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Biomedical subjects

D Maloney

Publications and source records attributed to D Maloney.

9 recordsLinked to original sources
PubMed1999

Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor.

We investigate here the effects of the incorporation of the nucleoside analogs araC (1-beta-D-arabinofuranosylcytosine) and ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl] guanine) into the DNA binding recognition sequence for the GATA-1 erythroid transcription factor. A 10-fold decrease in binding affinity was observed for the ganciclovir-substituted DNA complex in comparison to an unmodified DNA of the same sequence composition. AraC substitution did not result in any changes in binding affinity. 1H-15N HSQC and NOESY NMR experiments revealed a number of chemical shift changes in both DNA and protein in the ganciclovir-modified DNA-protein complex when compared to the unmodified DNA-protein complex. These changes in chemical shift and binding affinity suggest a change in the binding mode of the complex when ganciclovir is incorporated into the GATA DNA binding site.

Animals↗
PubMed1998

Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma.

BACKGROUND: Monoclonal antibodies are being utilized for treatment of patients with low-grade non-Hodgkin's lymphoma as well as other cancers. Results from phase I and II clinical studies has shown that the chimeric monoclonal antibody Rituximab has minimal toxicity and significant therapeutic activity in low grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: We have recently reported on a multicentre pivotal phase III clinical trial involving 166 patients with recurrent low-grade lymphoma who were treated with four infusions of Rituximab. Eighty patients (48%) achieved objective responses including 10 patients (6%) with complete responses. Overall, 126 patients (76%) had a > or = 20% reduction in overall tumor size. The median response duration and time to progression are 11.6 and 13.2 months, respectively. The infusional and long term toxicities were limited. RESULTS: In this report we describe the pharmacokinetic data obtained on these patients. Measurable concentrations of Rituximab were detected in all patients after the first infusion and increased throughout the treatment course. The half-life of the monoclonal antibody increased from 76.3 hours after the first infusion to 205.8 hours after the fourth infusion and was concomitant with a four-fold decrease in the antibody clearance. At three months and six months post-treatment, the median Rituximab serum levels were 20.3 micrograms/ml (range 0.0 to 96.8 micrograms/ml in 104 patients) and 1.3 micrograms/ml (range 0.0-28.7 micrograms/ml in 13 patients), respectively. A statistically significant correlation was found between the median antibody concentration and response for multiple time points during the treatment and followup. The mean serum antibody concentration was also inversely correlated with measurements of tumor bulk and with the number of circulating B cells at baseline. CONCLUSIONS: We conclude that Rituximab is therapeutically effective against B-cell lymphoma. Pharmacokinetic data suggests that certain subsets of patients may possibly benefit from increased dosing and studies to address this are currently underway.

Antibodies, Monoclonal↗
PubMed1996

Treatment of cutaneous T-cell lymphoma with chimeric anti-CD4 monoclonal antibody.

Chimeric anti-CD4 monoclonal antibody was administered intravenously as a single dose to eight patients with mycosis fungoides. The dose was escalated throughout the study between patients groups, and individual patients received 50, 100, or 200 mg per dose. Seven of eight patients responded to treatment with an average freedom from progression of 25 weeks (range, 6 to 52 weeks). The treatment was well tolerated, and there was no clinical evidence of immunosuppression. Following treatment, there was significant suppression of peripheral blood CD4 counts in all patients for 1 to 22+ weeks. Only one patient made a very low titer human antichimeric antibody response. All but two patients made primary antibody and T-cell proliferative responses to a foreign antigen administered 24 hours after antibody infusion. However, there was generally marked, but temporary suppression of T-cell proliferative responses in vitro to phytohemagglutinin (PHA), tetanus toxoid, and normal donor lymphocytes. We conclude that at the dose levels studied, this antibody (1) had clinical efficacy against mycosis fungoides; (2) was well tolerated; (3) had a low level of immunogenicity; (4) decreased T-cell proliferative responses in vitro, and (5) did not induce tolerance to a foreign antigen.

Adult↗
PubMed1994

Impending paradoxical embolism: a case report and literature review.

Paradoxical embolism occurs following the passage of embolic material from the venous to the arterial circulation through a right to left shunt--frequently a patent foramen ovale. The diagnosis is usually presumptive when arterial emboli occur in the appropriate clinical setting. We describe a case of impending paradoxical embolism in a patient with massive pulmonary embolism. Transoesophageal echocardiography revealed a thromboembolus straddling a patent foramen ovale. The patient underwent emergency removal of the intracardiac clot with closure of the patent foramen ovale.

Aged↗
PubMed1990

Microconversion between murine H-2 genes integrated into yeast.

Patchwork homology observed between divergent members of polymorphic multigene families is thought to reflect evolution by short-tract gene conversion (nonreciprocal recombination), although this mechanism cannot usually be confirmed in higher organisms. In contrast to meiotic conversions observed in laboratory yeast strains, apparent conversions between polymorphic sequences, such as the class I loci of the major histocompatibility complex (MHC), are short and do not seem to be associated with reciprocal recombination (crossover, exchanges). We have now integrated two nonallelic murine class I genes into yeast to characterize their meiotic recombination. We found no crossovers between the MHC genes, but short-tract 'microconversions' of 1-215 base-pairs were observed in about 6% of all meioses. Strikingly, one of these events was accompanied by a single base-pair mutation. These results underscore both the importance of meiotic gene conversion and sequence heterology in determining conversion patterns between divergent genes.

Animals↗
PubMed1983

Yeast contains small nuclear RNAs encoded by single copy genes.

We have identified a group of RNA molecules in Saccharomyces cerevisiae that appears to be equivalent to the U class of small nuclear RNAs previously described in other eucaryotes, resembling them in size, metabolic stability, 5' cap structure, presence of modified bases, and nuclear localization. However, the yeast snRNAs differ from their counterparts in several potentially important ways. First, they are present in very low abundance, less than 200 copies per cell, as compared to 10(5)-10(6) for mammalian U1-U6. Second, there appear to be more species in yeast than in any cell type previously examined. Finally, we have cloned five yeast snRNA genes, and find that each is present in a single copy per haploid genome, whereas all previously characterized snRNAs are encoded by multiple (5 to 100) gene copies. The presence of single copy genes in yeast will greatly facilitate the genetic analysis of snRNA function.

Base Sequence↗
PubMed1983

Treatment of small cell carcinoma of the bronchus by combined chemotherapy--clinicopathological correlation with response.

Thirty-seven consecutive patients, referred to a respiratory unit with a histological diagnosis of small cell carcinoma of the bronchus, were treated with a combined chemotherapy regime of adriamycin, vincristine and cyclophosphamide. Palliative radiotherapy was given for the control of symptoms. Thirty of 37 patients responded to treatment, 11/37 having a complete and 19/37 a partial response. The median survival of those patients with a complete response was 55 weeks, significantly higher (P less than 0.01) than either those with partial or no response to treatment. Those patients with limited disease survived longer. A high proportion of patients relapsed at the primary site of the tumour in the lungs. The relationship between the therapeutic response and the histological subtype of small cell carcinoma suffered from the limitations of the available pathological material. However, more of the patients with a complete response were of the lymphocytic-like pattern of small cell carcinoma. Useful survival in these patients with inoperable small cell carcinoma was achieved using this regime of chemotherapy, even in those patients with extensive disease, five of whom had survived for over one year.

Adult↗