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Biomedical subjects

Eiichi Ishikawa

Publications and source records attributed to Eiichi Ishikawa.

At least 19 recordsLinked to original sources
PubMed2006

Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood-brain barrier permeability.

Brain edema is a major and often mortal complication of brain ischemia. Vascular endothelial growth factor (VEGF) is also known as a potent vascular permeability factor and may play detrimental roles at the acute stage of brain infarction. Our goal in this study was to explore protective effects of gene transfer of soluble flt-1 (sFlt-1), a natural inhibitor of VEGF, on focal brain ischemia. Adenoviral vector encoding sFlt-1 or beta-galactosidase as control was injected into the lateral ventricle 90 mins after photochemical distal middle cerebral artery occlusion in male spontaneously hypertensive rats. The transduced sFlt-1 was released to the cerebrospinal fluid from the ventricular wall and significantly increased 6 h, 1 and 7 days after sFlt-1 transfection. One day after brain ischemia, sFlt-1 gene transfer significantly reduced infarct volume (by 35%), brain edema (by 35%), and blood-brain barrier permeability (Evans blue extravasation; by 69%) with diminished phosphorylation of focal adhesion kinase (FAKtyr397 and FAKtyr861) in the ischemic vessels. Seven days after ischemia, sFlt-1 gene transfer also significantly attenuated infarct volume (by 29%) and monocyte/macrophage infiltration (by 27%), although there were no reductions in angiogenesis by sFlt-1 overexpression. These results suggest that sFlt-1 gene therapy targeting brain edema in acute stage of brain ischemia may be useful for brain infarction.

Animals↗
PubMed2006

A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer.

PURPOSE: Human Valpha24 natural killer T (Valpha24 NKT) cells bearing an invariant Valpha24JalphaQ antigen receptor are activated by a glicolipid ligand alpha-galactosylceramide (alphaGalCer; KRN7000) in a CD1d-dependent manner. The human Valpha24 NKT cells activated with alphaGalCer and interleukin-2 have been shown to produce large amounts of cytokines, such as IFN-gamma, and also exerting a potent killing activity against various tumor cell lines. We did a phase I study with autologous activated Valpha24 NKT cell therapy. EXPERIMENTAL DESIGN: Patients with advanced or recurrent non-small cell lung cancer received i.v. injections of activated Valpha24 NKT cells (level 1: 1 x 10(7)/m2 and level 2: 5 x 10(7)/m2) to test the safety, feasibility, and clinical response of this therapeutic strategy. Immunomonitoring was also done in all cases. RESULTS: Six patients were enrolled in this study. No severe adverse events were observed during this study in any patients. After the first and second injection of activated Valpha24 NKT cells, an increased number of peripheral blood Valpha24 NKT cells was observed in two of three cases receiving a level 2 dose of activated Valpha24 NKT cells. The number of IFN-gamma-producing cells in peripheral blood mononuclear cells increased after the administration of activated Valpha24 NKT cells in all three cases receiving the level 2 dose. No patient was found to meet the criteria for either a partial or a complete response. CONCLUSIONS: The clinical trial with activated Valpha24 NKT cell administration was well tolerated and carried out safely with minor adverse events even in patients with advanced diseases.

Adult↗
PubMed2006

Valsartan improves the lower limit of cerebral autoregulation in rats.

The effects of angiotensin II type 1 receptor blockers (ARBs) on cerebral blood flow (CBF) autoregulation have not been fully clarified. Thus, we examined the acute effect of valsartan, the most selective ARB, on CBF autoregulation in spontaneously hypertensive rats. Intravenous administration of valsartan (0.3 mg/kg) reduced the mean arterial pressure (MAP) from 184+/-5 (mean+/-SEM) to 174+/-5 mmHg (p<0.001) without affecting CBF as measured by laser-Doppler flowmetry. The lower limit of CBF autoregulation (the MAP at which the CBF was 80% of the baseline value) in the valsartan-treated group (122+/-3 mmHg) was significantly lower than that in the control group (135+/-4 mmHg, p<0.05). Reverse transcribed-polymerase chain reaction and immunohistochemical staining demonstrated that both angiotensin II type 2 receptors and angiotensin II type 1 receptors (AT1Rs) were expressed in endothelial and smooth muscle cells of the rat cerebral arteries. These results suggest that specific inhibition of AT1Rs in the cerebral circulation causes the leftward shift of the lower limit of autoregulation.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Dendritic cell maturation by CD11c- T cells and Valpha24+ natural killer T-cell activation by alpha-galactosylceramide.

Human invariant Valpha24+ natural killer T (NKT) cells display potent antitumor activity upon stimulation. Activation of endogenous Valpha24+ NKT cells would be one strategy for the treatment of cancer patients. For example, dendritic cells (DCs) loaded with a glycolipid NKT cell ligand, alpha-galactosylceramide (alphaGalCer, KRN7000), are a possible tool for the activation and expansion of functional Valpha24+ NKT cells in vivo. In this report, we demonstrate that the levels of expansion and the ability to produce IFN-gamma of Valpha24+ NKT cells induced by alphaGalCer-loaded whole PBMCs cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs) were superior to those of cells induced by monocyte-derived CD11c+ DCs (moDCs) developed with IL-4 and GM-CSF. Interestingly, CD11c+ cells in the IL-2/GM-CSF-cultured PBMCs showed a mature phenotype without further stimulation and exerted potent stimulatory activity on Valpha24+ NKT cells to enable them to produce IFN-gamma preferentially at an extent equivalent to mature moDCs induced by stimulation with LPS or a cytokine cocktail. Cocultivation with CD11c- cells in the IL-2/GM-CSF-cultured PBMCs induced maturation of moDCs. In particular, CD11c-CD3+ T cells appeared to play important roles in DC maturation. In addition, TNF-alpha was preferentially produced by CD11c-CD3+ T cells in IL-2/GM-CSF-cultured PBMCs and was involved in the maturation of moDCs. Thus, the maturation of DCs induced by CD11c- T cells through TNF-alpha production appears to result in the efficient expansion and activation of Valpha24+ NKT cells to produce IFN-gamma preferentially.

Antigens, CD↗
PubMed2005

A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer.

PURPOSE: Human Valpha24 natural killer T (NKT) cells bearing an invariant Valpha24JalphaQ antigen receptor, the counterpart of murine Valpha14 NKT cells, are activated by a specific ligand, alpha-galactosylceramide (alphaGalCer, KRN7000), in a CD1d-dependent manner. I.v. administration of alphaGalCer-pulsed dendritic cells (DC) induces significant activation and expansion of Valpha14 NKT cells in the lung and resulting potent antitumor activities in mouse tumor metastatic models. We did a phase I dose escalation study with alphaGalCer-pulsed DCs in lung cancer patients. EXPERIMENTAL DESIGN: Patients with advanced non-small cell lung cancer or recurrent lung cancer received i.v. injections of alphaGalCer-pulsed DCs (level 1: 5 x 10(7)/m(2); level 2: 2.5 x 10(8)/m(2); and level 3: 1 x 10(9)/m(2)) to test the safety, feasibility, and clinical response. Immunomonitoring was also done in all completed cases. RESULTS: Eleven patients were enrolled in this study. No severe adverse events were observed during this study in any patient. After the first and second injection of alphaGalCer-pulsed DCs, dramatic increase in peripheral blood Valpha24 NKT cells was observed in one case and significant responses were seen in two cases receiving the level 3 dose. No patient was found to meet the criteria for partial or complete responses, whereas two cases in the level 3 group remained unchanged for more than a year with good quality of life. CONCLUSIONS: In this clinical trial, alphaGalCer-pulsed DC administration was well tolerated and could be safely done even in patients with advanced disease.

Aged↗
PubMed2005

Anti-angiogenic and immunomodulatory effect of the herbal medicine "Juzen-taiho-to" on malignant glioma.

Juzen-taiho-to (JTT) is known as a Japanese herbal medicine that increases the immune function via the enhancement of phagocytosis, cytokine induction, and antibody production. Anti-neoplastic effects on malignant gliomas have been reported by means of the enhancement of the immune function in both animals and humans. We evaluated whether JTT has anti-angiogenic effects on malignant glioma growth in vitro and in vivo. In vitro, the anti-proliferative effect of JTT on malignant glioma cells and endothelial cells was assessed by cell proliferation assay. In vivo, a subcutaneous model of malignant glioma with different-aged mice (old, 43 weeks; young, 8 weeks) was used. After oral administration of JTT to mice, their immunological function and angiogenic status of tumor tissues were assessed by flow cytometry and immunohistochemistry, respectively. JTT inhibited human endothelial cell, but not glioma cell, proliferation in vitro. In vivo, the NK (natural killer) cell ratio within PBMC (peripheral blood mononuclear cells) and NK activity of fresh splenocytes obtained from JTT-treated old mice were significantly increased compared to the ratio and activity in control mice. In old mice, the vessel area of tumor tissues in JTT treatment groups was significantly decreased. These enhancements of immunological function and the inhibition of angiogenic activity were not observed in young mice. JTT not only increased host immunological function but also exerted anti-angiogenic effects on malignant glioma growth. JTT would be useful as an adjuvant medicine for malignant gliomas through its enhancement of systemic immunological function and its anti-angiogenic action.

Angiogenesis Inhibitors↗
PubMed2005

Primary cerebral angiitis containing marked xanthoma cells with massive intraparenchymal involvement--case report--.

A 27-year-old woman was referred to our hospital with mild disorientation, bilateral abducens nerve palsy, and mild left hemiparesis. Magnetic resonance (MR) imaging revealed diffuse mass lesions resembling malignant glioma in the right frontal intraparenchymal region, with enhancement of multiple meningeal and intraparenchymal nodules. Partial resection of the frontal lesion was performed. Histological examination revealed that the specimens consisted of brain tissue, with marked perivascular infiltration of histiocytes and sheets of xanthomatous cells. The diagnosis was primary cerebral angiitis containing marked xanthoma cells. Steroid therapy was administered over 1 week. MR imaging showed that the remaining lesions resolved gradually, and had disappeared 2 years after surgery. No neurological symptoms or recurrence of the tumor has been observed during the 6-year period since the operation.

Abducens Nerve Diseases↗
PubMed2004

X-irradiation to human malignant glioma cells enhances the cytotoxicity of autologous killer lymphocytes under specific conditions.

PURPOSE: To clarify the effect of combining x-irradiation and human killer lymphocytes against autologous malignant glioma cells, we analyzed not only the alteration of surface antigen expression in irradiated tumor cells, but also the cytotoxic effects of human killer lymphocytes on the autologous tumor cells with and without x-irradiation. METHODS AND MATERIALS: Six malignant glioma cell-lines (MG 1-6) established from each patient with a malignant glioma in our institute, and U87MG, were used as materials. They were irradiated by 0-50 Gy of X-rays, and the alternations of their human histocompatability leukocyte antigen (HLA), HLA-ABC, HLA-DR, -DP, -DQ, and FAS expressions were examined. Then, three sets of autologous natural killer (NK) cells, and autologous tumor-specific T lymphocytes (ATTL) were induced from the peripheral blood mononuclear cells (PBMCs) of three patients, and in vitro cytotoxic effects of these killer cells on the irradiated autologous tumor cells were analyzed. RESULTS: Irradiation-enhanced HLA-DR, -DP, -DQ, and FAS expression in glioma cell lines with low p53 expression. However, there was no correlation between HLA-ABC expression and X-ray dose. After irradiation of the tumor cells, cytotoxicity was enhanced in four of six effectors; in particular, it was significantly elevated in two killer lymphocytes. It was speculated that the enhancing effect was influenced not only by the p53 status of the tumor, but also by the types of killer lymphocytes; the alteration of cytotoxicity in NK cells on irradiated tumor cells may be compensatory for alteration in ATTLs. CONCLUSION: It was indicated that irradiation of malignant tumor cells enhanced killer cell-mediated cytotoxicity in autologous models under specific conditions. These basic data should contribute to clinical trials using local radiotherapy and systemic adoptive immunotherapy with killer lymphocytes.

Cytotoxicity, Immunologic↗
PubMed2004

Surgery improves vision and cosmetic appearance of an adult patient with fibrous dysplasia of the frontal bone.

A 31-year-old woman with fibrous dysplasia (FD) of the left forehead was reported. Visual acuity impairment and diplopia were slowly progressive for 6 months associated with marked protrusion of her left forehead. Removal of left forehead lesion including the orbital ridge and total decompression of the optic canal and superior orbital fissure improved these visual symptoms dramatically. Reconstructive cranioplasty using artificial bone made by hydroxyapatite (Apaceram) was very satisfactory in cosmetic appearance. Surgical indication and neuroradiological findings of cranial FD are discussed as well as a review of the literatures.

Adult↗
PubMed2004

Structural study on polymorphism of long-chain dicarboxylic acids using oblique transmission method for micro FT-IR spectrometers.

Polymorphism and higher-order structures of even-number dicarboxylic acids from hexadecanedioic acid to eicosanedioic acid have been studied by micro-FTIR spectroscopy and microscopic observation. In order to obtain the three-dimensional structural information, the oblique transmission method was incorporated into a micro-FTIR spectrometer equipped with a couple of Cassegrain lenses. The IR spectra showed that the solid states of dicarboxylic acid bore a marked structural similarity to those of n-saturated fatty acids. It was found that a solution-grown single crystal of dicarboxylic acids was an aggregate of lamellae whose thickness exceeded by far their molecular length. The surfaces of lamellae were covered with hydrocarbon segments taking a hairpin structure, and the linkage of hydrogen-bonded dicarboxylic acids formed a folded chain structure. The result of oblique transmission measurements showed that the stacking mode of lamellae varied depending on crystallization conditions.

Biophysical Phenomena↗
PubMed2004

Intratumoral injection of IL-2-activated NK cells enhances the antitumor effect of intradermally injected paraformaldehyde-fixed tumor vaccine in a rat intracranial brain tumor model.

Combined therapy with a fixed-tumor cell vaccine and intratumoral injection of NK cells induced strong tumor regression of rat glioma. Rat 9L glioma cells were inoculated into syngeneic male rats at the flank (subcutaneous tumor model) or at the basal ganglia of the right hemisphere (intracranial tumor model). Rats were intradermally injected three times with vaccine comprising fixed 9L cells, IL-2- and GMCSF-microparticles, and tuberculin prior to (protective studies) or after (therapeutic studies) challenge with live 9L cells. In the protective studies, the vaccine alone achieved significant tumor growth inhibition and elongation of mean life span in both the subcutaneous and intracranial tumor models. No therapeutic effect was observed in the intracranial tumor model with the vaccine alone. However, intratumoral injection of rat NK cells strongly assisted the therapeutic effect of the vaccine in the brain tumor model and resulted in a statistically significant elongation of life span. We propose that intratumoral injection of NK cells may not only kill brain tumor cells directly, but also trigger a strong immune response in the focal lesion of the brain after vaccination.

Animals↗
PubMed2003

Effects of local injection of ex vivo expanded autologous tumor-specific T lymphocytes in cases with recurrent malignant gliomas.

PURPOSE: The aim of this report was to indicate both the advantages and disadvantages of local cell transfer therapy using ex vivo expanded autologous tumor-specific T lymphocytes (ATTLs) for recurrent cases of malignant gliomas. EXPERIMENTAL DESIGN: Subjects are 10 cases of malignant gliomas consisting of 7 cases of glioblastoma multiforme, 2 cases of anaplastic astrocytoma, and 1 case of anaplastic oligoastrocytoma. All cases were recurrences. ATTLs were induced by coculturing peripheral blood mononuclear cells with autologous tumor cells in medium containing interleukin-1, -2, -4, and -6 and administered into the local tumor site in total numbers of 3-247 x 10(7) cells. As end points, tumor response and survival time were analyzed observing clinical state. RESULTS: Five cases responded to this therapy (namely, one case showed complete remission, and four cases had a partial response). There were three cases of no change, and two cases of progressive disease. The overall tumor response rate was 50%. No complications were noticed, except for two cases of minor local hemorrhage and eight cases of temporary fever. Nine cases died of further tumor progression, and one case died of aspiration pneumonia, and the cause-specific survival analysis indicates that the median survival time was 5 months from the initial ATTL injection. CONCLUSIONS: The results suggest that local administration of ATTLs is effective in recurrent malignant gliomas in that it demonstrated a high benefit:risk ratio with minor side effects. Although its antitumor effect may be temporary in some advanced cases, it is highly possible that the tumor could be stabilized when conditions are optimal.

Adult↗
PubMed2002

Intratumoral hemorrhage due to hemangioblastoma arising from a cervical nerve root--a case report.

We describe a case of a 70 year old man suffering from sudden weakness of the left foot. Preoperative neuroimaging examinations showed an oval mass 2 cm in maximal diameter with intratumoral hemorrhage at the seventh cervical vertebra. The mass was supplied by the right lateral thoracocervical artery and was drained to the anterior spinal vein. The intraoperative findings showed the hard reddish tumor was not attached to the pia and the posterior root of the fifth cervical nerve was totally encased by the tumor. A histopathological examination revealed that hemangioblastoma encasing the posterior nerve root totally, so that the tumor was thought to arise from it. Unusual presentation of the neuroimaging examinations is described.

Aged↗
PubMed2002

Chondroblastoma of the temporal base with high mitotic activity.

A 24-year-old man presented with a rare chondroblastoma of the temporal base manifesting as local pain accompanied by difficulty in opening the mouth. Gross total removal was achieved at initial surgery, but the tumor demonstrated rapid and destructive regrowth from a very small residual volume without definite histological malignant transformation. Growth activity estimated by MIB-1 staining increased spontaneously from 2.5% at the initial operation to 18.7% at recurrence. Further extensive radical tumor removal by surgeons from multiple disciplines was performed. The patient has been free of recurrence for 3 years without radiotherapy. Chondroblastoma of the temporal bone is widely accepted as a benign tumor and regrowth after gross total removal is very rare. However, some cases of chondroblastoma have potentially high mitotic activity.

Adult↗
PubMed2002

Reversible dementia in patients with chronic subdural hematomas.

OBJECT: Neuropsychiatric changes following surgery for chronic subdural hematomas (CSDHs) were analyzed in 26 patients (21 men and five women) by using the Mini-Mental State Examination (MMSE) and the Hasegawa Dementia Scale-Revised (HDS-R) to determine factors that potentially contribute to neuropsychiatric recovery. METHODS: Burr hole irrigation was performed in every patient to treat the CSDH. The patients' profiles, including age and sex, neuroimaging findings (such as hematoma volume and thickness, as well as midline shift), and preoperative and postoperative scores on the MMSE, HDS-R, and activities of daily living (ADL) scale were recorded. According to preoperative MMSE scores, eight patients (30.8%) were classified as mentally healthy and 18 (69.2%) as suffering from dementia before surgery. Nine of the 18 patients with dementia recovered to a normal psychological state following surgery. Surgery improved not only the patients' independence in ADL (p = 0.0026), but also their neuropsychiatric functions such as orientation and calculation, as estimated by scores on the MMSE (p = 0.0002) and the HDS-R (p = 0.0008). Factors affecting neuropsychiatric status on admission were midline shift (p = 0.0398) and ADL score (p = 0.0124); factors that could be used to predict neuropsychiatric recovery after surgery were patient age (p = 0.0027) and ADL score (p = 0.0193). The results of a logistic regression analysis demonstrated that significant predictors of neuropsychiatric recovery after surgery include the following: patient age (p = 0.0049, odds ratio [OR] = 0.842) and preoperative ADL (p = 0.0056, OR = 0.471), MMSE (p < 0.0001, OR = 1.895), and HDS-R (p = 0.0073, OR = 1.303) scores. Results of subgroup analyses demonstrated that patients younger than 74 years of age and those who had preoperative scores lower than 5 on the converted ADL scale, higher than 10 on the MMSE, or higher than 9 on the HDS-R on admission were found to have a significantly better recovery of neuropsychiatric functions after surgery. CONCLUSIONS: Dementia is reversible in many patients with CSDH, and surgery can improve not only independence in ADL, but also neuropsychiatric functions. Patients who are younger and/or those who have lower preoperative ADL scores and/or higher preoperative MMSE or HDS-R scores will achieve a good recovery with regard to neuropsychiatric functions after surgery. Estimations of neuropsychiatric function based on MMSE and HDS-R scores were found to be useful in predicting functional outcomes in patients with CSDH.

Activities of Daily Living↗