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Biomedical subjects

T E Coyle

Publications and source records attributed to T E Coyle.

8 recordsLinked to original sources
PubMed1998

The hydroxyurea-induced loss of double-minute chromosomes containing amplified epidermal growth factor receptor genes reduces the tumorigenicity and growth of human glioblastoma multiforme.

OBJECTIVE: We investigated whether the hydroxyurea-induced loss of double-minute chromosomes containing amplified epidermal growth factor receptor (EGFR) genes would lead to a loss of tumorigenicity of a glioblastoma multiforme cell line. METHODS: Glioblastoma multiforme cells were treated in vitro with 0 (HU0) or 100 micromol/L (HU100) hydroxyurea and then injected into the flanks of nude mice. Survival and tumor volumes were evaluated. Pulsed-field gel electrophoresis, Southern blot hybridization, and slot-blot analysis were used to determine EGFR amplification levels. Flow cytometry and immunofluorescent staining were used for cell-cycle analysis and EGFR protein expression. RESULTS: Prior to injection, HU100 cells lost 95% of their amplified EGFR genes and developed into tumors 6 weeks after injection versus 3 weeks for HU0 cells. Mice with HU100 tumors had a median survival of 62 days versus 43 days for control mice with HU0 tumors. Pulse-field gel electrophoresis analysis showed that HU100 tumors had reamplified the EGFR gene as double-minute chromosomes of the same size as those originally present before hydroxyurea treatment. When HU100 cells were cultured in the absence of hydroxyurea, the EGFR gene also reamplified. HU100 cells grew at less than half the rate of untreated HU0 control cells in culture and showed a decreased number of cells entering the cell cycle. Immunofluorescent staining of HU150 (150 micromol/L) cells showed decreased EGFR protein expression. CONCLUSION: The EGFR gene is important for tumorigenicity in mice and growth in culture. Hydroxyurea induces the loss of double-minute chromosome-amplified EGFR genes against a selection gradient and significantly delays the onset of tumors. These results support the potential use of low-dose hydroxyurea for the treatment of human glioblastoma multiforme.

Animals↗
PubMed1997

Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors.

BACKGROUND: Procarbazine usage in brain tumors has a high incidence of hypersensitivity reactions compared with its use in other malignancies. Procarbazine oxidation to a reactive intermediate is enhanced by phenobarbital. Patients with primary brain tumors would have a preferential exposure to anticonvulsants compared to patients with other malignancies. OBJECTIVE: To determine whether anticonvulsant exposure is associated with procarbazine hypersensitivity reactions in patients with primary brain tumors. METHODS: This retrospective cohort study included 83 patients with primary brain tumors who were treated with procarbazine between 1981 and 1996 at a university hospital-based regional oncology center. Data were extracted by chart review. The data collected included age, sex, race, tumor type, smoking, alcohol usage, and all concomitant medications, as well as creatinine, aspartate aminotransferase, total bilirubin, and anticonvulsant serum levels. Anticonvulsant exposure was determined by the presence of detectable serum levels. Cases of procarbazine hypersensitivity reactions were identified through a review of progress notes. RESULTS: There were 20 patients with procarbazine hypersensitivity reactions. A significant association between the exposure to anticonvulsants and the development of procarbazine hypersensitivity reactions was found (p = 0.05). In addition, there was a significant dose-response association between the development of procarbazine hypersensitivity and the presence of therapeutic anticonvulsant serum levels (p = 0.03). CONCLUSIONS: Concomitant exposure to anticonvulsants is associated with procarbazine hypersensitivity reactions, possibly though a reactive intermediate generated by CYP3A isoform induction. All patients in this cohort received enzyme-inducing anticonvulsants. New anticonvulsants devoid of this property are available. These data support trials that use these newer agents for the prophylaxis of seizures in patients with brain tumors who are to receive procarbazine.

Adult↗
PubMed1997

Hematologic complications of human immunodeficiency virus infection and the acquired immunodeficiency syndrome.

The hematologic manifestations of HIV infection and AIDS are common and may cause symptoms that are life-threatening and impair the quality of life of these patients. The most important of these manifestations are cytopenias. Anemia and neutropenia are generally caused by inadequate production because of suppression of the bone marrow by the HIV infection through abnormal cytokine expression and alteration of the bone marrow microenvironment. Thrombocytopenia is caused by immune-mediated destruction of the platelets, in addition to inadequate platelet production. The incidence and severity of cytopenia are generally correlated to the stage of the HIV infection. Other causes of cytopenia in these patients include adverse effects of drug therapy, the secondary effects of opportunistic infections or malignancies, or other preexisting or coexisting medical problems that may be prevalent in the HIV-infected population. Diagnosis of the mechanism and cause of the cytopenia may allow for specific management. Optimal management of the underlying HIV infection is essential, and mild cytopenia in asymptomatic patients may need no specific management. Supportive care for anemia includes the use of erythropoietin in addition to the judicious use of red blood cell transfusions. Therapy for neutropenia includes the use of the myeloid growth factors G-CSF and GM-CSF. Immune-mediated thrombocytopenia may be treated with a combination of zidovudine, corticosteroids, IVGG, and splenectomy. Platelet transfusions are sometimes needed for the treatment of thrombocytopenia caused by decreased production. Other hematologic manifestations such as hypergammaglobulinemia and lupus anticoagulants are commonly asymptomatic and usually require no specific therapy, but they can rarely cause morbidity and require specific interventions.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Moderate hemophilia B Leyden: identification by polymerase chain reaction, sequencing, and oligomer restriction.

Hemophilia B Leyden is a rare form of congenital factor IX deficiency which is characterized by severe factor IX deficiency at birth, which ameliorates after puberty. It is caused by mutations in the factor IX gene promoter region and the postpubertal amelioration is thought to be mediated by the action of testosterone on an androgen response element located in the promoter region. Three kindreds have been previously reported with a milder form of hemophilia B Leyden, associated with a guanine to adenine transition at nucleotide position -6 of the promoter region. We now report a fourth kindred with this mutation. The proband was a newborn with a factor IX level of 2.5%, his 12-year-old half-brother had a level of 28%, and his mother's 56-year-old maternal cousin had a level of 60%. A G to A transition at nucleotide -6 of the promoter region was demonstrated by cloning and sequencing polymerase chain reaction products from the half brother, and the mother was demonstrated to be a carrier. The mutation eliminates a TaqI restriction endonuclease site normally present in the wild type promoter, and the mother's cousin was demonstrated to carry the mutation by the absence of digestion with TaqI. The identification of hemophilia B Leyden with this specific mutation has practical importance to the clinical management because of its unique natural history and significantly better prognosis than classical hemophilia B.

Base Sequence↗
PubMed1992

Large granular lymphocytosis terminating in a polymorphous B-lymphocytic proliferation after low-dose cyclophosphamide therapy: a case report with necropsy findings.

A 70-year-old man presented with clonal large granular lymphocytosis of T-suppressor/cytotoxic immunophenotype, neutropenia, paraproteinemia, and proneness to infection. The patient became severely leukopenic during 14 days of chemotherapy with low-dose cyclophosphamide, and remained so after discontinuation of the drug. Clinically, he was thought to have prolonged chemotherapy-induced marrow hypoplasia. At death, 16 days after the last dose of chemotherapy, autopsy confirmed bone marrow hypoplasia and revealed that well-differentiated, polymorphous, and (immunophenotypically and genotypically) polyclonal B-lymphocytes predominated in normal hematopoietic and lymphoid organs. A similar lymphoid infiltrate was intimately associated with multiple ulcers and smooth muscle necrosis in the stomach. These terminal findings resemble B-lymphoproliferative conditions described in certain forms of immune deficiency.

Aged↗