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Biomedical subjects

K Tsukuda

Publications and source records attributed to K Tsukuda.

At least 19 recordsLinked to original sources
PubMed2006

PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer.

Trastuzumab is the only HER2/neu-directed therapy to have received Food and Drug Administration approval for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumour and the patient's prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here, we propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level. The PI3K/Akt signalling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was low. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signalling pathway was also recognised. Moreover, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in cells with elevated PTEN expression. Along with the immune-system-associated cytotoxic mechanism, several mechanisms have been proposed for the effect of trastuzumab. PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated antitumour effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer.

Antibodies, Monoclonal↗
PubMed2005

Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in gastrointestinal tumour.

The human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumour-suppressor gene inactivated by methylation in several cancers. In this study, we analysed the methylation and expression status of hDAB2IP in gastrointestinal tumours. The promoter region of hDAB2IP was divided into two regions (m2a and m2b) based on our previous report, and the methylation status was determined by bisulphite DNA sequencing in gastric cancer cell lines. The gene expression was semiquantified by real-time RT-PCR, and the results indicated that the m2b promoter region might be an authentic methylation-mediated key regulator of the gene expression. Based on the sequence data, we developed a methylation-specific PCR (MSP) for the m2a and m2b regions and applied it to the samples. Methylation-specific PCR revealed aberrant methylation in the m2a region in eight of 12 gastric cancer cell lines (67%), 16 of 35 gastric cancer tissues (46%) and 29 of 60 colorectal cancer tissues (48%), and in the m2b region in eight of 12 cell lines (67%), 15 of 35 gastric cancer tissues (43%) and 28 of 60 colorectal cancer tissues (47%). On the other hand, seven (12%) and 11 (19%) of 59 gastrointestinal nonmalignant mucosal specimens showed methylation in the m2a and m2b regions, respectively, suggesting that hDAB2IP methylation might play a causative role in carcinogenesis. The 5-aza-2'-deoxycytidine treatment restored the gene expression in the m2b-methylated cell lines, confirming that the methylation caused gene downregulation. We also examined the relationship between hDAB2IP methylation and the clinicopathological features in patients with primary tumours, and determined that methylation in the m2b region was associated with location of the tumour in the stomach. In summary, our results demonstrated that hDAB2IP methylation is frequently present in gastrointestinal tumours and that the resulting gene silencing plays an important role in gastrointestinal carcinogenesis.

Azacitidine↗
PubMed2004

The relationship between aberrant methylation and survival in non-small-cell lung cancers.

The present study examined the relationship between methylation of five genes (p16(INK4a), RASSF1A, APC, RARbeta and CDH13) and patient survival in 351 cases of surgically resected lung cancers. While there was no relationship between the other genes and survival, p16(INK4a) methylation was significantly related to unfavourable prognosis in lung adenocarcinomas.

Adenocarcinoma↗
PubMed2003

Congenital heart disease with hypereosinophilic syndrome.

The idiopathic hypereosinophilic syndrome, common in adults, is a leukoproliferative disorder marked by a predilection to damage specific organs. This report describes a unique case of an infant with tricuspid stenosis, a hypoplastic right ventricle, severe pulmonary stenosis, patent ductus arteriosus, and a patent foramen ovale associated with hypereosinophilic syndrome. Although treatment with high-dose oral steroids failed to decrease the leukocyte counts, a right classic Blalock-Taussig shunt through a right thoracotomy resolved her cyanosis.

Female↗
PubMed2003

[Long-term results after the total cavopulmonary connection].

Between July, 1988 and November, 2002, 108 patients underwent total cavopulmonary connection (TCPC) at Kobe Children's Hospital. The primary malformation was univentricular heart in 40 tricuspid atresia in 21, mitral atresia in 16, and other complex cardiac defects in the remaining 31. Fenestrated TCPC, staged TCPC, and off-pump TCPC were performed in 39, 26, and 15 high risk patients, respectively. Nitric oxide inhalation was administered in 46 patients. The mean follow-up period was 4.3 years (range, 1 month to 14 years). There were 10 early deaths due to low cardiac output syndrome in 4, thrombosis in 3, tracheal bleeding in 2, and disseminated intravascular coagulation in 1. There were 5 late deaths due to congestive heart failure in 2 patients, arrhythmia in 1, cerebral infarction in 1, and subarachnoid hemorrhage in 1. Late complications included arrhythmia in 17 patients, systemic desaturation caused by abnormal systemic venous channels in 10, pleural or pericardial effusion in 3, chylothorax in 1, and aortic valve incompetence in 1.

Adolescent↗
PubMed2001

G649, an allelic variant of the human H2 receptor with low basal activity, is resistant to upregulation upon antagonist exposure.

Orange et al reported an allelic variant of the human histamine H2 receptor, in which adenine 649 was replaced with guanine, to be more frequent in the schizophrenic population than controls in British Caucasians. The A649 to G change causes an Asn to Asp transition at amino acid position 217 in the third intracellular region, which is postulated to be important for receptor function. Herein, we analyzed the functional significance of this variant using wild-type and variant receptors expressed in Chinese hamster ovary cells. The variant receptor was associated with markedly lower basal cAMP productions than the wild-type receptor. Histamine-dependent cAMP productions via the variant receptor were lower as well. Treatment of cells expressing variant receptors with 10(-5) M ranitidine for 24 h resulted in a reduced degree of receptor upregulation as compared with the wild-type receptor. Thus, this is the first report of an allelic variant of the human H2 receptor which confers altered receptor function. To analyze gastric acid secretion in individuals with this variant, we examined 100 Japanese control subjects. However, neither heterozygotes nor homozygotes were found, suggesting that this variant, if present, is uncommon in the Japanese population.

Alleles↗
PubMed2001

Bi-directional single anastomotic technique for the proximal anastomosis of free grafts (the saphenous vein or radial artery) to the ascending aorta in coronary artery bypass grafting surgery.

In an operation involving coronary bypass grafting, anastomoses to the ascending aorta with saphenous vein or radial artery grafts may increase the possibility of post-operative strokes by the dislodgement of embolic particles into the arterial vasculature. We report a bi-directional single anastomotic technique to decrease the possibility of intra and postoperative strokes and to allow earlier cardiac perfusion by the graft anastomosed to the ascending aorta, in case of CABG with 2 free grafts from there.

Anastomosis, Surgical↗
PubMed2001

[Reconstruction of the pulmonary outflow tract without external conduit].

Between October 1987 and December 2000, 50 patients underwent reconstruction of the pulmonary outflow tract without external conduit. The primary malformation was tetralogy of Fallot with pulmonary atresia in 37, double outlet of right ventricle in 4, corrected transposition of the great arteries in 4, transposition of the great arteries with ventricular septal defect and pulmonary stenosis in 4, and double outlet of left ventricle in 2. Mean age at operation was 7.2 years, and mean body weight was 18.3 kg. To reconstruct posterior wall of the pulmonary outflow tract, interposition of autologous pericardium was performed in 24, direct anastomosis between pulmonary trunk and ventriculotomy in 13, longitudinal incision from ventriculotomy through pulmonary trunk in 12, and interposition of left atrial appendage in 1. Anterior wall was reconstructed with monocusp valved outflow patch (MVOP). There was one hospital death and no late death. At 10 years, the freedom from reoperation for pulmonary outflow tract obstruction was 100%, and freedom from reoperation for any cause was 86.6%. Transcatheter stenting for peripheral pulmonary stenosis was performed in 6 patients 2 to 10 months after operation.

Adolescent↗
PubMed2000

A novel activating mutation of the K-ras gene in human primary colon adenocarcinoma.

We identified a novel type of point mutation at the 22nd codon of the K-ras gene in a primary colon cancer. The mutation was C to A transversion substituting lysine (AAG) for normal glutamine (CAG) codon. Biological activity of this mutant K-ras gene was tested by expression of full-length cDNA clones in NIH3T3 cells. Most of the K-ras Lys22-transfected cells exhibited an increased saturation density, a lower serum requirement, and transformed morphology reminiscent to the typical K-ras Val12 transformants. However, the tumorigenicity of K-ras Lys22 transformants in nude mice was significantly less potent than that of K-ras Val12 transformants; only a high copy number transformant produced tumors. Even though the activation is incomplete, the finding that the majority of tumor cells in the specimen carried the K-ras Lys22 mutation suggests that this mutation might be advantageous for growth of tumor cells in vivo.

3T3 Cells↗
PubMed2000

HD-PTP: A novel protein tyrosine phosphatase gene on human chromosome 3p21.3.

A human cDNA encoding a novel protein tyrosine phosphatase has been isolated. The phosphatase has unique features in its domain structure: a "Zn-hand" domain containing several SH3-binding motifs, a tyrosine phosphatase domain, a C-terminal PEST motif, and an N-terminal domain similar to yeast BRO1, an apoptosis-related mammalian AIP1 and to a RHO-binding protein, Rhophilin. The gene is located at chromosome 3p21.3, an area frequently deleted in many types of cancer, especially within the functionally defined narrow region. The gene may be a human homolog of the rat PTP-TD14 gene reported by others, which can suppress H-ras-mediated transformation. We identified a hemizygous missense mutation in a lung cancer cell line. Thus, the phosphatase gene may be a candidate for one of the tumor suppressor genes located on 3p21.3.

Amino Acid Sequence↗
PubMed2000

Ulnar artery graft for myocardial revascularization.

We present a 60-year-old man who underwent coronary artery bypass grafting using an ulnar artery as one of the grafts intended to release angina pectoris. Previously, his right leg had been amputated following a traffic accident. The blood supply of his left leg was reduced due to atherosclerotic stenotic change (left ankle pressure index 0.6). He had been under treatment for severe diabetes mellitus for 4 years. Coronary angiography revealed severe stenosis in the triple coronary artery system. Immediate myocardial revascularization was considered necessary. We considered that saphenous vein grafts and bilateral internal thoracic artery grafts were unsuitable for this patient. Moreover, Allen's test was positive in the bilateral forearms. Coronary artery bypass surgery consisted of left internal thoracic artery grafting to the left anterior descending artery, right gastroepiploic artery grafting to the right coronary artery, and left ulnar artery grafting to the diagonal branch. No myocardial or hand complications were observed after surgery. Following a review of the Japanese literature, we conclude that our case is the first report of an ulnar artery graft for coronary artery bypass grafting in Japan.

Angina Pectoris↗
PubMed2000

Minimally invasive coronary artery bypass grafting for the left anterior descending coronary artery.

OBJECTIVE: A single surgeon conducted One hundred and twelve patients underwent minimally invasive direct coronary artery bypass grafting for the left anterior descending coronary artery 112 patients at Yamato Seiwa Hospital from September 1996 until August 1999. METHODS: All procedures were performed via left anterior short thoracotomy using a stabilizer during graft anastomosis. RESULTS: No operative deaths occurred but 3 patients died while hospitalized due to noncardiac events. Graft occlusion was seen in 3 patients early postoperatively. Other angiography graft failure such as stenosis was seen in 11 patients. Occlusive lesions of other coronary arteries occurred in 77 patients (69%) and 53 patients underwent percutaneous transluminal coronary angioplasty the pre/postoperatively for those lesions. CONCLUSIONS: These results suggest that minimally invasive direct coronary artery bypass grafting is seen by cardiologists as a reasonable form of revascularization in conditioned patients having left anterior descending artery lesion, and that minimally invasive direct coronary artery bypass grafting has a spectrum of candidates different from that of conventional surgical revascularization for the coronary artery.

Adolescent↗
PubMed2000

Combination chemotherapy with risk factor-adjusted dose attenuation for high-risk myelodysplastic syndrome and resulting leukemia in the multicenter study of the Japan Adult Leukemia Study Group (JALSG): results of an interim analysis.

Forty-nine adult patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia that progressed from MDS were registered for the multicenter study of the Japan Adult Leukemia Study Group. Forty-three patients were evaluable for the analysis. Idarubicin 12 mg/m2 per day for 3 days and continuous cytosine arabinoside 100 mg/m2 per day for 7 days were given as induction therapy, followed by postremission chemotherapy after complete remission (CR). Because elderly patients and those with hypoplastic marrow usually have complications after intensive chemotherapy, often causing early death, the treatment dose was reduced to 60% or 80% according to the presence of 3 risk factors: age 60 years or older, performance status 2 or more, or presence of hypoplastic bone marrow. Of the 43 evaluable patients (median age, 58 years), 26 (60%) achieved CR. Two patients (5%) died within 2 months of completion of induction therapy. The CR rates for patients treated with 100%, 80%, and 60% of the chemotherapy dose were 55% (12 of 22), 63% (10 of 16), and 80% (4 of 5), respectively, indicating that the risk factor-adjusted dose attenuation was appropriately applied to those who might have had problems with the original dose, thus reducing regimen-related mortality rate. The median overall survival of the 43 patients was 8 months.

Acute Disease↗
PubMed1999

Cochlear histopathology associated with mitochondrial transfer RNA(Leu(UUR)) gene mutation.

Using dot-blot hybridization and Southern blotting, the authors detected a point mutation at nucleotide pair (np) 3243 in mitochondrial DNA from temporal bone sections of a woman with diabetes and deafness. The mutation could not be detected with agarose gel electrophoresis, suggesting that the degree of heteroplasmy is low. Histologically, there was marked degeneration of the stria vascularis and outer hair cells throughout the cochlea, as well as a reduction of spiral ganglion cells in the base. These findings suggest that the mutation affects these inner ear structures preferentially and that deafness can occur even when the proportion of np 3243 mutation is low.

Cochlea↗
PubMed1999

Transforming activity of the RL-akt gene, a c-akt gene activated by long terminal repeat insertion in murine leukemia RL(male symbol)1 cells.

The unique antigen peptide pRL1 on BALB/c radiation-induced leukemia RL(male symbol)1 cells is derived from the normally untranslated 5' region of the mouse c-akt gene. Insertion of an endogenous long terminal repeat into the first coding exon of the gene resulted in the enhanced production of an altered akt protein, RL-akt, and creation of the tumor rejection antigen peptide pRL1. In this study, we constructed an RL-akt-expressing vector to investigate the transforming ability and anti-apoptotic activity of RK-akt in NIH/3T3 cells. RL-akt-expressing clones formed more colonies than did c-akt-expressing clones in soft agar and exhibited increased saturation density, a lower serum requirement for growth, and tumorigenicity on athymic nude mice. Immunoblot analysis of subcellular protein distribution showed that a considerable proportion of RL-akt was distributed in the membrane fraction. Thus, RL-akt expressed in NIH/3T3 cells appeared to behave like the v-akt oncoprotein. Furthermore, the RL-akt gene conferred resistance to the apoptosis induced by the calcium ionophore A23187 and by ultraviolet irradiation of NIH/3T3 cells. These findings indicate that the RL-akt gene is able to transform cells and exerts an anti-apoptotic effect on recipient cells, thereby implicating the gene in leukemogenesis of RL(male symbol)1 cells.

3T3 Cells↗
PubMed1998

Genetic alterations in the retinoblastoma protein-related p107 gene in human hematologic malignancies.

Genetic alterations in the p107 gene, a close relative of the retinoblastoma tumor suppressor gene, have never been identified in human malignancies. When we searched for such alterations in human hematologic malignancies by Southern blot analysis, 2 of 21 cell lines and 1 of 88 primary disorders had genomic alterations within the gene. Particularly, an altered p107 gene in a diffuse-large B-cell lymphoma cell line, KAL-1, harbored an intragenic deletion of about 15 kbp leading to the expression of an altered p107 mRNA devoid of 819 nucleotides of the coding sequences, which predicts to encode an approximately 87-kDa protein. This cell line was found to express solely a p107 derivative of 84 kDa by immunoblotting analysis. These results suggest that alterations in the p107 gene are probably related to a limited subset of human hematologic malignancies.

Gene Deletion↗
PubMed1998

Development of Epstein-Barr virus-associated B cell lymphoma after intensive treatment of patients with angioimmunoblastic lymphadenopathy with dysproteinemia.

Evolution of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) into aggressive B cell lymphoma is thought to be a rare event and the cause of this transformation has not been fully elucidated. We describe two patients with AILD that progressed to aggressive large-cell lymphoma with a B cell phenotype. At presentation, the lymph nodes of both patients showed the typical features of AILD by hematoxylin-eosin staining. Immunohistochemical staining with monoclonal antibodies revealed positive staining of atypical cells with UCHL-1 and negative staining with L-26. In situ hybridization of EBV RNA showed rare positive cells in one patient and was negative in the other patient. At relapse, both patients showed systemic lymph nodes swelling, which is characteristic of diffuse large immunoblastic lymphoma. Single-cell analysis with monoclonal antibodies and immunohistochemical staining showed the monoclonal proliferation of B cells. Southern blot analysis of the lymph nodes showed a rearrangement in both patients of the Ig heavy chain gene and germ line configuration of the T cell receptor beta chain gene. Southern blot analysis using the EBV terminal repeat region probe detected clonal proliferation of EBV in the lymph nodes of both patients. In situ hybridization studies identified considerable EBV mRNA in both patients. These observations suggest that EBV proliferation plays an important role in the development of B cell lymphoma that arises from AILD. We suggest that infection or reactivation of EBV may occur in some patients with AILD, probably due to their immunodeficient state, and that this infection or reactivation is directly involved in the development of B cell lymphoma.

Herpesviridae Infections↗