Biomedical subjects

J Torkelson

Publications and source records attributed to J Torkelson.

6 recordsLinked to original sources

PubMed1999

Mechanisms of genome-wide hypermutation in stationary phase.

Stationary-phase mutation (a subset of which was previously called adaptive mutation) occurs in apparently nondividing, stationary-phase cells exposed to a nonlethal genetic selection. In one experimental system, stationary-phase reversion of an Escherichia coli F'-borne lac frameshift mutation occurs by a novel molecular mechanism that requires homologous recombination functions of the RecBCD system. Chromosomal mutations at multiple loci are detected more frequently in Lac+ stationary-phase revertants than in cells that were also exposed to selection but did not become Lac+. Thus, mutating cells represent a subpopulation that experiences hypermutation throughout the genome. This paper summarizes current knowledge regarding stationary-phase mutation in the lac system. Hypotheses for the mechanism of chromosomal hypermutation are discussed, and data are presented that exclude one hypothetical mechanism in which chromosomal mutations result from Hfr formation.

DNA Repair↗

PubMed1997

Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation.

Stationary-phase mutation in microbes can produce selected ('adaptive') mutants preferentially. In one system, this occurs via a distinct, recombination-dependent mechanism. Two points of controversy have surrounded these adaptive reversions of an Escherichia coli lac mutation. First, are the mutations directed preferentially to the selected gene in a Lamarckian manner? Second, is the adaptive mutation mechanism specific to the F plasmid replicon carrying lac? We report that lac adaptive mutations are associated with hypermutation in unselected genes, in all replicons in the cell. The associated mutations have a similar sequence spectrum to the adaptive reversions. Thus, the adaptive mutagenesis mechanism is not directed to the lac genes, in a Lamarckian manner, nor to the F' replicon carrying lac. Hypermutation was not found in non-revertants exposed to selection. Therefore, the genome-wide hypermutation underlying adaptive mutation occurs in a differentiated subpopulation. The existence of mutable subpopulations in non-growing cells is important in bacterial evolution and could be relevant to the somatic mutations that give rise to cancers in multicellular organisms.

Adaptation, Biological↗

PubMed1995

Optimal number of chemotherapy courses in advanced nonseminomatous testicular carcinoma.

BACKGROUND: Nonseminomatous germ cell tumors (NSGCT) (testicular carcinoma) are a curable disease. Stages I and II are nearly 100% curable. Stage III has had remarkable progress in attaining complete regression, but a substantial number fail to be cured. Using platinum-based regimens such as vinblastine, bleomycin, and cisplatin (VBP), or using etoposide instead of vinblastine (BEP), or without bleomycin (EP), four courses of chemotherapy have become a national standard. Based on our prior experience with mithramycin (plicamycin), which used six courses, six courses of VBP chemotherapy were utilized as our treatment goal. This report challenges the concept that "standard therapy" for stage III testicular carcinoma is four courses. METHOD: From 1976 to 1990, 74 patients with advanced NSGCT were treated with standard doses of plantinum-based chemotherapies. Five or more courses were delivered to 41 patients and fewer than five courses to 33 patients. The intent of therapy was to attain as close to six courses as possible. Because of physician preference, patient adherence, or toxicity, some patients did not reach that goal. RESULTS: Of 33 patients receiving less than five courses, there were 28 (85%) complete responders, and 26 (78.8%) are alive. Of 41 patients receiving five or more courses, 38 (92.7%) had complete responses, and 34 (83%) are alive. One person in each group is living with nonresectable teratoma present. In the group receiving 5+ courses, two died from causes unrelated to testis cancer and had no testis cancer present. As a result of the initial treatment, there was no evidence of cancer in 24 (72.8%) in the group receiving less than five courses and 35 (85.4%) had no cancer after five or more courses. In considering only patients with advanced level of stage III disease in contrast to minimal or moderate stage III disease, there were fewer complete regressions with less than five courses (64.3%) than with five or more courses (88.0%). CONCLUSIONS: For minimal stage III disease, four courses of chemotherapy may be adequate. For advanced stage III disease, more chemotherapy provides fewer treatment failures. Once a complete response is achieved without restriction to an arbitrary number of courses, two additional courses may constitute a more curative regimen.

Antibiotics, Antineoplastic↗

PubMed1995

Molecular handles on adaptive mutation.

In one experimental system, several handles on the molecular mechanism of apparent adaptive mutation have emerged. The system is reversion of a lac frameshift mutation in Escherichia coli. The molecular handles include a requirement for homologous recombination; the implication of DNA double-strand breaks as a molecular intermediate; a unique sequence spectrum of -1 deletions in mononucleotide repeats which implies polymerase errors, and also implies a failure of postsynthesis mismatch repair on those errors; and the involvement of sexual functions at some stage of the process. These molecular handles are revealing an unexpected new mechanism of mutagenesis.

Conjugation, Genetic↗

PubMed1983

Stage II nonseminomatous testicular cancer: a 10-year experience.

Between 1970 and 1980, 82 patients with pathologic stage II nonseminomatous germ cell testicular carcinoma were treated at the University of Minnesota. Of the 30 patients treated with a retroperitoneal lymph node dissection, 22 (77%) relapsed. Of the 18 patients treated with retroperitoneal lymph node dissection and adjuvant radiotherapy, 12 (63%) relapsed. Sixteen patients received adjuvant chemotherapy before 1976, and 14 (87.5%) relapsed. After 1976, 18 patients received adjuvant chemotherapy (11 with cisplatin) and 2 (11%) have relapsed. No patient treated with cisplatin-based adjuvant chemotherapy has relapsed. The toxicity has been modest. Cisplatin-based chemotherapy is an effective and a safe adjuvant therapy for stage II nonseminomatous germ cell testicular carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1982

Tumor classification and size in germ-cell testicular cancer: influence on the occurrence of metastases.

The influence of local tumor spread (T-classification) and of tumor size on the occurrence of metastases was studied in 241 patients with testicular germ-cell neoplasms. All patients underwent thorough clinical or pathologic staging, or both, and were treated at the University of Minnesota Hospitals. Spread of tumor through the tunica vaginalis (T2) was associated with abdominal lymph node or distant metastases in eight of nine patients. Local tumor extension to the spermatic cord (T4a) was associated with metastatic spread in 29 of 31 men. Tumor size did not appear to correlate with metastatic rate. These findings are an important aid in designing adjuvant therapy trials and in establishing a "no treatment" approach after orchiectomy.

Adolescent↗