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Biomedical subjects

K Kelly

Publications and source records attributed to K Kelly.

At least 145 records · Page 8Linked to original sources
PubMed1995

A phase I study of carboplatin and paclitaxel in non-small cell lung cancer: a University of Colorado Cancer Center study.

This phase I study was designed to determine the maximal tolerated doses of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), as well as the safety and efficacy of these agents, in patients with advanced, nonresectable stages IIIB and IV non-small cell lung cancer. Paclitaxel was given as a 3-hour intravenous infusion followed by a 30-minute infusion of carboplatin. Patients were assigned to one of seven treatment groups in which paclitaxel and carboplatin were given in doses ranging from 135 to 225 mg/m2 and from 250 to 400 mg/m2, respectively. Overall, the two-drug combination has been well tolerated. The major dose-limiting toxicity has not been reached but will likely be neutropenia. There appears to be a dose-response relationship: two partial responses (12%) were observed among 17 patients assigned to the lower-dose groups, whereas six (50%) of 12 evaluable patients in the higher-dose groups achieved partial responses. The maximal tolerated doses have not been reached yet, and will be at least 200 mg/m2 for paclitaxel and 400 mg/m2 for carboplatin.

Aged↗
PubMed1994

Immune protection and control of inflammatory tissue necrosis by gamma delta T cells.

Host defenses against experimental listeriosis in mice involve neutrophils, macrophages, NK cells, and alpha beta T cells. Recently gamma delta T cells have also been implicated in antilisterial resistance. However, their specific role has remained unclear. Here we show that efficient resistance to infection by this bacterium depends on the functions of both alpha beta and gamma delta T cells in both primary and secondary responses. We also present evidence that these functions are complementary. In the livers of alpha beta T cell-depleted mice, bacteria grow to large numbers within hepatocytes but are infrequently found extracellularly. Granulomatous lesions are more frequent and somewhat larger than in normal controls, but remain focal. Neutrophils are absent from liver lesions in these mice. In contrast, the livers of gamma delta T cell-depleted mice contain many extracellular bacteria, but do not show hepatocytes containing large numbers of Listeria. Liver lesions in gamma delta T cell-depleted mice are far more extensive than in normal controls or in alpha beta T cell-depleted mice, and contain large numbers of neutrophils. Particularly in secondary listeriosis, gamma delta T cell-depleted mice show vast coalescent areas of necrotic liver parenchyma within 48 h after infection. Because the bacterial numbers in gamma delta T cell-depleted mice remain lower than in alpha beta T cell-depleted mice, increased mortality in the former may be in part caused by liver failure. We conclude that gamma delta T cells are required to control inflammatory reactivity and to prevent excessive liver damage during the immune response to Listeria monocytogenes.

Animals↗
PubMed1994

Gem: an induced, immediate early protein belonging to the Ras family.

A gene encoding a 35-kilodalton guanosine triphosphate (GTP)-binding protein, Gem, was cloned from mitogen-induced human peripheral blood T cells. Gem and Rad, the product of a gene overexpressed in skeletal muscle in individuals with Type II diabetes, constitute a new family of Ras-related GTP-binding proteins. The distinct structural features of this family include the G3 GTP-binding motif, extensive amino- and carboxyl-terminal extensions beyond the Ras-related domain, and a motif that determines membrane association. Gem was transiently expressed in human peripheral blood T cells in response to mitogenic stimulation; the protein was phosphorylated on tyrosine residues and localized to the cytosolic face of the plasma membrane. Deregulated Gem expression prevented proliferation of normal and transformed 3T3 cells. These results suggest that Gem is a regulatory protein, possibly participating in receptor-mediated signal transduction at the plasma membrane.

Amino Acid Sequence↗
PubMed1994

Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1.

Intracellular signalling following mitogenic stimulation of quiescent cells involves the initiation of a phosphorylation cascade that leads to the rapid and reversible activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2. MAP kinase activation is mediated by dual phosphorylation within the motif Thr-Glu-Tyr by MAP kinase kinase (MEK). Following activation, the MAP kinases translocate into the nucleus where they phosphorylate several transduction targets, including transcription factors. We have previously identified PAC1 as an immediate-early mitogen-inducible tyrosine phosphatase in nuclei of T cells. Here we present several lines of evidence indicating that PAC1 is a physiologically relevant MAP kinase phosphatase. Recombinant PAC1 in vitro is a dual-specific Thr/Tyr phosphatase with stringent substrate specificity for MAP kinase. Constitutive expression of PAC1 in vivo leads to inhibition of MAP kinase activity normally stimulated by epidermal growth factor, phorbol myristyl acetate, or T-cell receptor crosslinking. The inactivation of MAP kinase by PAC1 results in inhibition of MAP kinase-regulated reporter gene expression.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1994

Immediate results of interventional devices for coronary ostial narrowing with angina pectoris.

Angioplasty of aorto-ostial lesions has had suboptimal results. This study reports on the immediate results of new debulking devices (atherectomy, excimer laser) in the treatment of aorto-ostial disease. Thirty-one vessels (29 patients) with an ostial lesion treated with a new device (group I) were compared with 15 vessels (13 patients) with an ostial lesion treated with angioplasty alone during the preceding 24 months (group II). Both groups were similar in their clinical characteristics. A larger proportion of vessels in group I (64%) compared with group II (7%) had unfavorable features for angioplasty. Procedural success was similar: 28 vessels in group I (91%) and 14 in group II (93%). Among the new devices, success was also similar: atherectomy in 8 arteries (89%), rotablator in 4 (100%) and excimer laser in 17 (94%). The acute gain was more significant with new devices: absolute reduction in percent stenosis was 66% for directional atherectomy, 67% for rotational atherectomy (p = 0.016 compared with angioplasty), 52% for excimer laser (p = 0.09) and 46% for angioplasty. In group I, 2 patients (6%) required emergency bypass surgery during our early experience; no deaths or Q-wave myocardial infarctions occurred. Group II had no complications. Therefore in aorto-ostial lesions, despite a much higher prevalence of unfavorable angiographic characteristics, new devices had (1) a success rate of > or = 90%, (2) a significantly larger acute gain compared with angioplasty alone, and (3) an acceptable complication rate. Larger studies with complete angiographic follow-up are needed to assess restenosis.

Aged↗
PubMed1994

Novel relationships of growth factors to the G1/S transition in cultured astrocytes from rat forebrain.

The cell cycle encompasses the sequential events regulating cell division. In mammalian brain, initiation of astrocyte cycling is critical during development and injury. To investigate the timing of growth factor requirements as they commit to passing through the G1 phase, primary and secondary rat astrocytes were stimulated to enter the cycle after serum or growth factor deprivation. Bromodeoxyuridine immunofluorescence was used to monitor S phase nuclei after growth factor re-addition (at time 0). Cycle kinetics were identical whether quiescent cultures were exposed to 10% (vol/vol) calf serum, or to a defined medium containing fibroblast growth factor, insulin, and epidermal growth factor. The control point in late G1 that represents commitment to achieving the G1/S transition was identified by cycloheximide (CHX, 0.1 microgram/ml) addition. Sensitivity to cycle arrest by CHX disappeared at 9-10 h. In contrast, shift-down to growth factor-deficient medium arrested cell cycling virtually until G1/S (12 h). With selective exposure during late G1 (9-12 h), no single agent permitted cycle progression. However, any two agents enabled cycling, and complementary or synergistic effects were apparent. These requirements were identical in astroglia from newborn and long-term cultures. Thus, temporal dissociation exists between the processes of escape from CHX sensitivity and from requirements for growth factors, two recognized hallmarks of commitment to cycle progression. Furthermore, simultaneous presence of at least two growth factors is necessary at or near G1/S. Both findings distinguish astrocytes from several other cell types.

Animals↗
PubMed1994

Regulation of bone marrow stromal cell differentiation by cytokines whose receptors share the gp130 protein.

The bone marrow stroma consists of a heterogeneous population of cells which participate in osteogenic, adipogenic, and hematopoietic events. The murine stromal cell line, BMS2, exhibits the adipocytic and osteoblastic phenotypes in vitro. BMS2 differentiation was examined in response to cytokines which share the gp130 signal transducing protein within their receptor complex. Four of the cytokines (interleukin 6, interleukin 11, leukemia inhibitory factor, and oncostatin M) inhibited hydrocortisone-induced adipocyte differentiation in a dose dependent manner based on lipid accumulation and lipoprotein lipase enzyme activity. Inhibition occurred only when the cytokines were present during the initial 24 h of the induction period; after 48 h their effects were diminished. Likewise, these cytokines increased alkaline phosphatase enzyme activity twofold in preadipocyte BMS2 cells. Both leukemia inhibitory factor and oncostatin M induced early active gene expression in resting preadipocyte BMS2 cells and decreased the steady state mRNA level of a unique osteoblastic gene marker, osteocalcin. A fifth cytokine whose receptor complex shares the gp130 protein, ciliary neurotrophic factor, did not significantly regulate stromal cell differentiation when added by itself. However, with the addition of a missing component of its receptor complex, ciliary neurotrophic factor receptor alpha protein, this cytokine also inhibited BMS2 adipogenesis. Together, these data indicate that the cytokines whose receptors share the gp130 protein can modulate stromal cell commitment to the adipocyte and osteoblast differentiation pathways.

Adipocytes↗
PubMed1994

Leuprolide acetate treatment of catamenial pneumothorax.

A 35-year-old nulligravid female with a 20 pack year history of smoking and continuous OC use since age 16 presented with recurrent pneumothoraces coinciding with the onset of menses at age 28. At that time she underwent a right partial pleurectomy and lobectomy, which demonstrated bullous disease but no glandular or stromal elements. Although catamenial respiratory discomfort persisted while on OCs, no pneumothoraces were documented until age 33 at which time she was given the diagnosis of catamenial pneumothorax. A diagnostic laparoscopy failed to demonstrate endometriosis or the presence of diaphragmatic defects. In an effort to preserve her fertility, she began a course of LA-GnRH-a therapy with depot LA. Because of disabling vasomotor and emotional side effects, continuous conjugated estrogens and MPA acetate were given as add-back therapy. She has remained symptom and side effect free for over 2 years on this regimen.

Adult↗
PubMed1994

B-cell non-Hodgkin's lymphoma of the paranasal sinuses.

Primary nasal, paranasal, oral and pharyngeal (NPOP) lymphoma, thought to be a distinct entity among childhood lymphomas, may present with a wide variety of common ENT symptoms such as nasal obstruction, rhinorrhoea, epistaxis or sinusitis. The diagnosis may only be recognized when the disease results in symptoms such as visual loss, facial paraesthesia or lymphadenopathy, or systemic symptoms, such as fatigue, bone pain or abdominal pain. Full radiological assessment plays a vital part in making the diagnosis and planning treatment. Computerized tomography (CT) gives excellent bony detail but magnetic resonance imaging (MRI) using T2-weighted images, allows differentiation of mucosal thickening and retained sinus secretions from the tumour. Extension into the surrounding spaces and the cranial fossa is best assessed by coronal and sagittal T2 images. MRI is the best technique for follow-up because no radiation is involved and better soft tissue delineation improves the distinguishing of tumour from fibrosis.

Child, Preschool↗
PubMed1994

Intelligence quotient profile in myotonic dystrophy, intergenerational deficit, and correlation with CTG amplification.

An abbreviated Wechsler Adult Intelligence Scale Revised (WAIS-R) was used to assess verbal and arithmetical cognitive performance in 55 subjects with myotonic dystrophy (DM), covering all grades of disease severity, and 31 controls at 50% risk of inheriting DM. Scaled scores from the assessment were converted into an intelligence quotient (IQ) estimation on each person. Significant IQ differences were found between: (1) all 55 DM subjects (mean 90.2, SD 16.1) and 31 controls (102.6, SD 9.4), with no sex differences in either group; (2) 15 affected parents (99.3, SD 12.2) and their affected children (88.1, SD 17.2), where significance was dependent on parental sex being female; and (3) 15 pairs of affected sibs (89.6, SD 13.2) and their normal sibs (100.2, SD 7.6). IQ steadily declined as (1) the age of onset of signs and symptoms decreased, and (2) the CTG expansion size increased. The correlation appeared to be more linear with age of onset. The correlation of IQ difference and CTG expansion difference in both the DM parent-child pairs and normal sib-affected sib pairs was poor, indicating that CTG expansion is not a reliable predictor of IQ either in individual persons or families. Further analysis of cognitive function in DM is required to clarify specific deficits characteristic of this patient group.

Adolescent↗
PubMed1994

Latex allergy: frequent occurrence of IgE antibodies to a cluster of 11 latex proteins in patients with spina bifida and histories of anaphylaxis.

Proteins and allergens in natural rubber latex were characterized by a two-dimensional immunoblot method with serum samples from 17 patients with latex allergy of whom 10 had spina bifida and 7 were health care workers. We demonstrated in rubber tree sap approximately 240 polypeptides of which 57 bound immunoglobulin E (IgE) in patient serum samples. Forty-six of the 57 allergens were identified by patients with spina bifida, 19 of 57 allergens by health care workers, and 8 of 57 allergens by both patient groups. IgE antibodies from all 5 patients with spina bifida with histories of anaphylaxis bound three allergens with molecular weights of 27 kd and isoelectric points ranging from pH 4.6 to pH 4.8. Four of these 5 patients also identified a complex of eight other allergens with molecular weights ranging from 13 kd to 27 kd and isoelectric points from pH 4.4 to pH 5.6. This cluster of 11 allergens was identified by none of the 7 health care workers and by only 1 of 5 patients with spina bifida without demonstrable anaphylaxis. These preliminary findings indicate that patients with spina bifida in whom latex hypersensitivity has developed exhibit a strong anti-latex IgE immune response, which seems to differ markedly from the immune response of health care workers with latex allergy. The characteristic anti-latex IgE profile in patients with spina bifida and with a history of an anaphylactic reaction may be valuable in the evaluation of pathogenetic processes in latex allergy.

Adolescent↗
PubMed1993

Topography of tetrahydrocannabinol in model membranes using neutron diffraction.

Small-angle neutron scattering was used to determine the intralamellar location of (-)-delta 8-tetrahydrocannabinol (delta 8-THC) in hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers. Nuclear scattering density profiles were calculated from measurements on deuterium and non-deuterium-labelled inclusions (8.3% (w/w)) of delta 8-THC in DPPC multilayer samples. By comparing pairs of such nuclear density profiles, the locations of the deuterium labels were determined. Present results on the topography of delta 8-THC in membranes are compared with earlier X-ray measurements using iodine labelling. Whereas the position of the phenolic hydroxy group is similar in both types of measurement, a difference is found in the conformation of the terminal methyl groups of the cannabinoid side-chains. The X-ray measurements on dimyristoylphosphatidylcholine (DMPC) indicated that the iodine-labelled cannabinoid side-chains assume an all-trans orientation with the terminal iodine atom pointing inward into the membrane away from the tricyclic region while the neutron measurements indicate that the terminal CH3 group of delta 8-THC aligns itself at the level of the tricyclic ring system implying that the side chain exists in a more compact conformation perpendicular to the DPPC hydrocarbons. A Gaussian function analysis of the data indicates that the delta 8-THC molecule is significantly delocalized in the DPPC membrane in the liquid crystal phase. The mean location of delta 8-THC suggests that the active site on a membrane-embedded receptor protein will lie near the polar interface at the base of the phospholipid headgroups.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1993

PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase.

Tyrosine phosphorylation of proteins is required for signal transduction in cells and for growth regulation. A mitogen-induced gene (PAC-1) has been cloned from human T cells and encodes a 32-kilodalton protein that contains a sequence that defines the enzymatic site of known protein phosphotyrosine phosphatases (PTPases). Other than this sequence, PAC-1 is different from several other known related PTPases exemplified by PTP-1b. PAC-1 is similar to a phosphatase induced by mitogens or heat shock in fibroblasts, a yeast gene, and a vaccinia virus-encoded serine-tyrosine phosphatase (VH1). PAC-1 was predominantly expressed in hematopoietic tissues and localized to the nucleus in transfected COS-7 cells and in mitogen-stimulated T cells.

Amino Acid Sequence↗
PubMed1993

Police surgeons.

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Alcoholic Intoxication↗
PubMed1993

Prospective trial evaluating immunocytochemical-based sputum techniques for early lung cancer detection: assays for promotion factors in the bronchial lavage.

To confirm the results of a previous report on the use of monoclonal antibodies in immunocytochemical assays of sputums for the early detection of lung cancer, we designed a new prospective trial in an independent clinical trial population. Since well-characterized Stage I resected non-small cell lung cancer patients have a low rate of tumor relapse and a high (1-3%/year) chance of developing a second primary lung cancer, they comprise a very favorable group for conducting an early lung cancer detection trial. The rate of new lung cancer is about 10-fold in excess of a standard "high" risk population of smokers. To optimize the chance for a favorable outcome, all of the technical components for the trial have been systematically evaluated to ensure that optimal procedures are employed. For example, automated immunostaining of the sputum specimens will be performed. Bronchial lavages will be analyzed in a subset of the trial participants to define additional targets for early lung cancer detection. Two markers will be quantitated, including gastrin releasing peptide and peptidyl glycine alpha-amidating monooxygenase activity. These two markers assess the epithelium's capacity to produce growth factors which may be central to the biology of tumor promotion. Since these assays have not been performed in this context before, we attempted to optimize the specimen handling to permit the receipt of the material from a range of collaborating clinical sites in a condition that permits accurate quantitation of these two biomarkers. Efforts to standardize the assay endpoint stimulated the development of computer-assisted methods of immunocytochemical analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Conditioned enhancement of antibody production using antigen as the unconditioned stimulus.

Antigen is the most salient stimulus for an unconditional activation of the immune system. BALB/c mice were given repeated immunizations with keyhole limpet hemocyanin (KLH) paired with a gustatory conditioned stimulus (CS). A classically conditioned enhancement of anti-KLH antibody titers was observed when conditioned mice were reexposed to the CS in the context of reexposure to a minimally immunogenic dose of that same antigen. An interaction between signals derived from the neuroendocrine and immune systems is hypothesized to mediate this conditioned immune response.

Animals↗