PubMed Health⌕ Search

Biomedical subjects

J Hamm

Publications and source records attributed to J Hamm.

At least 19 recordsLinked to original sources
PubMed1995

Phase II trial of 5-fluorouracil, folinic acid, and N,N1,N11-triethylenethiophosphoramide (thiotepa) in patients with advanced breast cancer.

A total of 35 women with advanced, metastatic breast cancer were treated with combination chemotherapy consisting of folinic acid 500 mg/m2 over 2 hours administered with 600 mg/m2 of 5FU at the midpoint of the folinic acid infusion weekly for 6 weeks, plus 60 mg/m2 of thiotepa on day 1 and day 28. The cycle was repeated every 8 weeks. Patients were evaluated for toxicity weekly. Response was evaluated at the end of each 8-week cycle. The median age was 55 years (range: 34-67). Prior to this study 30 patients had received chemotherapy; 13 had 1 regimen; 17 had 2 or more regimens; 8 had 5FU treatment. The overall response rate was 40% (1 complete and 13 partial); median duration of response was 4 months. Four of 8 patients with prior 5FU responded. Hematologic toxicity was significant; nadir WBC count: < 1,000/mm3 (10 patients); 1,000-1,999/mm (13 patients); nadir platelet count: < 20,000/mm3 (8 patients): 20,000-49,000/mm3 (8 patients); 50,000-99,000/mm3 (10 patients). We conclude that the combination of thiotepa, 5FU, and leucovorin had significant myelotoxicity and do not recommend its routine use in the treatment of metastatic breast cancer.

Adult↗
PubMed1994

Dose-ranging study of recombinant human granulocyte-macrophage colony-stimulating factor in small-cell lung carcinoma.

PURPOSE: This randomized, multicenter, dose-finding study was undertaken to determine the dose of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) that can safely reduce neutropenia after cyclophosphamide, doxorubicin, and etoposide (CAVP-16) chemotherapy in patients with small-cell lung cancer (SCLC). Secondary clinical end points included incidence of infection, intravenous (IV) antimicrobial use, and chemotherapy delivered. PATIENTS AND METHODS: A total of 290 newly diagnosed SCLC patients were to receive six cycles of standard CAVP-16 chemotherapy on days 1 to 3 of every 21 days alone or with rhGM-CSF at 5, 10, or 20 micrograms/kg, administered subcutaneously (SC) on days 4 to 13 of each cycle. RESULTS: In cycle 1, median absolute neutrophil count (ANC) nadirs were twofold to threefold higher in patients who received rhGM-CSF, although all values were less than 500/microliters, and recovery from neutropenia was faster at all rhGM-CSF dosages versus observation (P < or = .01). In cycle 2, 56% of all patients given rhGM-CSF received full chemotherapy dosages (87.5% to 112.5% of projected dose) versus 36% of observation patients. During days 5 to 21 of cycle 1, fewer patients who received 10 micrograms/kg of rhGM-CSF required antibiotics compared with observation patients (11% v 29%, P < or = .01). Adverse events that occurred more frequently in rhGM-CSF-treated patients included injection-site reaction, edema, asthenia, paresthesia, diarrhea, myalgia, musculoskeletal pain, Pruritus, and rash (P < or = .10). Fever occurred more frequently in the 10- and 20-micrograms/kg rhGM-CSF groups than in the observation groups. The incidence in the 5-microgram/kg group was comparable to that in observation patients. Patients who received rhGM-CSF had a higher incidence of thrombocytopenia. CONCLUSION: rhGM-CSF at 5 to 10 micrograms/kg reduces chemotherapy-associated neutropenia and should be the dose range used in future studies.

Adult↗
PubMed1992

Residual mediastinal mass after treatment of Hodgkin's disease: a decision analysis.

A residual mediastinal mass after completion of initial treatment for Hodgkin's disease is a frequent clinical problem. Investigators have suggested three possible approaches to this important problem: 1) observation, 2) additional diagnostic tests with subsequent action based upon test results, or 3) immediate treatment for high-risk patients. The method of decision analysis was applied to determine the optimal management for residual mediastinal abnormalities following treatment of Hodgkin's disease with combined modalities of MOPP chemotherapy and radiation therapy. The three parameters of the importance for making the best decision were: 1) the probability that the mass is truly active disease, 2) the salvage success rate using MOPP or ABVD treatment and 3) the specificity of the gallium scan. The analysis favored the gallium imaging strategy as an initial management choice when the probability was greater than 3% that the residual mass represented active disease and the specificity of gallium imaging was greater than 56%. This strategy proved to be the most cost effective, as well. Additional chemotherapy was favored only when there was a greater than 99% probability that the mass represented active disease. A nomogram has been constructed combining all three parameters of importance for graphically determining the best decision.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

GM-CSF in the treatment of Felty syndrome.

Many therapeutic agents have been tried with variable success in the treatment of Felty neutropenia, but the reports are anecdotal. We now describe the second trial of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), in a splenectomized, infected patient with Felty syndrome.

Felty Syndrome↗
PubMed1991

Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting.

Dronabinol (Marinol, Roxane Laboratories, Columbus, OH) and prochlorperazine were tested alone and in combination in a randomized, double-blind, parallel group, multicenter study. Patients were randomized to receive either 1) dronabinol 10 mg every 6 hr plus placebo; 2) placebo plus prochlorperazine 10 mg every 6 hr; or 3) dronabinol and prochlorperazine, each 10 mg every 6 hr. Antiemetic treatment was begun 24 hr prior to and continued for 24 hr after the last dose of chemotherapy; all was given orally. Only 29% of patients in group 3 versus 47% in group 1 and 60% in group 2 experienced nausea after chemotherapy. In addition, the median duration per episode and severity of nausea were significantly less with combination therapy. Vomiting occurred after chemotherapy in 41%, 55%, and 35% of patients in groups 1, 2, and 3, respectively. The median duration per episode of vomiting was 1 min in group 3 versus two in group 1 and four in group 2. Side effects, primarily CNS, were more common in group 1 than in group 2; addition of prochlorperazine to dronabinol appeared to decrease the frequency of dysphoric effects seen with the latter agent. The combination was significantly more effective than was either single agent in controlling chemotherapy-induced nausea and vomiting.

Adult↗
PubMed1990

Monomethylated cap structures facilitate RNA export from the nucleus.

RNA export from the nucleus has been analyzed in Xenopus oocytes. U1 snRNAs made by RNA polymerase II were exported into the cytoplasm, while U1 snRNAs synthesized by RNA polymerase III, and therefore with a different cap structure, remained in the nucleus. Export of the polymerase II-transcribed RNAs was inhibited by the cap analog m7GpppG. Spliced mRNAs carrying monomethylguanosine cap structures were rapidly exported, while hypermethylated cap structures delayed mRNA export. The export of a mutant precursor mRNA unable to form detectable splicing complexes was also significantly delayed by incorporation of a hypermethylated cap structure. The results suggest that the m7GpppN cap structure is likely to be a signal for RNA export from the nucleus.

Animals↗
PubMed1990

The trimethylguanosine cap structure of U1 snRNA is a component of a bipartite nuclear targeting signal.

The ability of series of U1 snRNAs and U6 snRNAs to migrate into the nucleus of Xenopus oocytes after injection into the cytoplasm was analyzed. The U snRNAs were made either by injecting U snRNA genes into the nucleus of oocytes or, synthetically, by T7 RNA polymerase, incorporating a variety of cap structures. The results indicate that nuclear targeting of U1 snRNA requires both a trimethylguanosine cap structure and binding of at least one common U snRNP protein. Using synthetic U6 snRNAs, it is further demonstrated that the trimethylguanosine cap structure can act in nuclear targeting in the absence of the common U snRNP proteins. These results imply that U snRNP nuclear targeting signals are of a modular nature.

Animals↗
PubMed1990

Multiple domains of U1 snRNA, including U1 specific protein binding sites, are required for splicing.

Domains of U1 snRNA which are functionally important have been identified using a splicing complementation assay in Xenopus oocytes. Mutations in, and deletions of, all three of the hairpin loop structures near the 5' end of the RNA are strongly deleterious. Similarly, mutation of the Sm binding site abolishes complementation activity. Analysis of the protein binding properties of the mutant U1 snRNAs reveals that three of the functionally important domains, the first two hairpin loops and the Sm binding site, are required for interaction with U1 snRNP proteins. The fourth functionally important domain does not detectably affect snRNP protein binding and is not evolutionarily conserved. All of the deleterious mutations are shown to have similar effects on in vivo splicing complex formation.

Animals↗
PubMed1989

Identification of the RNA binding segment of human U1 A protein and definition of its binding site on U1 snRNA.

The interaction between the U1 snRNP-specific U1 A protein and U1 snRNA has been analysed. The binding site for the protein on the RNA is shown to be in hairpin II, which extends from positions 48 to 91 in the RNA. Within this hairpin the evolutionarily conserved loop sequence is crucial for interaction with U1 A protein. U1 A protein can also bind the loop sequence when it is part of an artificial RNA which cannot form a stable hairpin structure. The region of the protein required to bind to U1 snRNA consists of a conserved 80 amino acid motif, previously identified in many ribonucleoprotein (RNP) proteins, together with (maximally) 11 N-terminal and 10 C-terminal flanking amino acids. Point mutations introduced into two of the most highly conserved regions of this motif abolish RNA binding. U1 snRNA mutants from which the U1 A binding site has been deleted are shown to be capable of assembly into RNP particles which are immunoprecipitable by patient antisera which recognize U1 A protein. The role of RNA-protein and protein-protein interactions in U snRNP assembly are discussed.

Animals↗
PubMed1989

An abundant U6 snRNP found in germ cells and embryos of Xenopus laevis.

The particle state of U snRNPs was analyzed in oocytes, eggs, embryos and testes from Xenopus laevis. In each case both the relative abundance and the composition of some U snRNPs were found to differ from that of somatic cells. U2 and U6 snRNPs were the most prominent U snRNPs in germ cells and early embryos. In particular, the concentration of U6 snRNA was 10-20 times higher than that of U4 snRNA. Most of the U6 snRNA was not associated with U4 snRNA and migrated on sucrose gradients as a U6 snRNP. The structure of this novel U snRNP was analyzed. A single protein of 50 kd was copurified with U6 snRNPs by a combination of gradient fractionation, immunodepletion with anti-Sm antibodies and immunoprecipitation with anti-6-methyl adenosine antibodies. Although the U6 snRNP did not contain Sm proteins it migrated into the nucleus when U6 snRNA was injected into the cytoplasm of oocytes. Two U6 snRNA elements have been identified. The first is essential for nuclear migration in oocytes, but not for the formation of U4/6 snRNPs in vitro and might be the binding site of a U6-specific protein. The second element was required for interaction with U4 snRNPs but not for nuclear targeting.

Animals↗
PubMed1989

Functional analysis of mutant Xenopus U2 snRNAs.

Methods for studying pre-mRNA splicing in Xenopus oocytes have been improved to allow simultaneous analysis of the splicing reaction and the formation of splicing complexes in vivo. The number, order of appearance, and dependence on intact U1 and U2 snRNPs of complexes formed in vivo on a pre-mRNA substrate are similar but not identical to those observed in vitro. The migration on native gels of the complexes formed in vivo and in vitro is, however, dissimilar. RNAase H-mediated inhibition of splicing caused by oligonucleotide microinjection can be overcome by coinjection of a gene encoding the U snRNA that is targeted for cleavage. Transcripts from the injected gene complement the defect in splicing by assembling into functionally active U snRNPs. Using this assay, mutant U2 snRNAs have been tested for their ability to function in splicing and in splicing complex formation. The results indicate that much of the U2 snRNA, including regions essential for detectable binding of the U2-specific proteins A' and B", is dispensable for splicing.

Animals↗
PubMed1989

Probing the structure and function of U2 snRNP with antisense oligonucleotides made of 2'-OMe RNA.

We have used oligonucleotides made of 2'-OMe RNA to analyze the role of separate domains of U2 snRNA in the splicing process. We show that antisense 2'-OMe RNA oligonucleotides bind efficiently and specifically to U2 snRNP and demonstrate that masking of two separate regions of U2 snRNA can inhibit splicing by affecting different steps in the spliceosome assembly pathway. Masking the 5' terminus of U2 snRNA does not prevent U2 snRNP binding to pre-mRNA but blocks subsequent assembly of a functional spliceosome. By contrast, masking of U2 sequences complementary to the pre-mRNA branch site completely inhibits binding of pre-mRNA. Hybrid formation at the branch site complementary region also triggers a specific change which affects the 5' terminus of U2 snRNA.

Cell Nucleus↗
PubMed1988

Loop I of U1 small nuclear RNA is the only essential RNA sequence for binding of specific U1 small nuclear ribonucleoprotein particle proteins.

The binding of the U1 small nuclear ribonucleoprotein (snRNP)-specific proteins C, A, and 70K to U1 small nuclear RNA (snRNA) was analyzed. Assembly of U1 snRNAs from bean and soybean and a set of mutant Xenopus U1 snRNAs into U1 snRNPs in Xenopus egg extracts was studied. The ability to bind proteins was analyzed by immunoprecipitation with monospecific antibodies and by a protein-sequestering assay. The only sequence essential for binding of the U1-specific proteins was the conserved loop sequence in the 5' hairpin of U1. Further analysis suggested that protein C binds directly to the loop and that the assembly of proteins A and 70K into the RNP requires mainly protein-protein interactions. Protein C apparently recognizes a specific RNA sequence rather than a secondary structural element in the RNA.

Animals↗
PubMed1987

The 5S gene internal control region is composed of three distinct sequence elements, organized as two functional domains with variable spacing.

Systematic oligonucleotide-directed mutagenesis within the internal control region of the Xenopus laevis somatic 5S RNA gene identifies three distinct sequence elements that regulate transcription activity: box A, containing the common, conserved class III promoter domain, and two 5S-gene-specific segments, termed intermediate element and box C. Analysis of the individual steps in the formation of the stable initiation complex reveals that the two 5S-gene-specific elements are the main determinants for the stable binding of TFIIIA. In contrast, TFIIIC binding appears to be dependent on interactions with TFIIIA and on direct DNA interactions in box A as well as probably in box C. Alterations of the spacing between the two major promoter domains of from -3 to +10 nucleotides are tolerated, although they reduce transcription activity and were found to prevent the formation of a stable initiation complex.

Animals↗