Biomedical subjects

Y Ohashi

Publications and source records attributed to Y Ohashi.

At least 253 records · Page 14Linked to original sources

PubMed1998

Vascularity in human adrenal cortex.

It has long been postulated that angiogenesis plays important roles in tumor cell proliferation and hormonal secretion of endocrine tumors, including adrenocortical neoplasms. Detailed examination of vascularity, however, has not been reported in adrenocortical tumors. In this study, we quantitatively examined vascularity in normal adrenal, adrenocortical adenoma, and carcinoma using an image analysis system to evaluate vascularity or angiogenesis in these lesions. Vascular density (VD: vessel number/mm2), endothelial area of each vessel (EA: microm2/vessel) and vascular area (VA: the percentage of EA per field) were examined using immunohistochemical analysis of CD34 and the CAS 200 image analysis system. EA and VA of adrenocortical carcinomas (EA, 113.4 +/- 33.1; VA, 6.34 +/- 2.03) were significantly higher than those of adenoma (EA, 66.1 +/- 43.0; VA, 3.11 +/- 1.56) and normal adrenal tissue (EA, 65.4 +/- 26.0; VA, 4.26 +/- 1.19). There were no significant differences in VD among normal cases (702.2 +/- 173.2), adenomas (488.9 +/- 153.2), and carcinomas (573.2 +/- 185.2). These results suggest that adrenocortical carcinoma might be associated with increased endothelial cell proliferation but not with an increased number of intratumoral microvessels. There were no significant differences in these parameters of vascularity examined in the zona glomerulosa, zona fasciculata, and zona reticularis of aldosteronomas, Cushing's adenomas, and nonfunctioning hormonally inactive adenomas nor between specimens from patients who died of the disease and those from patients who did not.

Adrenal Cortex↗

PubMed1998

Assessment of the total artificial heart (TAH) pulsatility: the coalition between pulsatility and ejection time in TAH in vitro study.

There are many types of pulsatile pumps with various pulsatile flow waveforms. These authors perceived that pulsatility was an important characteristic for a pulsatile pump. The effect of a total artificial heart (TAH) was estimated using a pulse power index (PPI) in a mock loop. This method helps in the development of a standard criterion for measurement of a pulsatile waveform. The pulsatility of the TAH was found to be useful as a physiological control method. At first the relationship between ejection time and dp/dt was examined and then the relation between PPI, ejection time and preload. The dp/dt was unchanged by ejection time and PPI was unchanged by preload. However, PPI was changed by the ejection time. There was an inverse correlation between ejection time and PPI (r = 0.80). The PPI at ejection time 150 msec was significantly higher than the other ejection time's PPI. These results suggest that the TAH should be driven with an ejection time of 150 msec, because this ejection time has a high pulsatility and can obtain a higher flow. This happens without increasing the dp/dt and this ejection time can be preplanned, because a fixed ejection time improves the durability of the actuator.

Biomechanical Phenomena↗

PubMed1998

Expression of cell cycle inhibitor p27 and Ki-67 in human adrenocortical neoplasms.

Recent immunohistochemical analysis of cell cycle-related proteins such as p27, a cell cycle inhibitory protein, and Ki-67, a proliferation marker, indicated their possible values in predicting the biologic behavior of various human neoplasms. In this study, we performed an immunohistochemical analysis of p27 and Ki-67 in 42 adrenocortical neoplasms (12 adrenocortical carcinomas, 24 adrenocortical adenomas) and 6 normal adrenal glands to evaluate their possible values in diagnosing adrenocortical malignancy and in predicting the biologic behavior of carcinomas. We detected Ki-67 and p27 immunoreactivity in the nuclei of all of our cases, and we observed a significant negative correlation (r = -0.572, P < .001) between the p27 and Ki-67 labeling indexes (LIs). The LIs of p27 and Ki-67 were 61.7+/-2.6 and 0.28+/-0.08 in the normal adrenal cortex and 59.4+/-6.5 and 0.33+/-0.11 in the adenomas, respectively, with no significant differences between the LIs of the adenomas and normal adrenals. The LIs of p27 and Ki-67 in the carcinomas were 48.9+/-7.5 and 630+/-6.21, respectively. The LI of p27 in the carcinomas was significantly lower than that in the adenomas. The LI of Ki-67 in the carcinomas was significantly higher than that in the adenomas (P < .01). Among carcinoma cases, the Ki-67 LI in living cases tended to be lower than that in deceased cases, and the p27 LI in living cases tended to be higher than that in deceased cases, but these differences did not reach statistical significance. These results indicated that decreased p27 protein expression might cause increased cell proliferation in adrenocortical carcinoma cells in combination with other positive and/or negative regulators of the cell cycle. These results also suggested that immunohistochemical analysis of p27 and Ki-67 might be useful in distinguishing between adrenocortical adenoma and carcinoma

Adenoma↗

PubMed1998

Influence of the allergic response on the mucociliary system in the eustachian tube.

The effect of systemic and local allergic responses on the mucociliary system of the Eustachian tube was investigated. Egg albumin was administered to guinea pigs via the jugular vein to evoke systemic anaphylaxis in animals previously sensitized with egg albumin. Ciliary activity in the Eustachian tube of sensitized animals was significantly higher than that of control animals. However, the mucociliary clearance time of the Eustachian tube in sensitized animals was significantly longer than in control animals. Local allergic response induced by intratympanic instillation of (BPO)61-BGG induced cilioexcitation and prolonged mucociliary clearance in the guinea pigs sensitized with BPO-BGG. A partial loss of the inner layer of the mucus blanket of the Eustachian tube was observed under electron microscopy. In conclusion, the systemic as well as the local allergic response accelerates ciliary activity but may affect the mucus blanket and induce mucociliary dysfunction in the Eustachian tube, resulting in a predisposition to middle ear diseases.

Allergens↗

PubMed1998

A comparative study of the clinical efficacy of immunotherapy and conventional pharmacological treatment for patients with perennial allergic rhinitis.

This study was designed to compare the clinical outcome of prolonged immunotherapy for perennial allergic rhinitis with that of pharmacological treatment. Patients with perennial allergic rhinitis due to Dermatophagoides farinae (D. farinae) were divided into two groups; a pharmacotherapy group and an immunotherapy group. The pharmacotherapy group was treated with conventional pharmacological treatment using antihistamine tablets and topical steroid sprays and the immunotherapy group was treated with D. farinae extracts for 5 successive years. None of symptom scores at enrollment differed significantly between the groups. At 6 months and 1 year after the start of treatment the rate of decrease in each score was significantly greater in the pharmacotherapy group than in the immunotherapy group. The rate of decrease in sneezing scores, but not in the other scores, at 2 years after the start of treatment was also greater in the pharmacotherapy group than in the immunotherapy group. However, at 3 years the rate of decrease in any of the scores did not differ significantly between groups. The differences between the groups became clear-cut again after 5 years of treatment, when the rate of decrease in all of the scores was significantly greater in the immunotherapy group than in the pharmacotherapy group. Therefore, short-term treatment with pharmacological agents is probably superior to immunotherapy but, in the long-term, immunotherapy is apparently superior to pharmacological treatment with respect to clinical efficacy. In addition, prolonged immunotherapy provided long-term clinical efficacy and might provide a long-standing cure even after discontinuation of the therapy. In a questionnaire interview, approximately half of patients were very satisfied with prolonged immunotherapy and three-quarters were fairly satisfied or more. Additionally, the magnitude of improvement in nasal stuffiness contributed significantly and exclusively to the patient evaluation of immunotherapy. We propose that prolonged immunotherapy is never inferior to anti-allergenic pharmacological treatment and that it is possible to achieve long-term clinical efficacy or long-standing cure even after the discontinuation of immunotherapy, and that patients with perennial allergic rhinitis will be very satisfied with this prolonged therapeutic technique if nasal stuffiness is considerably alleviated.

Adolescent↗

PubMed1998

Risk factors for adverse systemic reactions occurring during immunotherapy with standardized Dermatophagoides farinae extracts.

The most serious problem in practical immunotherapy is the risk of occasional, potentially life-threatening adverse systemic reactions. Elucidation of the incidence of, and possible risk factors for, systemic reactions would have a profound effect on the decision about how to manage allergic rhinitis. The aim of this retrospective study was to document the incidence and risk factors of adverse systemic reactions during immunotherapy using standardized Dermatophagoides farinae (D. farinae) extracts for perennial allergic rhinitis. This study included 386 patients (22,722 injections) with perennial allergic rhinitis who had received immunotherapy with standardized D. farinae extracts in our clinics for the past 5 years. The incidence of systemic reactions was 6.22% per patient and 0.12% per injection. The time of onset of systemic reactions ranged from 3 to 30 min (mean 11.3 min) after injections. Our study has demonstrated that asthma, atopic dermatitis and a high level of IgE in serum, but not a high level of specific IgE in serum, are important high risk factors that may induce severe adverse systemic reactions in patients who receive immunotherapy for perennial allergic rhinitis. The incidence of systemic reactions in those who had a high level of IgE (higher than 1000 U/ml) and asthma and/or atopic dermatitis was 66.67% (12/18) per patient. Conversely, the incidence of systemic reactions in those who had none of the risk factors was 1.64% per patient. Thus, the rate of systemic reactions is thought to be reduced by 75% if patients with high risk factors are strictly excluded from immunotherapy for allergic rhinitis.

Allergens↗

PubMed1998

The herbal medicine shoseiryu-to inhibits allergen-induced synthesis of tumour necrosis factor alpha by peripheral blood mononuclear cells in patients with perennial allergic rhinitis.

The herbal medicine shoseiryu-to is an effective agent in the treatment of allergic rhinitis. However, the mechanism by which it exerts its action in improving patient symptoms remains unclear. It might affect the allergen-induced TH1 and/or TH2 responses. This study investigated whether the herbal medicine could affect cytokine synthesis by peripheral blood mononuclear cells (PBMCs) in response to the major Dermatophagoides farinae (D. farinae) allergen, Der f 1. PBMCs were obtained from 15 patients with perennial allergic rhinitis due to D. farinae, and were stimulated for 96 h with 10 micrograms/ml Der f 1 in the presence or absence of 45 mg/ml shoseiryu-to. The culture supernatants were harvested to determine the synthesis of IgE, interleukin 5 (IL-5), IL-6, IL-10, interferon-gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha). The agent did not affect the allergen-induced synthesis of IL-5, IL-6 and IFN-gamma, but somewhat decreased the synthesis of IgE and IL-10. This study highlighted an interesting pharmacological action of shoseiryu-to to substantially inhibit the allergen-induced synthesis of TNF-alpha. Our study suggests that the shoseiryu-to may alleviate nasal symptoms in allergic rhinitis through control of the allergen-induced inflammatory process.

Allergens↗

PubMed1998

Suplatast tosilate affects the initial increase in specific IgE and interleukin-4 during immunotherapy for perennial allergic rhinitis.

Suplatast tosilate can inhibit IL-4 production and suppress IgE synthesis in vitro. However, the theory that the agent causes changes in production of IL-4 and IgE in vivo has little experimental support. Immunotherapy could decrease the specific IgE response, but such a favourable effect is only possible with prolonged therapy after an initial increase in specific IgE. The use of suplatast tosilate together with immunotherapy may blunt the initial rise in specific IgE and decrease serum levels of specific IgE more quickly. Eighty-three adult patients with perennial allergic rhinitis due to Dermatophagoides farinae (D. farinae) were treated for 6 months with one of 3 treatments. Seventeen patients were treated with oral administration of 300 mg/day suplatast tosilate alone. Forty-six patients were treated with immunotherapy using standardized D. farinae alone. Twenty patients were treated with immunotherapy together with concurrent oral administration of 300 mg/day suplatast tosilate. Serum samples were collected 3 times from each patient, at enrollment, at 3 months and at 6 months after enrollment. Oral administration of suplatast tosilate for 3 and 6 months significantly decreased serum levels of IL-4 and specific IgE, and the rate of decrease in specific IgE correlated significantly with the rate of decrease in IL-4. The rates of decrease in IL-4 and specific IgE at 3 and 6 months were significantly greater in the patients treated with suplatast tosilate and immunotherapy than in those treated with immunotherapy alone. In conclusion, suplatast tosilate is able significantly to decrease serum levels of IL-4 and specific IgE, and the use of the drug together with immunotherapy can blunt the initial increase in specific IgE during the first 6 months of immunotherapy.

Adult↗

PubMed1998

Cry j 1-induced synthesis of interleukin-5 and interferon-gamma by peripheral blood mononuclear cells of patients with seasonal allergic rhinitis due to Japanese cedar pollens.

This study comprised 130 adult patients with Japanese cedar pollen-specific IgE in the serum and 15 non-atopic individuals. Eighteen patients had no seasonal aggravation of nasal symptoms during the pollen season in 1998 (asymptomatic group). Forty-two patients had not been treated previously with immunotherapy and were treated with antihistamine tablets during the pollen season in 1998 (medication group). Sixty-one patients had undergone variable periods of immunotherapy using pollen extracts, and they were further divided into a good-IT group who responded markedly to immunotherapy and a poor-IT group who responded poorly to immunotherapy. The remaining nine patients had been treated with immunotherapy for more than 12 years and all of them had stopped immunotherapy by the end of May 1997 because they had no nasal symptoms for the last three pollen seasons and were considered to be cured of seasonal allergic rhinitis (cure group). Peripheral blood mononuclear cells (PBMCs) were collected from each subject during the cedar pollen season in 1998 and were stimulated for 96 h with 10 micrograms/ml Cry j 1. The concentrations of interleukin-5 (IL-5) and interferon-gamma (IFN-gamma) in the culture supernatant were determined using an enzyme-linked immunosorbent assay. The levels of IFN-gamma did not differ significantly among the non-atopic group, the asymptomatic group, the medication group, the poor-IT group and the good-IT group. The level of IL-5 in the asymptomatic group was not different from that in the non-atopic group. The levels of IL-5 in the medication group, the good-IT group and the poor-IT group were significantly higher than in the non-atopic group. The level of IL-5 in the good-IT group, but not in the poor-IT group, was significantly lower than in the medication group. The level of IL-5 in the cure group was not significantly different from in the non-atopic group, and the level of IFN-gamma in the cure group was significantly lower than in the non-atopic group. In conclusion, immunotherapy can decrease the pollen allergen-induced synthesis of IL-5, but not of IFN-gamma, and this immunological modulation is involved in the working mechanism of immunotherapy related to its clinical efficacy. A tolerance or anergy of both TH1 and TH2 cells under allergen stimulation may be an immunological indication of cure after the treatment of seasonal allergic rhinitis. Thus, the suppression of synthesis of IL-5 and IFN-gamma by allergen-stimulated PBMCs is likely to be a reliable criterion for a possible cure of seasonal allergic rhinitis after immunotherapy.

Adult↗

PubMed1998

Seasonal increase in specific IgE in serum induced by natural Japanese cedar pollen exposure in asymptomatic and symptomatic sensitized individuals.

The aim of this study was to determine whether there is a difference in the specific IgE response to pollen exposure between asymptomatic and symptomatic subjects who were already sensitized to Japanese cedar pollen. Sixty-four subjects with detectable serum levels of cedar pollen-specific IgE, which were apparent even before the pollen season in 1997, were enrolled in the study. Thirty-five had typical symptoms of seasonal allergic rhinitis during the pollen season in 1997 (symptomatic group) and the remainder had no seasonal aggravation during the pollen season in 1997 (asymptomatic group). Serum samples were collected twice from each subject, before and during the pollen season in 1997, to determine specific IgE by the lumiward immunoassay system. In both groups, the serum levels of specific IgE during the pollen season were significantly higher than those before the pollen season, and the rates of seasonal increase in specific IgE did not differ significantly between the groups. In conclusion, the specific IgE response during the pollen season is not a hallmark of clinical allergy and does not discriminate between symptomatic and asymptomatic individuals sensitive to the pollen.

Allergens↗

PubMed1998

Clinical evaluation of lumiward immunoassay system for detection of specific IgE associated with allergic rhinitis.

The detection of specific IgE is a critical prerequisite for both the definitive diagnosis and the therapeutic strategy of allergic rhinitis and other allergic disorders. The aim of the present study was thus to evaluate the clinical significance of the solid phase capture system (CAP) and the lumiward immunoassay system (LMD) in the diagnosis of allergic rhinitis due to Dermatophagoides farinae (D. farinae) and Japanese cedar (Cryptomeria japonica) pollens. The specificity of both the CAP and the LMD in the detection of D. farinae-specific IgE and Japanese cedar pollen-specific IgE was 100%. The sensitivity to detect D. farinae-specific IgE was 95.76% in the skin test, 86.53% in the CAP and 88.53% in the LMD, respectively. The combination of the nasal provocation test and the CAP substituted for the skin test resulted in correct diagnoses for 98.25% of the patients, and the combination of the nasal provocation test and the LMD substituted for the skin test resulted in correct diagnoses for 98.00% of the patients. Therefore, the diagnostic significance of the LMD for perennial allergic rhinitis is likely to be equal to that of the CAP. The sensitivity to detect Japanese cedar pollen-specific IgE was 94.50% in the skin test, 84.47% in the CAP, and 96.76% in the LMD, respectively. The sensitivity of the CAP in the detection of Japanese cedar pollen-specific IgE was inferior to that of the skin test, but the sensitivity of the LMD in the detection of pollen-specific IgE was somewhat superior to that of the skin test. In addition, the combination of the nasal provocation test and the CAP substituted for the skin test resulted in correct diagnoses for 98.38% of the patients, whereas the combination of the nasal provocation test and the LMD substituted for the skin test resulted in correct diagnoses for 100% of the patients. Therefore, the diagnostic significance of the LMD for seasonal allergic rhinitis due to Japanese cedar pollens is probably larger than that of the CAP. In conclusion, the LMD may be a better "gold standard" for the detection of Japanese cedar pollen-specific IgE than the skin test, and the combination of the nasal provocation test and the LMD is a better diagnostic tool for the detection of Japanese cedar pollen-induced seasonal allergic rhinitis than the combination of the nasal provocation test and the skin test or the CAP.

Allergens↗

PubMed1998

Positron emission tomographic imaging of pleomorphic adenoma in the parotid gland.

We studied the possible correlation between 2-18F-2-deoxy-D-glucose (FDG) uptake and histopathological findings in mass lesions of the parotid gland. Thirteen pleomorphic adenomas of the parotid gland were evaluated by computed tomography (CT), magnetic resonance imaging (MRI), Gallium scintigraphy, Technetium scintigraphy and FDG-positron emission tomography (PET). Standardized uptake values (SUV) and time-activity curves (TAC) were determined for all mass lesions. Pleomorphic adenomas were histologically classified into the following three types: epithelial, intermediate and mesenchymal, based on their dominant histological components. The numbers of epithelial, intermediate, and mesenchymal types were 5, 2, and 6, respectively. The levels of SUVs were 4.02 +/- 1.91 (range: 1.97-7.07) in the epithelial type, 5.05 +/- 1.12 (range: 4.26-5.58) in the intermediate type and 3.98 +/- 7.74 (range: 1.98-7.74) in the mesenchymal type, respectively. The accumulation of FDG did not differ significantly among the three types. Since the accumulation of FDG was significantly correlated with the tumor size, FDG-PET could reflect tumor growth ability more apparently than the other nuclear or imaging modalities.

Adenoma, Pleomorphic↗

PubMed1998

Nitrogen dioxide compromises defence functions of the airway epithelium.

The effect of nitrogen dioxide (NO2) exposure on airway epithelial defence functions, such as ciliary activity, mucociliary transport velocity and junctional barrier function, remains to be elucidated. Our study investigates the effect of 24-h exposure to 3.0 ppm of NO2 on the airway epithelial defence functions in the healthy rabbit. Fifty-two healthy rabbits were exposed to 3.0 ppm of NO2 (NO2 group) or pure air (control group) for 24 successive hours in exposure chambers. After completion of the exposure sequence, the ciliary activity in the trachea was examined by a photoelectric method, the mucociliary transport velocity in the trachea by an endoscopic method and epithelial permeability of the trachea to fluorescein isothiocyanate-dextrans (FD-70s; molecular weight: 70,000 daltons) by an in vitro tracheal sac method. In the NO2 group, all epithelial defence functions, including ciliary activity, mucociliary transport velocity and epithelial permeability were significantly inferior to those in the control group. Although there was considerable overlap in the parameters examined between the two groups, approximately two-thirds of the animals were susceptible to 24-h exposure to 3 ppm of NO2. Dysfunction of both the junctional barrier and the mucociliary system could allow easier entry of allergen molecules to the airway parenchyma, where immunocomponent cells exist. NO2 might be involved to some extent in the clinical manifestation of airway allergic disorders through epithelial dysfunction.

Air Pollutants↗

PubMed1998

Nitrogen dioxide modifies allergic inflammation in tracheal mucosa.

Our study was designed to investigate the possible role of nitrogen dioxide exposure in respiratory allergic disorders. Guinea pigs were treated with a combination of passive sensitization, antigen challenge and nitrogen dioxide exposure. Nitrogen dioxide accumulated eosinophils to the epithelium of the trachea. Neither passive sensitization nor antigen challenge with nitrogen dioxide exposure developed more prominent pathological changes than nitrogen dioxide exposure alone. However, antigen--antibody interaction with nitrogen dioxide exposure resulted in a disruption of epithelial cells so prominent that the basement membrane was denuded in areas. Activated eosinophils and free eosinophil-specific granules were considered to be responsible for the extreme epithelial injury. In conclusion, nitrogen dioxide exposure does not cause prominent epithelial injury by itself, but could be a trigger for hyperresponsiveness in allergic airways, and is probably involved in the pathogenesis of airway allergic disorders.

Air Pollutants↗

PubMed1998

Monitoring of response to radiotherapy with fluorine-18 deoxyglucose PET of head and neck squamous cell carcinomas.

We examined the usefulness of positron emission tomography (PET) using fluorine-18 deoxyglucose (FDG) in determining the therapeutic effects of irradiation and chemotherapy on head and neck malignant tumors. Twenty-two patients with head and neck lesions who underwent histological examinations were studied. Squamous cell carcinoma was histologically diagnosed in all cases. Sixteen of them underwent radiotherapy with approximately 40 Gy in combination with carboplatin therapy. The remaining 6 patients underwent radiotherapy alone. After these treatments, 11 underwent surgery. For PET study, each patient was injected with intravenous FDG 185-370 MBq. We evaluated the degree of FDG accumulation using scanned images taken 40-55 min after the injection. We measured the standardized uptake value (SUV), a semiquantative evaluation, ROI activity divided by the dosage per weight of each patient. FDG-PET, CT and MRI were performed twice for each patient, before and after treatment. FDG uptake, but not the tumor size in CT or MRI, was significantly reduced in each patient after the treatment. Therefore, our findings have clearly demonstrated that FDG-PET provides for more valuable therapeutic outcomes than conventional imaging such as CT and MRI. FDG-PET should thus provide a new dimension in the management of head and neck malignant tumors.

Carcinoma, Squamous Cell↗

PubMed1998

[A phase II study with high-dose cytarabine (NS-075) in adult patients with relapsed and refractory acute leukemia].

A multi-center phase II clinical study with high dose cytarabine (NS-075) was conducted in adult patients with relapsed and/or refractory acute leukemia. 2 g/m2 cytarabine was given 12 times by 3-hour intravenous infusion every 12 hrs. 46 patients were registered, and 44 were evaluable: 35 with acute myeloid leukemia (AML) and 9 with acute lymphoblastic leukemia (ALL). There were 28 males and 16 females, with a median age of 37.5 years (range 15-68), including 6 of more than 60 years. Among 35 patients with AML, there were 16 (45.7%) complete and 2 (5.7%) partial remissions. Among 9 patients with ALL, there were 2 (22.2%) complete and 1 (11.1%) partial remissions. The major non-hematologic toxicities were gastrointestinal symptoms such as nausea/vomiting, anorexia and diarrhea, as well as fever, infection, conjunctivitis, alopecia, hepatic and renal dysfunctions. Central nervous system (CNS) toxicity was mild and reversible. Therapy-related death occurred in 5 patients resulting from prolonged pancytopenia, which suggests the necessity of strict countermeasures for infections as well as good patient care. These results indicate that high-dose cytarabine is a promising therapy for treatment of relapsed and/or refractory acute leukemia.

Adolescent↗

PubMed1997

Altered tyrosine phosphorylation via the very late antigen (VLA)/beta1 integrin stimulation is associated with impaired T-cell signaling through VLA-4 after allogeneic bone marrow transplantation.

Our previous study showed that the cross-linking of very late antigen (VLA)/beta1 with anti-CD29 monoclonal antibody (MoAb), or interactions with extracellular matrix (ECM) proteins through VLA/beta1, failed to induce T-cell costimulation via the CD3/T cell receptor (TCR) pathway for over 1 year after allogeneic bone marrow transplantation (allo-BMT), although normal CD29 and CD3 expression was observed after 3 months following allo-BMT. Molecular analysis revealed altered tyrosine phosphorylation of cellular proteins by the solid-phase cross-linking of VLA/beta1 molecules in T cells from patients after allo-BMT. In T cells from early allo-BMT patients (<4 months), various sizes of highly tyrosine phosphorylated proteins were observed as high background even without the stimulation through VLA/beta1 integrin. The high tyrosine phosphorylation pattern gradually disappeared and it was finally returned to normal tyrosine phosphorylation patterns by 2 years after BMT. Interestingly, poor expression of focal adhesion kinase (pp125FAK), a VLA/beta1-mediated signaling molecule, was observed within 1 year after BMT. These results suggest that these molecular defects appear to be implicated in the impaired VLA/beta1-mediated signaling in T cells from patients after allo-BMT, and it could explain, in part, the persistent immunoincompetent state after allo-BMT at least 1 year.

Adolescent↗

PubMed1997

Tyrosine phosphorylation of Crk-associated substrates by focal adhesion kinase. A putative mechanism for the integrin-mediated tyrosine phosphorylation of Crk-associated substrates.

Integrin-ligand binding induces the tyrosine phosphorylation of various proteins including focal adhesion kinase (pp125(FAK)) and Crk-associated substrate (Cas). FAK is activated and autophosphorylated by the ligation of integrins, although the substrate of FAK has not been revealed. We show here that p130(Cas) and Cas-L are FAK substrates. FAK directly phosphorylates Cas proteins primarily at the YDYVHL sequence that is conserved among all Cas proteins. Furthermore, the phosphorylated YDYVHL sequence is a binding site for Src family protein-tyrosine kinases, and the recruited Src family kinase phosphorylates the other tyrosine residues within Cas. The Cas-L YDYVHL sequence is phosphorylated upon integrin-ligand binding, and this integrin-mediated tyrosine phosphorylation is inhibited by the cotransfection of the FAK COOH-terminal domain that does not contain a kinase domain. These findings strongly suggest that FAK initiates integrin-mediated tyrosine phosphorylation of Cas proteins; then, Src family tyrosine kinases, which are recruited to phosphorylated Cas and FAK, further phosphorylate Cas proteins.

Adaptor Proteins, Signal Transducing↗