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Biomedical subjects

N Shinohara

Publications and source records attributed to N Shinohara.

At least 19 recordsLinked to original sources
PubMed1998

5-fluorouracil and low-dose recombinant interferon-alpha-2a in patients with hormone-refractory adenocarcinoma of the prostate.

BACKGROUND: The effectiveness of a chemotherapy regimen including 5-fluorouracil (5-FU) and recombinant interferon-alpha-2a (rIFN-alpha-2a) was evaluated in hormone-refractory prostate cancer patients. METHODS: Patients received a continuous intravenous infusion of 5-FU at 600 mg/m2/day for 5 days (D1-D5), followed by a bolus injection of 5-FU on D15 and D22. Patients received intramuscular injection of rIFN-alpha-2a at 3 million IU on D1, D3, D5, D15, and D22. This schedule was repeated every 4 weeks. RESULTS: Between 1993 and 1995, 23 patients with hormone refractory prostate cancer were enrolled in this study. Two of five patients with nodal disease exhibited partial responses according to the NPCP criteria. Fourteen of 17 patients with bone disease showed stable disease. Of 21 patients assessible for response, 9 patients had a decrease in the PSA level greater than 50% of baseline. Bone pain disappeared partially or completely in 8 of 14 patients with this symptom at entry. The median overall survival was 18 months. The associate toxicity was well tolerable. CONCLUSIONS: Combination chemotherapy of 5-FU and low dose rIFN-alpha-2a in patients with hormone-refractory prostate cancer proved feasible, and with acceptable toxicity.

Adenocarcinoma↗
PubMed1998

Supernumerary ring chromosomes and nuclear blebs in some low-grade malignant soft tissue tumours: atypical lipomatous tumours and dermatofibrosarcoma protuberans.

We investigated the diagnostic significance of supernumerary ring chromosomes in low-grade soft-tissue neoplasms. Chromosome slides were prepared from 123 samples of soft-tissue tumours using the standard trypsin-Giemsa banding technique. Supernumerary ring chromosomes were found in 6 cases of soft tissue tumours: 5 cases of atypical lipomatous tumour (ALT) and 1 case of dermatofibrosarcoma protuberans (DFSP). By chromosome painting with fluorescence in situ hybridization (FISH), the ring chromosome in 1 ALT was painted over its entire length with the chromosome 12 probe. Nuclear blebs and micronuclei, which were observed in each case of ALT, also contained chromosome 12 material; and these structures may represent a topological distribution of ring or giant marker chromosomes in the interphase nuclei. Our findings suggest that supernumerary ring chromosomes are characteristic of some low-grade soft tissue neoplasms including ALT and DFSP.

Adult↗
PubMed1998

Ossifying renal tumor of infancy: the first Japanese case with long-term follow-up.

Presented is the first Japanese case of ossifying renal tumor of infancy (ORTI), which is an extremely rare tumor and of which only nine cases have been reported in the literature. The patient was a four-month-old Japanese boy presenting as hematuria. A small nodular tumor (approximately 1 cm in size) protruded into the right pelvis from the superior caliceal region. Histologically the tumor originated from the tip of one medullary papilla and consisted of small rounded cells with a dense arrangement and several foci of minimally calcified osteoid lesions, including fewer but larger cells. Transition from the small to larger cells was suggested. The small cell only expressed vimentin, but the larger coexpressed vimentin, desmin, and epithelial membrane antigen. These findings suggested that the small cells differentiated to the larger cells with an epithelial nature associated somehow with osteoid formation. Embryonal metaplasia was assumed to occur in the collecting ducts entrapped by the tumor. The patient has been well without recurrence for more than 23 years. This is the longest survival period compared with other reported cases and confirms the benign nature of ORTI. It is absolutely crucial to make an accurate diagnosis of ORTI to avoid unnecessary treatment.

Follow-Up Studies↗
PubMed1998

Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism.

Leprechaunism is the most severe form of insulin resistance, manifesting with abnormal glucose metabolism and retarded growth. In the present study, we investigated the biological actions of recombinant human insulin-like growth factor I (rhIGF-I) in fibroblasts derived from a patient with leprechaunism. In the same patient, we also investigated the pharmacokinetics of IGF-I and the long-term effect of rhIGF-I treatment on metabolic control and physical growth. The patient's fibroblasts showed normal binding of IGF-I, normal phosphorylation of the beta-subunit of the IGF-I receptor, and normal [3H]thymidine incorporation in response to IGF-I. The fibroblast studies suggested that the patient would respond to IGF-I therapy, but certainly did not exclude the possibility of IGF-I resistance in vivo. Administration of recombinant human GH at the dose of 2.0 IU/kg for 3 consecutive days induced a minimal response of serum total IGF-I and IGF-binding protein-3 (IGFBP-3), suggesting partial GH resistance. To increase the serum total IGF-I level, we administered rhIGF-I with combination therapy of intermittent and continuous s.c. injection. This sustained the serum total IGF-I level, but not the serum IGFBP-3 level, within the normal range. The patient was treated with combination therapy of rhIGF-I by both s.c. injection and continuous s.c. infusion for 6 yr and 10 months. Administration of rhIGF-I at total daily dose of 1.6 mg/kg maintained her growth rate and hemoglobin A1c level nearly within the normal range. These findings suggest 1) that this leprechaun patient has an IGF-I-deficient state and partial GH resistance, as reflected by impaired production of IGF-I and IGFBP-3; 2) that rhIGF-I treatment works effectively for preventing postnatal growth retardation and normalizing glucose metabolism in patients with extreme insulin resistance; 3) that this treatment requires relatively higher dose of rhIGF-I; and 4) that treatment appears to be safe and devoid of adverse effects.

Blood Glucose↗
PubMed1998

Obesity induced by neonatal monosodium glutamate treatment in spontaneously hypertensive rats: an animal model of multiple risk factors.

The present study was designed to develop an animal model of multiple risk factors, including obesity, hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia. Hypothalamic obesity was induced by neonatal monosodium glutamate (MSG) treatment in spontaneously hypertensive rats (SHR). Female newborn SHR were treated intraperitoneally with 2 or 4 mg/kg body weight of MSG for 5 days. Obesity developed in SHR treated with 4 mg/kg of MSG but not in SHR treated with 2 mg/kg of MSG. Obese SHR had impaired glucose tolerance, hyperinsulinemia, and hypertriglyceridemia. However, the severity of hypertension was attenuated in obese SHR as compared with control SHR. The degree of obesity was closely related to the metabolic abnormalities, but inversely correlated with the blood pressure level. Macrovascular changes were investigated in obese SHR at 14 months of age. Intimal thickening was accelerated in the carotid artery of obese SHR as compared with that of nonobese SHR. Aortic contents of DNA and total cholesterol were significantly increased in obese SHR. SHR associated with MSG-induced obesity showed major manifestations of metabolic syndrome X. This animal model may be useful to study the clustering of risk factors for the development of macrovascular diseases.

Animals↗
PubMed1998

[Complicated form of spastic paraplegia with congenital cataract: a case report].

We report a 33-year-old man who manifested spastic paraplegia with congenital cataract, dementia, deformity of the foot (pes cavus, high arch and hammer toes), ataxia, and peripheral neuropathy. Magnetic resonance imaging showed mild deformity of the trunk of the corpus callosum and atrophy of superior cerebellar vermis. Metabolic diseases were ruled out by the clinical course and special examinations. Other patients, including 2 of ours, with spastic paraplegia and thin corpus callosum have been reported, but the present case is different because of congenital cataract and the form of the corpus callosum. We consider that there may be a variety of complicated forms of spastic paraplegia. To assess the etiology of complicated forms of spastic paraplegia, further case accumulation is very important.

Adult↗
PubMed1998

[A case of bow hunter's stroke caused by bilateral vertebral artery occlusive change on head rotation to the right].

We report a case of bow hunter's stroke caused by simultaneous bilateral vertebral artery occlusive changes at the right C3-4 and the left C1-2 level on head rotation to the right side. The pathogenesis and surgical treatment for this particular case are discussed. A 61-year-old male with cervical spondylosis repeatedly experienced vertebrobasilar insufficiency when he rotated his head over 60 degree from the mid-position to the right side. Bilateral vertebral angiography demonstrated severe compression of the right vertebral artery by a lateral osteophyte and instability at the C3-4 level accompanied with the mechanical stenosis of the left vertebral artery at the C1-2 level only at the time of turning his head to the right. As the surgical treatment we performed osteophytectomy of the right uncovertebral joint at the C3-4 level in addition to anterior decompression with fusion using hydroxyapatite spacer and titanium plate at that level. Postoperatively, the patient had no ischemic episodes and there was angiographical resolution of the rotational stenosis at the C3-4 level. For the clinical manifestation of bow hunter's stroke on head rotation, it is indispensable that simultaneous severe occlusive changes present on bilateral vertebral arteries. In case of a vertebral occlusive change caused by lateral osteophyte at the unstable vertebral joint, anterior decompression and fusion with osteophytectomy may be a wiser approach than arterial decompression or posterior fusion at the C1-2 level to another vertebral artery occlusive lesion.

Cerebrovascular Disorders↗
PubMed1998

Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human osteosarcoma.

The Y-box-binding protein, YB-1, is a member of the DNA-binding protein family. It binds to the Y-box, an inverted CCAAT box, in the promoter region of the human multidrug resistance 1 gene, which encodes P-glycoprotein (P-gp). Nuclear localization of YB-1 protein has been reported to be associated with the intrinsic expression of P-gp in human breast cancer. We studied the immunohistochemical expression of YB-1 protein in 69 untreated biopsy specimens of conventional osteosarcomas and compared it with the expression of P-gp. Furthermore, cell proliferation, as determined by the MIB-1-labeling index (MIB-1-LI), was measured by immunohistochemistry. In all 69 untreated osteosarcomas, YB-1 protein was expressed in the cytoplasm. In 32 of 69 (46%) cases, YB-1 was also localized in the nucleus. The expression of P-gp was evident in 23 of these 32 cases, and there was a significant correlation between the nuclear expression of YB-1 and P-gp expression (P < 0.0001). Chondroblastic osteosarcoma expressed YB-1 in the nucleus more frequently (eight of nine cases) than did other types of osteosarcoma, whereas P-gp was also frequently expressed in chondroblastic subtype. There was no correlation between the nuclear expression of YB-1 and histological grade. The MIB-1-LI was significantly higher in cases showing the nuclear expression of YB-1 (MIB-1-LI averaged 22.56 in cases with only cytoplasmic expression of YB-1 but averaged 28.20 in cases with cytoplasmic and nuclear expression of YB-1; P = 0.0477). In human osteosarcoma, nuclear localization of YB-1 protein was associated with the expression of P-gp, suggesting that YB-1 could be a prognostic marker for multidrug resistance in osteosarcoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

[Application and limitation of neoadjuvant hormonal therapy for prostate cancer].

Of 156 patients, 111 (clinical stage T1a-b; 21, T1c; 17, T2a-b; 36, T2c; 27, T3; 10) immediately underwent radical prostatectomy (surgery group), and 45 (clinical stage T1a-b; 8, T1c; 4, T2a-b; 10, T2c; 9, T3; 14) received neoadjuvant hormonal therapy (NHT group). NHT offered probability of increasing organ-confined cancer(OCC; pathological stage pT2 or lower N0M0) in the following group, which contains (a) patients who had moderately differentiated adenocarcinoma in the biopsy specimen and T2b or lower diseases, and (b) those who had well differentiated adenocarcinoma, T2c diseases and PSA levels of 10 ng/ml or higher, referred to as "OCC suitable criteria". Of 156 patients, 51 (33%) met OCC suitable criteria. In those cases, the proportion of OCC in NHT group was significantly higher than that in surgery group (11/12 (92%) vs. 16/39 (41%), p = 0.002). NHT is useful for increasing OCC in patients who meet OCC suitable criteria.

Adenocarcinoma↗
PubMed1997

Lck-independent triggering of T-cell antigen receptor signal transduction by staphylococcal enterotoxins.

Superantigens (SAgs) activate T-cells in a manner specific to the Vbeta region of the T-cell antigen receptor. Stimulations by SAgs provoke drastic T-cell activation that leads to programmed cell death or the anergic state of responding cells. To characterize the signal transduction pathway initiated by SAgs, mutant lines derived from the human leukemic T-cell line Jurkat were tested for their reactivities against prototypic SAgs, staphylococcal enterotoxins. The J.CaM1.6 cell line, which lacks Lck expression and lost reactivity against T-cell antigen receptor-mediated stimulation, was activated by staphylococcal enterotoxins in a manner indistinguishable from the Jurkat cell line. In contrast, the J.45. 01 cell line, which lacks expression of functional CD45, showed severely impaired reactivity. The role of Lck appears to be replaced by another Src family protein-tyrosine kinase, Fyn. In J.CaM1.6 cells, Fyn was rapidly phosphorylated and activated after staphylococcal enterotoxin treatment. The kinase-inactive mutant of Fyn significantly suppressed the reactivity against staphylococcal enterotoxin E in J.CaM1.6 cells, and the expression of the active form of Fyn reconstituted reactivity against staphylococcal enterotoxin E in J.45.01 cells. These results demonstrate that SAgs activate T-cells in an Lck-independent pathway and that Fyn plays a critical role in the process.

Antigens, CD↗
PubMed1997

Comparative analysis of the gp120-binding area of murine and human CD4 molecules.

The structural basis for the difference between human and murine CD4 molecules in binding to HIV envelope protein gp120 has been intensively studied. Eighteen mutant human CD4 molecules were produced by segmental replacement of beta strands and loops in the gp120-binding area of the molecule with corresponding murine sequences or by single amino acid substitutions. Examination of these mutant CD4 molecules for gp120 binding indicated that murine CD4 molecule does not bind gp120 for the following three reasons: (a) The loops flanking the C" strand are longer than their human counterparts, causing significant difference in local tertiary structure; (b) valin, rather than phenylalanine, which is the key amino acid for the binding occupies position 43; (c) amino acids at positions 45 and 46 are different, causing further decrease in binding affinity. Furthermore, the present study indicated that the aromatic ring of Phe43 and the negative charge of Arg59 play key roles in gp120 binding.

Amino Acid Sequence↗
PubMed1997

Co-receptor-independent signal transduction in a mismatched CD8+ major histocompatibility complex class II-specific allogeneic cytotoxic T lymphocyte.

The contribution of co-receptors in signal transduction upon T cell receptor (TCR)-mediated recognition of major histocompatibility complex (MHC) class II antigen by mature T lymphocytes expressing TCR derived from the apparently co-receptor-independent, I-Ak-specific allogeneic CD8+ CTL clone QM11 has been examined. Mature double-negative, CD8+ and CD4+ bulk T cell lines and clones expressing TCR(QM11) were developed from TCR(QM11) transgenic mice. All these T cells, irrespective of co-receptor expression, showed specific lytic activity on cells expressing I-Ak. Furthermore, co-receptorless mutants were obtained from a CD4+ and CD8+ clone. The responses of these co-receptorless mutants upon specific recognition of the alloantigen, as judged by cytolytic activity, granule exocytosis, lymphokine production, proliferation, and tyrosine phosphorylation of the zeta chain, were comparable to those of the original clones. Thus, the results proved the co-receptor independence of the recognition of I-Ak by TCR(QM11) and further indicated there is no indispensable unique signal transduced by co-receptors. However, when the amount of the available antigen was limited by anti-I-Ak antibody, the CD4+ T cell clone showed a remarkable resistance to the inhibition whereas the mismatched CD8+ clone was readily inhibitable. The anti-I-Ak-resistant component of the CD4+ clone showed dependency on the CD4 molecule. Taken collectively, the results indicate that the role played by a co-receptor molecule in mature T cells is purely quantitative amplification of the signal through the formation of a TCR/MHC/co-receptor ternary complex, and also indicate that the role of co-receptor molecules as TCR-independent adhesion molecules is at best minimal.

Animals↗
PubMed1997

Reduced tissue oxygenation and its reversibility by glycemic control in diabetic patients.

Relationship of transcutaneous oxygen pressure (TcP(O2)) to glycemic control and diabetic complications was investigated in patients with non-insulin dependent diabetes mellitus. TcP(O2) was measured in 103 patients with non-insulin dependent diabetes mellitus. Correlation of TcP(O2) to HbA1c, fasting blood sugar (FBS), age, duration of diabetes, serum lipids, hypertension, and diabetic complications were examined. We divided the patients into three groups according to their glycemic control: good control group (HbA1c < 7.0%), fair control group (HbA1c, 7.0-8.9%) and poor control group (HbA1c > or = 9.0). We compared TcP(O2) of these three groups with 19 non-diabetic controls. In 103 patients, TcP(O2) at baseline correlated with HbA1c, FBS and age (P < 0.001, P < 0.01 and P < 0.05, respectively), but did not correlate with duration of diabetes mellitus, neuropathy, nephropathy or retinopathy. TcP(O2) of good and fair control group was not reduced comparing to the non-diabetic control (63 +/- 11, 59 +/- 10 and 64 +/- 12 mmHg, respectively). The poor control group had significantly reduced TcP(O2) (55 +/- 10 mmHg) comparing to non-diabetic control (P < 0.005) and good control group (P < 0.005). Furthermore, in an independent study, TcP(O2), arterial oxygen pressure (Pa(O2)), oxygen pressure of dorsal pedal vein (PV(O2)) and erythrocyte 2,3-diphosphoglycerate (2,3-DPG) in eight patients with poor glycemic control were followed prospectively. Six patients with improvement of glycemic control showed a significant increase of TcP(O2) and Pa(O2) (P < 0.001 and P < 0.005, respectively). However, two patients without improvement of hyperglycemia had no change in TcP(O2) and Pa(O2). PV(O2) and 2,3-DPG levels of erythrocytes were not changed in six patients. These findings suggest that tissue oxygenation in diabetic patients was deteriorated in relation to hyperglycemia and was reversed with glycemic control. Improvement of Pa(O2) might contribute partly to the increase of TcP(O2).

2,3-Diphosphoglycerate↗
PubMed1997

The significance of Ras guanine nucleotide exchange factor, son of sevenless protein, in renal cell carcinoma cell lines.

PURPOSE: The aim of the present study is to clarify the significance of the Ras guanine-nucleotide exchange reaction in the proliferation of human renal cell carcinoma cell lines. MATERIALS AND METHODS: We examined the expression of human son of sevenless-1 (hSos-1) protein and the epidermal growth factor (EGF) receptor in human renal cell carcinoma cell lines by Western blot analysis. Additionally, a dominant negative H-ras mutant, N116Y, which is known to inhibit the Ras guanine-nucleotide exchange reaction, was transfected into these cell lines by lipofection. RESULTS: Human renal cell carcinoma cell lines expressed much higher amounts of the EGF receptor and hSos-1 protein than normal kidney tissue. Moreover, the N116Y ras mutant could strongly suppress cellular proliferation in these cell lines. CONCLUSIONS: Augmentation of the Ras guanine-nucleotide exchange reaction might be essential to the proliferation of human renal cell carcinoma cells.

Carcinoma, Renal Cell↗
PubMed1997

Three novel mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita.

The DAX-1 [DSS (dosage sensitive sex)-AHC critical region on the X, gene 1] gene is responsible for X-linked adrenal hypoplasia congenita (AHC). However, DAX-1 protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the DAX-1 gene from seven patients in six kindreds with X-linked AHC and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291 Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human DAX-1 protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the DAX-1 protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the DAX-1 gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child.

Adrenal Insufficiency↗
PubMed1997

Cytokeratin subtyping in chordomas and the fetal notochord: an immunohistochemical analysis of aberrant expression.

Chordoma is a well-known bone tumor that shows epithelioid features and in which the expression of cytokeratins (CKs) has been reported to appear very frequently. Numerous immunohistochemical analyses of CK expression have been conducted using such monoclonal antibodies as CAM5.2, which react with CK8, CK18, and CK19, and AE1/AE3, which react with CKs 1-8, 10, 14-16 and 19 in chordoma. No detailed analysis, however, of the expression of each component of CK has yet been conducted in chordoma; thus, the subsets of CK expressed there have yet to be clarified. With the use of immunohistochemical techniques with a panel of monoclonal antibodies against each subset of CK, the authors studied the expression of CKs in 16 specimens of classic chordoma and 14 specimens of the fetal notochord to clarify the subsets of CK expressed in chordoma and to evaluate the similarities and differences of CK expression between chordoma and the fetal notochord. All of the chordoma specimens showed a strong positive immunoreactivity for CK8 and CK19, whereas nine (56.3%) chordoma specimens showed a positive immunoreaction for CK18. In addition, four chordoma specimens were focally positive for keratin-903, which reacts with high molecular weight CKs such as CK1, CK5, CK10, and CK14; one specimen also showed a strong CK7 expression. All of the notochord specimens were also positive for CK8 and CK19, but none showed a positive immunoreaction for keratin-903, CK7, or CK18. In addition, none of the chordoma or notochord specimens showed immunoreactivity for CK20. The expression of CK8 and CK19, observed in all of the chordoma and notochord specimens, was thus considered to be maintained throughout the neoplastic transformation, although some aberrant CK expressions (CK7, CK18, and keratin-903) also occurred in the chordoma specimens examined in this study.

Adult↗