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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.
doi:10.1038/ncomms4978
PMCID: PMC4052687  PMID: 24865297
2.  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.
doi:10.1038/srep03510
PMCID: PMC3863819  PMID: 24336483
3.  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.
doi:10.1091/mbc.E11-04-0279
PMCID: PMC3135482  PMID: 21613542
4.  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.
doi:10.3748/wjg.v17.i12.1642
PMCID: PMC3070137  PMID: 21472132
Colorectal tumor; Elderly patient; Morbidity; Carcinoembryonic antigen; C-reactive protein
5.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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
UMIN000003136
doi:10.1186/1471-2458-11-40
PMCID: PMC3037863  PMID: 21235825
6.  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.
doi:10.1155/2009/457936
PMCID: PMC2760320  PMID: 19830247
7.  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.
doi:10.1038/sj.bjc.6601711
PMCID: PMC2409683  PMID: 15054451
peptide; cancer vaccine; immunotherapy; colon cancer; CTL
8.  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
9.  Reduction of Reactive Oxygen Species Ameliorates Metabolism-Secretion Coupling in Islets of Diabetic GK Rats by Suppressing Lactate Overproduction 
Diabetes  2013;62(6):1996-2003.
We previously demonstrated that impaired glucose-induced insulin secretion (IS) and ATP elevation in islets of Goto-Kakizaki (GK) rats, a nonobese model of diabetes, were significantly restored by 30–60-min suppression of endogenous reactive oxygen species (ROS) overproduction. In this study, we investigated the effect of a longer (12 h) suppression of ROS on metabolism-secretion coupling in β-cells by exposure to tempol, a superoxide (O2−) dismutase mimic, plus ebselen, a glutathione peroxidase mimic (TE treatment). In GK islets, both H2O2 and O2− were sufficiently reduced and glucose-induced IS and ATP elevation were improved by TE treatment. Glucose oxidation, an indicator of Krebs cycle velocity, also was improved by TE treatment at high glucose, whereas glucokinase activity, which determines glycolytic velocity, was not affected. Lactate production was markedly increased in GK islets, and TE treatment reduced lactate production and protein expression of lactate dehydrogenase and hypoxia-inducible factor 1α (HIF1α). These results indicate that the Warburg-like effect, which is characteristic of aerobic metabolism in cancer cells by which lactate is overproduced with reduced linking to mitochondria metabolism, plays an important role in impaired metabolism-secretion coupling in diabetic β-cells and suggest that ROS reduction can improve mitochondrial metabolism by suppressing lactate overproduction through the inhibition of HIF1α stabilization.
doi:10.2337/db12-0903
PMCID: PMC3661648  PMID: 23349483
10.  Recruitment of cyclin G2 to promyelocytic leukemia nuclear bodies promotes dephosphorylation of γH2AX following treatment with ionizing radiation 
Cell Cycle  2013;12(11):1773-1784.
Cyclin G2 (CycG2) and Cyclin G1 (CycG1), two members of the Cyclin G subfamily, share high amino acid homology in their Cyclin G boxes. Functionally, they play a common role as association partners of the B′γ subunit of protein phosphatase 2A (PP2A) and regulate PP2A function, and their expression is increased following DNA damage. However, whether or not CycG1 and CycG2 have distinct roles during the cellular DNA damage response has remained unclear. Here, we report that CycG2, but not CycG1, co-localized with promyelocytic leukemia (PML) and γH2AX, forming foci following ionizing radiation (IR), suggesting that CycG2 is recruited to sites of DNA repair and that CycG1 and CycG2 have distinct functions. PML failed to localize to nuclear foci when CycG2 was depleted, and vice versa. This suggests that PML and CycG2 mutually influence each other’s functions following IR. Furthermore, we generated CycG2-knockout (Ccng2−/−) mice to investigate the functions of CycG2. These mice were born healthy and developed normally. However, CycG2-deficient mouse embryonic fibroblasts displayed an abnormal response to IR. Dephosphorylation of γH2AX and checkpoint kinase 2 following IR was delayed in Ccng2−/− cells, suggesting that DNA damage repair may be perturbed in the absence of CycG2. Although knockdown of B′γ in wild-type cells also delayed dephosphorylation of γH2AX, knockdown of B′γ in Ccng2−/− cells prolonged this delay, suggesting that CycG2 cooperates with B′γ to dephosphorylate γH2AX. Taken together, we conclude that CycG2 is localized at DNA repair foci following DNA damage, and that CycG2 regulates the dephosphorylation of several factors necessary for DNA repair.
doi:10.4161/cc.24878
PMCID: PMC3713135  PMID: 23656780
Cyclin G2; DNA damage; PML; PP2A B'γ; γH2AX
11.  Combination Chemotherapy of Azacitidine and Cetuximab for Therapy-Related Acute Myeloid Leukemia following Oxaliplatin for Metastatic Colorectal Cancer 
Case Reports in Oncology  2014;7(2):316-322.
Therapy-related leukemia (TRL) has been reported to occur after treatment with alkylating agents and/or topoisomerase II inhibitors. Oxaliplatin (OXP) is used as a key drug for the treatment of colorectal cancer (CRC). Cisplatin and carboplatin have been linked with TRL, but the involvement of OXP is questionable. A 74-year-old male was diagnosed with peritoneal metastasis from CRC in July 2011. The patient received nine cycles of 5-fluorouracil (5-FU), leucovorin (LV), and OXP (mFOLFOX-6 regimen) and three cycles of 5-FU and LV only, resulting in a clinical complete response. However, recurrence of CRC was detected by CT within 3 months after the last course of chemotherapy. In April 2013, laboratory tests showed pancytopenia and 15% blast cells. A bone marrow examination revealed multilineage dysplasia and 20.4% myeloblasts. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. The patient was diagnosed with TRL and treated with a combination of azacitidine (AZA) and cetuximab (Cmab) for both cancers. AZA might be useful in TRL when a patient needs to be treated simultaneously for more than one primary cancer because of its low toxicity. Moreover, Cmab is an effective therapeutic tool in TRL patients with metastatic CRC with the wild-type K-ras gene.
doi:10.1159/000363100
PMCID: PMC4049016  PMID: 24932174
Therapy-related leukemia; Colorectal cancer; Oxaliplatin; Azacitidine; Cetuximab
12.  Inflammatory pseudotumor of the liver diagnosed as metastatic liver tumor in a patient with a gastrointestinal stromal tumor of the rectum: report of a case 
Background
Inflammatory pseudotumor (IPT) of the liver is a rare benign lesion. A case of IPT of the liver found in association with a malignant gastrointestinal stromal tumor (GIST) is reported.
Case report
A 74-year-old man was admitted to our hospital for a liver tumor. He previously underwent rectal amputation for a malignant GIST. Computed tomography (CT) revealed a low-density area in the liver and dynamic contrast-enhanced MRI (EOB-MRI) showed that the tumor was completely washed out in the delayed phase. 18Fluorine-fluorodeoxyglucose positron emission tomography (FDG-PET) showed strong uptake in the liver. A diagnosis of liver metastasis was made and partial hepatectomy was performed. Microscopic examination showed that the tumor was an IPT.
Conclusion
Differential diagnosis between IPT and malignant neoplasms is difficult. Moreover, FDG-PET revealed strong uptake in the tumor. To our knowledge, this is the first patient reported to have an IPT in association with a rectal GIST. This patient is discussed along with a review of the literature.
doi:10.1186/1477-7819-12-140
PMCID: PMC4016664  PMID: 24886578
Inflammatory pseudotumors of the liver; Malignant gastrointestinal stromal tumor; FDG-PET
13.  Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer 
Oncology Reports  2014;31(6):2482-2492.
Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-μ (PFT-μ) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-μ enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-μ and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-μ markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer.
doi:10.3892/or.2014.3132
PMCID: PMC4055347  PMID: 24718854
HSP90; HSP70; Akt; bladder cancer; chemotherapy
14.  Construction of a scoring system for predicting the risk of severe gastrointestinal involvement in Henoch-Schönlein Purpura 
SpringerPlus  2014;3:171.
Objective
To evaluate the parameters associated with significant gastrointestinal (GI) involvement in Henoch-Schönlein Purpura (HSP), and construct a scoring system for the identification of patients at high risk of gross blood in stools.
Study design
Data for HSP patients hospitalized at each of seven institutes were retrospectively analyzed. Patients were divided into four groups according to the consequent severity of GI involvement. Identification of laboratory parameters at the time of admission were then used to differentiate the groups, and a scoring system to predict gross intestinal bleeding was constructed. Prognostic efficiency, correlation with the subsequent duration of abdominal pain, and association with manifestations excluding abdominal pain were also analyzed.
Results
An analysis of variance (ANOVA) test showed significant intergroup differences in white blood cell (WBC) count, neutrophil count, serum albumin, potassium, plasma D-dimer and coagulation factor XIII activity. A scoring system consisting of these parameters showed a good prognostic value for gross intestinal bleeding in a receiver operating characteristic (ROC) analysis, and a cut-off value of 4 points showed a sensitivity of 90.0% and specificity of 80.6%. The score was also correlated with the duration of abdominal pain after admission. A significantly higher score (s) was observed in patients presenting with nephritis, although the predictive value was poor.
Conclusion
A scoring system consisting of generally available parameters was of use in predicting severe GI involvement in HSP patients. Although further study is needed, initial therapy in accordance with disease activity may be taken into consideration using this scoring system.
doi:10.1186/2193-1801-3-171
PMCID: PMC4006069  PMID: 24808995
15.  Village health volunteers’ social capital related to their performance in Lao People’s Democratic Republic: a cross-sectional study 
Background
Improving the performance of community health workers (CHWs) is a global issue. The relationship between CHWs and their community may impact their performance. In Lao People’s Democratic Republic (Lao PDR), CHW are called village health volunteers (VHV). Lao PDR has a problem with VHV inactivity, especially in rural areas. This study focused on which aspects of social capital are related to VHV performance.
Methods
This research represents a cross-sectional study with a quantitative survey based primarily on interviews using a semi-structured questionnaire. Interviews were conducted with 149 VHVs living and working in the Sepon District. VHV performance evaluation was measured with scores on a 5-point scale, and the cutoff point for designating performance as good or poor was set at the median score. This evaluation of VHV performance was conducted as a self-evaluation by VHVs and by health center staff who were supervisors of the VHVs. Measurement of social capital was accomplished using the short version of the Adapted Social Capital Assessment Tool (SASCAT). For statistical analyses, logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI).
Results
The results of multiple logistic regression adjusted by moderator variables showed that citizenship activities in the structural social capital component of SASCAT were significantly related to performance in self-evaluation by VHVs (adjusted OR: 2.10, 95% CI: 1.19-3.71) and the evaluations by health center staff (adjusted OR: 1.67, 95% CI: 1.01-2.77). Support from groups (adjusted OR: 1.87, 95% CI: 1.27-2.76) and cognitive social capital (adjusted OR: 7.48, 95% CI: 2.14-26.10) were found to be significantly associated but only for VHV self-evaluation.
Conclusions
The results suggest that individuals who interact with important figures in the community and who cooperate with other villagers whenever problems arise, i.e., have social capital, exhibit good performance as VHVs. These findings suggest that increasing citizenship activities could increase the retention rate of CHWs and help improve their performance. Citizenship activities could also be used as a predictive indicator when selecting new CHWs.
doi:10.1186/1472-6963-14-123
PMCID: PMC3984685  PMID: 24620729
Community health worker; Social capital; Performance; Lao PDR
16.  An automated spring-loaded needle for endoscopic ultrasound-guided abdominal paracentesis in cancer patients 
AIM: To evaluate the feasibility of using an automated spring-loaded needle device for endoscopic ultrasound (EUS)-guided abdominal paracentesis (EUS-P) to see if this would make it easier to puncture the mobile and lax gastric wall for EUS-P.
METHODS: The EUS database and electronic medical records at Fukushima Medical University Hospital were searched from January 2001 to April 2011. Patients with a history of cancer and who underwent EUS-P using an automated spring-loaded needle device with a 22-gauge puncture needle were included. The needle was passed through the instrument channel and advanced through the gastrointestinal wall under EUS guidance into the echo-free space in the abdominal cavity and ascitic fluid was collected. The confirmed diagnosis of malignant ascites included positive cytology and results from careful clinical observation for at least 6 mo in patients with negative cytology. The technical success rate, cytology results and complications were evaluated.
RESULTS: We found 11 patients who underwent EUS-P with an automated spring-loaded needle device. In 4 cases, ascites was revealed only with EUS but not in other imaging modalities. EUS-P was done in 7 other cases because there was minimal ascitic fluid and no safe window for percutaneous abdominal aspiration. Ascitic fluid was obtained in all cases by EUS-P. The average amount aspirated was 14.1 mL (range 0.5-38 mL) and that was sent for cytological exam. The etiology of ascitic fluid was benign in 5 patients and malignant in 6. In all cases, ascitic fluid was obtained with the first needle pass. No procedure-related adverse effects occurred.
CONCLUSION: EUS-P with an automated spring-loaded needle device is a feasible and safe method for ascites evaluation.
doi:10.4253/wjge.v6.i2.55
PMCID: PMC3930891  PMID: 24567793
Ascetic fluid; Malignancy; Endoscopic ultrasound; Paracentesis; Fine needle aspiration
17.  Palmitate induces reactive oxygen species production and β‐cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling 
Abstract
Aims/Introduction
Chronic hyperlipidemia impairs pancreatic β‐cell function, referred to as lipotoxicity. We have reported an important role of endogenous reactive oxygen species (ROS) overproduction by activation of Src, a non‐receptor tyrosine kinase, in impaired glucose‐induced insulin secretion (GIIS) from diabetic rat islets. In the present study, we investigated the role of ROS production by Src signaling in palmitate‐induced dysfunction of β‐cells.
Materials and Methods
After rat insulinoma INS‐1D cells were exposed to 0.6 mmol/L palmitate for 24 h (palmitate exposure); GIIS, ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity were examined with or without exposure to10 μmol/L 4‐amino‐5‐(4‐chlorophenyl)‐7‐(t‐butyl)pyrazolo[3,4‐d]pyrimidine (PP2), a Src inhibitior, for 30 or 60 min.
Results
Exposure to PP2 recovered impaired GIIS and decreased ROS overproduction as a result of palmitate exposure. Palmitate exposure increased activity of NOX and protein levels of NOX2, a pathological ROS source in β‐cells. Palmitate exposure increased the protein level of p47phox, a regulatory protein of NOX2, in membrane fraction compared with control, which was reduced by PP2. Transfection of small interfering ribonucleic acid of p47phox suppressed the augmented p47phox protein level in membrane fraction, decreased augmented ROS production and increased impaired GΙIS by palmitate exposure. In addition, exposure to PP2 ameliorated impaired GIIS and decreased ROS production in isolated islets of KK‐Ay mice, an obese diabetic model with hyperlipidemia.
Conclusions
Activation of NOX through Src signaling plays an important role in ROS overproduction and impaired GΙIS caused by chronic exposure to palmitate, suggesting a lipotoxic mechanism of β‐cell dysfunction of obese mice.
doi:10.1111/jdi.12124
PMCID: PMC4025235  PMID: 24843732
Lipotoxicity; Pancreatic β‐cells; Reactive oxygen species
18.  A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin 
Blood Cancer Journal  2014;4(2):e180-.
Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death.
doi:10.1038/bcj.2014.2
PMCID: PMC3944660  PMID: 24510029
CD19; liposome; rapamycin; Burkitt's lymphoma
19.  The copy number of rice CACTA DNA transposons carrying MIR820 does not correlate with MIR820 expression 
Plant Signaling & Behavior  2013;8(8):e25169.
miR820 is a small RNA species (22 and 24 nucleotides), produced from transcripts originated from a region inside CACTA DNA transposons in rice. Because MIR820 is a transposon gene, its expression may depend on the transposon copy number. Here, we investigated the copy number of MIR820 and its expression levels in various cultivars and wild species of rice. We found no correlation between copy number and expression level, suggesting that MIR820 transcription is regulated not by the copy dosage but by the epigenetic state of each copy.
doi:10.4161/psb.25169
PMCID: PMC3999066  PMID: 23733074
transposon; Oryza sativa; DNA methyltransferase; miR820; OsDRM2
20.  nab-Paclitaxel in Combination with Carboplatin for a Previously Treated Thymic Carcinoma 
Case Reports in Oncology  2014;7(1):14-17.
We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patient's back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma.
doi:10.1159/000357938
PMCID: PMC3934614  PMID: 24575009
Thymic carcinoma; nab-Paclitaxel; Carboplatin; Chemotherapy
21.  Immunoaffinity Purification of Protein Complexes from Mammalian Cells 
In this chapter, we describe a purification scheme designed to isolate multisubunit protein complexes gently and quickly from crude extracts of mammalian cells using immunoaffinity purification of epitope tagged proteins and the multisubunit complexes with which they associate. As an example we describe isolation of the mammalian Mediator complex from HeLa S3 cells.
doi:10.1007/978-1-62703-284-1_22
PMCID: PMC3693849  PMID: 23436370
Multisubunit protein complex; Immunoaffinity purification; Epitope tag; Stable cell line
22.  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.
doi:10.7150/jca.8486
PMCID: PMC3963081  PMID: 24665348
lung cancer; LYVE-1; metastasis; survival; biomarker.
23.  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.
doi:10.7150/ijms.8919
PMCID: PMC4057484  PMID: 24936137
Adiponectin; Decline in FEV1; General population; Pulmonary function; Spirometry.
24.  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.
doi:10.1371/journal.pone.0083725
PMCID: PMC3862812  PMID: 24349548
25.  Synthetic cell division system: Controlling equal vs. unequal divisions by design 
Scientific Reports  2013;3:3475.
Cell division is one of the most fundamental and evolutionarily conserved biological processes. Here, we report a synthetic system where we can control by design equal vs. unequal divisions. We synthesized a micro-scale inverse amphipathic droplet of which division is triggered by the increase of surface to volume ratio. Using this system, we succeeded in selectively inducing equal vs. unequal divisions of the droplet cells by adjusting the temperature or the viscosity of the solvent outside the droplet cell accordingly. Our synthetic division system may provide a platform for further development to a system where intracellular contents of the parent droplet cell could be divided into various ratios between the two daughter droplet cells to control their functions and fates.
doi:10.1038/srep03475
PMCID: PMC3858794  PMID: 24327069

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