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Biomedical subjects

H Hatakeyama

Publications and source records attributed to H Hatakeyama.

At least 19 recordsLinked to original sources
PubMed2006

Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid.

For successful cancer gene therapy via intravenous (i.v.) administration, it is essential to optimize the stability of carriers in the systemic circulation and the cellular association after the accumulation of the carrier in tumor tissue. However, a dilemma exists regarding the use of poly(ethylene glycol) (PEG), which is useful for conferring stability in the systemic circulation, but is undesirable for the cellular uptake and the following processes. We report the development of a PEG-peptide-lipid ternary conjugate (PEG-Peptide-DOPE conjugate (PPD)). In this strategy, the PEG is removed from the carriers via cleavage by a matrix metalloproteinase (MMP), which is specifically expressed in tumor tissues. An in vitro study revealed that the PPD-modified gene carrier (Multifunctional Envelope-type Nano Device: MEND) exhibited pDNA expression activity that was dependent on the MMP expression level in the host cells. In vivo studies further revealed that the PPD was potent in stabilizing MEND in the systemic circulation and facilitating tumor accumulation. Moreover, the i.v. administration of PPD or PEG/PPD dually-modified MEND resulted in the stimulation of pDNA expression in tumor tissue, as compared with a conventional PEG-modified MEND. Thus, MEND modified with PPD is a promising device, which has the potential to make in vivo cancer gene therapy achievable.

Animals↗
PubMed2004

[Extrapleural pneumonectomy for malignant pleural mesothelioma].

Standard treatment for malignant pleural mesothelioma (MPM) has not been proved yet. However, it has been recognized that extrapleural pneumonectomy (EPP) is a treatment of choice for epithelial MPM when combined with adjuvant therapies though EPP may frequently cause fetal complications. We report 5 cases of MPM with EPP, including 1 with good prognosis. Sixteen patients with MPM were admitted to our hospital between 1988 and 2003. Five patients underwent EPP, among which 4 were male and 1 female with ages from 46 to 61 years old. Histologically, 3 of them were epithelial and 2 were biphasic. Those with biphasic experienced acute respiratory failure and empyema, and died 81 days and 8 months after the surgery respectively. Among those with epithelial MPM, 2 are alive with no recurrence at 129 and 29 months after the surgery, and the other, followed by postoperative radiotherapy, died at 12 months. More cases with EPP or randomized controlled trials regarding EPP are necessary to evaluate efficacy of EPP for MPM.

Female↗
PubMed2002

Antidiabetic effect of a nitrosamine-free dephostatin analogue, methoxime-3,4-dephostatin, in db/db mice.

Et-3,4-dephostatin, a protein-tyrosine phosphatase (PTPase) inhibitor, potentiates insulin-dependent signal transduction and shows an antidiabetic effect in mice. However, it contains a nitrosamine moiety that is often mutagenic and carcinogenic. Therefore, we previously designed and synthesized methoxime-3,4-dephostatin as a nitrosamine-free analogue of dephostatin. In the present paper, we studied in situ and in vivo antidiabetic effects of this PTPase inhibitor. Methoxime-3,4-dephostatin induced 2-deoxyglucose transport by mouse 3T3-L1 adipocytes and rat L6 myocytes without insulin. It also inhibited glucagon-induced glucose release from primary culture rat hepatocytes. When hepatocytes were prepared from starved rats, methoxime-3,4-dephostatin did not inhibit the release of glucose, indicating that the chemical may act on glycogenolysis. Oral administration of methoxime-3,4-dephostatin for 3-7 days inhibited the increase in the blood glucose level in type-2 diabetes model db/db mice. It also decreased food and water intakes of mice, but showed no liver or blood toxicity.

3T3 Cells↗
PubMed2001

Muscle layer- and region-dependent distributions of oxytocin receptors in the porcine myometrium.

The aim of the present study was to clarify smooth muscle- and region-dependent distributions of the oxytocin receptor that mediates oxytocin-induced contraction in the nonpregnant porcine myometrium by means of mechanical and radioligand ([3H]-oxytocin) binding studies. In Krebs solution, oxytocin (0.1-300 nM) caused concentration-dependent contractions of the cornual myometrium, and the longitudinal muscle was more sensitive than the circular muscle. [Arg8]-vasopressin and [deamino-Cys1, D-Arg8]-vasopressin also contracted the myometrium, and the order of the potency was oxytocin > [Arg8]-vasopressin > [deamino-Cys(1), D-Arg(8)]-vasopressin. Treatment with a high concentration of oxytocin selectively inhibited the contraction of oxytocin and [Arg8]-vasopressin without affecting the responses of acetylcholine and high-K+. Selective cross inhibition was also observed in the presence of a high concentration of [Arg(8)]-vasopressin. The oxytocin-induced contraction was resistant to tetrodotoxin and atropine, but was reduced by verapamil or by the removal of external Ca2+, indicating that oxytocin has a direct action on smooth muscle cells and that extracellular Ca2+ plays an important role for the contraction. In Kumagai solution, oxytocin caused contraction of the cornual longitudinal muscle (-logEC50 = 8.5) but not the circular muscle. Longitudinal muscles of other regions (corpus and cervix) were also responsive to oxytocin, but the -logEC50 value differed from region to region (cornua > corpus = cervix). On the other hand, oxytocin failed to cause contraction of the corpus and cervical circular muscles. 3H-Oxytocin bound to crude membrane preparations of the myometrium in a concentration-dependent (0.084-2.7 nM) saturable manner. Scatchard analysis of equilibrium binding data revealed the presence of a single class of binding site with an apparent dissociation constant (Kd, 1.1-1.5 nM), but receptor density (Bmax) differed in the two muscle layer types (longitudinal muscle: circular muscle = 5:1) and tended to decrease from the cornua to the cervix. In conclusion, the receptor specific for oxytocin is present in the porcine myometrium and mediates the contractile responses of both oxytocin and [Arg8]-vasopressin. The distribution of the oxytocin receptors differs according to the type of muscle layer (longitudinal muscle > circular muscle) and the region of the uterus.

Animals↗
PubMed2001

A study of piriform sinus fistula cases.

We have experienced five cases of piriform sinus fistula for the last 10 years. It is a relatively rare disease, and partly because of poor understanding of the disease, in one case infection had repeatedly recurred without being adequately treated for over 20 years, and in most cases there was a long time lapse before the diagnosis. In another case, it was difficult to image the fistula with contrast medium and fistulectomy was performed without identifying it on imaging. We have applied various devices to those cases where imaging of fistula was difficult, and achieved complete resection of fistula and have not observed recurrences of infection after resection.

Adult↗
PubMed2001

The property of a novel v2 receptor mutant in a patient with nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidneys to the action of arginine vasopressin (AVP); X-linked recessive NDI is caused by an inactivating mutation of the vasopressin type-2 (V2) receptor. Several missense mutations in the first or second extracellular loop of the V2 receptor have been reported, and some of these mutant receptors were confirmed to have reduced affinities for ligand binding. We detected a novel V2 receptor gene mutation, a substitution of cysteine for arginine-104 (R104C) located in the first extracellular loop of the V2 receptor, in a patient with congenital NDI. Functional analysis by transient expression studies with COS-7 cells showed binding capacity of R104C mutant diminished as 10% of wild type, but binding affinity was strong rather than wild type. In the result of AVP stimulation studies, maximum cAMP accumulation of R104C decreased as 50% of wild type. On the other hand, a designed mutant receptor, substituted serine for arginine-104 as a model of modified R104C mutant receptor removed the influence of the sulfhydryl group in cysteine-104, recovered binding capacity up to 50% of wild type and maximum cAMP accumulation as 82% of wild type. Our study demonstrated that the R104C mutation of the V2 receptor was a cause of NDI. The mechanism of renal resistance to AVP was the reduction of ligand binding, and adenylyl cyclase activation depended on the V2 receptor. In addition, we confirmed that the sulfhydryl group of the cysteine-104 caused most part of R104C mutant receptor dysfunction.

Amino Acid Sequence↗
PubMed2001

11beta-hydroxysteroid dehydrogenase activity in human aortic smooth muscle cells.

11beta-Hydroxysteroid dehydrogenases (11beta-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. There are two isoforms. The type 1 isoform (11beta-HSD1) catalyzes both 11beta-dehydrogenation (cortisol to cortisone) and the reverse oxoreduction (cortisone to cortisol), but the type 2 isoform (11beta-HSD2) catalyzes only 11beta-dehydrogenation. The diminished dehydrogenase activity has been demonstrated in resistance vessels of genetically hypertensive rats. However, the isoform(s) that plays a significant role in conferring the dehydrogenase activity on vasculature has not been determined. We investigated 11beta-HSD activities in human vascular smooth muscle cells by manipulating 11beta-HSD expressions with antisense oligonucleotides. The results showed that 11beta-HSD2 dominates functioning in the dehydrogenase mode in these cells. This indicates that impairment of 11beta-HSD2 activity in vascular wall may be related to the pathogenesis of hypertension.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

[A case of lung cancer underwent carinal resection with right upper lobectomy and carinal reconstruction with double-barreled anastomosis].

A 70-year-old male complaining cough was admitted to our hospital. Bronchoscopic examination revealed a tumor mass which occluded the orifice of the right upper lobe. Chest computed tomographic (CT) scans gave the image of tumor invasion at the carina. The pathological diagnosis of the tumor was squamous cell carcinoma. Operation was accomplished by right posterolateral thoracotomy approach through the fifth rib bed. The carinal resection with right upper lobectomy was followed by a double-barreled anastomosis of the right intermediate trunk and left main-stem bronchus into the carina. The operation was successfully performed and was considered curative. The length of resected airway measured 4.0 cm from tracheal line of resection to the divided the right intermediate trunk. Reinforcement of the anastomosis was not performed in this case. No postoperative complication occurred but mild ischemia of the anastomosis. The patient died of recurrent tumor in a year and 2 months after operation.

Aged↗
PubMed2001

[Is the bronchoscopic criteria of early lung cancer valid?].

We studied the validity of the bronchoscopic criteria of the early lung cancer using the surgical specimen excised between 1980 and 1999. Twenty-four cases with squamous cell carcinoma of the lung of clinical stage I were located subsegmental or more proximal bronchi and trachea, and the size less than 20 mm in greatest dimension. We histopathologically investigated the endoscopic features in relation to the width of superficial extent, the depth of cancer invasion, and lymph node metastasis. Tumors of the thickened type lesions less than 20 mm in greatest dimension showed no invasion into the cartilaginous layer and no lymph node metastasis. On the other hand, in the nodular and polypoid types, invasion beyond the cartilaginous layer was observed more or less, and lymph node metastasis was observed in 1 case. These cases would not be suitable for bronchoscopic (photodynamic) therapy. In conclusion, the bronchoscopic criteria of early lung cancer is valid in the thickened type, but not in the nodular type or polypoid type.

Aged↗
PubMed2000

Idiopathic hyperaldosteronism: analysis of aldosterone synthase gene.

We analyzed the CYP11B2, the gene encoding aldosterone synthase, in mononuclear leukocytes in eight patients with primary aldosteronism due to zona glomerulosa hyperplasia (idiopathic hyperaldosteronism) and compared the results with aldosterone-producing adenomas. In idiopathic hyperaldosteronism, aldosterone synthase activity was significantly increased in accordance with gene expression (P < 0.05), compared with aldosterone-producing adenomas. No genetic mutations were found in coding regions of DNA. The T (-344) C allele polymorphism was present in a similar frequency in the general population. In one patient with idiopathic hyperaldosteronism. de novo homozygous mutation in upstream of the 5' flanking region C (-463) T was detected, which cannot be explained by polymorphism. The pathophysiological significance of this mutation for aldosterone hypersecretion is not known. There were no mutations in the known promoter sequences for angiotensin II related cis-segments. Possible contribution of co-regulators for angiotensin 11-induced signalling pathway is discussed.

Adenoma↗
PubMed2000

11beta-hydroxysteroid dehydrogenase in human vascular cells.

Aldosterone selectivity in mineralocorticoid target tissues is mainly due to 11beta-hydroxysteroid dehydrogenase (11betaHSD), which converts cortisol to its inactive metabolite cortisone in humans. The defect of dehydrogenase activity would thus allow type 1 mineralocorticoid receptor (MR) to be occupied mostly by cortisol. It has been postulated that 11betaHSD type 2 (11betaHSD2) plays a significant role in conferring ligand specificity on the MR. We have demonstrated the diminished dehydrogenase activity in resistance vessels of genetically hypertensive rats. However, the mechanism that could link impaired vascular 11betaHSD activity and elevated blood pressure has been unclear. In this study, we showed the enzyme activity in human coronary artery smooth muscle cells. Glucocorticoids and mineralocorticoids increase vascular tone by up-regulating the receptors of pressor hormones such as angiotensin II (Ang II). Next, we found that physiological concentrations of a cortisol-induced increase in Ang II binding were significantly enhanced by the inhibition of dehydrogenase activity with an antisense DNA complementary to 11betaHSD2 mRNA, and the enhancement was partially but significantly abolished by a selective aldosterone receptor antagonist. This may indicate that impaired dehydrogenase activity in vascular wall results in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11betaHSD deficiency and after the administration of 11betaHSD inhibitors, suppression of dehydrogenase activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension. These results show that vascular 11betaHSD activity could influence blood pressure without invoking renal sodium retention.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2000

Functional adrenocorticotropic hormone receptor in cultured human vascular endothelial cells : possible role in control of blood pressure.

Hypertension is a prominent feature of patients with Cushing's disease and ectopic adrenocorticotropic hormone (ACTH) syndrome, who have elevated ACTH levels. Chronic administration of ACTH (1-24) also raises blood pressure in humans. This effect has been postulated to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. It is well known that cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones. In the present study, we show direct evidence that human aortic endothelial cells possess the ACTH receptor. 11beta-Dehydrogenation, converting cortisol to its inactive metabolite, cortisone, mediated by vascular 11beta-hydroxysteroid dehydrogenase type 2 is essential for the control of vascular tone, and the reduced activity may be relevant to the pathogenesis of hypertension. We found that ACTH (1-24) dose-dependently decreased the gene expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 2 in these cells, and the decrease was partially abolished by a selective ACTH receptor antagonist. This may indicate that ACTH potentiates the action of cortisol through its direct effect on the vasculature. Therefore, the present study provides important information for understanding the mechanism of ACTH-induced hypertension.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2000

[Surgical treatment for bilateral multiple lung cancers].

We reviewed 12 patients with contralateral bronchogenic carcinomas. Seven of them had metachoronous carcinomas and 5 had synchronous carcinomas. We treated 3 patients with lobectomy on both lungs, and 4 patients with lobectomy and segmentectomy, 2 patients with lobectomy and wedge resection, 2 patients with segmentectomy and thoracoscopic wedge resection, and one patient with lobectomy and ablation on each lung. Two patients who had lobectomy on both lungs were dead, one of whom of bronchofistula on operation and the other of respiratory failure 7 years and one month after second operation. The 5-year survival rate in 12 patients was 68.5% after first operation and 82.5% after second operation. We conclude that lobectomy on both lungs are not recommended because of high mortality rate and the limited resection should be considered to treat the other contralateral primary lung cancers. Because the patients with primary lung cancers have the possibility to suffer from new primary cancers in the different site of the lung, we need careful follow up of the patients after treatment on the first lung cancer.

Adenocarcinoma↗
PubMed2000

[Five cases of surgically resected chronic expanding hematoma in the chest].

We report surgically treated 5 cases of chronic expanding hematoma in the chest. Three were male and two were female, aged 53 to 76. All patients except one who was thought to have an early stage of chronic expanding hematoma, had severe dyspnea due to compression of lung parenchyma or heart. Complete removal of the hematoma with fibrous capsule was done in two cases, but in three cases the hematoma was removed but the capsule was not because of severe adhesion to the surrounding structures. Post operative course was different to each other. One patient whose capsule was not removed completely have recurrent hematoma in the chest. The pulmonary or cardiac function were improved greatly except for the two cases; an early stage case and a recurrent case. We conclude that surgical removal is the first treatment for chronic expanding hematoma and complete removal of it with capsule is recommended.

Aged↗
PubMed2000

[Validity and controversies in the new postoperative pathologic TNM classification based on the results of surgical treatment of non-small cell lung cancer].

In 1997, the latest revision of the International System for Staging Lung Cancer was published. To validate the new pathologic TNM classification for non-small cell lung cancer (NSCLC), we analyzed the survival data of 455 patients who underwent pulmonary resection and pathologic staging at our institution from January 1980 through December 1999. The overall 5-year survival rate was 51.0%. Using the revised new stage classification, the survival rate for each stage was as follows; IA: 74.2%, IB: 66.4%, IIA: 56.0%, IIB: 51.8%, IIIA: 21.0%, IIIB: 16.0%, and IV: 0%. The current TNM classification well reflected the long-term prognostic hierarchy. There were significant differences in survival rates between patients with stage IA and IB, and between patients with stage IIB and IIIA. However, there was no significant difference between patients with stage IIA and IIB. No significant difference in survival was observed among patients with stage IIIA, stage IIIB, and stage IV. Five-year survival rate of 48.3% in the T3N0M0 category was significantly better than that of 21.0% found in the new stage IIIA. The survival of patients with intrapulmonary metastases in the same lobe (pm1) was not significantly better than that found in the stage IV. The TNM staging system accurately reflects the prognosis in NSCLC, but some stage definitions can be discussed.

Adolescent↗
PubMed2000

[Progressive paralysis of divergence in an adult with midbrain angioma].

A 37-year-old woman was admitted to the hospital with the complaint of progressive horizontal diplopia of six years' duration when viewing distant objects. On admission she had a slight left convergent strabismus. Homonymous diplopia was present beyond 50 cm and increased on distance fixation. Both eyes were fully mobile in the horizontal plane with a mild decrease in the velocity of horizontal eye movement to the left, and slight impairment of upward eye movement. The left eye did not fully adduct during convergence. The right pupil was slightly larger than the left. Prism cover test showed 6 delta esophoria at 30 cm and 14 delta esophoria at 5 m. The Hess chart showed a convergent deviation. MRI revealed a small right-side paramedian lesion of the midbrain tegmentum lying ventral to the aqueduct of Sylvius, at the level between the superior colliculi and the intercollicular area. A venous angioma with arteriovenous shunts in the right midbrain was diagnosed by angiography. We suggest that lesions that damage the divergence neurons in the tegmentum of the midbrain and also interrupt the supranuclear fibers having an inhibitory effect on the convergence neurons may produce homonymous diplopia on distant fixation combined with the esotropia.

Adult↗
PubMed1999

Effects of cytokines on the binding of leukocytes to cultured rat hepatocytes and on the expression of ICAM-1 by hepatocytes.

Adhesions of leukocytes to hepatocytes and sinusoidal endothelial cells mediates the induction and progression of hepatic injury. However, in contrast to endothelial cells, information regarding the regulation of interactions between leukocytes and hepatocytes is limited. In the present study, we investigated the effect of inflammatory mediators including lipopolysaccharide (LPS), staphylococcal enterotoxin B (SEB), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) on the adhesion of polymorphonuclear leukocytes or lymphocytes to primary cultured rat hepatocytes, and on the expression of intercellular adhesion molecule-1 (ICAM-1) gene in hepatocytes. Both polymorphonuclear leukocyte and lymphocyte adhesion to hepatocytes were enhanced after exposure of hepatocytes to IFN-gamma and TNF-alpha, but not after exposure to LPS, SEB or IL-1beta. The adhesion induced by either IFN-gamma or TNF-alpha was inhibited by monoclonal antibodies against ICAM-1 or lymphocyte function-associated antigen-1 (LFA-1). Nonstimulated hepatocytes expressed faintly ICAM-1 mRNA, which increased slightly during the culture period. ICAM-1 mRNA expression was up-regulated to a greater extent by incubating hepatocytes with IFN-gamma or TNF-alpha, and peaked after 12 hr of incubation with TNF-alpha and after 24 hr with IFN-gamma. These results indicate that IFN-gamma and TNF-alpha induce the expression of ICAM-1 on parenchymal hepatocytes and that the LFA-1-ICAM-1 pathway plays an important role in the interaction between hepatocytes and neutrophils or lymphocytes.

Animals↗