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Biomedical subjects

K Kelly

Publications and source records attributed to K Kelly.

At least 19 recordsLinked to original sources
PubMed1995

Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial.

This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count < 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P < .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.

Adolescent↗
PubMed1995

Genomic organization and chromosomal localization of the DUSP2 gene, encoding a MAP kinase phosphatase, to human 2p11.2-q11.

The mitogen-induced gene, DUSP2, encodes a nuclear protein, PAC1, that acts as a dual-specific protein phosphatase with stringent substrate specificity for MAP kinase. MAP kinase phosphorylation and consequent enzymatic activation is a central and often obligatory component in signal transduction initiated by growth factor stimulation or resulting from various types of oncogenic transformation. DUSP2 downregulates intracellular signal transduction through the dephosphorylation/inactivation of MAP kinases. To facilitate assessment of the possible role of DUSP2 in growth processes, the genomic structure and chromosomal location of the gene have been determined. DUSP2 has been localized to the pericentromeric region of human chromosome 2 (2p11.2-q11) by analysis of somatic cell hybrids, in situ chromosome hybridization, and genetic linkage analysis using a single-strand conformational polymorphism (SSCP) that has been identified in the 3' UTR of the gene. No consistent translocations or deletions at this chromosomal site have been reported in hematopoietic neoplasias or other tumors.

Base Sequence↗
PubMed1995

Long-term production of neurotrophic factors by astrocyte cultures from hemiparkinsonian rat brain.

Transplantation of dopaminergic or neurotrophic tissues is an experimental treatment of Parkinson's Disease. However, in animal models sustained recovery may occur after surgical trauma to affected brain areas even in the absence of grafted tissue. Consequently, brain tissue reacting to local trauma in these experiments must be capable of substantial neurotrophic responses. To evaluate the potential of astrocytes in these neurotrophic responses, cultures were obtained from gelatin implants into striatal cavities that were created in hemiparkinsonian rats. The type 1 astrocyte phenotype as determined immunocytochemically was maximal at day 7 in vitro and paralleled the glial reaction in the adjacent brain parenchyma. Neurite-promoting activity of the culture medium was determined in a chick dorsal root ganglion bioassay and also was established by 7 days. Nerve growth factor antibodies neutralized only around 40% of this activity. Neurotrophic activity was absent with assay of media from early or long-term newborn rat astrocytes, and of medium conditioned by a monoyte/macrophage cell line. Passage after several months yielded astrocyte cultures that repeated a surge of neurite-promoting activity. This long-term potential to produce multiple neurotrophic factors indicates that autologous astrocytes in affected brain regions may serve either as targets for or agents of therapy of Parkinsonism.

Animals↗
PubMed1995

Bone morphogenetic proteins inhibit adipocyte differentiation by bone marrow stromal cells.

The bone morphogenetic proteins were originally identified based on their ability to induce ectopic bone formation in vivo and have since been identified as members of the transforming growth factor-beta gene superfamily. It has been well established that the bone morphogenetic cytokines enhance osteogenic activity in bone marrow stromal cells in vitro. Recent reports have described how bone morphogenetic proteins inhibited myogenic differentiation of bone marrow stromal cells in vitro. In vivo, bone marrow stromal cells differentiate along the related adipogenic pathway with advancing age. The current work reports the inhibitory effects of the bone morphorphogenetic proteins on adipogenesis in a multipotent murine bone marrow stromal cell line, BMS2. When exposed to bone morphogenetic protein-2, the pre-adipocyte BMS2 cells exhibited the expected induction of the osteogenic-related enzyme, alkaline phosphatase. Following induction of the BMS2 cells with adipogenic agonists, adipocyte differentiation was assessed by morphologic, enzymatic, and mRNA markers. Flow cytometric analysis combined with staining by the lipophilic fluorescent dye, Nile red, was used to quantitate the extent of lipid accumulation within the BMS2 cells. By this morphologic criteria, the bone morphogenetic proteins inhibited adipogenesis at concentrations of 50 to 500 ng/ml. This correlated with decreased levels of adipocyte specific enzymes and mRNAs. The BMS2 pre-adipocytes constitutively expressed mRNA encoding bone morphogenetic protein-4 and this was inhibited by adipogenic agonists. Together, these findings demonstrate that bone morphogenetic proteins act as adipogenic antagonists. This supports the hypothesis that adipogenesis and osteogenesis in the bone marrow microenvironment are reciprocally regulated.

Adipose Tissue↗
PubMed1995

Differential regulatory effects of cAMP-elevating agents on human normal and neoplastic B cell functional response following ligation of surface immunoglobulin and CD40.

The B cell response to ligation of surface immunoglobulin (sIg) and CD40 is dependent on the stage of cellular differentiation of the population studied. Cross-linking sIg promotes proliferation of follicular mantle (FM) B cells, rescues germinal center (GC) B cells from spontaneous apoptosis but induces apoptosis in susceptible Burkitt lymphoma (BL) B cells; signals transduced through CD40 induce resting FM B cells to enter cell cycle while promoting GC and BL B cell survival. This study investigates whether the 3', 5'-cyclic adenosine monophosphate (cAMP)-dependent second-messenger pathway plays a role in the regulation of these sIg- and CD40-promoted B cell responses, using prostaglandin E2 (PGE2) and forskolin to artificially increase intracellular levels of cAMP. The Epstein-Barr virus (EBV)-genome-negative BL B cell line Ramos is susceptible to growth arrest and apoptosis triggered by calcium ionophore, anti-IgM and forskolin but not by PGE2; forskolin does not affect the outcome of anti-IgM treatment. Anti-CD40 rescues Ramos-BL B cells from ionophore- and anti-IgM-triggered but not forskolin-triggered growth arrest and apoptosis; moreover, forskolin and anti-CD40 act additively and independently for enhanced growth inhibition. By contrast, both forskolin and PGE2 potentiate the proliferative response of FM B cells cultured with anti-Ig and anti-CD40 together but not individually. Forskolin and PGE2 fail to affect the spontaneous apoptosis and anti-Ig- and anti-CD40-promoted survival of GC B cells. Thus, the cAMP-dependent second messenger pathway can differentially influence the BL, FM, and GC B cell functional response to signals transduced through sIg and CD40.

Adjuvants, Immunologic↗
PubMed1995

Immediate-early genes induced by antigen receptor stimulation.

Immediate early genes induced by triggering of the TCR frequently encode proteins that act in signal transduction cascades. Recent advances concerning several immediate-early proteins have been made, including signal-induced regulation of NF-kappa B by I kappa-B, the role of Nur77 in T-cell selection and apoptosis, and the function of PAC-1 in regulating the Ras/ERK pathway.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1995

Ascertainment of myotonic dystrophy through cataract by selective screening.

Myotonic dystrophy (DM) almost always results from the expansion of an unstable (CTG)n repeat. The mutation can be detected directly. Affected patients with cataracts may have minimal additional signs of the disorder, but all are at risk of life threatening complications. We have studied the efficacy of detecting new families with myotonic dystrophy by selectively screening cataract patients. Selection criteria were: age under 60 with no obvious precipitating factor (except non-insulin dependent diabetes mellitus (NIDDM)); patients of any age with other signs suggestive of myotonic dystrophy detected by the ophthalmologist. Ninety-six patients were tested prospectively; 17 others under 55 were screened retrospectively. All patients were counselled by a clinical geneticist before testing. The patients' DNA was analysed using the DNA probe/restriction enzyme combinations GB2.6/EcoRI, KB1.4/BglI and polymerase chain reaction (PCR). Six patients have been found to have a mutation, three (3.1%) in the prospective group and three (17.6%) in the retrospective group. Three of these patients had minimal myotonic dystrophy and three had classical DM.

Adolescent↗
PubMed1995

Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group.

PURPOSE: This phase III randomized trial was designed to determine if granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the hematologic toxicity and morbidity induced by chemoradiotherapy in limited-stage small-cell lung cancer (SCLC). METHODS: This multicenter prospective trial randomized 230 patients to receive chemotherapy and radiotherapy (RT) with or without GM-CSF given on days 4 to 18 of each of six cycles. The primary end point was hematologic toxicity. Secondary end points included the following: nonhematologic toxicities; days of (1) fever, (2) antibiotics, (3) hospitalization, and (4) infection; number of transfusions; drug doses delivered; and response rates and survival. RESULTS: There was a statistically significant increase in the frequency and duration of life-threatening thrombocytopenia (P < .001) in patients randomized to GM-CSF. GM-CSF patients had significantly more toxic deaths (P < .01), more nonhematologic toxicities, more days in hospital, a higher incidence of intravenous (IV) antibiotic usage, and more transfusions. Patients randomized to GM-CSF had higher WBC and neutrophil nadirs (P < .01), but no significant difference in the frequency of grade 4 leukopenia or neutropenia. Patients randomized to GM-CSF had a lower complete response rate (36% v 44%), but the differences were not significant (P = .29). There were no significant differences in survival (median, 14 months on GM-CSF and 17 months on no GM-CSF; P = .15). CONCLUSION: GM-CSF, as delivered in this study, should not be included with concurrent chemoradiotherapy treatment programs for limited-stage SCLC. The simultaneous use of hematopoietic colony-stimulating factors (CSFs) and chemoradiotherapy should be performed only in experimental settings. Chemoradiotherapy programs with cisplatin and etoposide ([VP-16] PE) and simultaneous chest RT produce grade 4 neutropenia and thrombocytopenia in a small-enough proportion of patients that prophylactic hematopoietic growth factors are clinically unnecessary.

Adult↗
PubMed1995

"Unselling" drugs: the marketing of prevention.

By borrowing from the field of social marketing, the examination and execution of drug prevention strategies should be more rigorous and disciplined by the year 2000. This article briefly describes marketing strategies and techniques which can assist in the maximization of drug prevention communications and programs.

Adolescent↗
PubMed1995

New treatment agents for advanced small cell and non-small cell lung cancer.

The cure rate for lung cancer remains low (13%) primarily due to early systemic spread and the inability to cure systemic disease. These facts have led to pessimism regarding the role of chemotherapy, especially in non-small cell lung cancers. However, recent randomized trials demonstrated that chemotherapy significantly prolongs survival in advanced (stages IIIB and IV) and locally advanced (stages IIIA and IIIB) non-small cell lung cancers. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is an active agent in both non-small and small cell lung cancers, producing objective response rates as high as any other active agent. Early combination studies show even higher response rates when paclitaxel is combined with cisplatin or carboplatin. Ultimately, randomized trials will be needed to define the optimal use of paclitaxel and other recently developed new agents in lung cancer.

Antineoplastic Combined Chemotherapy Protocols↗
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↗
PubMed1992

Risk factor correlates of coronary calcium as evaluated by ultrafast computed tomography.

Coronary artery calcium is invariably associated with atherosclerosis and has been linked to an increased risk of coronary events. Ultrafast computed tomography (CT) was recently used to document the presence and relative quantity of coronary calcium. The use of the self-reported coronary risk factors to identify persons with coronary calcium as documented by ultrafast CT screening was examined in 458 men and 139 women aged 26 to 81 years (88% asymptomatic). All subjects underwent ultrafast CT scanning, and received a questionnaire and underwent an interview regarding medical and risk factor history. Total calcium score was calculated as the sum of lesion-specific scores, each calculated as the product of density > or = 130 Hounsfield units and area > or = 0.51 mm2. The prevalence of coronary calcium increased significantly (p < 0.01) by age group, and the greater the number of risk factors present, the greater the likelihood of calcium. From multiple logistic regression, age (p < 0.01), male sex (relative risk [RR] 3.03; p < 0.01), and history of smoking (RR 1.85; p < 0.01) and hypertension (RR 1.65; p < 0.05) were independently associated with the probability of detectable calcium. Among asymptomatic subjects, an association with hypercholesterolemia was also seen (RR 1.56; p < 0.05). The results demonstrate that cardiovascular risk factors can help in identifying the likelihood of coronary calcium.

Age Factors↗
PubMed1992

The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition.

The candidate oncogene bcl-3 was discovered as a translocation into the immunoglobulin alpha-locus in some cases of B-cell chronic lymphocytic leukaemias. The protein Bcl-3 contains seven so-called ankyrin repeats. Similar repeat motifs are found in a number of diverse regulatory proteins but the motifs of Bcl-3 are most closely related to those found in I kappa B proteins in which the ankyrin repeat domain is thought to be directly involved in inhibition of NF-kappa B activity. No biological function has yet been described for Bcl-3, but it was noted recently that Bcl-3 interferes with DNA-binding of the p50 subunit of NF-kappa B in vitro. Here we demonstrate that Bcl-3 can aid kappa B site-dependent transcription in vivo by counteracting the inhibitory effects of p50/NF-kappa B homodimers. Bcl-3 may therefore aid activation of select NF-kappa B-regulated genes, including those of the human immunodeficiency virus.

Animals↗
PubMed1992

Immediate and long-term results of delayed recanalization of occluded acute myocardial infarction-related arteries using coronary angioplasty.

Recent evidence suggests that late reperfusion of an occluded infarct-related artery after acute myocardial infarction (AMI) may convey a better prognosis. The clinical outcome of percutaneous transluminal coronary angioplasty (PTCA) as a means of mechanical reperfusion in this particular setting has not been clearly delineated. Ninety-seven patients with AMI underwent PTCA of the occluded infarct-related artery after the acute phase of the AMI (48 hours to 2 weeks, mean 8 +/- 4 days). The study consisted of 72 men (74%) (mean age 56.5 +/- 12 years) and 25 women. Seventy-seven patients (79%) had a Q-wave AMI and 20 patients (21%) a non-Q-wave AMI. Seventy-six patients (79%) had angina after AMI and 4 had previously undergone coronary bypass surgery. Clinical success was achieved in 85 patients (87%). Angiographic success was obtained in 90 of the 97 occluded arteries (93%) and was similar for all 3 major vessels: right coronary 97%, left anterior descending 93% and circumflex 85% (p = not significant). Major complications (AMI, emergency bypass and death) occurred in 3 patients (3.1%). Long-term follow up (3.7 +/- 0.8 years) revealed symptomatic recurrence in 20 (23%), whereas 51 (58%) remained asymptomatic. Most recurrences (16 of 20) were in the form of restenosis rather than reocclusion, with a high success rate for repeat dilation (93%). These results indicate that mechanical reperfusion of an occluded infarct artery, performing PTCA 48 hours to 2 weeks after AMI, has a high success rate, a low complication rate and low symptomatic restenosis.

Adult↗
PubMed1992

Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. The Medical Research Council Working Party for Leukaemia in Adults.

Both melphalan and cyclophosphamide increase life expectancy in patients with myelomatosis, but few large randomised studies have compared combination chemotherapy regimens with these single agents. In the Vth MRC myelomatosis trial, the survival of 314 patients randomised to receive ABCM (adriamycin, BCNU, cyclophosphamide, and melphalan) as first-line treatment was significantly longer than that of 316 patients given intermittent melphalan (M7) (p = 0.0003). The 75%, median, and 25% survivals were 7, 24, and 42 months, respectively, with M7 and 10, 32, and 56 months, respectively, with ABCM. Stable disease with few symptoms (plateau) was achieved by 61% of patients given ABCM and 49% of those given M7 (p = 0.004). Myelotoxicity was comparable between regimens. Cross-trial analysis suggests that M7 is comparable to melphalan and prednisone or melphalan, prednisone, and vincristine; that the efficacy of ABCM in the Vth trial and VIth MRC trials is comparable; and that ABCM gave better survival than intermittent melphalan regimens in the prognostic groups analysed. The results indicate that ABCM is an acceptable regimen that is more effective than melphalan, with or without prednisone, for first-line treatment of myelomatosis.

Aged↗
PubMed1992

Is stage I epithelial ovarian cancer overtreated both surgically and systemically? Results of a five-year cancer registry review.

OBJECTIVE: To review the incidence of Stage I epithelial ovarian carcinoma in the West Midlands region and to identify prognostic factors that have a significant effect on survival. DESIGN: A retrospective review of all Stage I ovarian cancer patients registered from 1.1.80 to 31.12.84. SETTING: West Midlands Regional Cancer Registry. POPULATION: 457 patients with Stage I ovarian cancer--373 with epithelial ovarian carcinoma. MAIN OUTCOME MEASURES: Survival at censor date of 30.6.89. RESULTS: 28% developed recurrent disease, and the overall 5-year survival of the group was 70%. Univariate analysis of all possible prognostic factors showed that stage, adjuvant chemotherapy, histological grade and type, surgical rupture of the tumour, intact capsule histologically, clinical finding of ascites and the performance of peritoneal washings were significantly associated with survival. Adequate surgical staging as defined by FIGO was not significantly associated with survival. A multivariate analysis based on the Cox proportional hazard model identified histological grade, adjuvant chemotherapy, patient age and peritoneal washings as having independent prognostic effects. Surprisingly adjuvant chemotherapy and peritoneal washings had negative effects on survival. CONCLUSIONS: Although a retrospective review has limitations, it would appear that adequate surgical staging and adjuvant chemotherapy confer no benefit in terms of survival in Stage I disease.

Adolescent↗