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1.  Klebsormidium flaccidum genome reveals primary factors for plant terrestrial adaptation 
Nature Communications  2014;5:3978.
The colonization of land by plants was a key event in the evolution of life. Here we report the draft genome sequence of the filamentous terrestrial alga Klebsormidium flaccidum (Division Charophyta, Order Klebsormidiales) to elucidate the early transition step from aquatic algae to land plants. Comparison of the genome sequence with that of other algae and land plants demonstrate that K. flaccidum acquired many genes specific to land plants. We demonstrate that K. flaccidum indeed produces several plant hormones and homologues of some of the signalling intermediates required for hormone actions in higher plants. The K. flaccidum genome also encodes a primitive system to protect against the harmful effects of high-intensity light. The presence of these plant-related systems in K. flaccidum suggests that, during evolution, this alga acquired the fundamental machinery required for adaptation to terrestrial environments.
Plant colonization of land is an important evolutionary event. Here, the authors sequence the genome of a filamentous terrestrial alga and, through a comparative analysis with related algae and land plant species, provide insight into how aquatic algae adapted to terrestrial environments.
PMCID: PMC4052687  PMID: 24865297
2.  Caenorhabditis elegans chaperonin CCT/TRiC is required for actin and tubulin biogenesis and microvillus formation in intestinal epithelial cells 
Molecular Biology of the Cell  2014;25(20):3095-3104.
Caenorhabditis elegans chaperonin CCT is required for the biogenesis of actin and tubulin and is thereby essential for microvillus formation in intestinal cells. Loss of CCT/TRiC had no strong effects on intermediate filament protein IFB-2 or cytoskeletal linker protein ERM-1, suggesting that CCT/TRiC exhibits clear substrate specificity in living animals.
Intestinal epithelial cells have unique apical membrane structures, known as microvilli, that contain bundles of actin microfilaments. In this study, we report that Caenorhabditis elegans cytosolic chaperonin containing TCP-1 (CCT) is essential for proper formation of microvilli in intestinal cells. In intestinal cells of cct-5(RNAi) animals, a substantial amount of actin is lost from the apical area, forming large aggregates in the cytoplasm, and the apical membrane is deformed into abnormal, bubble-like structures. The length of the intestinal microvilli is decreased in these animals. However, the overall actin protein levels remain relatively unchanged when CCT is depleted. We also found that CCT depletion causes a reduction in the tubulin levels and disorganization of the microtubule network. In contrast, the stability and localization of intermediate filament protein IFB-2, which forms a dense filamentous network underneath the apical surface, appears to be superficially normal in CCT-deficient cells, suggesting substrate specificity of CCT in the folding of filamentous cytoskeletons in vivo. Our findings demonstrate physiological functions of CCT in epithelial cell morphogenesis using whole animals.
PMCID: PMC4196862  PMID: 25143409
3.  Rer1p regulates the ER retention of immature rhodopsin and modulates its intracellular trafficking 
Scientific Reports  2014;4:5973.
Rhodopsin is a pigment in photoreceptor cells. Some rhodopsin mutations cause the protein to accumulate in the endoplasmic reticulum (ER), leading to photoreceptor degeneration. Although several mutations have been reported, how mutant rhodopsin is retained in the ER remains unclear. In this study, we identified Rer1p as a modulator of ER retention and rhodopsin trafficking. Loss of Rer1p increased the transport of wild-type rhodopsin to post-Golgi compartments. Overexpression of Rer1p caused immature wild-type rhodopsin to accumulate in the ER. Interestingly, the G51R rhodopsin mutant, which has a mutation in the first transmembrane domain and accumulates in the ER, was released to the plasma membrane or lysosomes in Rer1-knockdown cells. Consistent with these results, Rer1p interacted with both wild-type and mutant rhodopsin. These results suggest that Rer1p regulates the ER retention of immature or misfolded rhodopsin and modulates its intracellular trafficking through the early secretory pathway.
PMCID: PMC4122963  PMID: 25096327
4.  Effect of baseline HbA1c level on the development of diabetes by lifestyle intervention in primary healthcare settings: insights from subanalysis of the Japan Diabetes Prevention Program 
To determine the effects of a lifestyle intervention on the development of type 2 diabetes mellitus (T2DM) among participants with impaired glucose tolerance (IGT), in particular in the subgroup with baseline glycated hemoglobin (HbA1c) levels ≥5.7%, in primary healthcare settings.
Randomized controlled trial.
32 healthcare centers in Japan.
Participants with IGT, aged 30–60 years, were randomly assigned to either an intensive lifestyle intervention group (ILG) or a usual care group (UCG).
During the initial 6 months, participants in the ILG received four group sessions on healthy lifestyles by public health providers. An individual session was further conducted biannually during the 3 years. Participants in the UCG received usual care such as one group session on healthy lifestyles.
Outcome measures
The primary endpoint was the development of T2DM based on an oral glucose tolerance test.
The mean follow-up period was 2.3 years. The annual incidence of T2DM were 2.7 and 5.1/100 person-years of follow-up in the ILG (n=145) and UCG (n=149), respectively. The cumulative incidence of T2DM was significantly lower in the ILG than in the UCG among participants with HbA1c levels ≥5.7% (log-rank=3.52, p=0.06; Breslow=4.05, p=0.04; Tarone-Ware=3.79, p=0.05), while this was not found among participants with HbA1c levels <5.7%.
Intensive lifestyle intervention in primary healthcare setting is effective in preventing the development of T2DM in IGT participants with HbA1c levels ≥5.7%, relative to those with HbA1c levels <5.7%.
Trial registration number
PMCID: PMC4212559  PMID: 25452854
HbA1c; Type 2 Diabetes; Impaired Glucose Tolerance; Intervention Groups
5.  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.
6.  Structural basis of a nucleosome containing histone H2A.B/H2A.Bbd that transiently associates with reorganized chromatin 
Scientific Reports  2013;3:3510.
Human histone H2A.B (formerly H2A.Bbd), a non-allelic H2A variant, exchanges rapidly as compared to canonical H2A, and preferentially associates with actively transcribed genes. We found that H2A.B transiently accumulated at DNA replication and repair foci in living cells. To explore the biochemical function of H2A.B, we performed nucleosome reconstitution analyses using various lengths of DNA. Two types of H2A.B nucleosomes, octasome and hexasome, were formed with 116, 124, or 130 base pairs (bp) of DNA, and only the octasome was formed with 136 or 146 bp DNA. In contrast, only hexasome formation was observed by canonical H2A with 116 or 124 bp DNA. A small-angle X-ray scattering analysis revealed that the H2A.B octasome is more extended, due to the flexible detachment of the DNA regions at the entry/exit sites from the histone surface. These results suggested that H2A.B rapidly and transiently forms nucleosomes with short DNA segments during chromatin reorganization.
PMCID: PMC3863819  PMID: 24336483
7.  Caenorhabditis elegans SNAP-29 is required for organellar integrity of the endomembrane system and general exocytosis in intestinal epithelial cells 
Molecular Biology of the Cell  2011;22(14):2579-2587.
Caenorhabditis elegans SNAP-29 is required for the proper morphology and functions of the Golgi and endosomes and general exocytosis.
It is generally accepted that soluble N-ethylmaleimide–sensitive factor attachment protein receptors mediate the docking and fusion of transport intermediates with target membranes. Our research identifies Caenorhabditis elegans homologue of synaptosomal-associated protein 29 (SNAP-29) as an essential regulator of membrane trafficking in polarized intestinal cells of living animals. We show that a depletion of SNAP-29 blocks yolk secretion and targeting of apical and basolateral plasma membrane proteins in the intestinal cells and results in a strong accumulation of small cargo-containing vesicles. The loss of SNAP-29 also blocks the transport of yolk receptor RME-2 to the plasma membrane in nonpolarized oocytes, indicating that its function is required in various cell types. SNAP-29 is essential for embryogenesis, animal growth, and viability. Functional fluorescent protein–tagged SNAP-29 mainly localizes to the plasma membrane and the late Golgi, although it also partially colocalizes with endosomal proteins. The loss of SNAP-29 leads to the vesiculation/fragmentation of the Golgi and endosomes, suggesting that SNAP-29 is involved in multiple transport pathways between the exocytic and endocytic organelles. These observations also suggest that organelles comprising the endomembrane system are highly dynamic structures based on the balance between membrane budding and fusion and that SNAP-29–mediated fusion is required to maintain proper organellar morphology and functions.
PMCID: PMC3135482  PMID: 21613542
8.  Comparison between surgical outcomes of colorectal cancer in younger and elderly patients 
AIM: To compare the outcome of surgical treatment of colorectal adenocarcinoma in elderly and younger patients.
METHODS: The outcomes of 122 patients with colorectal adenocarcinoma who underwent surgical treatment between January 2004 and June 2009 were analyzed. The clinicopathological and blood biochemistry data of the younger group (< 75 years) and the elderly group (≥ 75 years) were compared.
RESULTS: There were no significant differences between the two groups in operation time, intraoperative blood loss, hospital stay, time to resumption of oral intake, or morbidity. The elderly group had a significantly higher rate of hypertension and cardiovascular disease. The perioperative serum total protein and albumin levels were significantly lower in the elderly than in the younger group. The serum carcinoembryonic antigen level was lower in the elderly than in the younger group, and there was a significant decreasing trend after the operation in the elderly group.
CONCLUSION: The short-term outcomes of surgical treatment in elderly patients with colorectal adenocarcinoma were acceptable. Surgical treatment in elderly patients was considered a selectively effective approach.
PMCID: PMC3070137  PMID: 21472132
Colorectal tumor; Elderly patient; Morbidity; Carcinoembryonic antigen; C-reactive protein
9.  Prevention of type 2 diabetes in a primary healthcare setting: Three-year results of lifestyle intervention in Japanese subjects with impaired glucose tolerance 
BMC Public Health  2011;11:40.
A randomized control trial was performed to test whether a lifestyle intervention program, carried out in a primary healthcare setting using existing resources, can reduce the incidence of type 2 diabetes in Japanese with impaired glucose tolerance (IGT). The results of 3 years' intervention are summarized.
Through health checkups in communities and workplaces, 304 middle-aged IGT subjects with a mean body mass index (BMI) of 24.5 kg/m2 were recruited and randomized to the intervention group or control group. The lifestyle intervention was carried out for 3 years by public health nurses using the curriculum and educational materials provided by the study group.
After 1 year, the intervention had significantly improved body weight (-1.5 ± 0.7 vs. -0.7 ± 2.5 kg in the control; p = 0.023) and daily non-exercise leisure time energy expenditure (25 ± 113 vs. -3 ± 98 kcal; p = 0.045). Insulin sensitivity assessed by the Matsuda index was improved by the intervention during the 3 years. The 3-year cumulative incidence tended to be lower in the intervention group (14.8% vs.8.2%, log-rank test: p = 0.097). In a sub-analysis for the subjects with a BMI > 22.5 kg/m2, a significant reduction in the cumulative incidence was found (p = 0.027).
The present lifestyle intervention program using existing healthcare resources is beneficial in preventing diabetes in Japanese with IGT. This has important implications for primary healthcare-based diabetes prevention.
Trial registration number
PMCID: PMC3037863  PMID: 21235825
10.  Growth Inhibition of Re-Challenge B16 Melanoma Transplant by Conjugates of Melanogenesis Substrate and Magnetite Nanoparticles as the Basis for Developing Melanoma-Targeted Chemo-Thermo-Immunotherapy 
Melanogenesis substrate, N-propionyl-cysteaminylphenol (NPrCAP), is selectively incorporated into melanoma cells and inhibits their growth by producing cytotoxic free radicals. Magnetite nanoparticles also disintegrate cancer cells and generate heat shock protein (HSP) upon exposure to an alternating magnetic field (AMF). This study tested if a chemo-thermo-immunotherapy (CTI therapy) strategy can be developed for better management of melanoma by conjugating NPrCAP on the surface of magnetite nanoparticles (NPrCAP/M). We examined the feasibility of this approach in B16 mouse melanoma and evaluated the impact of exposure temperature, frequency, and interval on the inhibition of re-challenged melanoma growth. The therapeutic protocol against the primary transplanted tumor with or without AMF exposure once a day every other day for a total of three treatments not only inhibited the growth of the primary transplant but also prevented the growth of the secondary, re-challenge transplant. The heat-generated therapeutic effect was more significant at a temperature of 43°C than either 41°C or 46°C. NPrCAP/M with AMF exposure, instead of control magnetite alone or without AMF exposure, resulted in the most significant growth inhibition of the re-challenge tumor and increased the life span of the mice. HSP70 production was greatest at 43°C compared to that with 41°C or 46°C. CD8+T cells were infiltrated at the site of the re-challenge melanoma transplant.
PMCID: PMC2760320  PMID: 19830247
11.  A phase I trial of cytotoxic T-lymphocyte precursor-oriented peptide vaccines for colorectal carcinoma patients 
British Journal of Cancer  2004;90(7):1334-1342.
PMCID: PMC2409683  PMID: 15054451
peptide; cancer vaccine; immunotherapy; colon cancer; CTL
12.  A rapid biosensor chip assay for measuring of telomerase activity using surface plasmon resonance 
Nucleic Acids Research  2003;31(2):e4.
Considerable interest has been focused on telomerase because of its potential use in assays for cancer diagnosis, and for anti-telomerase drugs as a strategy for cancer chemotherapy. A number of assays based on the polymerase chain reaction (PCR) have been developed for evaluation of telomerase activity. To overcome the disadvantages of the conventional telomerase assay [telomeric repeat amplification protocol (TRAP)] related to PCR artifacts and troublesome post-PCR procedures, we have developed a telomeric repeat elongation (TRE) assay which directly measures telomerase activity as the telomeric elongation rate by biosensor technology using surface plasmon resonance (SPR). 5′-Biotinylated oligomers containing telomeric repeats were immobilized on streptavidin-pretreated dextran sensor surfaces in situ using the BIACORE apparatus. Subsequently, the oligomers associated with the telomerase extracts were elongated in the BIACORE apparatus. The rate of TRE was calculated by measuring the SPR signals. We examined elongation rates by the TRE assay in 18 cancer and three normal human fibroblast cell lines, and 12 human primary carcinomas and matching normal tissues. The elongation rates increased in a concentration- and time-dependent manner. Those of cancer cells were two to 10 times higher than fibroblast cell lines and normal tissues. Telomerase activities and its inhibitory effects of anti-telomerase agents as measured by both the TRE and TRAP assays showed a good correlation. Our assay allows precise quantitative comparison of a wide range of human cells from somatic cells to carcinoma cells. TRE assay is suitable for practical use in the assessment of telomerase activity in preclinical and clinical trials of telomerase-based therapies, because of its reproducibility, rapidity and simplicity.
PMCID: PMC140529  PMID: 12527793
13.  Wnt5a promotes cancer cell invasion and proliferation by receptor-mediated endocytosis-dependent and -independent mechanisms, respectively 
Scientific Reports  2015;5:8042.
Wnt5a activates the Wnt/β-catenin-independent pathway and its overexpression is associated with tumor aggressiveness enhancing invasive activity. For this action, Wnt5a-induced receptor endocytosis with clathrin is required. Wnt5a expression was previously believed to be associated with cancer cell motility but not proliferation. Recently, it was reported that Wnt5a is also implicated in cancer cell proliferation, but the mechanism was not clear. In this study, we generated a neutralizing anti-Wnt5a monoclonal antibody (mAb5A16) to investigate the mechanism by which Wnt5a regulates cancer cell proliferation. Wnt5a stimulated both invasion and proliferation of certain types of cancer cells, including HeLaS3 cervical cancer cells and A549 lung cancer cells although Wnt5a promoted invasion but not proliferation in other cancer cells such as KKLS gastric cancer cells. mAb5A16 did not affect the binding of Wnt5a to its receptor, but it suppressed Wnt5a-induced receptor-mediated endocytosis. mAb5A16 inhibited invasion but not proliferation of HeLaS3 and A549 cells. Wnt5a activated Src family kinases (SFKs) and Wnt5a-dependent cancer cell proliferation was dependent on SFKs, yet blockade of receptor-mediated endocytosis did not affect cancer cell proliferation and SFK activity. These results suggest that Wnt5a promotes invasion and proliferation of certain types of cancer cells through receptor-mediated endocytosis-dependent and -independent mechanisms, respectively.
PMCID: PMC4306915  PMID: 25622531
14.  Fucosylated TGF-β receptors transduces a signal for epithelial–mesenchymal transition in colorectal cancer cells 
British Journal of Cancer  2013;110(1):156-163.
Transforming growth factor-β (TGF-β) is a major inducer of epithelial–mesenchymal transition (EMT) in different cell types. TGF-β-mediated EMT is thought to contribute to tumour cell spread and metastasis. Sialyl Lewis antigens synthesised by fucosyltransferase (FUT) 3 and FUT6 are highly expressed in patients with metastatic colorectal cancer (CRC) and are utilised as tumour markers for cancer detection and evaluation of treatment efficacy. However, the role of FUT3 and FUT6 in augmenting the malignant potential of CRC induced by TGF-β is unclear.
Colorectal cancer cell lines were transfected with siRNAs for FUT3/6 and were examined by cell proliferation, invasion and migration assays. The expression and phosphorylation status of TGF-β downstream molecules were analysed by western blot. Fucosylation of TGF-β receptor (TβR) was examined by lectin blot analysis.
Inhibition of FUT3/6 expression by siRNAs suppressed the fucosylation of type I TβR and phosphorylation of the downstream molecules, thereby inhibiting the invasion and migration of CRC cells by EMT.
Fucosyltransferase 3/6 has an essential role in cancer cell adhesion to endothelial cells by upregulation of sialyl Lewis antigens and also by enhancement of cancer cell migration through TGF-β-mediated EMT.
PMCID: PMC3887298  PMID: 24253505
colorectal cancer; fucosyltransferase; TGF-β; EMT
15.  Biomedical advances from tissue culture 
Cytotechnology  2013;65(6):967-971.
The demonstration that the “dedifferentiation” of cells commonly observed in the early days of tissue culture was due to selective overgrowth of fibroblasts led to enrichment culture techniques (alternate animal and culture passage) designed to give a selective advantage to functionally differentiated tumor cells. These experiments resulted in the derivation of a large number of functionally differentiated clonal strains of a range of cell types. These results gave rise to the hypothesis that cells in culture accurately represent cells in vivo but without the complex in vivo environment. This concept has been strengthened with the development of hormonally defined culture media in combination with functionally differentiated clonal cell lines, which have augmented the potential of tissue culture studies. The use of hormonally defined media in place of serum-supplemented media demonstrates that hormonal responses and dependencies can be discovered in culture. Discoveries of hormonal dependencies of cancer cells has led to therapies targeting intracellular signaling pathways while discoveries of hormonal responses of pluripotent cells are helping to identify the potential application of stem cells. In these and other ways tissue culture technology will continue to contribute to solving problems of human health.
PMCID: PMC3853639  PMID: 23828098
Hormonally defined serum-free culture; Erbitux (cetuximab); Dedifferentiation; Functional cell culture; Growth factors
16.  Cellular Dynamics Drives the Emergence of Supracellular Structure in the Cyanobacterium, Phormidium sp. KS  
Life  2014;4(4):819-836.
Motile filamentous cyanobacteria, such as Oscillatoria, Phormidium and Arthrospira, are ubiquitous in terrestrial and aquatic environments. As noted by Nägeli in 1860, many of them form complex three-dimensional or two-dimensional structures, such as biofilm, weed-like thalli, bundles of filaments and spirals, which we call supracellular structures. In all of these structures, individual filaments incessantly move back and forth. The structures are, therefore, macroscopic, dynamic structures that are continuously changing their microscopic arrangement of filaments. In the present study, we analyzed quantitatively the movement of individual filaments of Phormidium sp. KS grown on agar plates. Junctional pores, which have been proposed to drive cell movement by mucilage/slime secretion, were found to align on both sides of each septum. The velocity of movement was highest just after the reversal of direction and, then, attenuated exponentially to a final value before the next reversal of direction. This kinetics is compatible with the “slime gun” model. A higher agar concentration restricts the movement more severely and, thus, resulted in more spiral formation. The spiral is a robust form compatible with non-homogeneous movements of different parts of a long filament. We propose a model of spiral formation based on the microscopic movement of filaments.
PMCID: PMC4284469  PMID: 25460162
cyanobacteria; Phormidium; supracellular structure; biofilm; spiral formation; emergence of order; slime gun model
17.  Novel Matrix Proteins of Pteria penguin Pearl Oyster Shell Nacre Homologous to the Jacalin-Related β-Prism Fold Lectins 
PLoS ONE  2014;9(11):e112326.
Nacreous layers of pearl oyster are one of the major functional biominerals. By participating in organic compound-crystal interactions, they assemble into consecutive mineral lamellae-like photonic crystals. Their biomineralization mechanisms are controlled by macromolecules; however, they are largely unknown. Here, we report two novel lectins termed PPL2A and PPL2B, which were isolated from the mantle and the secreted fluid of Pteria penguin oyster. PPL2A is a hetero-dimer composed of α and γ subunits, and PPL2B is a homo-dimer of β subunit, all of which surprisingly shared sequence homology with the jacalin-related plant lectin. On the basis of knockdown experiments at the larval stage, the identification of PPLs in the shell matrix, and in vitro CaCO3 crystallization analysis, we conclude that two novel jacalin-related lectins participate in the biomineralization of P. penguin nacre as matrix proteins. Furthermore, it was found that trehalose, which is specific recognizing carbohydrates for PPL2A and is abundant in the secreted fluid of P. penguin mantle, functions as a regulatory factor for biomineralization via PPL2A. These observations highlight the unique functions, diversity and molecular evolution of this lectin family involved in the mollusk shell formation.
PMCID: PMC4223035  PMID: 25375177
18.  Angiopoietin-like protein 2 induces androgen-independent and malignant behavior in human prostate cancer cells 
Oncology Reports  2014;33(1):58-66.
Angiopoietin-like proteins (ANGPTLs), which comprise 7 members (ANGPTL1-ANGPTL7), structurally resemble angiopoietins. We investigated the roles of ANGPTLs in the acquisition of androgen independence and the malignant behavior of human prostate cancer cells. Expression of ANGPTL messenger RNA (mRNA) and proteins were ascertained using RT-qPCR and western blot analysis in human prostate cancer cell lines. Androgen-dependent LNCaP and androgen-independent LNCaP/AI cells, respectively, were cultured in fetal bovine and charcoal-stripped medium. Cell proliferation, androgen dependence, migration and invasion, respectively, were examined under the overexpression and knockdown of ANGPTL2 by transfection of ANGPTL2 cDNA and its small-interfering RNA (siRNA). The effects of exogenous ANGPTL2 and blocking of its receptor, integrin α5β1, were also investigated. Human prostate cancer cell lines predominantly expressed ANGPTL2 among the members. Interrupting ANGPTL2 expression with siRNA suppressed the proliferation, migration and invasion of LNCaP cells. LNCaP/AI cells showed a higher ANGPTL2 expression than that of LNCaP cells. Furthermore, siRNA led to apoptosis of LNCaP/AI cells. The ANGPTL2-overexpressing LNCaP cells markedly increased proliferation, epithelial-to-mesenchymal transition (EMT) and malignant behavior in androgen-deprived medium. The migration rates were increased depending on the concentration of ANGPTL2 recombinant protein and were inhibited by anti-integrin α5β1 antibodies. To the best of our knowledge, this is the first study to elucidate the expression of ANGPTL2 in human prostate cancer cells. ANGPTL2 may be important in the acquisition of androgen independency and tumor progression of prostate cancer in an autocrine and/or paracrine manner via the integrin α5β1 receptor. Targeting ANGPTL2 may therefore be an efficacious therapeutic modality for prostate cancer.
PMCID: PMC4254678  PMID: 25370833
ANGPTL2; prostate cancer; EMT; apoptosis; integrin α5β1
19.  Immunolocalization of Corticotropin-Releasing Hormone (CRH) and Its Receptors (CRHR1 and CRHR2) in Human Endometrial Carcinoma 
Supplemental digital content is available in the text.
Corticotropin-releasing hormone (CRH), a major regulator of the stress response, regulates various biological functions through its interaction with CRH receptors 1 (CRHR1) and 2 (CRHR2). CRH, CRHR1, and CRHR2 have recently been reported in several types of carcinoma, but the significance of these proteins has remained largely unknown in human endometrial carcinoma.
Materials and Methods
A total of 87 endometrial carcinoma specimens were obtained from Japanese female patients who underwent surgical treatment, fixed in 10% formalin, and embedded in paraffin wax. Immunohistochemistry for CRH, CRHR1, and CRHR2 was performed, and clinical data were obtained from the medical records.
Immunopositivity of CRH, CRHR1, and CRHR2 in the specimens was 26%, 15%, and 10%, respectively. Univariate analysis revealed that immunohistochemical CRH status was positively associated with CRHR1 and CRHR2 status and that CRHR1 status was significantly associated with the risk of recurrence and poorer clinical outcome, whereas CRHR2 status was marginally associated with better prognosis for overall survival. Multivariate analysis demonstrated CRHR1 status as an independent prognostic factor for both disease-free and overall survival.
These results suggest that intratumoral CRH-CRHR1 signaling plays an important role in the progression of endometrial carcinoma and that CRHR1 is a potent prognostic factor in patients with this disease.
PMCID: PMC4215916  PMID: 25254562
Corticotropin-releasing hormone; Corticotropin-releasing hormone receptor 1; Endometrial cancer; Immunohistochemistry; Prognosis
20.  Efficacy of Enteral Supplementation Enriched with Glutamine, Fiber, and Oligosaccharide on Mucosal Injury following Hematopoietic Stem Cell Transplantation 
Case Reports in Oncology  2014;7(3):692-699.
The combination of glutamine, fiber and oligosaccharides (GFO) is thought to be beneficial for alleviating gastrointestinal mucosal damage caused by chemotherapy. A commercial enteral supplementation product (GFO) enriched with these 3 components is available in Japan. We performed a retrospective study to test whether oral GFO decreased the severity of mucosal injury following hematopoietic stem cell transplantation (HSCT). Of 44 HSCT patients, 22 received GFO and 22 did not. Severity of diarrhea/mucositis, overall survival, weight loss, febrile illness/documented infection, intravenous hyperalimentation days/hospital days, engraftment, acute and chronic GVHD, and cumulative incidence of relapse were studied. Sex, age, performance status, diagnosis, disease status, and treatment variables were similar in both groups. There were fewer days of diarrhea grade 3–4 in patients receiving GFO than in those who did not (0.86 vs. 3.27 days); the same was true for days of mucositis grade 3–4 (3.86 vs. 6.00 days). Survival at day 100 was 100% in the GFO group, but only 77.3% for the patients not receiving GFO (p = 0.0091, log-rank test). Weight loss and the number of days of intravenous hyperalimentation were better in the GFO group (p < 0.001 and p = 0.0014, respectively). Although not significant, less gut bacterial translocation with Enterococcus species developed in the GFO group (p = 0.0728) than in the non-GFO group. Other outcomes were not affected. To the best of our knowledge, this is the first comparative clinical study of GFO supplementation to alleviate mucosal injury after allo-HSCT. We conclude that glutamine, fiber and oligosaccharide supplementation is an effective supportive therapy to decrease the severity of mucosal damage in HSCT.
PMCID: PMC4255989  PMID: 25493082
Glutamine; Fiber; Oligosaccharide; GFO; Mucosal injury; Hematopoietic stem cell transplantation
21.  Intrauterine Ischemic Reperfusion Switches the Fetal Transcriptional Pattern from HIF-1α- to P53-Dependent Regulation in the Murine Brain 
PLoS ONE  2014;9(10):e110577.
Ischemic reperfusion (IR) during the perinatal period is a known causative factor of fetal brain damage. So far, both morphologic and histologic evidence has shown that fetal brain damage can be observed only several hours to days after an IR insult has occurred. Therefore, to prevent fetal brain damage under these circumstances, a more detailed understanding of the underlying molecular mechanisms involved during an acute response to IR is necessary. In the present work, pregnant mice were exposed to IR on day 18 of gestation by clipping one side of the maternal uterine horn. Simultaneous fetal electrocardiography was performed during the procedure to verify that conditions resulting in fetal brain damage were met. Fetal brain sampling within 30 minutes after IR insult revealed molecular evidence that a fetal response was indeed triggered in the form of inhibition of the Akt-mTOR-S6 synthesis pathway. Interestingly, significant changes in mRNA levels for both HIF-1α and p53 were apparent and gene regulation patterns were observed to switch from a HIF-1α-dependent to a p53-dependent process. Moreover, pre-treatment with pifithrin-α, a p53 inhibitor, inhibited protein synthesis almost completely, revealing the possibility of preventing fetal brain damage by prophylactic pifithrin-α treatment.
PMCID: PMC4201554  PMID: 25329663
22.  Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma 
British Journal of Cancer  2013;109(8):2072-2078.
We previously reported that expressions of the pro-angiogenic cytokines angiopoietin-2 (Ang-2), follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor were associated with the response to sorafenib in patients with advanced hepatocellular carcinoma (HCC). The aim of the present study is to examine the same relationship in a larger cohort.
In the current retrospective cohort study, we measured serum levels of the eightcytokines in 120 consecutive HCC patients who were treated with sorafenib. We evaluated the effects of increased expression of serum cytokines on progression-free survival (PFS) and overall survival (OS).
Elevated expression of Ang-2 correlated both with significantly shorter PFS (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.21–2.81), and OS (HR, 1.95; 95% CI, 1.21–3.17). Patients with more than three cytokines expressed above the median similarly had significantly shorter PFS (HR, 1.98; 95% CI, 1.30–3.06) and OS (HR, 1.94; 95% CI, 1.19–3.22). Differences in OS were evident in cases with the evidence of macroscopic vascular invasion or extrahepatic metastasis.
High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib.
PMCID: PMC3798958  PMID: 24045661
angiogenesis; angiopoietin-2; cytokine; hepatocellular carcinoma; sorafenib
23.  Topical steroid addiction in atopic dermatitis 
The American Academy of Dermatology published a new guideline regarding topical therapy in atopic dermatitis in May 2014. Although topical steroid addiction or red burning skin syndrome had been mentioned as possible side effects of topical steroids in a 2006 review article in the Journal of the American Academy of Dermatology, no statement was made regarding this illness in the new guidelines. This suggests that there are still controversies regarding this illness. Here, we describe the clinical features of topical steroid addiction or red burning skin syndrome, based on the treatment of many cases of the illness. Because there have been few articles in the medical literature regarding this illness, the description in this article will be of some benefit to better understand the illness and to spur discussion regarding topical steroid addiction or red burning skin syndrome.
Video abstract
PMCID: PMC4207549  PMID: 25378953
topical steroid addiction; atopic dermatitis; red burning skin syndrome; rebound; corticosteroid; eczema
24.  Intrahepatic Splenosis in a Chronic Hepatitis C Patient with no History of Splenic Trauma Mimicking Hepatocellular Carcinoma 
Patient: Male, 58
Final Diagnosis: Intrahepatic splenosis
Symptoms: —
Medication: —
Clinical Procedure: Hepatectomy
Specialty: Gastroenterology and Hepatology
Rare disease
Intrahepatic splenosis (IHS) is the autotransplantation of splenic tissue that mostly develops after abdominal injury and is often misdiagnosed as hepatocellular carcinoma (HCC) because of similarities in radiological features. We had an opportunity to treat an extremely rare case of intrahepatic splenosis, which were found in a patient without any history of splenic injury. To the best of our knowledge, this is the first such case report in the world.
Case Report:
A 58-year-old man with chronic hepatitis C was referred to our hospital for further examination of liver function abnormality. Abdominal ultrasonography incidentally revealed a low echoic tumor in the posterior segment of the liver, with high echoic capsule, which is possibly different from tumor capsule of HCC, known as halo. Abdominal contrast-enhanced computed tomography and gadoxetic acid-enhanced magnetic resonance imaging showed that the tumor had an inhomogeneous enhancement in the arterial phase and diminished enhancement in the equilibrium phase, diagnosed as HCC. The patient underwent right lateral segmentectomy of the liver, and histopathological study confirmed a diagnosis of intrahepatic splenosis.
This case presents a new understanding of IHS in a patient without any splenic injury. We also focused on the differences in echo patterns of the tumor capsule between HCC and IHS, which can be used to efficiently diagnose IHS.
PMCID: PMC4179547  PMID: 25261602
Hepatitis; Chronic; Liver Neoplasms; Splenosis
25.  Retrieval and in vitro maturation of human oocytes from ovaries removed during surgery for endometrial carcinoma: a novel strategy for human oocyte research 
To collect human oocytes from ovaries removed as part of surgical treatment for endometrial carcinoma, and to induce in vitro maturation of such oocytes to obtain material for research on human ovarian aging.
Design: Prospective clinical study. Setting: University Hospital. Patients: Eight patients aged 35–44 years with a preoperative diagnosis of Stage I endometrial cancer agreed to participate in this project. Interventions: Surgically removed ovaries were punctured; oocytes were collected from follicular fluid and matured in vitro. Immunofluorescent detection of microtubules and DNA labeling were performed after in vitro maturation. Main Outcome Measures: Number of oocytes collected and their in vitro maturation stage.
In total, 87 oocytes were collected, 11 of which had completed metaphase II. Of the oocytes collected, 75 % were from three patients in their 30s, while the remaining 25 % were from five patients in their 40s. Several stages of oocytes were collected and the detection of microtubule arrangement and chromatin in various stages using fluorescence was possible.
Material for research on human ovarian aging can be obtained from ovaries removed during surgery for endometrial cancer.
PMCID: PMC3800521  PMID: 23842746
Human oocytes; In vitro maturation; Microtubules

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