Biomedical subjects

Takeharu Yamanaka

Publications and source records attributed to Takeharu Yamanaka.

13 recordsLinked to original sources

PubMed2007

Changes in estrogen receptors alpha and beta expression in the brain of mice exposed prenatally to bisphenol A.

The expression of ERs alpha and beta and serotonergic neurons were evaluated in the brains of mice prenatally exposed to Bisphenol A, a known endocrine disrupting chemical (EDc). Bisphenol A was administered orally at a dose of 2ng/g body weight on gestinational days 11-17 to pregnant ICR mice. Newborn male offspring (Bis-A mice) were evaluated for the immunoreactivity of ERs alpha and beta, serotonin, and serotonin transporter positive cells in the dorsal raphe nucleus (DRN). The serum testosterone level was also evaluated. In the Bis-A mice, the expression of ERs alpha and beta at 5 and 13 weeks was increased compared with the controls (P<0.04), but this difference disappeared by the 9th week. The serotonin, serotonin transporter, and testosterone level differences between two groups did not reach significance. Exposure to bisphenol A may have changed the expression of ERs in the brain, but did not directly affect serotonin neurons in the DRN.

Animals↗

PubMed2006

Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma.

Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression.

Breast Neoplasms↗

PubMed2006

Genetic structure of the dopamine receptor D4 gene (DRD4) and lack of association with schizophrenia in Japanese patients.

In order to investigate the contribution of genetic variation in the human dopamine receptor D4 gene (DRD4) to the risk of developing schizophrenia, we carried out a genetic analysis of 27 polymorphisms in 216 schizophrenic patients and 243 healthy controls from the Kyushu region of Japan. Twenty-two single nucleotide polymorphisms (SNPs) and five insertion/deletion polymorphisms were analyzed in this study, including four novel SNPs and a novel mononucleotide repeat. Linkage disequilibrium (LD) and haplotype analyses reveal weak LD across the DRD4 gene. In univariate analysis female individuals with allele -521C had a higher risk for schizophrenia. However, this finding was not significant after correction for multiple hypothesis testing. No other polymorphisms or haplotypes differed between schizophrenic patients and controls. Likewise, multivariate analyses did not reveal any statistically significant associations.

Adolescent↗

PubMed2006

Gene interaction network analysis suggests differences between high and low doses of acetaminophen.

Bayesian networks for quantifying linkages between genes were applied to detect differences in gene expression interaction networks between multiple doses of acetaminophen at multiple time points. Seventeen (17) genes were selected from the gene expression profiles from livers of rats orally exposed to 50, 150 and 1500 mg/kg acetaminophen (APAP) at 6, 24 and 48 h after exposure using a variety of statistical and bioinformatics approaches. The selected genes are related to three biological categories: apoptosis, oxidative stress and other. Gene interaction networks between all 17 genes were identified for the nine dose-time observation points by the TAO-Gen algorithm. Using k-means clustering analysis, the estimated nine networks could be clustered into two consensus networks, the first consisting of the low and middle dose groups, and the second consisting of the high dose. The analysis suggests that the networks could be segregated by doses and were consistent in structure over time of observation within grouped doses. The consensus networks were quantified to calculate the probability distribution for the strength of the linkage between genes connected in the networks. The quantifying analysis showed that, at lower doses, the genes related to the oxidative stress signaling pathway did not interact with the apoptosis-related genes. In contrast, the high-dose network demonstrated significant interactions between the oxidative stress genes and the apoptosis genes and also demonstrated a different network between genes in the oxidative stress pathway. The approaches shown here could provide predictive information to understand high- versus low-dose mechanisms of toxicity.

Acetaminophen↗

PubMed2006

Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer.

BACKGROUND: Angiogenesis plays an important role in tumorigenesis and has attracted interest as a potential target in cancer treatment. PATIENTS AND METHODS: We examined the prognostic value of the expression of vascular endothelial growth factor (VEGF) and of the VEGF receptors (VEGFRs) fms-like tyrosine kinase receptor-1 (flt-1) and kinase insert domain-containing receptor (KDR) in non-small-cell lung cancer (NSCLC). Sixty patients with surgical stage I NSCLC who had not undergone induction therapy or adjuvant therapy were selected from among 170 patients with NSCLC who had undergone surgery from January to December 1995. Specimens obtained at surgical resection were subjected to immunohistological staining, and the relationship between postoperative outcome and the expression of VEGF and its receptors was investigated. All patients included in the analysis had been followed up for 5 years or longer or until death. RESULTS: Patients with tumors expressing VEGF or KDR tended to have poorer outcomes, and VEGF expression and KDR expression were positively correlated. In contrast, flt-1 expression was not correlated with VEGF expression or outcome. Outcomes were poor in patients with tumors positive for both VEGF and VEGFRs. Multivariate analysis identified expression of both flt-1 and KDR and VEGF and KDR as possible independent prognostic factors. CONCLUSIONS: Our results suggest that expression of VEGF and VEGFR are associated with a poor prognosis via autocrine and paracrine growth stimulation of cancer cells. Moreover, tumors expressing both flt-1 and KDR may have greater malignant potential and are associated with a poor prognosis.

Adenocarcinoma↗

PubMed2006

Methodological aspects of current problems in target-based anticancer drug development.

Differently from the conventional antineoplastic agents, target-based drugs are designed a priori, based on our knowledge of various physiological molecules that has been obtained by the development of molecular biology. This "Copernican revolution" in drug development may imply a paradigm shift in this field. However, contrary to the initial expectations, many drugs developed by this approach are now faced with difficulties, mainly because of the fundamental and theoretical limits of this approach. All of the physiological functions are not always known in all target molecules. In low-molecular-weight drugs, i.e., "inhibitors," targets disperse, due to the structural similarities in physiological molecules. This double-faced "out-of-focusing" causes many problems in various steps of drug development, drug design, clinical trials, and administration to patients. Many drugs are now being abandoned because of unexpectedly lower response rates or unforeseeable adverse effects, and the variety of the drugs exhibits a kaleidoscopic appearance. The double-faced "out-of-focusing" derives from the methodological limits in molecular biology, i.e., elementalism, and limits in our techniques for drug development. To overcome these currently inevitable limits, it appears essential to elucidate the specific changes in target molecules that chiefly promote tumor growth and, consequently, strongly predict response to the administered drugs. Precise and efficient detection of responder populations is the key to the development and establishment of target-based anticancer therapies.

Antibodies, Monoclonal↗

PubMed2004

Gene interaction network suggests dioxin induces a significant linkage between aryl hydrocarbon receptor and retinoic acid receptor beta.

Gene expression arrays (gene chips) have enabled researchers to roughly quantify the level of mRNA expression for a large number of genes in a single sample. Several methods have been developed for the analysis of gene array data including clustering, outlier detection, and correlation studies. Most of these analyses are aimed at a qualitative identification of what is different between two samples and/or the relationship between two genes. We propose a quantitative, statistically sound methodology for the analysis of gene regulatory networks using gene expression data sets. The method is based on Bayesian networks for direct quantification of gene expression networks. Using the gene expression changes in HPL1A lung airway epithelial cells after exposure to 2,3,7,8-tetrachlorodibenzo-(Italic)p(/Italic)-dioxin at levels of 0.1, 1.0, and 10.0 nM for 24 hr, a gene expression network was hypothesized and analyzed. The method clearly demonstrates support for the assumed network and the hypothesis linking the usual dioxin expression changes to the retinoic acid receptor system. Simulation studies demonstrated the method works well, even for small samples.

Animals↗

PubMed2004

The TAO-Gen algorithm for identifying gene interaction networks with application to SOS repair in E. coli.

One major unresolved issue in the analysis of gene expression data is the identification and quantification of gene regulatory networks. Several methods have been proposed for identifying gene regulatory networks, but these methods predominantly focus on the use of multiple pairwise comparisons to identify the network structure. In this article, we describe a method for analyzing gene expression data to determine a regulatory structure consistent with an observed set of expression profiles. Unlike other methods this method goes beyond pairwise evaluations by using likelihood-based statistical methods to obtain the network that is most consistent with the complete data set. The proposed algorithm performs accurately for moderate-sized networks with most errors being minor additions of linkages. However, the analysis also indicates that sample sizes may need to be increased to uniquely identify even moderate-sized networks. The method is used to evaluate interactions between genes in the SOS signaling pathway in Escherichia coli using gene expression data where each gene in the network is over-expressed using plasmids inserts.

Algorithms↗

PubMed2002

Association of meteorological and day-of-the-week factors with emergency hospital admissions in Fukuoka, Japan.

We carried out a statistical study of the influence of meteorological and day-of-the-week factors on the intrinsic emergency patients transported to hospitals by ambulance. Multiple piecewise linear regression analysis was performed on data from 6,081 emergency admissions for 1 year between April 1997 and March 1998 in Fukuoka, Japan. The response variable was the daily number of emergency patients admitted with three types of disease: cerebrovascular, respiratory and digestive diseases. The results showed that the number of emergency patients admitted daily with cerebrovascular disease was significantly associated with temperature on the day of admission and whether the day was Sunday. As it became colder than 12 degrees C, emergency admissions of patients with cerebrovascular disease increased drastically, reaching a plateau at 4 degrees C. On the 3rd and 7th days after the temperature fell below 10 degrees C, the daily admission of patients with respiratory disease significantly increased. We also observed a weak association between emergency admissions of patients suffering from digestive disease and rising barometric pressure on the day of admission.

Atmospheric Pressure↗

PubMed2002

MR relative cerebral blood flow mapping of Alzheimer disease: correlation with Tc-99m HMPAO SPECT.

RATIONALE AND OBJECTIVES: To evaluate the value of magnetic resonance (MR) perfusion imaging for diagnosis of Alzheimer disease (AD), the authors compared relative cerebral blood flow (CBF) maps obtained with MR perfusion imaging and technetium-99m hexamethyl-propyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) in patients with AD. MATERIALS AND METHODS: Eight patients with AD were studied with MR perfusion imaging and HMPAO SPECT. The relative CBF maps from the two techniques were spatially coregistered, and relative CBF values in 13 cerebral gray matter regions (total, 26 regions of interest) were compared with regression analysis. To evaluate the degree of deviation of each brain region from the regression line, a P value for the residual was calculated for each region. RESULTS: A significant overall correlation was seen between the relative CBF values produced by the two techniques (r = .68, P < .0001). Smaller P values for the residuals were obtained in the anterior cingulate cortex (P = .05) and posterior cingulate cortex (P < .001), indicating larger deviations in these regions. When data from these two regions were eliminated, the correlation coefficient rose to 0.80 (P < .0001). CONCLUSION: Despite fairly large discrepancies in the anterior and posterior cingulate cortices, the relative CBF map obtained with MR imaging is generally in close agreement with the HMPAO SPECT map, suggesting that MR perfusion imaging can provide clinically useful information regarding CBF abnormalities in patients with AD.

Adult↗

PubMed2002

A simple method for calculating the financial balance of a hospital, based on proportional dividing.

It is necessary to estimate financial status to determine hospital management policy. The costs and revenues (financial balance) of each hospital division are one good index. However, it is difficult to calculate the financial balance for each division, since clinics and central services are intricately involved with each other There are no reports on a pragmatic method for calculating the financial balance. We devised a simple method based on proportional dividing. Consequently, one individual was able to complete the calculation for our hospital, which consists of 1300 beds and 23 clinics, without using the central hospital computer system.

Accounting↗

PubMedDate not supplied

Morphologic approach to hepatocellular carcinoma development in man: de novo or the so-called 'dysplastic nodule-carcinoma' sequence?

The so-called dysplastic nodule-carcinoma sequence in the liver is generally accepted because hepatocellular carcinoma is not an uncommon finding in precancerous lesions. In order to evaluate the existence and frequency of de novo hepatocarcinogenesis we studied 112 surgically resected early well-differentiated hepatocellular carcinomas showing replacing growth without less differentiated component in themselves. They were divided into two groups: carcinoma in dysplastic area (type A) and carcinoma without dysplastic area (type B) and were analyzed clinicopathologically. We encountered 77 cases of type A (68.8%) and 35 of type B (31.2%). The frequency of type A in cirrhotic group (74.7%) is statistically higher than that of non-cirrhotic group (54.5%) (p=0.0453). Using multivariate analysis, the occurrence of type A was related with higher age, the presence of cirrhosis and hepatitis B surface antigen positive. The tumor size and the presence of fatty change in the tumor tended to relate with type A. We propose two pathways morphologically in early hepatocarcinogenesis, one of which has a close relation to hepatitis B virus and/or cirrhosis.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

Distributions in CEA doubling time differ in patients with recurrent colorectal carcinomas.

BACKGROUND/AIMS: Serum carcinoembryonic antigen (CEA) is often measured during follow-up of patients surgically treated for colorectal cancer. We determined characteristic findings in serum CEA concentrations or CEA doubling time (DT) depending on the different tumor distributions in colorectal cancer patients. METHODOLOGY: Serum CEA levels were measured monthly until the patients expired in 32 colorectal cancers after operations. CEA DT was based on semilogarithmic plots of time courses of CEA concentrations. RESULTS: In cases who were preoperatively CEA positive, the maximum serum CEA levels for proximal colon, distal colon and rectal cancers were 384.8+/-586.1 ng/mL, 1395.7+/-1954.6 ng/mL and 1343.4+/-1478.3 ng/mL, respectively. The maximum serum CEA level in cases of the proximal colon in preoperative CEA positive patients was lower than that in cases of distal colon or rectum. The average CEA DT on the proximal colon, distal colon and rectal cancers was 71.62+/-43.77 days, 31.07+/-15.98 days and 73.97+/-36.66 days, respectively. The CEA DT with distal colon cancers was also significantly shorter than that with proximal colon or rectal cancers (p<0.05, p<0.02). The CEA DT for lung metastasis was significantly longer than that for liver metastasis, locally or lymph node metastasis or multiple metastases (p<0.02, p<0.02, p<0.001). CONCLUSIONS: CEA DT serves to predict life expectancy for patients with recurrent colorectal cancers with different tumor distributions. We propose that precise measurements of serum CEA are needed so as not to overlook recurrent tumors. Detailed follow-up after operations is necessary for such patients, that CEA DT was noted in case of distal colon cancers.

Aged↗