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Biomedical subjects

I Kinoshita

Publications and source records attributed to I Kinoshita.

At least 19 recordsLinked to original sources
PubMed2006

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations.

Retrospective analysis has shown that activating mutations in exons 18-21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48-93%). After a median follow-up of 12.7 months (range, 3.1-16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7-11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.

Administration, Oral↗
PubMed2004

Endobronchial ultrasonography with guide-sheath for peripheral pulmonary lesions.

The usefulness of endobronchial ultrasonography (EBUS) with guide-sheath (GS) as a guide for transbronchial biopsy (TBB) for diagnosing peripheral pulmonary lesions (PPL)s and for improving diagnostic accuracy was evaluated in this study. EBUS-GS-guided TBB was performed in 24 patients with 24 PPLs of < or =30 mm in diameter (average diameter=18.4 mm). A 20-MHz radial-type ultrasound probe, covered with GS was inserted via a working bronchoscope channel and advanced to the PPL in order to produce an EBUS image. The probe with the GS was confirmed to reach the lesion by EBUS imaging and X-ray fluoroscopy. When the lesion was not identified on the EBUS image, the probe was removed and a curette was used to lead the GS to the lesion. After localising the lesion, the probe was removed, and TBB and bronchial brushing were performed via the GS. Nineteen peripheral lesions (79.2%) were visualised by EBUS. All patients whose PPLs were visible on EBUS images subsequently underwent an EBUS-GS-guided diagnostic procedure. A total of 14 lesions (58.3%) were diagnosed. Even when restricted to PPLs <20 mm in diameter, the diagnostic sensitivity was 53%. In conclusion, endobronchial ultrasonography with guide sheath-guided transbronchial biopsy was feasible and effective for diagnosing peripheral pulmonary lesions.

Adult↗
PubMed2003

Somatic embryogenesis and plant regeneration from immature zygotic embryos of Cryptomeria japonica D. Don.

This report describes the successful plant regeneration via somatic embryogenesis from immature zygotic embryos of Cryptomeria japonica D. Don. For the induction of embryogenic tissue, we determined that the optimal medium contained N6-benzyladenine and 2,4-dichlorophenoxyacetic acid. Immature zygotic embryos that were collected at the end of June yielded embryogenic tissue at the highest frequency. Embryogenic tissues that had proliferated in liquid medium included small and loosely packed cells and elongating or elongated cells. We used ten cell lines to determine the optimal medium for the development of somatic embryos. Induced somatic embryos germinated with synchronous sprouting of cotyledons, hypocotyls and roots. Gibberellin A3 in the germination medium had a positive effect on both the elongation of hypocotyls and the survival of seedlings. The frequencies of induction and germination of somatic embryos differed among the cell lines examined. Most of the seedlings grew normally. This system of somatic embryogenesis required 4-5 months for the regeneration of C. japonica plantlets from immature zygotic embryos.

Cryptomeria↗
PubMed2002

N-acetylgalactosaminyl transferase-3 is a potential new marker for non-small cell lung cancers.

N-acetylgalactosaminyl transferase-3 (GalNAc-T3) is an enzyme involved in the initial glycosylation of mucin-type O-linked proteins. In the present study, we used immunohistochemistry to examine GalNAc-T3 expression in 215 surgically resected non-small cell lung cancers. We analysed the biological and clinical importance of GalNAc-T3 expression, especially with regard to its potential as a prognostic factor. We found that normal bronchial epithelial cells, bronchial gland cells, and alveolar pneumocytes showed cytoplasmic immunostaining for GalNAc-T3. Low expression of GalNAc-T3, observed in 93 of 215 tumours (43.4%), was found more frequently in tumours from smokers than those from nonsmokers (P=0.001), in squamous cell carcinomas than nonsquamous cell carcinomas (P<0.0001), and in moderately and poorly differentiated tumours than well differentiated tumours (P=0.0002). Multivariate logistic regression analysis showed that an association of low GalNAc-T3 expression with squamous cell carcinomas was the only one significant relationship of GalNAc-T3 expression with various factors (P<0.0001). Moreover, tumours losing GalNAc-T3 expression had a significantly higher Ki-67 labelling index than tumours retaining GalNAc-T3 expression (P=0.0003). Patients with low GalNAc-T3 expression survived a significantly shorter time than patients with high GalNAc-T3 expression in 103 pStage I non-small cell lung cancers (5-year survival rates, 58% and 78%, respectively; P=0.02 by log-rank test) as well as in 61 pStage I nonsquamous cell carcinomas (5-year survival rates, 63% and 85%, respectively; P=0.03). Low GalNAc-T3 expression was an unfavourable prognostic factor in pStage I non-small cell lung cancers (hazards ratio, 2.04; P=0.03), and in pStage I nonsquamous cell carcinomas (hazards ratio, 2.70; P=0.03). These results suggest that GalNAc-T3 is a new marker of non-small cell lung cancers with specificity for histology and prognosis.

Aged↗
PubMed2001

Unprecedented sugar-dependent in vivo antitumor activity of carbohydrate-pendant cis-diamminedichloroplatinum(II) complexes.

Eight carbohydrate-pendant platinum(II) complexes have been synthesized from carbohydrate-diamine conjugates. D-Glucose, D-mannose, D-galactose, D-xylose, and L-glucose are attached to the dichloroplatinum(II) moiety by 1,3- or 1,2-diaminopropane chelates through with an O-glycoside bond. All the carbohydrate moieties reduced the toxicity inherent with platinum(II) complexes.

Animals↗
PubMed2001

Sugar-pendant diamines.

A set of 1,3-propanediamine derivatives connected to carbohydrates (5) has been prepared in four steps from peracetylated sugar and 1,3-dibromo-2-propanol in 60-73% yields. D-Glucose, D-mannose, D-galactose, D-xylose, D-ribose, and maltose are utilized as sugar molecules in this work. The diamine moiety was connected to the C1 carbon of the glycopyranose ring via an O-glycoside bond. All of the anomeric configurations and sugar puckering conformations, except in the D-maltose derivative, were determined by X-ray crystallography of the diazido or dibromo precursors. While glycosidation of peracetylated galactopyranose with 1,3-dibromo-2-propanol in the presence of boron trifluoride afforded both anomers, the neighboring group participation of the 2-acetoxy group yielded a single anomer for the other substrates. This method has been used to synthesize a library of sugar-pendant diamines including an OH-protected derivative (6), and an N,N'-diisopropyl-substituted derivative (7). A similar series of reactions using 2,3-dibromo-1-propanol gave ethylenediamine-type derivatives (11), and bis(bromomethyl)bis(hydroxymethyl)methane (12) gave bisglucose-pendant derivatives (16).

Carbohydrate Sequence↗
PubMed2001

[Guillain-barré syndrome associated Campylobacter jejuni serotype Penner 2: a case report].

We described a 15-year-old male who had Guillain-Barré syndrome(GBS). Nine days after watery diarrhea, the patient developed pain and weakness of foot muscles. On admission, the nerve conduction studies revealed peripheral neuropathy with axonal degeneration and demyelination. Campylobacter jejuni(C. jejuni) with serotype of Lior 4, Penner 2 was isolated from his stool culture. IgM anti-GM 1 antibody and other various anti-ganglioside antibodies were detected in his serum. After receiving plasma exchange and intravenous immunoglobulin therapy, he was able to walk without assistance. In general, C. jejuni with the serotype Penner 19 has been isolated from many GBS patients. In this patient, C. jejuni with the serotype of Penner 2 was isolated. The serotype is detected commonly in Miller Fisher syndrome.

Adolescent↗
PubMed2001

[A case of brainstem encephalitis associated with Epstein-Barr virus infection: differentiation of acute disseminated encephalomyelitis and Bickerstaff's brainstem encephalitis].

A 28-year-old woman initially suffered high fever and headache (day 1). Aseptic meningitis was diagnosed on day 3. Limb ataxia, however, appeared on day 7, and external ophthalmoplegia and drowsiness were recognized on day 8. Urinary disturbance and orthostatic hypotension appeared on day 13. Cerebrospinal fluid showed moderately high cell counts(mononuclear cells, 51/microliter; polynuclear cells, 9/microliter). MRI T2-weighted images showed high intensity lesions in the pons and mesencephalon. No serum anti-GQ1b IgG antibody was detected on day 4. Epstein-Barr virus (EBV) viral capsid antigen-IgG antibody was positive, and EBV determined nuclear antigen antibody was seroconverted. EBV-DNA was detected in the CSF by PCR. These findings indicate prior infection by EBV. After intravenous dexamethasone therapy, these symptoms rapidly disappeared. Our patient showed external ophthalmoplegia, ataxia, and disturbance of consciousness, which are the cardinal signs in Bickerstaff's brainstem encephalitis. The time course of her neurological symptoms, the presence of meningitis, and the MRI findings, however, indicated the pathogenesis of acute disseminated encephalomyelitis rather than Bickerstaff's brainstem encephalitis. We diagnosed this patient as a brainstem encephalitis associated with EBV infection.

Adult↗
PubMed1999

Vascular cell adhesion molecule-1-mediated matrix metalloproteinase-2 induction in peripheral blood T cells is up-regulated in patients with HTLV-I-associated myelopathy.

We investigated whether matrix metalloproteinase-2 (MMP-2) is induced in peripheral blood T cells after their contact with tumor necrosis factor-alpha (TNF-alpha)-stimulated glioblastoma cell line (T98G), expressing vascular cell adhesion molecule-1 (VCAM-1), in patients with HTLV-I-associated myelopathy (HAM) compared to control patients with other neurological disorders (OND). Gelatin zymography revealed that the incremental ratio of gelatinolytic activity of MMP-2 in culture supernatants derived from T cells cocultured with TNF-alpha-stimulated T98G to that of supernatants derived from cultures of T cells alone was significantly higher in HAM patients than in control patients with OND. Immunoblot analysis of immunoprecipitates of culture supernatant showed that increased gelatinolytic activity of MMP-2 was due to increased production of MMP-2 protein in T cells. Increased gelatinolytic activity of MMP-2 in T cells of HAM patients was blocked by pretreatment of TNF-alpha-stimulated T98G with anti-VCAM-1 antibody before coculture with T cells, indicating that MMP-2 induction was VCAM-1-mediated. Although no significant differences were noted in the percentage of VLA-4-positive cells in cultured T cells between HAM patients and control patients with OND, our results indicate that VCAM-1-mediated MMP-2 induction is up-regulated in T cells of HAM patients.

Adult↗
PubMed1999

Direct Observation by Electrospray Ionization Mass Spectrometry of

The use of methanol as solvent is essential for the formation of the double-bookshelf-type oxide cluster [(Cp*Rh)(2)Mo(6)O(20)(OMe)(2)](2-) from [{Cp*Rh(µ-Cl)Cl}(2)] and four equivalents of [Mo(2)O(7)](2-). The reaction proceeds via [Cp*RhMo(3)O(8)(OMe)(5)](-). The proposed structure for this key intermediate (shown schematically) is supported by electrospray ionization mass spectrometry and labeling experiments with CD(3)OD as solvent. Cp*=eta(5)-C(5)Me(5).

Journal Article↗
PubMed1999

Predictive value of expression of p16INK4A, retinoblastoma and p53 proteins for the prognosis of non-small-cell lung cancers.

The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53 proteins for prognosis was evaluated in 76 patients with non-small-cell lung cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995, using the results of immunostaining analyses of these proteins as reported in our previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16 protein expression and eight (11%) Rb protein, while 30 (39%) showed positive (altered) p53 protein expression. Survival of patients with p16-negative tumours was not significantly different from that of patients with p16-positive tumours (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of patients with Rb-negative tumours significantly different from that of patients with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P = 0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb-negative) tumours was not significantly different from that of patients with p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67% and 68% respectively, P = 0.7). In contrast, survival of patients with p53-positive (altered) tumours tended to be shorter than that of patients with p53-negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P = 0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb proteins were not significant prognostic factors in the present cohort of potentially curatively resected NSCLCs. Altered p53 protein status tended to be a negative prognostic factor (P = 0.06 by the univariate analysis). These results indicate that loss of p16 protein alone, or in combination with loss of Rb protein, does not predict the clinical outcome of patients with resected NSCLCs.

Adult↗
PubMed1999

Cyclin D1 expression in non-small-cell lung cancers: its association with altered p53 expression, cell proliferation and clinical outcome.

Cyclin D1, like p16INK4 (p16) and retinoblastoma (RB) proteins, participates in the cell cycle control at the G1-S transition. We have previously demonstrated altered p16 and RB protein status in non-small-cell lung cancers (NSCLCs) and their potential synergistic effect with altered p53 protein on proliferative activity (Kinoshita et al (1996) Cancer Res 56: 5557-5562). In the present study, cyclin D1 expression was studied by immunohistochemistry in the same cohort of 111 resected NSCLCs as in our previous study, and the amount of the cyclin D1 gene was analysed by Southern blot analysis in 29 NSCLCs. Cyclin D1 expression was analysed in relation to the status of p53, p16 and RB proteins, and proliferative activity determined by the Ki-67 index. It was also analysed in relation to survival of 77 patients with NSCLCs which were potentially curatively resected between 1990 and 1995. We found that: (1) cyclin D1 was expressed in 13 (11.7%) of 111 NSCLCs; (2) the cyclin D1 gene was neither significantly amplified nor rearranged; (3) cyclin D1 expression significantly correlated with altered p53 protein expression (P = 0.04), whereas it did not correlate with p16 and RB protein status; (4) proliferative activity tended to be higher in cyclin D1-positive (+) tumours than in cyclin D1-negative (-) tumours, although this difference was not statistically significant (P = 0.08); and (5) patients with cyclin D1+ tumours survived longer than patients with cyclin D1- tumours (5-year survival rates, 89% and 64% respectively, by the Kaplan-Meier method; P = 0.045 by the log-rank test), and cyclin D1 expression tended to be a favourable prognostic factor (P = 0.08 in univariate analysis). These findings suggest the involvement of cyclin D1 in the development and progression of NSCLCs, their proliferative activity and clinical outcome of NSCLC patients.

Aged↗
PubMed1998

Frequent loss of gelsolin expression in non-small cell lung cancers of heavy smokers.

Most lung and bladder cancers have been shown to be associated with smoking. We have previously demonstrated the frequent loss of gelsolin expression and its tumor suppressor activity in bladder cancer (M. Tanaka et al., Cancer Res., 55: 3228-3232, 1995). Here, we examined gelsolin expression in 12 cultured non-small cell lung cancer (NSCLC) cell lines. Furthermore, we analyzed gelsolin expression in relation to patients' smoking habits in 88 surgically resected NSCLCs to investigate whether gelsolin could be a molecular target for tobacco-induced carcinogenesis of lung cancer. All 12 NSCLC cell lines showed low-to-undetectable expression of the gelsolin gene, compared to that in normal lung tissue, by Northern blot analysis. On the other hand, Southern blot analysis of genomic DNA did not show any gross rearrangements or deletions of the gene in the NSCLC cell lines. Western blot analysis of gelsolin expression showed low-to-undetectable gelsolin expression in all 12 NSCLC cell lines, compared to normal lung tissue. Immunocytochemical analysis of gelsolin expression in NSCLC cell lines showed results that were consistent with those obtained by Western blot analysis, using normal bronchial epithelial cells as a positive control: two cell lines with lower gelsolin expression by Western blot analysis had reduced but positive cytoplasmic immunostaining of gelsolin, compared with primary normal bronchial epithelial cells, whereas no such immunostaining was observed in two cell lines with much lower or undetectable gelsolin expression by Western blot analysis. Therefore, gelsolin expression was analyzed in surgically resected NSCLCs by immunohistochemistry. Reduced or undetectable gelsolin expression was observed in 48 of 88 (55 %) resected NSCLCs. Such altered gelsolin expression significantly correlated with heavy smoking of patients (> or =20 pack-years; P = 0.008 by the chi2 test and P = 0.03 by multivariate logistic regression analysis), whereas there was no significant correlation between gelsolin expression and histological type, pathological tumor-node-metastasis (pTNM) stage, or survival. These findings suggest that the frequent loss of gelsolin expression may be involved in the development of NSCLCs as a potential molecular target of tobacco-induced carcinogenesis.

Aged↗
PubMed1998

Transplantation of myoblasts from a transgenic mouse overexpressing dystrophin prduced only a relatively small increase of dystrophin-positive membrane.

Myoblast cultures from normal and Tg-MDA (transgenic mouse overexpressing dystrophin 50-fold) mice were transplanted into dystrophin-deficient mdx mouse muscles. Four weeks after transplantation, dystrophin-positive fibers were observed four times more frequently in cross sections of muscles injected with Tg-MDA. Myoblasts from Tg-MDA mice also expressing the beta-gal transgene (Tg-MDA/beta-gal) and myoblasts from beta-gal transgenic mice containing one normal dystrophin gene (normal/beta-gal) were also transplanted into mdx mouse muscles. Four weeks after transplantation, the fiber length positive for dystrophin (nuclear domain) was shorter (439 +/- 326 microm) than the beta-gal nuclear domain (1466 +/- 713 microm) of the same fiber when normal/beta-gal myoblasts were transplanted, but increased (1302 +/- 487 microm) when Tg-MDA/beta-gal myoblasts were used. These experiments show that despite the presence in Tg-MDA myoblasts of constructions which lead in vivo in transgenic mice to an overexpression of dystrophin 50-fold, the membrane area over which dystrophin was expressed was increased only threefold. This observation is also expected for vector-mediated gene therapy.

Animals↗
PubMed1998

Evidence of mdx mouse skeletal muscle fragility in vivo by eccentric running exercise.

Duchenne muscular dystrophy is an X-linked devastating disease due to the lack of expression of a functional dystrophin. Unfortunately, the dystrophin-deficient mdx mouse model does not present clinical signs of dystrophy before the age of 18 months, and the role of dystrophin in fiber integrity is not fully understood. The fragility of the skeletal muscle fibers was investigated in transgenic mice expressing beta-galactosidase under the control of a muscle specific promoter. Adult mdx/beta-galactosidase (dystrophin-negative) and normal/beta-galactosidase (dystrophin-positive) mice were submitted to one short session of eccentric, downhill running exercise. The leakage of muscle enzymes creatine kinase and beta-galactosidase was investigated before, 1 h after, and 3 days after the running session. A significant and transient rise in the level of these enzymes was noted in the serum of mdx mice following the exercise session. Thus, the lack of dystrophin in the mdx model led to local microdamages to the exercised muscle allowing leakage of proteins from the fibers. The peak leakage was transient, suggesting that muscle fiber lesions were rapidly repaired following this short, noninvasive eccentric running session.

Animals↗