questions about diabetes self-management: 1) What do individuals report being told to do? 2) What are their self-reported levels and patterns of self-care? 3) Are there differences on self-reported self-management recommendations and levels across various subgroups? RESEARCH DESIGN AND METHODS: Mailed surveys were returned by 2,056 individuals (73.4% response rate). Of the total, 13.8% had IDDM and the remainder had NIDDM, with 65% of the NIDDM group using insulin. RESULTS: The levels and patterns of self-management were consistent with those found in previous studies, i.e., individuals most regularly followed their prescribed medication regimen and least regularly followed recommendations for lifestyle changes of diet and exercise. There were significant differences on reported self-management recommendations across different subgroups. Comparisons on level of self-management across diabetes type revealed significant differences for diet and glucose testing. Differences were also found on self-management levels for a number of individual characteristics, including age, working status, and type of insurance, along with knowledge of the Diabetes Control and Complications Trial findings. CONCLUSIONS: These findings provide important information on perceived self-management recommendations and the specific self-management levels and patterns in individuals with diabetes. The current findings may help health professionals better understand the levels and correlates of diabetes self-management and direct future research.

Adult↗
PubMed1997

Overview of the randomized phase III trials in non-small cell lung cancer in North America.

Lung cancer is the leading cause of deaths due to cancer in the United States. Although surgery can be curative for the small group of patients with early stage disease, the majority of patients present with advanced disease, for which treatment is ineffective, resulting in a 5-year overall survival rate of only 13%. Research to discover and evaluate new treatment strategies that will result in a meaningful survival benefit for patients with lung cancer is constantly ongoing. However, the process is cumbersome and requires stringent evaluation of the candidate treatment during each phase of testing. The final step in this long process is to validate the benefit of a new treatment by comparing it with the current standard treatment in the setting of a randomized phase III clinical trial. The new promising treatments for non-small cell lung cancer that are currently in phase III testing in North America are reviewed, and upcoming phase III trials are discussed.

Antineoplastic Combined Chemotherapy Protocols↗