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Colon cancer cells express the carbohydrate determinant sialyl Lewisx, while they exhibit markedly decreased the expression of its sulfated derivative, sialyl 6-sulfo Lewisx. In contrast, normal colonic epithelial cells strongly express sialyl 6-sulfo Lewisx, but they virtually do not express sialyl Lewisx. Impaired sulfation was therefore suggested to occur during the course of malignant transformation of colonic epithelial cells and was assumed to be responsible for the increased sialyl Lewisx expression in cancers. To elucidate the molecular biological background of the impaired sulfation in cancers, we studied the expression levels of mRNA for 6-O-sulfotransferase isoenzymes, PAPS synthases and transporters, and a cell membrane sulfate transporter, DTDST, in cancer tissues. The most striking decrease in cancer cells compared with nonmalignant epithelial cells was noted in the transcription of the DTDST gene (P = 0.0000014; n = 20). Most cultured colon cancer cells had a diminished DTDST transcription, which was restored when cultured with histone deacetylase inhibitors. Suppression of DTDST transcription under the control of a tet-off inducible promoter resulted in increased sialyl Lewisx expression and reduced sialyl 6-sulfo Lewisx expression. Unexpectedly, the growth rate of the cancer cells was markedly enhanced when transcription of DTDST was suppressed. These results show that the decrease in the transcription of the sulfate transporter gene is the major cause of decreased expression of sialyl 6-sulfo Lewisx and increased expression of sialyl Lewisx in colon cancers. The results also suggest that the diminished DTDST expression is closely related to enhanced proliferation of cancer cells. Cancer Res; 70(10); 4064–73. ©2010 AACR. more...

Supplementary Figure Legends 1-4 from Epigenetic Silencing of the Sulfate Transporter Gene DTDST Induces Sialyl Lewisx Expression and Accelerates Proliferation of Colon Cancer Cells

Although numerous attempts have been made to clarify traits associated with the invasiveness of exotic species, the effect of the biogeographical origin of exotic species on trait variability in invaded regions in a community level remains poorly understood. In this study, we examined how biogeographical origin affects the flowering phenology of exotic herbaceous plant communities. We collected flowering phenology data for herbaceous plants in Japan based on three types of independent data source: records of 537 exotic species from a picture book; records of 319 exotic and native species from field surveys in 1994–2015 conducted using a citizen science approach; and records of 186 exotic and native species from a field survey conducted over a 1-year period. We used generalized linear models to examine the effects of three attributes (family, lifeform, and biogeographical origin) on the flowering phenology of exotic plant communities. For comparisons between exotic and native communities, we included habitat factors in the analyses. The results indicated that biogeographical origin has a significant effect on the flowering phenology of exotic plant communities. In Japan, exotic plants of European origin flower significantly earlier than those of North American origin and native plants. The findings of this study highlight the need to consider biogeographical origin when assessing the traits of exotic species. more...

β-Conglycinin is the major storage protein in soybeans. Pre-clinical animal models and human clinical studies have demonstrated the triglyceride-lowering effect of this protein, suggesting that it could be put into practical use as a functional food material. To date, however, there are no accurate and simple assays for quantification of β-conglycinin. In this study, samples were pretreated by mixing them with rice flour powder prior to extraction of proteins. Then, we used commercially available ELISA kits for detection of allergens that could be present in any contaminating soybean residue. This enabled accurate and highly reproducible quantitation of β-conglycinin content in several processed soybean foods. more...

Diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) have been used as imaging biomarkers in adults with high-grade gliomas (HGGs). We incorporated free-breathing DW-MRI and DCE-MRI, at a single time point, in the routine follow-up of five children (median age 9 years, range 8-15) with histologically confirmed HGG within a prospective imaging study. It was feasible to incorporate DW-MRI and DCE-MRI in routine assessments of children with HGG. DW and DCE parameters were repeatable in paediatric HGG. Higher median ADC100-1000 significantly correlated with longer survival in our sample. more...

The microbiota&ndash, gut&ndash, brain axis has attracted increasing attention in the last decade. Here, we investigated whether okara, a soybean by-product rich in dietary fiber, can attenuate cognitive impairment in senescence-accelerated mouse prone 8 (SAMP8) mice by altering gut microbial composition. Mice were fed either a standard diet, or a diet containing okara (7.5% or 15%, w/w) for 26 weeks. In the memory test, the 7.5% okara-fed mice showed a longer step-through latency and the 15% okara-fed mice had a short escape latency compared with control mice. The 15% okara-fed mice displayed decreased body weight, increased fecal weight, and altered cecal microbiota composition compared with the control group, however, there was no significant difference in the serum lactic acid and butyric acid levels among these mice groups. The 7.5% okara-fed mice had significantly higher NeuN intensity in the hippocampus compared with control mice. Furthermore, a decrease in inflammatory cytokine TNF- and an increase in brain-derived neurotrophic factor (BDNF) was observed in the 7.5% okara-fed group. The expression of synthesizing enzyme of acetylcholine was increased by the okara diets, and the acetylcholine level in the brain was higher in the 7.5% okara-fed group than in the control. These suggest that oral administration of okara could delay cognitive decline without drastically changing gut microbiota. more...

Purpose To assess the repeatability of apparent diffusion coefficient (ADC) estimates in extracranial soft-tissue diffusion-weighted magnetic resonance imaging across a wide range of imaging protocols and patient populations. Materials and Methods Nine prospective patient studies and one prospective volunteer study, performed between 2006 and 2016 with research ethics committee approval and written informed consent from each subject, were included in this single-institution study. A total of 141 tumors and healthy organs were imaged twice (interval between repeated examinations, 45 minutes to 10 days, depending the on study) to assess the repeatability of median and mean ADC estimates. The Levene test was used to determine whether ADC repeatability differed between studies. The Pearson linear correlation coefficient was used to assess correlation between coefficient of variation (CoV) and the year the study started, study size, and volumes of tumors and healthy organs. The repeatability of ADC estimates from small, medium, and large tumors and healthy organs was assessed irrespective of study, and the Levene test was used to determine whether ADC repeatability differed between these groups. Results CoV aggregated across all studies was 4.1% (range for each study, 1.7%-6.5%). No correlation was observed between CoV and the year the study started or study size. CoV was weakly correlated with volume (r = -0.5, P = .1). Repeatability was significantly different between small, medium, and large tumors (P.05), with the lowest CoV (2.6%) for large tumors. There was a significant difference in repeatability between studies-a difference that did not persist after the study with the largest tumors was excluded. Conclusion ADC is a robust imaging metric with excellent repeatability in extracranial soft tissues across a wide range of tumor sites, sizes, patient populations, and imaging protocol variations. Online supplemental material is available for this article. more...

Objectives To examine repeatability of parameters derived from non-Gaussian diffusion models in data acquired in children with solid tumours. Methods Paediatric patients (30 %) over the histogram. ADC, D, DDCα, and DDCK were strongly correlated (ρ > 0.9), DDCα and α were not correlated (ρ = 0.083). Conclusion Perfusion- and kurtosis-related parameters displayed larger, more variable CV across the histogram, indicating observed clinical changes outside of D/DDC in these models should be interpreted with caution. Centiles below 5th for all parameters show high CV and are unreliable as diffusion metrics. The stretched exponential model behaved well for both DDCα and α, making it a strong candidate for modelling multiple-b-value diffusion imaging data. Key Points • ADC has good repeatability as low 5th centile of the histogram distribution. • High CV was observed for all parameters at extremes of histogram. • Parameters from the stretched exponential model showed low coefficients of variation. • The median ADC, D, DDC α , and DDC K are highly correlated and repeatable. • Perfusion/kurtosis parameters showed high CV variations across their histogram distributions. more...

Aorto-femoral (A-F) bypass surgery has been performed commonly and safely as an interventional therapy for iliac arterial stenosis or obstruction. Recently, catheter intervention has increasingly replaced this modality. However, no consensus has been reached as to a lesion-specific treatment choice between bypass surgery and catheter intervention. We investigated the patency rates after A-F bypasses according to TransAtlantic Inter-Society Consensus (TASC) classifications. This is a multicenter retrospective analysis of 281 patients on whom A-F bypasses were performed between 1991 and 2000. Follow-up extended to a maximum of 10.0 years, with a mean of 3.6 years (±2.6 years). The overall primary patency rate for all grafts was 94.9% at 5 years. The patency rate for the TASC type-B lesion was lower than that of type-D lesion, with a survival rate at 5 years of 88.0%. The logistic regression analysis revealed that no variables were responsible for the primary patency rate. Renal failure, and peripheral arterial occlusive disease were correlated with a decreased survival rate. We conclude that the late results of A-F bypasses are satisfactory. For the type B lesion, catheter intervention may have a better indication. Chronic renal failure and peripheral arterial occlusive disease may decrease the survival rate. The operative indications should be carefully determined for these cases. more...

The glycan molecules that preferentially appear in cancers are clinically utilized as serum tumor markers. The exact reason, however, why glycans are useful as tumor markers remain elusive. Here, we will summarize lessons learned from well-established cancer-associated glycans, and propose strategies to develop new cancer markers. Our recent results on cancer-associated glycans, sialyl Lewis A and sialyl Lewis X, indicated that the repressed transcription of some glycan genes by epigenetic silencing during early carcinogenesis, and the transcriptional induction of some other glycan genes by tumor hypoxia accompanying cancer progression at locally advanced stages, are two major factors determining cancer-associated glycan expression. Multiple genes are involved in glycan synthesis, and epigenetic silencing of a part of such genes leads to accumulation of glycans having truncated incomplete structures, which are readily detected by specific antibodies. Glycans are very unique and advantageous as marker molecules because they are capable of reflecting epigenetic silencing in their structures. Transcriptional induction of some glycan genes by tumor hypoxia at the later stages produces further glycan modifications, such as an unusual increase of the N-glycolyl sialic acid residues in the glycan molecules. The entire process of malignant transformation thus creates abnormal glycans, whose structures reveal the effects of both epigenetic silencing and tumor hypoxia. The second advantage of a glycan marker over a proteinous marker is that they can reflect the plurality of genetic anomalies in a singular molecule, as it is synthesized by the cooperative action of multiple genes. Glycans are sometimes covalently bound to well-known cancer-associated proteins, such as CD44v, and this eventually contributes to a high cancer specificity and functional relevancy in cancer progression. more...

ObjectiveLimited endothelial cell (EC) coverage and anastomotic intimal hyperplasia contribute to thrombosis and failure of prosthetic grafts. Lipid accumulation and lipid oxidation are associated with decreased EC migration and intimal hyperplasia. The goal of this study was to assess the ability of antioxidants to improve graft healing in hypercholesterolemic animals.MethodsRabbits were placed in one of four groups: chow plus N-acetylcysteine (NAC), chow plus probucol, chow with 1% cholesterol plus NAC, or chow with 1% cholesterol plus probucol. After 2 weeks, expanded polytetrafluoroethylene grafts (12 cm long × 4-mm internal diameter) were implanted in the abdominal aorta. Grafts were removed after 6 weeks and analyzed for cholesterol content, EC coverage, anastomotic intimal thickness, and the cellular composition of the neointima. Plasma samples were obtained to assess systemic oxidative stress. The data were compared with previously reported data from animals fed diets of chow and chow with 1% cholesterol.ResultsProsthetic grafts from rabbits fed chow with 1% cholesterol had significantly greater anastomotic intimal thickening and lower EC coverage than grafts from rabbits fed a regular chow diet. In hypercholesterolemic rabbits, antioxidant therapy decreased global oxidative stress as evidenced by a 40% decrease in plasma thiobarbituric acid reactive substances. In rabbits fed the chow with 1% cholesterol diet, NAC decreased intimal hyperplasia at the proximal anastomosis by 29% and significantly increased graft EC coverage from 46% to 71% (P = .03). Following a similar pattern, probucol decreased intimal hyperplasia by 43% and increased graft EC coverage to 53% in hypercholesterolemic rabbits.ConclusionsGlobal oxidative stress and anastomotic intimal hyperplasia are increased, and endothelialization of prosthetic grafts is significantly reduced in rabbits fed a high-cholesterol diet. Antioxidant treatment improves EC coverage and decreases intimal hyperplasia. Reducing oxidative stress may promote healing of prosthetic grafts.Clinical RelevanceHypercholesterolemia is associated with an increased inflammatory response, elevated oxidative stress, and increased intimal hyperplasia after stent or vein graft placement in animal models and in humans. Reduced endothelialization is seen after stent or graft placement in hypercholesterolemic animals, and reduced endothelial cell growth and patency of endothelial cell-seeded grafts is found in humans with elevated serum lipid levels. Our results suggest that antioxidants are effective in reducing this pathologic response and in improving graft healing. more...

Uncontrolled growth of malignant cells produces hypoxic regions in locally advanced tumors. Recently we showed that tumor hypoxia-induced transcription of multiple genes involved in glycan synthesis, leading to expression of useful glycolipid tumor markers, such as gangliosides having N-glycolyl sialic acid. Our subsequent studies indicated that the ceramide portion of glycolipids, as well as their glycan moiety, was also significantly affected by hypoxia. Tumor hypoxia-induced marked accumulation of sphinganine (dihydrosphingosine) long-chain base, and significant reduction of unsaturated very long-chain fatty acids in the ceramide moiety. Mass-spectrometry, which yields information on both glycan- and ceramide moieties, is expected to be clinically useful in detecting such distinct molecular species of cancer-associated glycolipids having combined alteration in both glycan- and ceramide moieties. more...

In this study, the authors focused on light wind from the sea and its thermal environment relaxation effect during periods of calm conditions during the night when there is a concern that the urban... more...

To investigate whether cilostazol, a cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor, suppresses intimal hyperplasia in canine vein grafts, and to elucidate its mechanisms in terms of cell proliferation and apoptosis. Bilateral reversed jugular vein interposition grafts of the common carotid artery were performed in 12 beagle dogs. Starting from 7 days before surgery, either cilostazol (30 mg/day; n = 6) or a placebo (n = 6) was given orally twice daily. Vein grafts were harvested at 1 or 4 weeks, and fixed under pressure for histological examination. By 1 week after implantation, the cilostazol group showed significantly less cell proliferation than the placebo group. By 4 weeks after implantation, intimal and medial thickness was significantly thinner in the cilostazol group than in the placebo group. There was significantly more apoptosis in the placebo group than in the cilostazol group at both time points. Cilostazol suppressed the development of intimal hyperplasia in canine autogenous vein grafts. Thus, it may be associated with the modulation of cell proliferation and apoptosis. more...

Incomplete synthesis and neo-synthesis are two major concepts for cancer-associated alterations of cell surface carbohydrate determinants, formulated by Hakomori and collaborators almost 25 years ago. These concepts are still as relevant and useful as ever for cancer-associated alteration of carbohydrate determinants. Incomplete synthesis of carbohydrate determinants occurs through the epigenetic silencing of glycogenes through DNA methylation and/or histone modification in the early stage cancers. The natural selection of more malignant cancer cells occurs through acquisition of hypoxia resistance by constitutively activated hypoxia inducible factors (HIFs) in the advanced stages of cancers. HIFs induce transcription of several important glycogenes, and lead to neo-synthesis of carbohydrate determinants. For instance, expression of sialyl Lewis A/X is induced by epigenetic silencing of glycogenes in the early stages, and is further accelerated in the advanced stages by hypoxia-induced transcription of several glycogenes. Expression of GM2 ganglioside is induced in cancers by altered glycosyltransferase activities, and its N-glycolyl sialic acid content increases by hypoxia-induced transcription of a sialic acid transporter gene. N-glycolyl GM2 thus reflects two cancer-associated genetic abnormalities in a single determinant, and has high cancer specificity. Every carbohydrate determinant is synthesized through multiple steps, each of which is affected by cancer-associated genetic abnormality. Superiority of carbohydrate determinants as cancer-specific molecules over protein determinants is demonstrated in that a single carbohydrate determinant can reflect multiple cancer-associated genetic abnormalities. more...

近年、日本のコンタクトレンズ(以下CLとする)装用者人口は1500万人を超えるといわれている。その中でCL装用者の25%がドライアイであるとの報告もある。今回、我々は、大島眼科病院でのCL希望者に対しドライアイの早期検出を目的に涙液スペキュラー検査(DR-1®興和社製)を実施し、有効な結果が得られたので報告する。対象は2006年11月から2007年5月までにCL作成を希望した100名(200眼)。方法は涙液スペキュラー(DR-1®興和社製)で涙液油層のドライアイGrade分類と涙液の自然破壊(Non-Invasive Break-Up以下NIBUとする)の有無とを観察し評価した。結果はGrade分類ではGrade 1・2は153眼、Grade 3は37眼、Grade 4は10眼、Grade 5は0眼であった。診察の結果、ドライアイと診断された眼数は31眼(15.5%)であった。またGrade分類別のドライアイ検出率はGrade 1・2が3眼/153眼(1.9%)、Grade 3が18眼/37眼(48.6%)、Grade 4は10眼/10眼(100%)とGrade分類の3・4が最も多く検出された。またNIBUは11眼に観察され、その内6眼(54.5%)がドライアイであった。涙液スペキュラーは操作も簡便でありドライアイ検出に適した有効な検査であると考えられた。 more...

健常者を被験者として車いす特性や環境評価に関する研究を行う際, 上位脊髄損傷者では顕著に認められない下肢や体幹の活動を伴う可能性を考慮する必要がある. 今回, 拘束条件のない状態での健常者の車いす駆動特性に関する基礎資料を得るため, 登坂時の上肢・下肢筋活動, 足底荷重, 体幹移動等について分析した. その結果, 上肢筋活動の様相はこれまでの低位脊髄損傷者における報告と類似し, その活動量は傾斜勾配が増すとともに増加した. 一方, 下肢筋では勾配の急な登坂時において, 駆動終期から惰行期初めにかけて平目筋, 腓腹筋の足底屈筋群の活動が顕著にみられた. また大腿直筋など他の下肢筋活動も勾配とともに増加した. 体幹は急勾配登坂時で駆動期における前傾が顕著であり, 足底荷重は駆動初期から駆動後期にかけて減少し, 駆動終期から惰行前期にかけて増大した. このように, 健常者では, 車いす登坂時に, 駆動力増大と安定走行のために下肢や体幹を積極的に利用する状況が示された. そのため, 健常者による脊髄損傷者の障害シミュレーションでは下肢や体幹の利用を制約する考慮が必要であると考えられた. more...

The aim of this study was to assess early hemodynamic improvement after a stripping operation or saphenofemoral ligation by means of air plethysmography. This prospective study assessed 109 limbs of 71 patients treated between May 2000 and December 2001 for primary varicose veins due to greater saphenous insufficiency. Eighty-nine limbs were treated by stripping surgery (stripping group), and 20 limbs were treated with saphenofemoral ligation (saphenofemoral ligation group). To evaluate venous hemodynamic changes, air plethysmography was performed before surgery and 7-14 days after surgery. A significant decrease and normalization of the venous filling index and residual volume function was observed in the two groups. A decrease in venous volume was observed in the ligation group, but the change was not statistically significant. In contrast, a significant decrease in venous volume was observed in the stripping group. The ejection fraction was not improved in either of the groups. From these results we conclude that hydrostatic forces can be controlled by means of a stripping operation as well as by saphenofemoral ligation in the early postoperative period. more...

Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment. These changes are achieved at least partly by the action of transcriptional factors called hypoxia-inducible factors (HIFs). We investigated gene expression in cultured human colon cancer cells induced by hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity by using DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis x and sialyl Lewis a determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin. The transcription of genes for fucosyltransferase VII ( FUT7 ), sialyltransferase ST3Gal-I ( ST3O ), and UDP-galactose transporter-1 ( UGT1 ), which are all known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture. In addition, a remarkable induction was detected in the genes for syndecan-4 ( SDC4 ) and α5-integrin ( ITGA5 ), the cell-adhesion molecules involved in the enhanced adhesion of cancer cells to fibronectin. The transcriptional induction by hypoxia was reproduced in the luciferase-reporter assays for these genes, which were significantly suppressed by the co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis of cancers and tumor angiogenesis. more...

Malignant transformation is associated with abnormal glycosylation, resulting in the synthesis and expression of altered carbohydrate determinants including sialyl Lewis a and sialyl Lewis x . The sialyl Lewis a and sialyl Lewis x determinants appear in the sera of patients with cancer, and are extensively utilized for serum diagnosis of cancers in Japan. Sialyl Lewis a and sialyl Lewis x are involved in selectin-mediated adhesion of cancer cells to vascular endothelium, and these determinants are thought to be closely associated with hematogenous metastasis of cancers. Recent progress in this area includes the following: 1. Substantial increases in solid clinical statistics that further confirm the contribution of these determinants in the progression of a wide variety of cancers; 2. Elucidation of the ligand specificity of the three family members of selectins and evaluation of the roles of these molecules in cancer cell adhesion; and 3. Advances in the study of the mechanism that leads to the enhanced expression of the sialyl Lewis a/x determinants in malignant cells. These recent results have confirmed that these determinants are not merely markers for cancers, but are functionally implicated in the malignant behavior of cancer cells. The results also suggested that the increase of these determinants in malignant cells is an inevitable consequence of the malignant transformation of cells. Considerable new knowledge has also been accumulated regarding the therapeutic implications for suppression of hematogenous metastasis targeting this cell adhesion system. more...

Purpose. To study early changes in venous hemodynamics in stripping operation with preservation of the calf saphenous veins. Patients and methods. From October 1999 to December 2000, 110 extremities of 73 patients were treated for primary varicose veins. Based on preoperative ascending venography, 40 extremities underwent the groin-to-knee stripping of the GSV, 20 underwent the proximal division of the LSV, and 50 received combinations of both surgeries. To evaluate venous hemodynamic changes, air plethysmography was performed before operation and 7–14 days after operation. Results. The venous volume, venous filling index and residual volume fraction were improved after surgery, but the ejection fraction did not change. The overall incidence of nerve injury was 4.5% (five limbs). Conclusions. In stripping operations, the preservation of the calf saphenous veins, which is shown to be advantageous in reducing saphenous or sural nerve injuries, does not adversely affect early venous hemodynamic improvement. more...