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Biomedical subjects

A Hirano

Publications and source records attributed to A Hirano.

At least 55 records · Page 3Linked to original sources

[Breast cancer].

Neoadjuvant chemotherapy (NAC) represents a new approach based on sound theoretical, pharmacokinetic, and experimental principles. The purpose of NAC is to improve control of the primary site by downstaging and to improve control of micrometastatic disease. NAC has been standard therapy in the management of locally advanced breast cancer. Patients with earlier stage breast cancer may also benefit from treatment with NAC. Recently some investigators have mentioned that NAC can be used instead of adjuvant chemotherapy and would be most appropriate for patients who wish to preserve their breast but who have tumors too large for breast conserving surgery. In this article, we reviewed the present status of NAC (indication, clinical response, pathologic response, survival, possibility of breast conservation, prognostic/predictive factors, neoadjuvant endocrine therapy) and discussed several unanswered questions on NAC (survival benefit, optimal number of treatment cycles, optimal regimens) and future direction. Combined modality therapy including NAC appears to provide excellent local control, the possibility of breast conservation, and, probably, an increased survival rate, at least for some subsets of patients. Furthermore, through sequential sampling, NAC provides indeed the opportunity to identify molecular mechanisms associated with pathologic response and to study the possibility to guide the choice for induction treatment and patient populations submitted to neoadjuvant chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

Functional modulation of human macrophages through CD46 (measles virus receptor): production of IL-12 p40 and nitric oxide in association with recruitment of protein-tyrosine phosphatase SHP-1 to CD46.

Human CD46, formerly membrane cofactor protein, binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic measles infection. Suppression of cell-mediated immunity, including down-regulation of IL-12 production, has been reported on macrophages (Mphi) by cross-linking their CD46. The intracellular events responsible for these immune responses, however, remain unknown. In this study, we found that 6- to 8-day GM-CSF-treated peripheral blood monocytes acquired the capacity to recruit protein-tyrosine phosphatase SHP-1 to their CD46 and concomitantly were able to produce IL-12 p40 and NO. These responses were induced by stimulation with mAbs F(ab')(2) against CD46 that block MV binding or by a wild-type MV strain Kohno MV strain (KO; UV treated or untreated) that was reported to induce early phase CD46 down-regulation. Direct ligation of CD46 by these reagents, but not intracellular MV replication, was required for these cellular responses. Interestingly, the KO strain failed to replicate in the 6- to 8-day GM-CSF-cultured Mphi, while other MV strains replicated to form syncytia under the same conditions. When stimulated with the KO strain, rapid and transient dissociation of SHP-1 from CD46 was observed. These and previous results provide strong evidence that CD46 serves as a signal modulatory molecule and that the properties of ligands determine suppression or activation of an innate immune system at a specific maturation stage of human Mphi.

Animals↗

Intraocular Lens Calculation for Cataract Treated with Photorefractive Keratectomy Using Ray Tracing Method.

Purpose: Conventional methods (such as the SRK-II formula) do not accurately calculate the power of the intraocular lens (IOL) after refractive surgery. Therefore, we compared a new formula including a ray tracing method to the conventional method for foldable IOL lens implantation.Method: Foldable IOLs (MA 60 BM) were implanted in 26 patients (32 eyes) using the phakoemulsification technique. The power of the IOL was measured preoperatively using the SRK-II formula in all cases. From the results of postoperative refractive errors of these cases, the power of IOL calculated by the ray tracing method was compared to the SRK-II formula. Cataract patients first treated with photorefractive keratectomy (PRK) received IOL implants using our ray tracing method and their postoperative refraction was measured.Results: The average postoperative refractive error was 1.32 D in SRK-II formula, 0.95 D in the ray tracing method with Ray 1 used and 0.89 D with Ray 2 used. Postoperative refraction of both eyes first treated with PRK was -1.00 D.Conclusion: The average postoperative refractive error was reduced in the ray tracing method using Olsen's predicted ACD (Ray 2) compared to SRK-II formula. This new tracing method appears to be useful for determination of IOL power and it may be applied for IOL calculation for cataract surgery after refractive surgery.

Journal Article↗

Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS).

Twelve cases of adult-onset progressive muscular atrophy variant of amyotrophic lateral sclerosis (PMA/ALS) were studied in a small rural population of 1500 in the Republic of Belarus (former Soviet Union). The patients were members of three apparently related kindreds, each showing autosomal dominant pattern of disease inheritance. The average age at clinical onset ranged from 26 to 57 years (mean, 40 years). Each patient suffered from skeletal muscle weakness and wasting, starting in the limbs and spreading to the trunk and neck, with very limited bulbar and no upper motor neuron involvement. Death from respiratory failure occurred from 13 to 48 months (mean, 28 months) after first symptoms. Dramatically decreased number of spinal motor neurons was the most characteristic neuropathologic feature in two autopsied cases. Most of the remaining degenerating neurons contained intracytoplasmic hyaline inclusion bodies. A D101N mutation in exon 4 of the SOD1 gene was identified in a PMA/ALS patient and in one of her three unaffected children. Our data support the view that some subtypes of familial ALS associated with SOD1 mutations may present as PMA. Diagnostic criteria of ALS should be accordingly modified to include the PMA variant of familial ALS.

Adult↗

Evaluation and comparison of ion permeation and agonist selectivities for N-methyl-d-aspartate receptor channels with different subunit compositions in bilayer lipid membranes based on integrated single-channel currents.

To quantify the ion-permeation ability of the recombinant epsilon1-4/zeta1 channel activated by agonists, the magnitude of agonist-induced integrated single-channel currents for the epsilon2-4/zeta1 N-methyl-d-aspartate (NMDA) channels in bilayer lipid membranes (BLMs) was evaluated electrochemically based on the single-channel recordings. The recombinant epsilon2-4/zeta1 channels were purified from Chinese hamster ovary cells expressing each channel and incorporated in BLMs formed by the tip-dip method. Three typical agonists, l-glutamate, NMDA, and (2S, 3R, 4S) isomer of 2-(carboxycyclopropyl)glycine (l-CCG-IV), were investigated at a concentration of 50 microM. The magnitude of l-glutamate-induced integrated current was found to depend on the epsilon-subunit composition and to increase in the order of epsilon2/zeta1 > epsilon1/zeta1 approximately epsilon4/zeta1 > epsilon3/zeta1, which differs from that of the reported binding affinities (EC(50)) between l-glutamate and each channel type. On the other hand, the magnitude of the integrated currents induced by NMDA and l-CCG-IV did not vary among the four channel types. The order of agonist selectivity toward the epsilon2-4/zeta1 channels in terms of the magnitude of the integrated current was l-glutamate > l-CCG-IV approximately NMDA for the epsilon2/zeta1 channel, l-CCG-IV > NMDA > l-glutamate for the epsilon3/zeta1 channel, and l-CCG-IV approximately l-glutamate > NMDA for the epsilon4/zeta1 channel, suggesting that the agonist selectivity also depends on the epsilon-subunit composition. The present study shows that each epsilon1-4/zeta1 channel has its own ability of ion permeation, i.e., its own signal transduction ability, which is not parallel to its binding ability.

Animals↗

Fragmentation of the Golgi apparatus of the anterior horn cells in patients with familial amyotrophic lateral sclerosis with SOD1 mutations and posterior column involvement.

The Golgi apparatus (GA) of the anterior horn cells in the spinal cord was examined by immunohistological methods with an antibody against the MG-160 protein, a conserved intrinsic membrane sialoglycoprotein of the medial cisternae of the GA, in three patients with familial amyotrophic lateral sclerosis (FALS) with posterior column involvement. Large motor neurons in the anterior horns were markedly reduced in number and 10 of total 14 remaining large motor neurons showed fragmentation and a reduction in the number of the elements of the GA. The fragmentation of the GA was identical to that previously reported in motor neurons of the spinal cord and motor cortex from patients with sporadic ALS and in transgenic mice expressing the G93A mutation of the gene encoding the Cu/Zn superoxide dismutase months before the onset of paralysis. This is the first report of fragmented GA of the anterior horn cells in patients with FALS with posterior column involvement. The findings suggest that the GA is a common target in the neuronal degeneration in sporadic and FALS.

Amino Acid Substitution↗

Risk factors for posttransfusion graft versus host disease, mediastinitis, and late cardiac tamponade in heart surgery. Survey of 119 Japanese institutions.

OBJECTIVE: Correlations and risk factors remain to be unclarified for post-heart-surgery posttransfusion graft-versus-host disease, mediastinitis, and late cardiac tamponade caused by deteriorated host-defense mechanisms due to cardiopulmonary bypass both with and without steroid usage. METHODS: We sent questionnaires to 298 Japanese cardiovascular institutions asking for institution profiles, including infection control, steroid use in cardiopulmonary bypass, and prevalence of mediastinitis, late cardiac tamponade, and posttransfusion graft-versus-host disease during 1994. The overall prevalence of posttransfusion graft-versus-host disease since the start of service (from establishment of institution to date) was also requested. RESULTS: The number of pump cases at the 119 institutions responding (40%) were 91.6 +/- 67.9 cases/institution (total = 10,904). The prevalence of mediastinitis was 1.2 +/- 1.8 and that of late cardiac tamponade 1.0 +/- 1.8%. Posttransfusion graft-versus-host disease occurred in 1 of 10,904 patients (0.01%) during 1994 at an institution where steroids and nonirradiated blood were used in surgery. The simple institutional mean prevalence of posttransfusion graft-versus-host disease since establishing institutions was 0.08 +/- 0.13%. Of the 119 institutions surveyed, 86 used steroids in all pump cases (72%); 11 institutions used steroids in a limited number of cases (9%). The institutional mean of methylprednisolone-converted steroid dose was 21.5 +/- 16.4 mg/kg (n = 119). In multivariate regression analysis, operation time (p = 0.005) for mediastinitis, steroid usage (all, limited, or no cases) (p = 0.01) and % aneurysm (p = 0.05) for late cardiac tamponade, and steroid dosage (p = 0.002) for posttransfusion graft-versus-host disease were identified as significant risk factors. CONCLUSION: Our results suggest that massive steroid administration for cardiopulmonary bypass may increase the risk of posttransfusion graft-versus-host disease and late cardiac tamponade, but not mediastinitis.

Aged↗

Midkine, a new neurotrophic factor, is present in glial cytoplasmic inclusions of multiple system atrophy brains.

The glial cytoplasmic inclusion (GCI) is a histological hallmark for multiple system atrophy (MSA): these inclusions are found in oligodendrocytes and consist of abnormal granule-coated fibrils of approximately 24- to 40-nm diameter. To clarify the significance of the presence of midkine (MK) in these GCIs, we carried out immunohistochemical, electron and immunoelectron microscopical, and Western blot analyses of MSA brains using a monoclonal antibody against the C-terminal region of human MK. Immunohistochemically, most of the GCIs were intensely stained by the antibody to MK. Electron and immunoelectron microscopy showed that the GCIs were composed of MK-positive granule-coated fibrils that were essential constituents of these inclusions. No significant MK immunoreactivity was observed in oligodendrocytes, astrocytes and neurons of the normal control subjects. The presence of MK in MSA brain but not in normal brain was confirmed by Western blotting. Together with the fact that MK is associated with fetal morphogenesis during the midgestation period, the presence of MK immunoreactivity in oligodendroglial GCIs may suggest the existence of a repair mechanism on the basis of morphogenesis in the degenerated oligodendrocytes themselves as well as the affected neurons and their axons through the oligodendrocyte-axon-neuron relationship.

Aged↗

Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)-positive inclusions are common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with a G85R mutation.

To clarify the biological significance of the neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions characteristically found in patients with familial amyotrophic lateral sclerosis with superoxide dismutase-1 (SOD1) gene mutations and in transgenic mice expressing human SOD1 with G85R mutation, the detailed protein composition in both types of inclusions was immunohistochemically analyzed using 45 different antibodies. Both types of inclusions had very strong immunoreactivity for SOD1. The SOD1-positive inclusions in both cell types were also immunoreactive for the insoluble advanced glycation endproducts (AGEs) such as Nepsilon-(carboxymethyl)lysine (CML), pyrraline and pentosidine: both inclusions in both conditions were ultrastructurally composed of the granule-coated fibrils that had immunoreactivities to CML and pyrraline. Both types of inclusions were negative for stress-response proteins (SRPs), 4-hydroxy-2-nonenal (HNE), acrolein, nitric oxide synthases (NOSs) and nitrotyrosine as representative markers of oxidative stress. The neurons and astrocytes of the normal individuals and non-transgenic mice showed no significant immunoreactivity for SOD1, AGEs, SRPs, HNE, acrolein, NOSs or nitrotyrosine. Our results suggest that a portion of the SOD1 composing both type of inclusions, probably toxic mutant SOD1, is modified by the AGEs, and that the formation of the AGE-modified SOD1 is one of the mechanisms responsible for the aggregation involving no significant oxidative mechanisms.

Adult↗

Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation.

To assess a role for oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS), we analyzed the immunohistochemical localization of 8-hydroxy2'-deoxyguanosine (OHdG) as a nucleic acid oxidation product, acrolein-protein adduct and 4-hydroxy-2-nonenal (HNE)-protein adduct as lipid peroxidation products, Nepsiloncarboxymethyl-lysine (CML) as a lipid peroxidation or protein glycoxidation product, pentosidine as a protein glycoxidation product, and imidazolone and pyrraline as nonoxidative protein glycation products in the spinal cord of three familial ALS patients with superoxide dismutase(SOD 1) A4V mutation, six sporadic ALS patients, and six age-matched control individuals. The spinal cord sections of the control cases did not show any distinct immunoreactivities for these examined products. In the familial ALS cases, intense immunoreactivities for pyrraline and CML were confined to the characteristic Lewy body-like hyaline inclusions, and imidazolone immunoreactivity was located in the cytoplasm of the residual motor neurons. No significant immunoreactivities for other examined products were detected in the familial ALS spinal cords. In the sporadic ALS cases, intense immunoreactivities for pentosidine, CML and HNE-protein adduct were seen in the cytoplasm of the degenerated motor neurons, and OHdG immunoreactivity was located in the cell nuclei of the residual neurons and glial cells. The present results indicate that oxidative reactions are involved in the disease processes of sporadic ALS, while there is no evidence for increased oxidative damage except for CML deposition in the familial ALS spinal cords. Furthermore, it is likely that the accumulation of pyrraline and imidazolone supports a nonoxidative mechanism in SOD1-related motor neuron degeneration.

8-Hydroxy-2'-Deoxyguanosine↗

Evaluation of agonist selectivity for the NMDA receptor ion channel in bilayer lipid membranes based on integrated single-channel currents.

A new method for evaluating chemical selectivity of agonists to activate the N-methyl-D-aspartate (NMDA) receptor was presented by using typical agonists NMDA, L-glutamate and (2S, 3R, 4S)-2-(carboxycyclopropyl)glycine (L-CCG-IV) and the mouse epsilon1/zeta1 NMDA receptor incorporated in bilayer lipid membranes (BLMs) as an illustrative example. The method was based on the magnitude of an agonist-induced integrated single-channel current corresponding to the number of total ions passed through the open channel. The very magnitudes of the integrated single-channel currents were compared with the different BLMs as a new measure of agonist selectivity. The epsilon1/zeta1 NMDA receptor was partially purified from Chinese hamster ovary (CHO) cells expressing the epsilon1/zeta1 NMDA receptor and incorporated in BLMs formed by the tip-dip method. The agonist-induced integrated single-channel currents were obtained at 50 microM agonist concentration, where the integrated current for NMDA was shown to reach its saturated value. The obtained integrated currents were found to be (4.5 +/- 0.55) x 10(-13) C/s for NMDA, (5.8 +/- 0.72) x 10(-13) C/s for L-glutamate and (6.6 +/- 0.61) x 10(-13) C/s for L-CCG-IV, respectively. These results suggest that the agonist selectivity in terms of the total ion flux through the single epsilon1/zeta1 NMDA receptor is in the order of L-CCG-IV approximately = L-glutamate > NMDA.

Amino Acids, Dicarboxylic↗

Graft hyporeactivity induced by immature donor-derived dendritic cells.

Immature dendritic cells (DCs) are deficient in surface co-stimulatory molecules and have been shown to exhibit a 'tolerogenic' potential. We investigated the allostimulatory activity of immature DCs in one-way mixed leukocyte reactions and their capacity to inhibit anti-donor cytolytic activity in the sponge matrix allograft model. Immature DCs (CD80 and CD86 deficient) were derived from bone marrow cells propagated in GM-CSF and TGF-beta1. Mature DCs (CD80+ and CD86+) were derived from bone marrow cells propagated in GM-CSF and IL-4. Either 2 x 10(6) DBA/2J (DBA, H-2d) immature DCs or 2 x 10(6) mature DCs were injected intravenously into C57BL/6J (B6, H-2b) mice 7 days prior to sponge matrix allograft implantation. On day 12, the sponge was harvested and the graft-infiltrating cells were tested in vitro for cytotoxic T lymphocyte (CTL) activity. Immature dendritic cell (DC) infused significantly and markedly inhibited intra-graft CTL activity compared to mature DCs and syngeneic bone marrow control cells. The administration of immature DCs directly into the sponge allograft failed to induce hyporeactivity. Thus, the only systemic infusion of immature donor DCs was able to recapitulate the donor-specific transfusion effect, and the capacity of donor bone marrow cells to induce donor-specific hyporeactivity in the sponge allograft model.

Animals↗

Keloid fibroblasts resist ceramide-induced apoptosis by overexpression of insulin-like growth factor I receptor.

Keloids are benign dermal tumors, characterized by overgrowth of lesions, invasiveness beyond the original boundary of the insult, and recurrence of lesions. The exact etiology is unknown, however. Our hypothesis is that keloids are acquired as a result of an abnormal or prolonged wound healing process, with persistent proliferation and extracellular matrix production of fibroblasts that should otherwise discontinue in normal wound healing. In this study, we examined the response of keloid fibroblasts to proapoptotic signaling. Cell-permeable ceramide, N-acetyl-D-sphingosine, induced apoptosis of dermal fibroblasts in a dose- and time-dependent manner, which was detected by phase contrast microscopy, fluorescent microscopy, the TUNEL method, flow cytometric analysis, and WST-1 assay. In contrast, keloid fibroblasts resisted apoptosis induced by N-acetyl-D-sphingosine (percent survival with 40 mM ceramide treatment for 12 h, normal versus keloid: 9.6% +/- 6.6% vs 66.8% +/- 5.5%). Western blotting analysis showed insulin-like growth factor I receptor overexpression in keloid fibroblasts, but not in normal fibroblasts. Exogenously added insulin-like growth factor I enhanced the resistance of keloid fibroblasts to ceramide-induced apoptosis. Wort- mannin, a phosphatidylinositol 3 kinase inhibitor, suppressed the antiapoptotic action of insulin-like growth factor I in keloid fibroblasts. Our results suggest that keloid fibroblasts overexpressing insulin-like growth factor I receptor are resistant to apoptosis, thus allowing persistent proliferation and production of excessive extracellular matrix. J Invest Dermatol 115:1065-1071 2000

Apoptosis↗

Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron system involvement, and is epidemiologically subclassified into sporadic, familial and endemic forms. About 20% of ALS families are associated with mutations in the gene for superoxide dismutase-1 (SOD1) encoded on chromosome 21q22.1. Several studies have pointed to a variety of functions of mutant SOD1, which has enhanced catalytic activity of the peroxynitrite-mediated tyrosine nitration, readily releases the reactive Cu ions, induces apoptotic cell death, has enhanced peroxidase activity, damages the mitochondria to release Ca2+, and forms SOD1-containing aggregates in the cytoplasm. Many of these studies have obtained evidence for increased oxidative damage in ALS. On the other hand, some reports disagree with oxidative damage involvement in SOD1 mutant ALS. In considering the findings of increased oxidative damage in mutant SOD1-expressing transgenic mice, it should be remembered that overexpression of mutant SOD1 may enhance oxidative stress generation from this enzyme. In this review, we present the clinicopathological features of SOD1 mutant familial ALS and its transgenic mouse model, and also discuss SOD1 mutation-related neurotoxicity, including SOD1 protein aggregation and post-translational protein modification.

Amyotrophic Lateral Sclerosis↗