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1.  Genetic mechanisms underlying yield potential in the rice high-yielding cultivar Takanari, based on reciprocal chromosome segment substitution lines 
BMC Plant Biology  2014;14(1):295.
Increasing rice yield potential is a major objective in rice breeding programs, given the need for meeting the demands of population growth, especially in Asia. Genetic analysis using genomic information and high-yielding cultivars can facilitate understanding of the genetic mechanisms underlying rice yield potential. Chromosome segment substitution lines (CSSLs) are a powerful tool for the detection and precise mapping of quantitative trait loci (QTLs) that have both large and small effects. In addition, reciprocal CSSLs developed in both parental cultivar backgrounds may be appropriate for evaluating gene activity, as a single factor or in epistatic interactions.
We developed reciprocal CSSLs derived from a cross between Takanari (one of the most productive indica cultivars) and a leading japonica cultivar, Koshihikari; both the cultivars were developed in Japan. Forty-one CSSLs covered most of the Takanari genome in the Koshihikari background and 39 CSSLs covered the Koshihikari genome in the Takanari background. Using the reciprocal CSSLs, we conducted yield trials under canopy conditions in paddy fields. While no CSSLs significantly exceeded the recurrent parent cultivar in yield, genetic analysis detected 48 and 47 QTLs for yield and its components in the Koshihikari and Takanari backgrounds, respectively. A number of QTLs showed a trade-off, in which the allele with increased sink-size traits (spikelet number per panicle or per square meter) was associated with decreased ripening percentage or 1000-grain weight. These results indicate that increased sink size is not sufficient to increase rice yield in both backgrounds. In addition, most QTLs were detected in either one of the two genetic backgrounds, suggesting that these loci may be under epistatic control with other gene(s).
We demonstrated that the reciprocal CSSLs are a useful tool for understanding the genetic mechanisms underlying yield potential in the high-yielding rice cultivar Takanari. Our results suggest that sink-size QTLs in combination with QTLs for source strength or translocation capacity, as well as careful attention to epistatic interactions, are necessary for increasing rice yield. Thus, our findings provide a foundation for developing rice cultivars with higher yield potential in future breeding programs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0295-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4243286  PMID: 25404368
Chromosome segment substitution lines (CSSLs); Quantitative trait locus (QTL); Rice; Yield potential
2.  Long-term survivor of a resected undifferentiated pancreatic carcinoma with osteoclast-like giant cells who underwent a second curative resection: A case report and review of the literature 
Oncology Letters  2014;8(4):1499-1504.
An undifferentiated carcinoma with osteoclast-like giant cell tumors (UC-OGC) is a rare type of tumor, which predominantly occurs in the pancreas. Due to the rarity of UC-OGC, sufficient clinical data are not available and its prognosis following surgical resection remains unclear. In the current report the case of a 37-year-old female is presented, in whom an UC-OGC of the pancreas was removed and following this, a second carcinoma of the remnant pancreas was removed during a second surgical procedure. At the patient’s initial admission, the preoperative images demonstrated a well-demarcated mass with a marked cystic component at the pancreatic head. The patient underwent a pylorus-preserving pancreaticoduodenectomy. The final pathological diagnosis was UC-OGC of the pancreas and the tumor was considered to have been curatively resected based on the histopathological findings. Four years after the initial surgery, a small mass was detected in the remnant pancreas and a partial resection of the remnant pancreas was subsequently performed. Histopathologically, the tumor consisted of a poorly differentiated tubular adenocarcinoma. A retrospective pathological analysis showed a segment of a poorly differentiated tubular adenocarcinoma in the initial resected specimen. Therefore, the final diagnosis was considered to be an intra-pancreatic recurrence of UC-OGC. The patient survived 66 months following the initial surgery and 18 months since the second resection. A meta-analysis was performed in the current study by comparing UC-OGC patients who survived more than two years following surgical resection (long-term survivors) with those who succumbed less than one year following surgical resection (short-term survivors). The characteristics of the short-term survivors were patients of an older age, males, and those exhibiting smaller tumors, positive lymph node metastasis, and concomitant components of ductal adenocarcinoma, as well as pleomorphic giant cell carcinoma. The concomitant component of mucinous cystic neoplasm was not considered to be a prognostic factor. To the best of our knowledge, the patient in the current report is the first five-year survivor following a curative second resection.
PMCID: PMC4156164  PMID: 25202356
second resection; osteoclast-like giant cells; undifferentiated pancreatic carcinoma; intra-pancreatic metastasis; long-term survivor
3.  Deep rooting conferred by DEEPER ROOTING 1 enhances rice yield in paddy fields 
Scientific Reports  2014;4:5563.
To clarify the effect of deep rooting on grain yield in rice (Oryza sativa L.) in an irrigated paddy field with or without fertilizer, we used the shallow-rooting IR64 and the deep-rooting Dro1-NIL (a near-isogenic line homozygous for the Kinandang Patong allele of DEEPER ROOTING 1 (DRO1) in the IR64 genetic background). Although total root length was similar in both lines, more roots were distributed within the lower soil layer of the paddy field in Dro1-NIL than in IR64, irrespective of fertilizer treatment. At maturity, Dro1-NIL showed approximately 10% higher grain yield than IR64, irrespective of fertilizer treatment. Higher grain yield of Dro1-NIL was mainly due to the increased 1000-kernel weight and increased percentage of ripened grains, which resulted in a higher harvest index. After heading, the uptake of nitrogen from soil and leaf nitrogen concentration were higher in Dro1-NIL than in IR64. At the mid-grain-filling stage, Dro1-NIL maintained higher cytokinin fluxes from roots to shoots than IR64. These results suggest that deep rooting by DRO1 enhances nitrogen uptake and cytokinin fluxes at late stages, resulting in better grain filling in Dro1-NIL in a paddy field in this study.
PMCID: PMC4080195  PMID: 24988911
4.  Relationship between Serum Level of Lymphatic Vessel Endothelial Hyaluronan Receptor-1 and Prognosis in Patients with Lung Cancer 
Journal of Cancer  2014;5(3):242-247.
Background: Lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) is a hyaluronic acid receptor that is selectively expressed in the endothelia of lymphatic capillaries. The density of lymphatic vessels expressing LYVE-1 on immunohistochemistry negatively correlates with prognosis of patients with non-small-cell lung cancer. However, the relationship between LYVE-1 serum levels and lung cancer staging is unknown.
Methods: We collected blood samples from 58 lung cancer patients before treatment and measured LYVE-1 serum levels using an enzyme-linked immunosorbent assay.
Results: Mean serum LYVE-1 levels were 1,420 pg/mL. Serum LYVE-1 levels correlated positively with serum albumin levels, but inversely with primary tumor size, leukocyte counts, and platelet counts by Pearson's product-moment correlation coefficient. A high cancer staging, occurrence of lymph-node metastases, and occurrence of distant metastases were significantly associated with low LYVE-1 levels. Moreover, multiple logistic regression analyses revealed that LYVE-1 levels were predictive of the presence of lymph node and distant metastases, independently of the other factors. Kaplan-Meier analysis showed that the survival of patients with serum LYVE-1 ≤1,553 pg/mL was significantly poorer than that of patients with serum LYVE-1 >1,553 pg/mL. This survival difference relative to LYVE-1 levels remained statistically significant after adjusting for age and gender by the Cox proportional-hazard analysis.
Conclusion: Serum LYVE-1 is significantly low in lung cancer patients with metastasis, compared with those without. Measuring LYVE-1 levels in lung cancer patients may be useful for evaluating lung cancer progression.
PMCID: PMC3963081  PMID: 24665348
lung cancer; LYVE-1; metastasis; survival; biomarker.
5.  Association between Plasma Adiponectin Levels and Decline in Forced Expiratory Volume in 1 s in a General Japanese Population: The Takahata Study 
Background:Adiponectin is an anti-inflammatory and cardio-protective cytokine. However, several studies have demonstrated that plasma adiponectin levels were inversely associated with pulmonary function in patients with chronic obstructive pulmonary disease, suggesting a proinflammatory or pulmonary-destructive role. It is still unclear whether adiponectin is a potent biomarker predicting declines in pulmonary function. The aim of this study was to investigate the association between adiponectin and pulmonary function among Japanese individuals who participated in an annual health check-up.
Methods:Spirometry and blood sampling, including measurements of plasma adiponectin, were performed for 3,253 subjects aged 40 years or older who participated in a community-based annual health check-up in Takahata, Japan from 2004 to 2006. In 2011, spirometry was re-performed, and the data from 872 subjects (405 men and 467 women) were available for a longitudinal analysis.
Results:Plasma adiponectin levels were found to be significantly associated with age, body mass index (BMI), and alanine aminotransferase (ALT), triglycerides (TG), and high-density lipoprotein-cholesterol (HDL-c) levels among both men and women in the study population. Plasma adiponectin levels were found to be associated with lifetime cigarette consumption (Brinkman index, BI) in men only. Plasma adiponectin levels were inversely correlated with forced expiratory volume in 1 s (FEV1) per forced vital capacity in both men and women. In addition, the annual change in FEV1 was inversely associated with plasma adiponectin levels in both genders. A multiple linear regression analysis revealed that this association was independent of other confounding factors such as age, BMI, BI, ALT, TG, and HDL-c.
Conclusions:The results of the present study suggest that adiponectin levels are predictive of declines in FEV1 in the general population.
PMCID: PMC4057484  PMID: 24936137
Adiponectin; Decline in FEV1; General population; Pulmonary function; Spirometry.
6.  Inhibition of Elastase-Pulmonary Emphysema in Dominant-Negative MafB Transgenic Mice 
Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.
PMCID: PMC4147222  PMID: 25170302
Pulmonary emphysema; MafB; alveolar macrophage; matrix metalloproteinase; gene targeted mouse.
7.  A Lower Level of Forced Expiratory Volume in 1 Second Is a Risk Factor for All-Cause and Cardiovascular Mortality in a Japanese Population: The Takahata Study 
PLoS ONE  2013;8(12):e83725.
Chronic obstructive pulmonary disease is a known risk factor for cardiovascular death in Western countries. Because Japan has a low cardiovascular death rate, the association between a lower level of forced expiratory volume in 1 s (FEV1) and mortality in Japan’s general population is unknown. To clarify this, we conducted a community-based longitudinal study. This study included 3253 subjects, who received spirometry from 2004 to 2006 in Takahata, with a 7-year follow-up. The causes of death were assessed on the basis of the death certificate. In 338 subjects, airflow obstruction was observed by spirometry. A total of 127 subjects died. Cardiovascular death was the second highest cause of death in this population. The pulmonary functions of the deceased subjects were significantly lower than those of the subjects who were alive at the end of follow-up. The relative risk of death by all causes, respiratory failure, lung cancer, and cardiovascular disease was significantly increased with airflow obstruction. The Kaplan–Meier analysis showed that all-cause and cardiovascular mortality significantly increased with a worsening severity of airflow obstruction. After adjusting for possible factors that could influence prognosis, a Cox proportional hazard model analysis revealed that a lower level of FEV1 was an independent risk factor for all-cause and cardiovascular mortality (per 10% increase; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.82–0.98; and HR, 0.72; 95% CI, 0.61–0.86, respectively). In conclusion, airflow obstruction is an independent risk factor for all-cause and cardiovascular death in the Japanese general population. Spirometry might be a useful test to evaluate the risk of cardiovascular death and detect the risk of respiratory death by lung cancer or respiratory failure in healthy Japanese individuals.
PMCID: PMC3862812  PMID: 24349548
8.  Relationships between Values of Antibodies to Several Connective Tissue Disease Autoantigens and Pulmonary Function in a Japanese General Population: The Takahata Study 
PLoS ONE  2013;8(12):e81678.
Accumulating evidence suggests the involvement of an autoimmune mechanism in the pathogenesis of respiratory dysfunction. The aim of this study was to investigate the relationship between pulmonary function and serum antibodies to several connective tissue disease autoantigens (ACTDA) levels, which has not been investigated in a general population.
Blood sampling and spirometry were performed for subjects (n = 3,257) aged ≥40 years who participated in a community-based annual health check in Takahata, Japan, from 2004 to 2006. ACTDA was measured by enzyme immunoassay, and subjects with ACTDA values ≥20 were defined as positive.
In males, there were significant inverse relationships between logarithmically transformed ACTDA values and spirometric parameters, including % predicted values for forced expiratory volume in 1 s (FEV1) and maximal midexpiratory flow (MMF) as well as FEV1/forced vital capacity (FVC). Multiple linear regression analysis revealed that except for the relationship between ACTDA and FEV1/FVC, these relationships were still significant after adjustment for Brinkman index (a measure of inhaled cigarette consumption). The prevalence of positive ACTDA was greater in male never-smokers with mixed ventilation disorders and relatively severe airflow obstruction (% predicted FEV1 below the median value).
Autoimmunity may be involved in the mechanism of impaired pulmonary function in the general population.
PMCID: PMC3849382  PMID: 24312572
9.  Elevated Serum Iron Is a Potent Biomarker for Spirometric Resistance to Cigarette Smoke among Japanese Males: The Takahata Study 
PLoS ONE  2013;8(9):e74020.
Chronic obstructive pulmonary disease is a common disability among elderly subjects with a heavy cigarette smoking habit. In contrast to the population that is susceptible to smoking, in whom pulmonary function worsens with the length of exposure to cigarette smoke, there are elderly individuals whose pulmonary function is not impaired. However, to date, the characteristics of this resistant smoking population have not been investigated. We aimed to identify a biomarker in individuals in whom lung health is maintained despite smoking. Blood sampling and spirometry were performed on 3,257 subjects who participated in a community-based annual health check in Takahata, Japan, from 2004 to 2006. We selected 117 elderly smokers (age ≥70, Brinkman index ≥600, smoking years ≥30). The ‘smoking resistant’ group met the following criteria: FEV1/FVC ≥0.7, and FEV1%predicted ≥80. Spirometry was re-evaluated in 147 male, current smokers in 2009. Baseline serum iron (sFe) levels were higher in the smoke resistant group compared with the non-resistant group. In those with low sFe levels, FEV1/FVC was reduced in male subjects. These spirometric measures were positively associated with sFe levels in men. Multiple linear regression analysis revealed that sFe levels were predictive for spirometric values, independent of other clinical factors. In addition, sFe levels were predictive for a decline in FEV1.Serum iron levels may be a biomarker for the spirometric susceptibility of individuals to cigarette smoke.
PMCID: PMC3767599  PMID: 24040149
10.  The aspartate aminotransferase to platelet ratio before chemotherapy predicts adverse events for FOLFOX and XELOX regimens including bevacizumab as the first-line therapy for stage IV, recurrent and metastatic colorectal cancer 
Oxaliplatin-based chemotherapy for colorectal liver metastasis can induce hepatotoxicity, which increases the risk of liver resection. We previously reported that the aspartate aminotransferase to platelet ratio (APR) before chemotherapy can indicate oxaliplatin-induced splenomegaly and also predict the occurrence of adverse events during chemotherapy. Bevacizumab (BEV) was recently reported to reduce oxaliplatin-induced splenomegaly. Therefore, the aim of the present study was to investigate whether the APR before chemotherapy can predict the splenomegaly and adverse events associated with FOLFOX/BEV or XELOX/BEV in patients with stage IV or recurrent colorectal cancer.
We performed CT volumetry of the spleen before and 12 weeks after FOLFOX/BEV and XELOX/BEV in 63 patients. The incidence of adverse events, haematological parameters, and biochemistry and urinalysis results were assessed during treatment.
An increase in the splenic volume was not observed in the FOLFOX/BEV group, but was significant in the XELOX/BEV group (+5.0% vs. +18.8%, P=0.01). The APR before chemotherapy did not indicate the presence of splenomegaly in the 63 patients, however, it did significantly predict the development of grade 2 or higher adverse events during chemotherapy.
An APR of 0.15 or higher before chemotherapy did not indicate the presence of splenomegaly, but could predict the development of adverse events due to FOLFOX/BEV and XELOX/BEV treatment.
PMCID: PMC3635181  PMID: 23730517
Aspartate aminotransferase; platelet; splenomegaly; chemotherapy; colorectal cancer
11.  A patient who showed a pathologically complete response after undergoing treatment with XELOX plus bevacizumab for synchronous liver metastasis of grade H2 from sigmoid colon cancer 
We herein report the case of a patient who showed a pathological complete response after undergoing chemotherapy with capecitabine, oxaliplatin and bevacizumab. The patient presented with synchronous solitary liver metastasis from sigmoid colon cancer. The maximum diameter of the liver deposit was 5.7 cm and the grade of the liver metastasis was H2 according to the Japanese classification. Deferred hepatectomy after sigmoidectomy was performed, followed by the administration of neoadjuvant chemotherapy. After undergoing sigmoidectomy, the patient received 1,000 mg/m2 of capecitabine and 130 mg/m2 of oxaliplatin without bevacizumab as the first cycle of chemotherapy followed by eight cycles of chemotherapy with bevacizumab (7.5 mg/kg) every three weeks. The liver deposit was reduced to 2.2 cm in diameter and the patient showed a partial response to chemotherapy. The patient then underwent metastasectomy of segment 8 of the liver instead of the central hepatectomy that was possibly needed before chemotherapy. Histopathologically, the tumor consisted of fibrous tissue, and no cancer cells were detected in the resected specimen. A pathological complete response in a patient with H2 liver metastasis is considered rare and suggests that capecitabine, oxaliplatin and bevacizumab are efficacious as neoadjuvant chemotherapy.
PMCID: PMC3635190  PMID: 23730524
XELOX + Bevacizumab; pathological complete response; synchronous colorectal liver metastasis (H2)
12.  Low-molecular-weight lipoprotein (a) and low relative lymphocyte concentration are significant and independent risk factors for coronary heart disease in patients with type 2 diabetes mellitus: Lp(a) phenotype, lymphocyte, and coronary heart disease 
The aim of the present prospective study was to examine whether lipoprotein (a) [Lp(a)] phenotypes and/or low relative lymphocyte concentration (LRLC) are independently associated with coronary heart disease (CHD) in patients with type 2 diabetes mellitus (T2DM).
Serum Lp(a) concentration, Lp(a) phenotypes, and RLC were analyzed in 214 subjects. Lp(a) phenotypes were classified into 7 subtypes according to sodium dodecyl sulfate-agarose gel electrophoresis by Western blotting. Subjects were assigned to the low-molecular-weight (LMW (number of KIV repeats: 11–22) ) and high-molecular-weight (HMW( number of KIV repeats: >22 )) Lp(a) groups according to Lp(a) phenotype and to the LRLC (RLC: <20.3%) and normal RLC (NRLC; RLC: ≥20.3%) groups according to RLC. A CHD event was defined as the occurrence of angina pectoris or myocardial infarction during the follow-up period.
During the follow-up period, 30 cases of CHD events were verified. Neutrophil count showed no correlation with CHD, while relative neutrophil concentration and RLC showed positive and negative correlations, respectively, with CHD. The Cox proportional hazard model analysis revealed the following hazard ratios adjusted for LMW Lp(a), LRLC, and LMW Lp(a) + LRLC: (4.31; 95% confidence interval [CI], 1.99-9.32; P < 0.01, 3.621; 95% CI, 1.50-8.75; P < 0.05, and 7.15; 95% CI, 2.17-23.56; P < 0.01, respectively).
Our results suggest that both LMW Lp(a) and LRLC are significant and independent risk factors for CHD and that the combination thereof more strongly predicts CHD in patients with T2DM.
PMCID: PMC3606419  PMID: 23496967
Lipoprotein (a) phenotype; Relative lymphocyte concentration; Coronary heart disease
13.  Exogenous Fibroblast Growth Factor-10 Induces Cystic Lung Development with Altered Target Gene Expression in the Presence of Heparin in Cultures of Embryonic Rat Lung 
Pathobiology  2012;79(3):127-143.
Signaling by fibroblast growth factor (FGF) receptor (FGFR) 2IIIb regulates branching morphogenesis in the mammalian lung. FGFR2IIIb is primarily expressed in epithelial cells, whereas its ligands, FGF-10 and keratinocyte growth factor (KGF; FGF-7), are expressed in mesenchymal cells. FGF-10 null mice lack lungs, whereas KGF null animals have normal lung development, indicating that FGF-10 regulates lung branching morphogenesis. In this study, we determined the effects of FGF-10 on lung branching morphogenesis and accompanying gene expression in cultures of embryonic rat lungs.
Embryonic day 14 rat lungs were cultured with FGF-10 (0–250 ng/ml) in the absence or presence of heparin (30 ng/ml) for 4 days. Gene expression profiles were analyzed by Affymetrix microchip array including pathway analysis. Some of these genes, functionally important in FGF-10 signaling, were further analyzed by Northern blot, real-time PCR, in situ hybridization and immunohistochemistry.
Exogenous FGF-10 inhibited branching and induced cystic lung growth only in cultures containing heparin. In total, 252 upregulated genes and 164 downregulated genes were identified, and these included Spry1 (Sprouty-1), Spry2 (Sprouty-2), Spred-1, Bmp4 (bone morphogenetic protein-4, BMP-4), Shh(sonic hedgehog, SHH), Pthlh (parathyroid hormone-related protein, PTHrP), Dusp6 (MAP kinase phosphatase-3, MKP-3) and Clic4 (chloride intracellular channel-4, CLIC-4) among the upregulated genes and Igf1 (insulin-like growth factor-1, IGF-1), Tcf21 (POD), Gyg1 (glycogenin 1), Sparc (secreted protein acidic and rich in cysteine, SPARC), Pcolce (procollagen C-endopeptidase enhancer protein, Pro CEP) and Lox (lysyl oxidase) among the downregulated genes. Gsk3β and Wnt2, which are involved in canonical Wnt signaling, were up- and downregulated, respectively.
Unlike FGF-7, FGF-10 effects on lung branching morphogenesis are heparin-dependent. Sprouty-2, BMP-4, SHH, IGF-1, SPARC and POD are known to regulate branching morphogenesis; however, potential roles of CLIC-4 and MKP-3 in lung branching morphogenesis remain to be investigated. FGF-10 may also function in regulating branching morphogenesis or inducing cystic lung growth by inhibiting Wnt2/β-catenin signaling.
PMCID: PMC3290038  PMID: 22261751
Cystic lung development; Microarray; Fibroblast growth factor-10; Heparin; Keratinocyte growth factor
14.  Immunolocalization of Sprouty-1 and Sprouty-2 in Developing Rat Lung 
Pathobiology  2012;79(1):34-44.
Sprouty, a common antagonist of fibroblast growth factor (FGF) and epidermal growth factor signaling, is a key player regulating tracheal branching and eye development in Drosophila. Four Sprouty homologs have been identified in vertebrates and all share a cysteine-rich region. However, the physiological function(s) of the individual Sprouty homologs is unknown. mRNA of Sprouty homologs is expressed during mouse lung development. In the present study, we investigated the immunolocalization of Sprouty proteins in rat lung at different stages of development.
Rabbit antibodies were raised against peptides derived from rat Sprouty-1 and Sprouty-2 and were used in Western blot analysis to determine Sprouty distribution in subcellular fractions (pellets and supernatant centrifuged at 5,000 and 20,000 g) and bronchoalveolar lavage fluid (BAL) from adult rat lungs or used in immunohistochemistry.
Western blot analysis revealed a 30-kDa Sprouty-1 band and a 34-kDa Sprouty-2 band in the supernatant and pellet fractions centrifuged at 20,000 g. BAL contained a band of approximately 16 kDa with Sprouty-1 antibody derived from proteolytic fragmentation of Sprouty-1. In embryonic day (E) 14 and E16 lungs, Sprouty-1 and Sprouty-2 were expressed both in epithelial and peripheral mesenchymal cells. In adult rat lung, bronchiolar and alveolar type II epithelial cells showed staining for both Sprouty-1 and Sprouty-2. Sprouty-1 expression was also seen in alveolar type I epithelial cells.
In light of the proximity of the distribution of Sprouty to that of FGF-10 (peripheral mesenchyme) and its receptor FGFR2IIIb (distal tubular epithelium) in lung development, and the finding that FGF-9, which is expressed in mesothelial cells, upregulates FGF-10, it appears that Sprouty expression in epithelial and mesenchymal cells during branching morphogenesis is closely related to signaling by FGF-9 and FGF-10.
PMCID: PMC3270822  PMID: 22236546
Lung; Development; Immunolocalization; Sprouty-1; Sprouty-2; Fibroblast growth factor-10; Caveolin
15.  Retrospective Analysis of the Relationship between Decline in FEV1 and Abdominal Circumference in Male Smokers: the Takahata Study 
Background:Metabolic syndrome (Mets) is reportedly associated with chronic obstructive pulmonary disease (COPD). However, the relationship between abdominal circumference (AC) and decline in FEV1 has not been elucidated. We aimed to investigate this relationship among male current smokers.
Methods:Spirometry was performed on subjects (n = 3,257) ≥ 40 years of age, who participated in a community-based annual health check in Takahata, Japan, from 2004 through 2006 (visit 1). Spirometry was re-evaluated, and AC was assessed in 147 of the male current smokers in 2009 (visit 2). The diagnosis of Mets was based on the criteria used in the Hisayama Study.
Results:No significant relationships were observed between AC and spirometric parameters such as % predicted forced vital capacity (FVC), % predicted forced expiratory volume in 1 s (FEV1) and FEV1/FVC. However, decline in FEV1 was significantly correlated with AC. Multivariate logistic regression analysis showed that AC was a significant discriminating factor for decline in FEV1, independently of age, Brinkman index and change in body mass index from visit 1 to visit 2. At visit 2, there was a greater prevalence of decline in FEV1 among subjects with Mets (n=17) than among those without Mets. Although there were no differences in % predicted FVC, % predicted FEV1 or FEV1/FVC between subjects with or without Mets, the rate of decline in FEV1 was significantly greater in subjects with Mets than in those without.
Conclusions:This retrospective analysis suggested that measuring AC may be useful for discriminating male smokers who show a decline in FEV1.
PMCID: PMC3534871  PMID: 23288999
decline in FEV1; abdominal circumference; smoker; health check.
16.  Relationship between Plasma Fibrinogen Levels and Pulmonary Function in the Japanese Population: The Takahata Study 
Background:Plasma fibrinogen is considered a biomarker of respiratory disease, owing to the relationship between plasma fibrinogen and pulmonary function established in Western populations. However, such a relationship has not yet been confirmed in an Asian population. We assessed this relationship in the general Japanese population.
Methods:Totally, 3,257 men and women aged ≥40 years who participated in a community-based annual health checkup in Takahata, Japan, from 2004 to 2006, underwent spirometry, and their plasma fibrinogen levels were determined.
Results:We found an inverse relationship between spirometric measures (percent predicted forced vital capacity [%FVC] and forced expiratory volume in 1s [%FEV1], and FEV1/FVC) and plasma fibrinogen levels in men, but not in women. The plasma fibrinogen levels were significantly higher in subjects with restrictive, obstructive, and mixed ventilatory disorders than in those with normal spirometry results. Multiple linear regression analysis revealed that in men, plasma fibrinogen levels were predictive for %FVC and %FEV1 (independent of age, body mass index, and cigarette smoking) but not for FEV1/FVC.
Conclusions:Plasma fibrinogen was significantly associated with pulmonary function in Japanese men, and as such, plasma fibrinogen might be a potent biomarker for pulmonary dysfunction in men.
PMCID: PMC3775111  PMID: 24046528
Chronic Obstructive Pulmonary Disease; Decline in FEV1; Fibrinogen; Pulmonary function; Smoker; Spirometry
17.  The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance 
Previous studies have demonstrated that postprandial hyperglycemia attenuates brachial artery flow-mediated dilation (FMD) in prediabetic patients, in diabetic patients, and even in normal subjects. We have previously reported that postprandial hyperinsulinemia also attenuates FMD. In the present study we evaluated the relationship between different degrees of postprandial attenuation of FMD induced by postprandial hyperglycemia and hyperinsulinemia and differences in ingested carbohydrate content in non-diabetic individuals.
Thirty-seven healthy subjects with no family history of diabetes were divided into 3 groups: a 75-g oral glucose loading group (OG group) (n = 14), a test meal group (TM group) (n = 12; 400 kcal, carbohydrate content 40.7 g), and a control group (n = 11). The FMD was measured at preload (FMD0) and at 60 minutes (FMD60) and 120 (FMD120) minutes after loading. Plasma glucose (PG) and immunoreactive insulin (IRI) levels were determined at preload (PG0, IRI0) and at 30 (PG30, IRI30), 60 (PG60, IRI60), and 120 (PG120, IRI120) minutes after loading.
Percentage decreases from FMD0 to FMD60 were significantly greater in the TM group (−21.19% ± 17.90%; P < 0.001) and the OG group (−17.59% ± 26.64%) than in the control group (6.46% ± 9.17%; P < 0.01), whereas no significant difference was observed between the TM and OG groups. In contrast, the percentage decrease from FMD0 to FMD120 was significantly greater in the OG group (−18.91% ± 16.58%) than in the control group (6.78% ± 11.43%; P < 0.001) or the TM group (5.22% ± 37.22%; P < 0.05), but no significant difference was observed between the control and TM groups. The FMD60 was significantly correlated with HOMA-IR (r = −0.389; P < 0.05). In contrast, FMD120 was significantly correlated with IRI60 (r = −0.462; P < 0.05) and the AUC of IRI (r = −0.468; P < 0.05). Furthermore, the percentage change from FMD0 to FMD120 was significantly correlated with the CV of PG (r = 0.404; P < 0.05), IRI60 (r = 0.401; p < 0.05) and the AUC of IRI (r = 0.427; P < 0.05). No significant correlation was observed between any other FMDs and glucose metabolic variables.
Differences in the attenuation of postprandial FMD induced by different postprandial insulin levels may occur a long time postprandially but not shortly after a meal.
PMCID: PMC3471039  PMID: 22891922
Flow-mediated dilation; Carbohydrate content; Postprandial; Glucose metabolism; Non-diabetic individuals
18.  TRAM Is Involved in IL-18 Signaling and Functions as a Sorting Adaptor for MyD88 
PLoS ONE  2012;7(6):e38423.
MyD88, a Toll/interleukin-1 receptor homology (TIR) domain-containing adaptor protein, mediates signals from the Toll-like receptors (TLR) or IL-1/IL-18 receptors to downstream kinases. In MyD88-dependent TLR4 signaling, the function of MyD88 is enhanced by another TIR domain-containing adaptor, Mal/TIRAP, which brings MyD88 to the plasma membrane and promotes its interaction with the cytosolic region of TLR4. Hence, Mal is recognized as the “sorting adaptor” for MyD88. In this study, a direct interaction between MyD88-TIR and another membrane-sorting adaptor, TRAM/TICAM-2, was demonstrated in vitro. Cell-based assays including RNA interference experiments and TRAM deficient mice revealed that the interplay between MyD88 and TRAM in cells is important in mediating IL-18 signal transduction. Live cell imaging further demonstrated the co-localized accumulation of MyD88 and TRAM in the membrane regions in HEK293 cells. These findings suggest that TRAM serves as the sorting adaptor for MyD88 in IL-18 signaling, which then facilitates the signal transduction. The binding sites for TRAM are located in the TIR domain of MyD88 and actually overlap with the binding sites for Mal. MyD88, the multifunctional signaling adaptor that works together with most of the TLR members and with the IL-1/IL-18 receptors, can interact with two distinct sorting adaptors, TRAM and Mal, in a conserved manner in a distinct context.
PMCID: PMC3369926  PMID: 22685567
19.  Cross-cultural comparison of the sleep-disordered breathing prevalence among Americans and Japanese 
To compare the sleep-disordered breathing prevalence among Hispanic and white Americans and Japanese, we performed a one-night sleep study with a single channel airflow monitor on 211 Hispanics and 246 whites from the Minnesota Field Center of the Multi-Ethnic Study of Atherosclerosis (MESA), and 978 Japanese from three community-based cohorts of the Circulatory Risk in Communities Study (CIRCS) in Japan.
The respiratory disturbance index and sleep-disordered breathing, defined as respiratory disturbance index ≥ 15 disturbances/hr, were estimated. The sleep-disordered breathing prevalence was higher in men (34.2%) than women (14.8%), and higher among Hispanics (36.5%) and whites (33.3%) than among Japanese (18.4%), corresponding to differences in body mass index. Within body mass index strata, the race difference in sleep-disordered breathing was attenuated. This was also true when we adjusted for body mass index instead of stratification. The strong association between body mass index and sleep-disordered breathing was similar in Japanese and Americans.
The sleep-disordered breathing prevalence was lower among Japanese than the Americans. However, the association of body mass index with sleep-disordered breathing was strong, and similar among the race/ethnic groups studied. The majority of the race/ethnic difference in sleep-disordered breathing prevalence was explained by a difference in body mass index distribution.
PMCID: PMC2895689  PMID: 20110399
cross-sectional study; epidemiology; prevalence; sleep apnea
20.  Characterization of the role of the tumor marker Nup88 in mitosis 
Molecular Cancer  2010;9:119.
Nuclear pore complexes are massive multiprotein channels responsible for traffic between the nucleus and cytoplasm, and are composed of approximately 30 proteins, termed nucleoporins (Nup). Our recent studies indicated that the nucleoporins Rae1 and Tpr play critical roles in maintaining the spindle bipolarity during cell division. In the present study, we found that another nucleoporin, Nup88, was localized on the spindles together with Nup214 during mitosis. Nup88 expression is linked to the progression of carcinogenesis, Nup88 has been proposed as a tumor marker. Overexpression of Nup88 enhanced multinucleated cell formation. RNAi-mediated knockdown of Nup88 disrupted Nup214 expression and localization and caused multipolar spindle phenotypes. Our data indicate that proper expression of Nup88 is critical for preventing aneuploidy formation and tumorigenesis.
PMCID: PMC2890605  PMID: 20497554
21.  Contrast-enhanced intraoperative ultrasonography equipped with late Kupffer-phase image obtained by sonazoid in patients with colorectal liver metastases 
AIM: To find occult metastases during hepatectomy in patients with colorectal cancer liver metastases (CRCLM), contrast-enhanced intraoperative ultrasonography (CE-IOUS) was performed using a new microbubble agent, sonazoid, which provides a parenchyma-specific contrast image based on its accumulation in the Kupffer cells.
METHODS: Eight patients with CRCLM underwent CE-IOUS using sonazoid before hepatectomy. The liver was investigated during a late Kupffer-phase imaging, which is a valuable characteristic of sonazoid.
RESULTS: CE-IOUS using sonazoid provided the early vascular- and sinusoidal-phase images for
10 min followed by the late Kupffer-phase image up to 30 min after the injection of sonazoid. IOUS did not provide new findings of metastatic lesion in the 8 patients. However, during the late Kupffer-phase image of sonazoid, a metastatic lesion was newly found in two of the 8 patients. These newly detected lesions were removed by an additional hepatectomy and histopathologically diagnosed as a metastasis.
CONCLUSION: CE-IOUS using sonazoid can allow surgeons to investigate the whole liver with enough time and to find new metastases intraoperatively.
PMCID: PMC2712854  PMID: 18506927
Contrast-enhanced intraoperative ultrasonography; Late Kupffer-phase image; Sonazoid; Colorectal cancer liver metastases; Occult hepatic lesions
22.  A Genetic Variant of the CD14 C-159T in Patients with Functional Dyspepsia (FD) in Japanese Subjects 
Inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia (FD). However, detailed data regarding the relationship between the genetic regulatory factors of inflammation and FD are not available. CD14 is an important mediator of the inflammatory response in the first line of host defense by recognition of Lipopolysaccharide (LPS). We aimed to investigate the association between CD14 promoter C-159T polymorphism and FD in a Japanese population. 108 patients with FD and 99 non-dyspeptic subjects enrolled in this study. Dyspeptic symptoms were divided according to Rome III criteria. CD14 gene C-159T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. In the non-dyspeptics, the CD14 genotype distribution was 28CC (28.3%), 51CT (51.5%), 21TT (21.2%). Meanwhile, the CD14 genotype distribution in FD was 31CC (28.4%), 56CT (51.4%), 22TT (20.2%). The genotype distribution was not significantly different. There was no significant difference between two groups in the genotype distribution. We did not found any association between CD14 genotypes and dyspeptic patients in different gender and Helicobacter pylori infection status. No significant association was also found between CD14 polymorphism and any of different subtypes of FD according to Rome III while there was a weak correlation between TT genotype and PDS in male subjects (TT vs others, OR = 3.18, 95% CI = 0.98−10.26, p = 0.06). In conclusion, our results suggest that CD14 polymorphism is unlikely to associate with susceptibility of dyspeptic symptoms. The role of inflammation related-gene polymorphisms to the development of dyspepsia needs to further evaluation.
PMCID: PMC2266053  PMID: 18385826
functional dyspepsia; CD14; polymorphism
23.  The Role of Mannan-Binding Lectin (MBL) Gene Polymorphism in Ulcerative Colitis 
Series studies suggest that enteropathogenic microorganisms play a substantial role in the clinical initiation and relapses of ulcerative colitis (UC). Mannan-binding lectin (MBL) is an important constituent of the innate immune system, and deficiency of MBL has been reported to increase the overall susceptibility of an individual to infectious disease. This study was aimed to investigate the associations between polymorphisms of the MBL gene and UC. Recruited in this study were 108 Japanese patients with UC and 144 healthy control subjects. Polymorphism at codon 54 of exon 1 of the MBL gene was investigated by polymerase chain reaction based restriction fragment length polymorphism. In general, no significant difference in MBL polymorphism was found between UC patients and health controls. However, the frequency of A carriers was significantly higher in the relapsing cases than controls (Odds ration = 2.19, 95%CI, 1.10–4.34; p = 0.023), and similar tendency was also found in A/A genotype. In conclusion, the polymorphism at codon 54 of exon 1 of the MBL gene associated with the susceptibility to the relapsing phenotype of ulcerative colitis. It suggests that codon 54 A variants of MBL gene may have an increased risk for the flare-ups of UC.
PMCID: PMC2212342  PMID: 18231631
genetic polymorphism; mannan-binding lectin; ulcerative colitis
24.  A rare case of concomitant huge exophytic gastrointestinal stromal tumor of the stomach and Kasabach-Merritt phenomenon 
We report an extremely rare case of concomitant huge exophytic GIST of the stomach and Kasabach-Merritt phenomenon (KMP).
Case presentation
The patient was a 67-year-old man experiencing abdominal distension since September 2006. A physical examination revealed a 25 × 30 cm hard mass that was palpable in the middle and lower left abdomen minimal intrinsic mobility and massive ascites. Since the admitted patient was diagnosed with DIC, surgery could not be performed. The patient received a platelet transfusion and the DIC was treated. Due to this treatment, the platelet count recovered to 7.0 × 104; tumor resection was performed at 16 days after admission. Laparotomy revealed a huge extraluminal tumor arising from the greater curvature of the stomach that measured 25 × 30 cm and had not ruptured into the peritoneal cavity or infiltrated other organs. Partial gastric resection was performed. The resected mass measured 25 × 25 × 20 cm. In cross section, the tumor appeared hard and homogenous with a small polycystic area. Histopathology of the resected specimen showed large spindle cell GIST with >5/50 HPF (high-power field) mitotic activity. The postoperative course was uneventful, and the coagulopathy improved rapidly.
Since the characteristic of tumor in this case was hypervascularity with bleeding and necrotic lesions, coagulopathy was thought to be caused by the trapping of platelets within a large vasculized tumor mass.
PMCID: PMC1892781  PMID: 17540038
25.  Analysis of Beta-Tubulin Gene Exon 4 Mutations in Advanced Stage III or IV Gastric Cancer 
The mechanisms that cause chemoresistance of gastric cancer have yet to be elucidated. Taxanes and promising agents that were recently approved for treatment of advanced or recurrent gastric cancer. Mutations of beta-tubulin, which is a target of taxianes, have been shown to confer chemoresistance against these agents. The aim of the present study is to investigate the presence of mutations of the beta-tubulin in gastric cancer tissues. Sixty-six patients with advanced stage III or IV gastric cancer patients enrolled in this study. Paired samples of gastric cancer tissue and normal mucosa were obtained by endoscopy. The guanosine 5'-triphosphate (GTP)-binding site in exon 4 of the beta-tubulin gene was examined by polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP) analysis, followed by sequencing of the products with abnormally shifted bands. SSCP analysis showed abnormal bands upstream of the GTP-binding site in 7 of the 66 patients, but sequence analysis found no nucleotide substitutions in these patients. Three variant bands were also detected down stream of the the GTP-binding site, but the sequences of the 3 products corresponded to those of two independent pseudogenes. Thus, none of the tumor samples showed mutation of the beta-tubulin exon 4 GTP-binding site. In conclusion, these findings suggest that mutations of the beta-tubulin gene are rare and are unlikely to be an important cause of taxane resistance to taxians.
PMCID: PMC2275766  PMID: 18398498
gastric cancer; beta-tubulin; exon 4; mutation; SSCP

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