Search PubMed⌕ Search

Biomedical subjects

T Ashizawa

Publications and source records attributed to T Ashizawa.

At least 55 records · Page 3Linked to original sources
PubMed2000

Genetic localization of the Ca2+ channel gene CACNG2 near SCA10 on chromosome 22q13.

PURPOSE: Voltage-dependent calcium channel mutations have been associated with spinocerebellar ataxia in humans (SCA6) and with ataxia, progressive cerebellar degeneration, and epilepsy in mice (tottering, lethargic, and stargazer). A novel autosomal dominant spinocerebellar ataxia syndrome with epilepsy (SCA10) was recently mapped to chromosome 22q13. The human ortholog of the mouse stargazer locus, the calcium channel gamma subunit gene CACNG2, also is located in this region. Because the phenotypes of stargazer mice and SCA10 patients were similar, consisting of both cerebellar ataxia and seizures, we hypothesized that CACNG2 was a likely candidate for the SCA10 locus. METHODS: Polymerase chain reaction (PCR) based assays were developed for two polymorphic microsatellite markers near CACNG2. The location of CACNG2 was determined by linkage and haplotype analysis of the genotypes of 22 individuals from a human pedigree segregating SCA10. RESULTS: SCA10 was previously localized distal to marker D22S1177 on chromosome 22q13. We determined that CACNG2 was linked to D22S283 and D22S1177 with the marker order: centromere-D22S283-bcmDLB1 (CACNG2)-D22S1177-D22S423-telomere. Thus CACNG2 is located proximal to the SCA10 recombinant interval. CONCLUSIONS: Here we report the first genetic linkage of CACNG2 on chromosome 22q13 and exclude it as a candidate for SCA10. In addition, our data clarify the relation between the physical and genetic linkage maps of this region and will facilitate isolation of the SCA10 gene.

Alleles↗
PubMed2000

[Two cases of recurrent gastric cancer for which combination chemotherapy with pirarubicin, cis-platinum and 5-fluorouracil were markedly effective].

In the treatment of 2 patients with recurrent gastric cancer who showed bone metastasis and lymph node recurrence, we administered 30 mg/body of pirarubicin (THP) on the first day of treatment, and 30 mg/body of cis-platinum (CDDP) and 500 mg/m2 of 5-fluorouracil (5-FU) for 3 days (FP therapy). Marked effects were achieved. Gastric cancer of Borrmann IV type was diagnosed in Case 1, and total gastrectomy was performed. The histological type was poorly differentiated adenocarcinoma, and the histological classification was II. A bone metastasis was found three years after operation. The patient was CR after three courses of treatment, and has survived for 2 years. In Case 2, advanced gastric cancer was treated with neoadjuvant chemotherapy and distal gastrectomy. The histological type was moderately differentiated adenocarcinoma, and the histological classification was IIIa. Obstructive jaundice due to lymph node recurrence developed 6 years after operation. Two courses of treatment were provided after PTCD, and PR was observed. The patient has survived for 3 months. Both patients exhibited mild side effects such as anemia and leukocytopenia, but no serious complications were observed. Although various dosage regimens of FP therapy have been investigated, there has been a certain limit to the response rate achieved by this therapy, and new protocols have been explored. We achieved marked effects in 2 patients by adding THP to FP therapy. These cases are reported here together with some discussion of cases reported in the literature.

Adenocarcinoma↗
PubMed2000

[Prediction of the clinical efficacy of hepatic arterial chemotherapy for metastatic hepatic cancer by intraarterial infusion of 99mTc-MIBI].

SPECT was performed in 11 patients with metastatic hepatic cancer by intraarterial infusion of 99mTc-MIBI before hepatic arterial chemotherapy was started, and the degree of accumulation and clinical efficacy were compared. Early and delayed SPECT images were obtained and various parameters were calculated, including early ratio (ER), delayed ratio (DR), washout rate (WR), and retention index (RI). Judgement of clinical efficacy was made by CT before and after hepatic arterial chemotherapy and was classified as effective, unchanged, and progressive groups. The mean values of ER and DR in the effective group were higher than those in the progressive group. No relationships were noted among the WR and RI values of the groups. The assessment of ER and DR using 99mTc-MIBI intraarterial SPECT is considered to be useful for prediction of the clinical efficacy of hepatic arterial chemotherapy for metastatic hepatic cancer.

Adult↗
PubMed2000

[Analysis of the salvage synthesis within biosynthesis of nucleic acid route in colon cancer].

Orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), uridine phosphorylase (UP), dihydropyrimidine dehydrogenase (DPD), and thymidylate synthetase (TS) are enzymes which analyze the salvage synthesis within the biosynthesis of the nucleic acid route of colon cancer. These enzymes were measured in carcinoma and normal tissue. OPRT was 0.065 +/- 0.041 nmol/min/mg protein, TP 4.04 +/- 2.81 nmol/min/mg protein, UP 1.79 +/- 1.19 nmol/min/mg protein, DPD 23.8 +/- 12.0 pmol/min/mg protein, and TS 6.1 +/- 4.4 pmol/g tissue in the normal tissue, and OPRT was 0.199 +/- 0.146 nmol/min/mg protein, TP 13.63 +/- 6.04 nmol/min/mg protein, UP 5.84 +/- 2.37 nmol/min/mg protein, DPD 22.0 +/- 13.4 pmol/min/mg protein, TS 16.9 +/- 7.8 pmol/g tissue in the carcinoma. OPRT, TP, and UP in the carcinoma mainly existed about 3.06-3.37 times that in normal tissue and TS at about 2.77 times. No significant difference was seen in DPD. A correlation was found between OPRT in normal tissue and carcinoma. Biosynthesis of nucleic acid via salvage synthesis is actively stimulated. Enzymatic activity related to uracil was high, and was thought to be closely connected to the growth of the cancer.

Aged↗
PubMed1999

Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy.

We investigated a family with a new type of autosomal dominant cerebellar ataxia (ADCA) in which pure cerebellar ataxia is often accompanied with epilepsy. No CAG repeat expansions were detected at the spinocerebellar ataxia (SCA) type 1, 2, 3, 6, or 7 locus, and SCAs 4 and 5 were excluded by linkage analysis. We found linkage between the disease locus and D22S274 (Zmax = 3.86 at theta = 0.00) and two other makers in 22q13-qter. Haplotype analysis of the crossover events and the multipoint linkage mapping localized the disease locus to an 8.8-cM region between D22S1177 and D22S1160.

Chromosome Mapping↗
PubMed1999

Somatic sequence variation at the Friedreich ataxia locus includes complete contraction of the expanded GAA triplet repeat, significant length variation in serially passaged lymphoblasts and enhanced mutagenesis in the flanking sequence.

The vast majority of Friedreich ataxia patients are homozygous for large GAA triplet repeat expansions in intron 1 of the X25 gene. Instability of the expanded GAA repeat was examined in 23 chromosomes bearing 97-1250 triplets in lymphoblastoid cell lines passaged 20-39 times. Southern analyses revealed 18 events of significant changes in length ranging from 69 to 633 triplets, wherein the de novo allele gradually replaced the original over 1-6 passages. Contractions and expansions occurred with equal frequency and magnitude. This behavior is unique in comparison with other large, non-coding triplet repeat expansions [(CGG)(n)and (CTG)(n)] which remain relatively stable under similar conditions. We also report a rare patient who, having inherited two expanded alleles, showed evidence of contracted GAA repeats ranging from nine to 29 triplets in DNA from two independent peripheral blood samples. The GAA triplet repeat is known to adopt a triplex structure, and triplexes in transcribed templates cause enhanced mutagenesis. The poly(A) tract and a 135 bp sequence, both situated immediately upstream of the GAA triplet repeat, were therefore examined for somatic mutations. The poly(A) tract showed enhanced instability when in cis with the GAA expansion. The 135 bp upstream sequence was found to harbor a 3-fold excess of point mutations in DNA derived from individuals homozygous for the GAA triplet repeat expansion compared with normal controls. These data are likely to have important mechanistic and clinical implications.

Base Sequence↗
PubMed1999

Very large (CAG)(n) DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males.

Genetic anticipation, i.e. increasing disease severity and decreasing age of onset from one generation to the next, is observed in a number of diseases, including myotonic dystrophy type 1, Huntington's disease and several of the spinocerebellar ataxias. All of these disorders are associated with the expansion of a trinucleotide repeat and array length is positively correlated with disease severity and inversely correlated with the age of onset. The expanded repeat is highly unstable and continues to expand from one generation to the next, providing a molecular explanation for anticipation. Spinocerebellar ataxia type 7 (SCA7) is one of the latest additions to the list of triplet repeat diseases and is distinct from the other SCAs in that it is accompanied by retinal degeneration. Pedigree analyses have previously revealed that the SCA7 repeat is highly unstable and liable to expand, in particular when transmitted by a male. Surprisingly, though, an under-representation of male transmission has also been reported. We now demonstrate directly by single molecule analyses that the expanded repeat is extraordinarily unstable in the male germline and biased toward massive increases. Nearly all of the mutant sperm of two SCA7 males contain alleles that are so large that most of the affected offspring would at best have a severe infantile form of the disease. Indeed, the gross under-representation of such very large expanded alleles in patients suggests that a significant proportion of such alleles might be associated with embryonic lethality or dysfunctional sperm.

Alleles↗
PubMed1999

Antitumor activity of KF22678, a novel thioester derivative of leinamycin.

KF22678, a novel thioester derivative of leinamycin with the 1-oxo-1,2-dithiolane-3-one moiety, was examined for anti-tumor activity, toxicity in mice and activation mechanism. KF22678 showed a broad antitumor spectrum against human carcinoma xenografts (lung, colon, ovary and prostate). The efficacy of KF22678 was significantly higher than that of cisplatin. KF22678 exhibited low cross-resistance against various drug-resistant cell lines of MDR1 or MRP overexpressing human tumors, and, in addition, exhibited more potent antitumor activity in vivo than ADM against A2780/ADM and KB/MRP xenograft. DL-Buthionine sulfoximine (BSO) pretreatment significantly reduced intracellular glutathione (GSH) level in human lung carcinoma A549 cells, leading to decrease in the cytotoxicity of KF22678, whereas the cytotoxicity of melphalan was augmented by BSO pretreatment. DNA single-strand breaks (SSB) were observed in A549 cells treated with KF22678 and bleomycin. DNA SSB induced by KF22678 was greatly reduced in the presence of BSO in the cells, whereas DNA SSB induced by bleomycin was not. In addition, the antitumor activity of KF22678 against BSO-pretreated human lung carcinoma PC-9 tumor was significantly decreased. These results suggest that the activation of KF22678 by intracellular GSH might be important for DNA SSB and antitumor activity in vitro and in vivo.

Animals↗
PubMed1999

Immunohistochemical and molecular analysis of giant cell carcinoma of the pancreas: a report of three cases.

We performed molecular biological studies as well as immunohistochemical analysis of three cases of giant cell carcinoma of the pancreas. Histologically, one case was a pleomorphic giant cell carcinoma consisting of pleomorphic giant/ small cells and spindle cells, one an osteoclast-like giant cell tumor composed of osteoclastoid giant cells and pleomorphic small cells, and one a pleomorphic giant cell carcinoma with osteoclastoid giant cells. Immunohistochemically, pleomorphic giant cells and small pleomorphic cells were positive for epithelial and mesenchymal markers throughout the cases. Osteoclastoid cells were strongly positive for PG-M1 (CD68), but negative for lysozyme and epithelial markers. Pleomorphic spindle cells showed the same immunoreactivity as pleomorphic giant/small cells. Genetically, all cases contained a mutation in the K-ras (codons 12, 13) oncogene, but neither p53 (exons 5-8) nor p16INK4 (exons 1, 2) gene mutations were found in any case. Furthermore, Loss of heterozygosity (LOH) of the p53, p161NK4. APC, and DPC4 gene loci was not found in any of the cases. Immunohistochemical study demonstrated this tumor to be of epithelial origin with mesenchymal differentiation. Genetically, initiation of the tumor is similar to that of usual ductal adenocarcinoma, but progression might be rather different. The peculiar histologic and biologic features of this tumor would be the result of changes in other functional genes.

Aged↗
PubMed1998

The G209A mutation in the alpha-synuclein gene is not detected in familial cases of Parkinson disease in non-Greek and/or Italian populations.

OBJECTIVE: To determine whether the G-to-A substitution at nucleotide 209 (G209A) mutation in the alpha-synuclein gene is responsible for familial Parkinson disease (PD) in the US population. DESIGN: Polymerase chain reaction-based DNA analysis of consecutive patients with PD and family history of PD. SETTING: A university-affiliated movement disorder clinic and a Veterans Affairs clinical research laboratory. PATIENTS: Forty-four patients with PD and family history of PD and 29 patients with sporadic PD, all with no known Greek and/or Italian background. RESULTS: None of the DNA samples showed the G209A mutation. CONCLUSION: The G209A mutation is rare in US patients with familial PD.

Adult↗