Developing Britain's police surgeon service.
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Coroners and Medical Examiners↗
Biomedical subjects
K Kelly
Publications and source records attributed to K Kelly.
Chromosomal organization and transcriptional regulation of human GEM and localization of the human and mouse GEM loci encoding an inducible Ras-like protein.
The mitogen-induced gene, GEM, encodes a GTP-binding protein that belongs to a new family within the Ras superfamily. The regulated expression pattern of Gem suggests a role for this protein in cellular responses to growth stimulation. To facilitate the assessment of the possible role of GEM in heritable and spontaneous disease processes, the genomic organization of human GEM and the chromosomal localization of human and murine GEM have been determined. GEM has been localized to the long arm of human chromosome 8 (8q13-q21) between the D8S85 and CA2 loci by genetic linkage analysis using an MspI restriction fragment length polymorphism within GEM. No consistent somatic chromosomal alterations or heritable diseases are associated with this region. Mouse Gem maps to the proximal region of chromosome 4 between Mos and Cga. To gain insight into the transcriptional regulation of GEM, we have established the transcriptional initiation site of GEM in human T cells and defined a 5' upstream region sufficient for mitogen-responsive, inducible transcription.
Animals↗
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↗
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↗
Prophylactic cranial irradiation for patients with small-cell lung cancer.
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Brain Neoplasms↗
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↗
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↗
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↗
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↗
A consensus polymerase chain reaction-oligonucleotide hybridization approach for the detection of chromosomal translocations in pediatric bone and soft tissue sarcomas.
Chromosomal translocations have been identified that are consistently associated with alveolar rhabdomyosarcoma and Ewing's sarcoma. Molecular diagnostic assays for these chromosomal translocations are important tools for the differential diagnosis of pediatric small round cell tumors presenting in the bones or soft tissues. However, the occurrence of variant chromosomal translocations in these cancers has complicated these molecular diagnostic approaches. To simplify the molecular detection of typical and variant translocations, the authors have developed an approach consisting of consensus reverse transcriptase-polymerase chain reaction and oligonucleotide hybridization steps. In the first step, consensus primers for each tumor type permit amplification of the chimeric transcripts resulting from both the common and variant translocations. In the second step, the common and variant translocations are distinguished by hybridization with gene-specific oligonucleotide probes. This approach provides a sensitive, specific, and efficient strategy for the detection of these chromosomal translocations.
Base Sequence↗
Chest pain and cardiomegaly without pulmonary involvement: an atypical presentation of pediatric mycobacterial disease.
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Biopsy↗
Lipopolysaccharide regulation of lipoprotein lipase expression in murine macrophages.
The enzyme lipoprotein lipase is expressed in a number of cell types and plays a central role in lipid metabolism. Multiple factors regulate its expression in a tissue-specific manner. In murine macrophages, lipopolysaccharide inhibits lipoprotein lipase enzyme activity. The current work examines this process in the established J774 macrophage line and primary peritoneal macrophages from endotoxin-sensitive (C3HeB/Fej) and endotoxin-resistant (C3H/Hej) murine strains. Lipopolysaccharide inhibition of macrophage lipoprotein lipase occurred at the enzyme and mRNA levels in a time- and concentration-dependent manner. Cells from endotoxin-resistant animals maintained their expression of lipoprotein lipase following treatment with lipopolysaccharide. Results of gel retention assays showed that lipopolysaccharide treatment of the J774 macrophages altered the level of nuclear proteins recognizing and binding the lipoprotein lipase promoter DNA. Nuclear extracts from resting J774 cells contained proteins which bound specifically to the octamer motif and to the CAAT box within the lipoprotein lipase promoter. Exposure of the J774 cells to lipopolysaccharide for 16 h increased the level of protein-octamer DNA complexes. Similar responses were obtained in endotoxin-sensitive, but not endotoxin-resistant, primary macrophages following in vitro treatment with lipopolysaccharide. This finding suggests that transcriptional events may contribute to the lipopolysaccharide regulation of macrophage lipoprotein lipase expression.
Animals↗
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↗
Role of recombinant interferon alfa-2a maintenance in patients with limited-stage small-cell lung cancer responding to concurrent chemoradiation: a Southwest Oncology Group study.
PURPOSE: This study was designed to determine if recombinant interferon alfa-2a (rIFN alpha-2a) could prolong remission duration and/or survival in patients with limited-stage small-cell lung cancer (SCLC) who achieved an objective response to chemoradiotherapy. A secondary end point was to assess the toxicity of chronic IFN administration. PATIENTS AND METHODS: One hundred seventy-one of 215 eligible patients achieved an objective response and were eligible to receive rIFN alpha-2a (3 million units [MU]/m2 subcutaneously three times per week escalated to 9 MU/m2 as tolerated) or observation for 2 years. RESULTS: One hundred thirty-two of 140 registered patients were eligible. Sixty-four patients were randomized to receive IFN and 68 to observation alone. The median time from randomization to progression was 9 months on the IFN arm and 10 months on the observation arm (P = .72). The overall median survival time was 16 months on the observation arm versus 13 months on the IFN arm (P = .77). Significant toxicities occurred in the rIFN alpha-2a arm. Grade 3 or higher toxicities included malaise, fatigue, and/or lethargy (30%), leukopenia (14%), neutropenia (13%), dyspnea (13%), nausea (11%), and respiratory infection (6%). Forty-three patients discontinued treatment due to intolerable side effects. CONCLUSION: rIFN alpha-2a in the dose and schedule used in this study failed to prolong response duration or survival in patients with limited-stage SCLC who had previously responded to an induction chemoradiotherapy program. Failure may have been partly related to poor tolerance and inability to complete therapy.
Adult↗
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↗
Assessing community readiness for prevention.
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Consumer Behavior↗
"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↗
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↗