Search PubMed⌕ Search

Biomedical subjects

Shunichi Yamashita

Publications and source records attributed to Shunichi Yamashita.

At least 19 recordsLinked to original sources
PubMed2007

Different structural components of conventional papillary thyroid carcinoma display mostly identical BRAF status.

Activating BRAF(T1799A) mutation is closely associated with a papillary thyroid carcinoma (PTC) histotype. The transversion is frequently detected in the conventional type, Warthin-like and tall cell variants, but is rare in the follicular variant of PTC. Conventional PTC is often presented with tumors of mixed architecture, which besides the papillary structures also contain areas with follicular and solid morphology in which the details of BRAF mutational status are unknown. We set out to differentially investigate the presence of mutated BRAF in the individual structural components microdissected from 44 formalin-fixed, paraffin-embedded PTC tissues from 40 patients. The mutation was detected in at least 1 structural component in 23 tumors (52%). Different structural components of the same tumor had identical BRAF status in 41/44 tumors (93%). In 3 tumors the BRAF(T1799A) mutation was found only in the papillary, but not in the follicular component. Mutational patterns identical to those in the primary tumors were found in 11/12 lymph node metastases (92%, including both BRAF(T1799A)-positive and -negative cases). The high concordance of the BRAF mutational status in structurally distinct areas suggests a rather homogeneous distribution of neoplastic epithelial cells in a conventional PTC tumor in most cases. These results imply the reliability of preoperative molecular diagnosis of PTC regardless of the type of tumor component at the site of biopsy sampling and suggest that the majority of patients with BRAF mutation-positive PTC may benefit from the targeted pharmacotherapy.

Adult↗
PubMed2007

Fibrotic response to angiotensin II is blunted in the kidney, but not in the heart, in insulin-sensitive long-lived transgenic dwarf rats.

Insulin resistance is a characteristic feature of cardiovascular and renal diseases, and angiotensin II (Ang II) has been suggested to induce insulin resistance. The aims of this study were to elucidate the effect of chronic Ang II infusion on vascular reactivity and organ damage in insulin-sensitive rats. We confirmed the following three points. First, there was no significant difference in pressor response to chronic Ang II infusion (600 ng/kg/min) between insulin-sensitive transgenic rats (Tg) and control rats (C). Second, there was no significant difference in cardiac hypertrophy and fibrosis by chronic Ang II infusion between the two groups. However, third, fibrotic response to chronic Ang II infusion evaluated by histopathological scoring in the kidney was significantly decreased in insulin-sensitive transgenic rats (renal fibrosis and nephropathy score: C+Ang II vs Tg+Ang II; 2.5 vs 1.3; p<0.05). Furthermore, the expression of TGF-beta, a fibrosis indicator, was also significantly suppressed in the kidneys of the transgenic rats (TGF-beta1/GAPDH ratio: C+Ang II vs Tg+Ang II; 1.15 vs 0.81; p<0.05). This result indicates that the growth hormone/insulin-like growth factor-1 axis is critically involved in the development of renal injury and fibrosis, rather than hypertension, cardiac hypertrophy, and cardiac fibrosis induced by chronic Ang II administration.

Angiotensin II↗
PubMed2006

Evaluation of fat-free mass by whole-body counter in Japanese healthy young adults.

Whole-body counters (WBCs) are special instruments for measuring internal irradiation doses and are usually housed within or around nuclear facilities in the event of unexpected radiation emergencies. As a substantial proportion of total body potassium (TBK) is found in fat-free mass (FFM), FFM volume can be predicted from WBC-measured (40)K. We screened TBK in Japanese healthy young adults using a WBC and found strong linear correlations between TBK and lean body mass (LBM) and body mass index (r = 0.97, P < 0.01 and r = 0.47, P < 0.01, respectively). Multiple linear regression analysis, following adjustments for sex, indicates that only LBM has a significant correlation with TBK (P < 0.01). These results strongly support the feasibility of using WBCs for estimating FFM.

Absorptiometry, Photon↗
PubMed2006

BRAFV600E promotes invasiveness of thyroid cancer cells through nuclear factor kappaB activation.

The BRAFV600E mutation is closely linked to tumorigenesis and malignant phenotype of papillary thyroid cancer. Signaling pathways activated by BRAFV600E are still unclear except a common activation pathway, MAPK cascade. To investigate the possible target of BRAFV600E, we developed two different cell culture models: 1) doxycycline-inducible BRAFV600E-expressing clonal line derived from human thyroid cancer WRO cells originally harboring wild-type BRAF; 2) WRO, KTC-3, and NPA cells infected with an adenovirus vector carrying BRAFV600E. BRAFV600E expression induced ERK phosphorylation and cyclin D1 expression in these cells. The BRAFV600E-overexpressing cells also showed an increase of nuclear factor kappaB (NF-kappaB) DNA-binding activity, resulting in up-regulation of antiapoptotic c-IAP-1, c-IAP-2, and X-linked inhibitor of apoptosis. Furthermore, BRAFV600E expression also induced the expression of matrix metalloproteinase and cell invasion into matrigel through NF-kappaB pathway. Increased invasive ability by BRAFV600E expression was significantly inhibited by a specific NF-kappaB inhibitor, racemic dehydroxymethylepoxyquinomicin. These data indicate that BRAFV600E activates not only MAPK but also NF-kappaB signaling pathway in human thyroid cancer cells, leading to an acquisition of apoptotic resistance and promotion of invasion. Inactivation of NF-kappaB may provide a new therapeutic modality for thyroid cancers with BRAFV600E.

Carcinoma, Papillary↗
PubMed2006

No evidence of ARAF, CRAF and MET mutations in BRAFT1799A negative human papillary thyroid carcinoma.

The MAPK signaling pathway plays a crucial role in tumorgenesis and cell proliferation in human papillary thyroid carcinoma (PTC). Ret/PTC rearrangements, RAS and BRAF mutations, the main non-overlapping genetic alterations all leading to MAPK cascade activation, are cumulatively identified in 60-80% of PTCs. In approximately one-fourth of the cases, oncogenic background potentially contributing to MAPK activation in PTC might be different. We therefore attempted to evaluate the mutational status of genes encoding other members of RAF family known to act upstream of MAPKs, ARAF and CRAF (RAF-1). In addition we also analyzed the MET gene that encodes hepatocyte growth factor/scatter factor receptor overexpressed in most of PTCs and a MAPK cascade contributor. In 129 Japanese patients with PTC, BRAF(T1799A) was detected in 65 cases (50.4%), and the remaining 64 tumor specimens were subjected to mutation analysis of kinase domains of ARAF, CRAF and MET genes, and hotspots of K- and N-RAS genes. No ARAF, CRAF, MET, K- and N-RAS mutations were revealed. Based on these observations, we concluded that despite the fact that ARAF, CRAF and MET are actively expressed, alterations of these genes are rare in PTC and unlikely to play a perceptible role in the molecular pathogenesis of this type of human malignancy.

Carcinoma, Papillary↗
PubMed2006

Effects of antiarrhythmic drugs on apoptotic pathways in H9c2 cardiac cells.

Antiarrhythmic drugs may induce cellular apoptosis in the heart. By using representatives of 5 different categories of antiarrhythmic drugs, that is, pilsicainide, propranolol, nifekalant, verapamil, and amiodarone, we investigated whether these ion channel blockers or beta-antagonists affect cardiac apoptosis in cell cultures. Cultured H9c2 cells were treated with the drugs at varying concentrations. To determine the degree of apoptosis, the percentage of hypodiploid cells, mitochondrial transmembrane potential (DeltaPsi(m)), and activities of caspases were measured quantitatively. At 24 h after administration, only amiodarone induced apoptosis in the H9c2 cells. Amiodarone at a concentration of 14.8 microM or higher decreased DeltaPsi(m) and activated caspase-2 within 3 h of administration, and it caused the appearance of hypodiploid cells and activation of caspases-3 and -9 at 6 h or later. Thus, amiodarone, but none of the other antiarrhythmic drugs tested, possesses a pro-apoptotic effect, mainly via the mitochondrial pathway, suggesting that this effect is distinct from the blocking action of Na+, K+, and Ca2+ channels or the beta-adrenergic receptor. Furthermore, induction of apoptosis in a dose-dependent manner by amiodarone indicates the importance of monitoring the serum concentration in order to avoid its adverse effects.

Amiodarone↗
PubMed2006

Cancer consequences of the Chernobyl accident: 20 years on.

26 April 2006 marks the 20th anniversary of the Chernobyl accident. On this occasion, the World Health Organization (WHO), within the UN Chernobyl Forum initiative, convened an Expert Group to evaluate the health impacts of Chernobyl. This paper summarises the findings relating to cancer. A dramatic increase in the incidence of thyroid cancer has been observed among those exposed to radioactive iodines in childhood and adolescence in the most contaminated territories. Iodine deficiency may have increased the risk of developing thyroid cancer following exposure to radioactive iodines, while prolonged stable iodine supplementation in the years after exposure may reduce this risk. Although increases in rates of other cancers have been reported, much of these increases appear to be due to other factors, including improvements in registration, reporting and diagnosis. Studies are few, however, and have methodological limitations. Further, because most radiation-related solid cancers continue to occur decades after exposure and because only 20 years have passed since the accident, it is too early to evaluate the full radiological impact of the accident. Apart from the large increase in thyroid cancer incidence in young people, there are at present no clearly demonstrated radiation-related increases in cancer risk. This should not, however, be interpreted to mean that no increase has in fact occurred: based on the experience of other populations exposed to ionising radiation, a small increase in the relative risk of cancer is expected, even at the low to moderate doses received. Although it is expected that epidemiological studies will have difficulty identifying such a risk, it may nevertheless translate into a substantial number of radiation-related cancer cases in the future, given the very large number of individuals exposed.

Body Burden↗
PubMed2006

Pediatric CT scan usage in Japan: results of a hospital survey.

PURPOSE: The aim of this study was to examine the usage parameters of diagnostic computed tomography (CT) in children because of concerns of possible overuse in Japanese hospitals, including the "technical" CT exposure settings and the "clinical" grounds for CT requests. MATERIALS AND METHODS: We examined the methodology at the radiology department to reduce radiation exposure to children and performed a retrospective study on pediatric CT requests during a 1-year period at Nagasaki University Hospital. The parameters of diagnostic CT usage for minor head trauma and acute appendicitis were studied in detail. RESULTS: CT radiation dose settings are adjusted for children based on guidelines issued by the Japan Radiological Society, with few limitations. CT requests were made for 62% of minor head trauma cases and 76% of cases clinically suspected to be acute appendicitis. These figures are considerably higher than those reported by studies in the United Kingdom, Canada, or the United States. No specific guidelines are advocated regarding CT usage for minor head trauma. The diagnosis of acute appendicitis in children is almost routinely referred for "confirmation" by CT. CONCLUSION: CT radiation risks to children at Japanese hospitals need to be considered more seriously. Physicians should be encouraged to follow diagnostic algorithms that help avoid unnecessary CT usage in children.

Adolescent↗
PubMed2006

Selective pharmacologic inhibition of c-Jun NH2-terminal kinase radiosensitizes thyroid anaplastic cancer cell lines via induction of terminal growth arrest.

CONTEXT: The high radioresistance of anaplastic thyroid cancer (ATC) and cultured ATC cells stipulates for the means of increasing their radiosensitivity. It has been shown that c-Jun NH(2)-terminal kinase (JNK) activation is one of the manifestations of radiation response in ATC cells. OBJECTIVE: Assessment of the effect of selective JNK inhibition on ATC cell radiosensitivity and clarification of the associated mechanisms. RESULTS: The JNK inhibitor markedly suppressed ATC cell growth in a reversible cytostatic manner. The combination treatment with JNK inhibitor plus ionizing radiation induced a significant decrease in clonogenic survival of irradiated cells as compared with either singular treatment. The effect was not due to apoptosis of exposed cells but to a profound senescence-like terminal growth arrest occurring irrespectively of cells' p53 mutational status. Postradiational DNA damage repair was also significantly compromised in the presence of SP600125. CONCLUSIONS: JNK signaling is an essential component of ATC cell proliferation and survival after radiation therapy. Hence, pharmacological interference with JNK pathway in combination with radiotherapy may be a promising treatment of ATC.

Activating Transcription Factor 2↗
PubMed2006

Comprehensive clinical assessment of 740 cases of surgically treated thyroid cancer in children of Belarus.

OBJECTIVE: A retrospective study was designed to evaluate the results of surgical treatment and follow-up data in thyroid cancer patients less than 15 years old at the time of surgery. SUMMARY BACKGROUND DATA: Pediatric thyroid carcinomas have a high rate of lymph nodal and distant metastases. Risk factors for recurrences and postoperative morbidity have not been assessed yet in a representative series. METHODS: The group included 740 pediatric patients with thyroid cancer. Total thyroidectomy was performed in 426 (57.6%), lobectomy in 248 (33.5%), subtotal thyroidectomy in 58 (7.8%) cases, and 8 patients (1.1%) underwent partial lobectomy. RESULTS: The mean follow-up period was 115.8 months (range, 1.5-236.4 months). Recurrence was diagnosed in 204 cases (27.6%), including 73 local relapses (9.9%), 90 distant metastases (12.2%), and a combination of local and distant recurrences in 41 (5.5%) patients. Multivariate statistical assessment revealed the following independent parameters significantly associated with the risk of recurrent nodal disease: a young age at diagnosis, multifocal carcinomas, N1 status, and lack of neck lymph node dissection. For lung metastases, the significant risk factors were female gender, young age at diagnosis, and presence of symptoms. The observed 5- and 10-year survival for the entire group was 99.5% and 98.8%, respectively. Postoperative hypoparathyroidism was significantly associated with multifocal tumors, central compartment removal, and ipsilateral dissection. CONCLUSIONS: Total thyroidectomy followed by radioiodine therapy is an optimal treatment strategy that makes it possible to achieve a cure in a vast majority of pediatric patients with differentiated thyroid carcinomas. Risk of recurrence is strongly associated with tumor stage, extent of surgery, the young patient's age, and presence of symptoms at diagnosis.

Adolescent↗
PubMed2006

Heat-directed suicide gene therapy mediated by heat shock protein promoter for gastric cancer.

The prognosis of patients with metastatic gastric cancer, particularly peritoneal carcinomatosis, remains poor despite intensive interventions. Gene therapy and hyperthermia can be promising strategies for such advanced disease. The study was conducted to explore the possible effective therapeutic approach of suicide gene therapy with herpes simplex virus thymidine kinase (HSV-tk) in combination with hyperthermia for advanced gastric cancer. The heat shock protein (hsp) 70B gene promoter-oriented HSV-tk (HSP-tk)/ganciclovir (GCV) system directed by heat shock was developed. Hsp promoter activity under the control of heating was assessed by dual luciferase assay in gastric cancer cell lines and implanted tumors of nude mice. In vitro cytotoxic assay was performed using the HSP-tk/GCV delivered by the hemagglutinating virus of Japan (HVJ) liposome, with or without heating. Mice with subcutaneously xenografted tumors and peritoneal carcinomatosis were treated with hyperthermia and gene therapy using the HVJ-liposome-carrying HSP-tk. Assessment by luciferase assay demonstrated highly inducible and tumor-specific promoter activity in vitro and in vivo. Cytotoxic assays showed that cells transfected with HSP-tk became more sensitive to GCV with heating. A synergistic effect was also observed when treated with a non-heat-inducible cytomegalovirus (CMV) promoter-mediated HSV-tk/GCV and heating, indicating bystander killing. The HVJ-liposome-carrying HSP-tk/GCV combined with hyperthermia significantly inhibited the growth of subcutaneous tumors and prolonged survival of mice with peritoneal carcinomatosis. We conclude that the combination of suicide gene therapy with hyperthermia can provide a promising treatment modality for advanced gastric cancer.

Animals↗
PubMed2006

TP53 codon 72 polymorphism in radiation-associated human papillary thyroid cancer.

The study investigated an association between the germline polymorphism at TP53 codon 72 and the development of papillary thyroid cancer (PTC) following exposure to radiation from the Chernobyl accident. TP53 genotype was examined in 48 pediatric/adolescent (age at diagnosis <18 years) and 68 adult post-Chernobyl patient with PTC, 53 adult patients with sporadic PTC and 313 healthy individuals from Russian-Ukrainian population. In addition, we evaluated loss of heterozygosity for TP53 and the allele expression ratio. The genotype of the patients was correlated with clinicopathological data. Arg TP53 homozygotes were found to be significantly underrepresented among adults with post-Chernobyl PTC, but not in children and adolescents when compared with sporadic PTC cases and the general population. In the tumors, cell transformation did not lead to allelic loss or biased TP53 allele expression in heterozygous individuals. None of TP53 genotypes specifically associated with tumor stage and morphology, however there were particular correlations with lymph node status in certain age groups of radiation-associated cases not seen in sporadic PTCs. The findings suggest TP53 allele combinations other than Arg/Arg may contribute to the risk of development of PTC in individuals exposed to radiation during their late childhood, adolescence or in young adulthood.

Adolescent↗
PubMed2006

Childhood thyroid carcinoma with BRAFT1799A mutation shows unique pathological features of poor differentiation.

The prevalence of BRAFT1799A mutation in papillary thyroid carcinomas (PTCs) displays a marked age association: relatively high in adults and exceedingly low in childhood. We report a case of a 12-year-old Japanese female with PTC, the only one case that harbored BRAFT1799A mutation in a series of 46 childhood thyroid cancer tissues. On histology, the findings were so atypical that pathologists had repeatedly examined tumor sections to agree on the diagnosis of poorly differentiated follicular carcinoma. Upon molecular investigation, BRAFT1799A was detected in DNA extracted from paraffin-embedded material, whereas TP53 was wild-type. Since BRAFT1799A is strictly limited to PTCs, immunohistochemical staining for CD15, a specific marker for papillary carcinoma, was performed to verify the diagnosis. A small tumor area with papillary-like structure was stained positive. These findings strongly suggest that this case is a poorly differentiated carcinoma that arose from PTC and implies a possible association of BRAF mutation with dedifferentiated phenotype of PTCs.

Carcinoma, Papillary↗