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1.  Giant Polypoid Tumor Expressing on the Pyloric Ring 
Case Reports in Medicine  2015;2015:986971.
A 66-year-old Japanese man was referred to our hospital because of suspected duodenal cancer. Upper gastric endoscopy revealed a giant polypoid-type tumor that extended from the duodenum bulb to the pyloric ring. A computed tomography scan revealed a slightly enhanced lobular tumor protruding into the duodenum bulb. Positron emission tomography showed an accumulation of 18F-fluorodeoxyglucose in the area extending from the antrum of the stomach to the duodenum bulb. Since an endoscopic ultrasound test suggested that the tumor might invade the muscular tunic, indications of endoscopic mucosal resection were not favored, and the tumor was curatively removed via distal gastrectomy. The histopathologic diagnosis was papillary adenocarcinoma, and the invasion depth was the mucosal layer without vascular invasion, which was different from the preoperative diagnosis. Our case suggests the difficulties in precise diagnosis of the invasion depth of the giant polypoid cancer.
PMCID: PMC4320937
2.  Anticancer efficacy of a supramolecular complex of a 2-diethylaminoethyl–dextran–MMA graft copolymer and paclitaxel used as an artificial enzyme 
The anticancer efficacy of a supramolecular complex that was used as an artificial enzyme against multi-drug-resistant cancer cells was confirmed. A complex of diethylaminoethyl–dextran–methacrylic acid methylester copolymer (DDMC)/paclitaxel (PTX), obtained with PTX as the guest and DDMC as the host, formed a nanoparticle 50–300 nm in size. This complex is considered to be useful as a drug delivery system (DDS) for anticancer compounds since it formed a stable polymeric micelle in water. The resistance of B16F10 melanoma cells to PTX was shown clearly through a maximum survival curve. Conversely, the DDMC/PTX complex showed a superior anticancer efficacy and cell killing rate, as determined through a Michaelis–Menten-type equation, which may promote an allosteric supramolecular reaction to tubulin, in the same manner as an enzymatic reaction. The DDMC/PTX complex showed significantly higher anticancer activity compared to PTX alone in mouse skin in vivo. The median survival times of the saline, PTX, DDMC/PTX4 (particle size 50 nm), and DDMC/PTX5 (particle size 290 nm) groups were 120 h (treatment (T)/control (C), 1.0), 176 h (T/C, 1.46), 328 h (T/C, 2.73), and 280 h (T/C, 2.33), respectively. The supramolecular DDMC/PTX complex showed twice the effectiveness of PTX alone (p < 0.036). Above all, the DDMC/PTX complex is not degraded in cells and acts as an intact supramolecular assembly, which adds a new species to the range of DDS.
PMCID: PMC4273266  PMID: 25551057
artificial enzyme; diethylaminoethyl–dextran–MMA; graft copolymer; multi-drug resistance of cancer cells; paclitaxel; supramolecular complex
3.  Comparison between Bilateral C2 Pedicle Screwing and Unilateral C2 Pedicle Screwing, Combined with Contralateral C2 Laminar Screwing, for Atlantoaxial Posterior Fixation 
Asian Spine Journal  2014;8(6):777-785.
Study Design
A retrospective study.
To compare clinical and radiological outcomes between bilateral C2 pedicle screwing (C2PS) and unilateral C2PS, combined with contralateral C2 laminar screwing (LS), for posterior atlantoaxial fixation.
Overview of Literature
Posterior fixation with C1 lateral mass screwing (C1LMS) and C2PS (C1LMS-C2PS method) is an accepted procedure for rigid atlantoaxial stabilization. However, conventional bilateral C2PS is not always allowed in this method due to anatomical variations of C2 pedicles and/or asymmetry of the vertebral artery. Although unilateral C2PS plus contralateral LS (C2PS+LS) is an alternative in such cases, the efficacy of this procedure has not been evaluated in controlled studies (i.e., with bilateral C2PS as a control).
Clinical and radiological records of patients who underwent the C1LMS-C2PS method, using unilateral C2PS+LS (n=9), and those treated using conventional bilateral C2PS (n=10) were compared, with a minimum two years follow-up.
Postoperative complications related to the unilateral C2PS+LS technique included one case of spontaneous spinous process fracture of C2. A C1 anterior arch fracture occurred after a fall in one patient, who underwent bilateral C2PS and C1 laminectomy. No significant differences were seen between the groups in reduction of neck pain after surgery or improvement of neurological status, as evaluated using the Japanese Orthopaedic Association score. A delayed union occurred in one patient each of the groups, with the final fusion rate being 100% in both groups.
Clinical and radiological outcomes of unilateral C2PS+LS were comparable with those of the bilateral C2PS fixation technique for the C1LMS-C2PS method.
PMCID: PMC4278983  PMID: 25558320
Cervical spine; Atlantoaxial instability; Laminar screw; Pedicle screw
4.  Metabolomics Evaluation of Serum Markers for Cachexia and Their Intra-Day Variation in Patients with Advanced Pancreatic Cancer 
PLoS ONE  2014;9(11):e113259.
Cancer cachexia is a multifactorial syndrome characterized by progressive loss of weight and muscle atrophy. Using metabolomics, we investigated serum markers and their intra-day variation in advanced pancreatic cancer patients with cachexia.
Patients were enrolled in two groups: those with or without cachexia. Blood samples collected at 6:30 AM, 11:30 AM, 4:30 PM, and 9:30 PM were analyzed using metabolomics, and serum levels of IL-6, TNF-α, and leptin were measured and compared between the two groups. Intra-day variation was then evaluated.
Twenty-one patients were enrolled in total. In the cachexia group (n = 9), median body weight loss rate over 6 months was greater, performance status was poorer, and anorexia was more severe than in the non-cachexia group (n = 12). Each metabolites level showed substantial intra-day variation, and some of them displayed significant differences between the two groups. Levels of paraxanthine remained markedly lower in the cohort with cachexia at all measurement points. Besides, median IL-6 and TNF-α levels appeared higher and leptin concentration appeared lower in the cachexia group, albeit without statistical significance.
Some metabolites and some serological marker levels were affected by cancer cachexia. Although paraxanthine levels were consistently lower in patients with cachexia, we identified that many metabolites indicated large intra- and inter-day variation and that it might be necessary to pay attention to intra-day variation in metabolomics research.
PMCID: PMC4239056  PMID: 25411961
5.  Gossypiboma 19 years after laminectomy mimicking a malignant spinal tumour: a case report 
Gossypiboma is rare and mostly asymptomatic in chronic cases. It can be confused with other soft tissue masses.
Case presentation
Our patient was an 87-year-old Japanese man with a history of surgery for a lumbar lesion causing lumbar canal stenosis 19 years earlier. Computed tomography showed a soft tissue mass with osteolysis and periosteal thickening of the vertebral lamina. On magnetic resonance imaging, the mass showed heterogeneous signal intensity on T2-weighted imaging, suggesting a malignancy. At the time of biopsy, small pieces of retained surgical sponge were collected. Surgical treatment was performed to excise the soft tissue tumour.
Gossypiboma should be included in the differential diagnosis of soft tissue masses in the paraspinal region in patients with a history of previous spinal surgery.
PMCID: PMC4177374  PMID: 25236490
Foreign body; Gossypiboma; Laminectomy; Malignant spinal tumour; Retained surgical sponge; Spinal surgery
6.  Metabolomics for Biomarker Discovery in Gastroenterological Cancer 
Metabolites  2014;4(3):547-571.
The study of the omics cascade, which involves comprehensive investigations based on genomics, transcriptomics, proteomics, metabolomics, etc., has developed rapidly and now plays an important role in life science research. Among such analyses, metabolome analysis, in which the concentrations of low molecular weight metabolites are comprehensively analyzed, has rapidly developed along with improvements in analytical technology, and hence, has been applied to a variety of research fields including the clinical, cell biology, and plant/food science fields. The metabolome represents the endpoint of the omics cascade and is also the closest point in the cascade to the phenotype. Moreover, it is affected by variations in not only the expression but also the enzymatic activity of several proteins. Therefore, metabolome analysis can be a useful approach for finding effective diagnostic markers and examining unknown pathological conditions. The number of studies involving metabolome analysis has recently been increasing year-on-year. Here, we describe the findings of studies that used metabolome analysis to attempt to discover biomarker candidates for gastroenterological cancer and discuss metabolome analysis-based disease diagnosis.
PMCID: PMC4192679  PMID: 25003943
metabolomics; biomarker; serum; gastroenterological cancer; mass spectrometry
7.  Detection of Middle East respiratory syndrome coronavirus using reverse transcription loop-mediated isothermal amplification (RT-LAMP) 
Virology Journal  2014;11:139.
The first documented case of Middle East Respiratory Syndrome coronavirus (MERS-CoV) occurred in 2012, and outbreaks have continued ever since, mainly in Saudi Arabia. MERS-CoV is primarily diagnosed using a real-time RT-PCR assay, with at least two different genomic targets required for a positive diagnosis according to the case definition of The World Health Organization (WHO) as of 3 July 2013. Therefore, it is urgently necessary to develop as many specific genetic diagnostic methods as possible to allow stable diagnosis of MERS-CoV infections.
Reverse transcription-loop-mediated isothermal amplification (RT-LAMP) is a genetic diagnostic method used widely for the detection of viral pathogens, which requires only a single temperature for amplification, and can be completed in less than 1 h. This study developed a novel RT-LAMP assay for detecting MERS-CoV using primer sets targeting a conserved nucleocapsid protein region.
The RT-LAMP assay was capable of detecting as few as 3.4 copies of MERS-CoV RNA, and was highly specific, with no cross-reaction to other respiratory viruses. Pilot experiments to detect MERS-CoV from medium containing pharyngeal swabs inoculated with pre-titrated viruses were also performed. The RT-LAMP assay exhibited sensitivity similar to that of MERS-CoV real-time RT-PCR.
These results suggest that the RT-LAMP assay described here is a useful tool for the diagnosis and epidemiologic surveillance of human MERS-CoV infections.
PMCID: PMC4132226  PMID: 25103205
Meddle East respiratory syndrome (MERS); MERS coronavirus (MERS-CoV); RT-LAMP; Genetic diagnostic method
8.  ARF regulates the stability of p16 protein via REGγ-dependent proteasome degradation 
Molecular cancer research : MCR  2013;11(8):828-833.
The cell cycle regulatory gene INK4A-ARF (CDKN2A) has two alternative transcripts that produce entirely different proteins, namely p14ARF and p16, which have complementary functions as regulators of p53 and pRB tumor suppressor pathways, respectively. The unusual organization of INK4A-ARF has long led to speculation of a need for coordinated regulation of p14ARF and p16. We now show that p14ARF (ARF) regulates the stability of p16 protein in human cancer cell lines, as well as in mouse embryonic fibroblasts (MEFs). In particular, ARF promotes rapid degradation of p16 protein, which is mediated by the proteasome and, more specifically, by interaction of ARF with one of its subunits, REGγ. Furthermore, this ARF-dependent destabilization of p16 can be abrogated by knock-down of REGγ or by pharmacological blockade of its nuclear export. Thus our findings have uncovered a novel crosstalk of two key tumor suppressors mediated by a REGγ-dependent mechanism.
PMCID: PMC3748223  PMID: 23817020
p14ARF; p19Arf; p16; REGγ; proteasome; nuclear export
9.  Ink4a/Arf−/− and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f− quiescent cells 
Oncogene  2013;33(4):440-448.
Intratumoral heterogeneity within individual breast tumors is a well-known phenomenon that may contribute to drug resistance. This heterogeneity is dependent on several factors, such as types of oncogenic drivers and tumor precursor cells. The purpose of our study was to engineer a mouse mammary tumor model with intratumoral heterogeneity by using defined genetic perturbations. To achieve this, we used mice with knockout (−/−) of Ink4a/Arf, a tumor suppressor locus; these mice are known to be susceptible to non-mammary tumors such as fibrosarcoma. To induce mammary tumors, we retrovirally introduced an oncogene, HRAS(G12V), into Ink4a/Arf−/− mammary cells in vitro, and those cells were inoculated into syngeneic mice mammary fat pads. We observed 100% tumorigenesis. The tumors formed were negative for estrogen receptor, progesterone receptor, and HER2. Further, they had pathological features similar to those of human triple-negative breast cancer (e.g. pushing borders, central necrosis). The tumors were found to be heterogeneous and included two subpopulations: CD49f− quiescent cells and CD49f+ cells. Contrary to our expectation, CD49f− quiescent cells had high tumor-initiating potential and CD49f+ cells had relatively low tumor-initiating potential. Gene expression analysis revealed that CD49f− quiescent cells overexpressed epithelial-to-mesenchymal transition-driving genes, reminiscent of tumor-initiating cells and claudin-low breast cancer. Our animal model with intratumoral heterogeneity, derived from defined genetic perturbations, allows us to test novel molecular targeted drugs in a setting that mimics the intratumoral heterogeneity of human triple-negative breast cancer.
PMCID: PMC3957346  PMID: 23376849
Ink4a/Arf; HRAS(G12V); Triple negative breast cancer; Intratumoral heterogeneity; Tumor-initiating cell
10.  Sphingosine-1-Phosphate Transporters as Targets for Cancer Therapy 
BioMed Research International  2014;2014:651727.
Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the “inside-out” signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development.
PMCID: PMC4123566  PMID: 25133174
11.  Esophageal intramucosal hematoma after peripheral blood stem cell transplantation: case report and review of literature 
Esophageal complications occur after hematopoietic stem cell transplantation (HSCT). There are, however, only limited reports on the etiology or management of esophageal complications. Here, we report the occurrence of intramucosal hematoma presenting continuous esophageal hemorrhage in a 34 year-old man following the second peripheral blood stem cell transplantation for acute myeloid leukemia. His hematemesis started 2 months after HSCT and was repeated in supportive care. On day 156, he underwent total esophagectomy as a result of uncontrollable massive hematemesis. Histopathological testings of the resected esophagus confirmed intramucosal hematoma as a cause of hematemesis. This case highlights intramucosal hematoma as one of the important etiologies of esophageal complications following HSCT.
PMCID: PMC4069927  PMID: 24966988
Esophageal hemorrhage; intramucosal hematoma; esophagectomy; hematopoietic stem cell transplantation
12.  Hepatitis B virus X stimulates redox signaling through activation of ataxia telangiectasia mutated kinase 
Hepatitis B virus X (HBX) protein plays a crucial role in carcinogenesis, but its mechanism is unclear. The involvement of ataxia telangiectasia mutated (ATM) kinase in the enhanced redox system was investigated by examining the phosphorylation level of ATM in HBX gene-transfected cells and in transgenic mice following redox system manipulation by treatment with hydrogen peroxide (H2O2) or antioxidant. Western blotting and immunostaining showed that phospho-ATM was significantly increased by HBX both in vitro (3.2-fold; p<0.05) and in vivo (4-fold; p<0.05), and this effect was abrogated by antioxidant treatment. The level of PKC-δ in HBX-expressing cells was increased 3.5-fold compared to controls. Nuclear localized NF-E2-related factor 2 (Nrf2) was increased in HBX-expressing cells exposed to H2O2, but remained at lower levels after the treatment with rottlerin, KU55933, or caffeine. The levels of anti-oxidant molecules were increased in HBX expressing cells and in transgenic mice, indicating that HBX stimulates the Nrf2-mediated redox system. The levels of intracellular reactive oxygen species (ROS) were significantly increased in HBX-expressing cells treated with hydrogen peroxide in the presence of ATM inhibitor KU55933 or caffeine. Treatment of HBX-expressing cells with KU55933 or caffeine before the exposure to H2O2 increased the ratio of cell apoptosis to 33 ± 4% (p<0.05) and 22 ± 4% (p<0.05), respectively. Collectively, HBX stimulates the ATM-mediated PKC-δ/Nrf2 pathway, and maintains the enhanced activity of the redox system. Therefore, manipulating ATM kinase activity might be a useful strategy for treating HBX-induced carcinogenesis.
PMCID: PMC4069949  PMID: 24966912
Hepatitis B virus X; ataxia telangiectasia mutated; reactive oxygen species
13.  Dengue transmission model by means of viremic adult immuno-competent mouse 
Parasites & Vectors  2014;7:143.
Dengue virus infection manifests in three distinct forms in humans: dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Infection with the virus is a fatal disease; no vaccine is available and prevention depends on interruption of the chain of transmission. The study of dengue viral transmission by mosquitoes is hindered due to the lack of an affordable animal model. In general, immuno-competent mice are used as a simple and inexpensive animal model, but mice are not susceptible to dengue virus infection and therefore viremia will not occur following the inoculation of the virus in such mice. Here, we report a method for creating artificial viremia in immuno-competent mice, and further demonstrate the use of viremic mice to simultaneously infect a large number of Aedes aegypti.
We infected K562 cells with DENV-2 in the presence of an antibody against DENV-4. We then incubated the cells for 2 d before injecting the infected cells into C3H mice. After 5 h incubation, we allowed 100–150 female Aedes aegypti to feed on blood from the mice directly. We collected blood samples from the mice and from randomly selected Ae. aegypti at 2, 6, 12, and 24 h post-blood meal and screened the samples for DENV-2 genome as well as for virus concentration.
Our procedure provided high virus concentrations in the mice for at least 7 h after viral inoculation. We found that 13 out of 14 randomly picked mosquitoes were infected with DENV-2. High concentrations of virus were detected in the mosquitoes until at least 12 h post-infection.
Using the viremic immuno-competent mouse, we show that mass infection of Ae. aegypti is achievable. Compared to other infection techniques using direct inoculation, membrane-feeding, or immuno-deficient/humanized mice, we are confident that this method will provide a simpler and more efficient infection technique.
PMCID: PMC3976050  PMID: 24685121
Aedes aegypti; Dengue virus type 2; Mass-infection; Viremia; Immuno-competent mouse
14.  Valproic acid overcomes transforming growth factor-β-mediated sorafenib resistance in hepatocellular carcinoma 
Sorafenib is a multi-kinase inhibitor approved for hepatocellular carcinoma, but rarely causes tumor regression in patients with chronic liver diseases. To investigate whether growth factor-mediated signaling is involved in sorafenib resistance, HepG2 and PLC/PRF/5 hepatoma cells were exposed to epidermal growth factor (EGF), hepatocyte growth factor (HGF) or transforming growth factor-β (TGF-β) prior to treatment with sorafenib. Furthermore, to identify an effective combination treatment with sorafenib, growth factor-sensitized cells were treated with sorafenib alone or in combination with celecoxib, lovastatin or valproic acid (VPA). Trypan blue staining and Annexin V assays showed that the cytotoxic effect of sorafenib was inhibited by 15-54% in cells sensitized to TGF-β (P<0.05). Western blotting analysis showed that TGF-β significantly activated extracellular signal-regulated kinase (ERK)-mediated AKT signaling, and sorafenib failed to suppress both ERK and AKT in TGF-β-sensitized cells. The decreased anti-tumor effect of sorafenib was rescued by chemical inhibition of ERK and AKT. When TGF-β-sensitized cells were treated with sorafenib plus VPA, the levels of phosphorylated ERK and AKT were considerably suppressed and the numbers of dead cells were increased by 3.7-5.7-fold compared with those exposed to sorafenib alone (P<0.05). Moreover, low dose sorafenib-induced cell migration was effectively suppressed by combination treatment with sorafenib and VPA. Collectively, TGF-β/ERK/AKT signaling might play a critical role in sorafenib resistance in hepatoma cells, and combination treatment with VPA may be effective against this drug resistance.
PMCID: PMC4014211  PMID: 24817927
Sorafenib; TGF-β; hepatocellular carcinoma
15.  The Expression Profile of Phosphatidylinositol in High Spatial Resolution Imaging Mass Spectrometry as a Potential Biomarker for Prostate Cancer 
PLoS ONE  2014;9(2):e90242.
High-resolution matrix-assisted laser desorption/ionization imaging mass spectrometry (HR-MALDI-IMS) is an emerging application for the comprehensive and detailed analysis of the spatial distribution of ionized molecules in situ on tissue slides. HR-MALDI-IMS in negative mode in a mass range of m/z 500–1000 was performed on optimal cutting temperature (OCT) compound-embedded human prostate tissue samples obtained from patients with prostate cancer at the time of radical prostatectomy. HR-MALDI-IMS analysis of the 14 samples in the discovery set identified 26 molecules as highly expressed in the prostate. Tandem mass spectrometry (MS/MS) showed that these molecules included 14 phosphatidylinositols (PIs), 3 phosphatidylethanolamines (PEs) and 3 phosphatidic acids (PAs). Among the PIs, the expression of PI(18:0/18:1), PI(18:0/20:3) and PI(18:0/20:2) were significantly higher in cancer tissue than in benign epithelium. A biomarker algorithm for prostate cancer was formulated by analyzing the expression profiles of PIs in cancer tissue and benign epithelium of the discovery set using orthogonal partial least squares discriminant analysis (OPLS-DA). The sensitivity and specificity of this algorithm for prostate cancer diagnosis in the 24 validation set samples were 87.5 and 91.7%, respectively. In conclusion, HR-MALDI-IMS identified several PIs as being more highly expressed in prostate cancer than benign prostate epithelium. These differences in PI expression profiles may serve as a novel diagnostic tool for prostate cancer.
PMCID: PMC3938652  PMID: 24587297
16.  Is Early Enteral Nutrition Initiated Within 24 Hours Better for the Postoperative Course in Esophageal Cancer Surgery? 
Early enteral nutrition within 24 h after surgery has become a recommended procedure. In the present study, we retrospectively examined whether initiating EN within 24 h after esophagectomy improves the postoperative course.
Among 103 patients who underwent thoracic esophagectomy for esophageal cancer, we enrolled the cases in which EN was initiated within 72 h after surgery. The patients were divided into two groups: EN started within 24 h (Group D1) and EN started at 24 - 72 h (Group D2-3). Clinical factors including days for first fecal passage, dose of postoperative albumin infusion, difference in serum albumin between pre- and postoperation, incidence of postoperative infection, and use of total parenteral nutrition were compared. Statistical analyses were performed by the Mann-Whitney U test and Chi square test, with significance defined as P < 0.05.
There was no significant difference between the groups in clinical factors. While pneumonia was significantly more frequent in Group D1 than in Group D2-3 (P = 0.0308), the frequency of infectious complications was comparable between the groups.
Initiating EN within 24 h showed no advantage for the postoperative course in esophageal cancer, and thus EN should be scheduled within 24 - 72 h, based on the patient condition.
PMCID: PMC3881990  PMID: 24400032
Early enteral nutrition; Esophageal cancer; Infectious complication; Pneumonia
17.  The diaphragms of fenestrated endothelia – gatekeepers of vascular permeability and blood composition 
Developmental cell  2012;23(6):1203-1218.
Fenestral and stomatal diaphragms are endothelial subcellular structures of unknown function that form on organelles implicated in vascular permeability: fenestrae, transendothelial channels and caveolae. PV1 protein is required for diaphragm formation in vitro. Here, we report that deletion of the PV1-encoding Plvap gene in mice results in the absence of diaphragms and decreased survival. Loss of diaphragms did not affect the fenestrae and transendothelial channels formation but disrupted the barrier function of fenestrated capillaries causing a major leak of plasma proteins. This disruption results in early death of animals due to severe non-inflammatory protein loosing enteropathy. Deletion of PV1 in endothelium, but not the hematopoietic compartment, recapitulates the phenotype of global PV1 deletion, whereas endothelial reconstitution of PV1 rescues the phenotype. Taken together, these data provide genetic evidence for the critical role of the diaphragms in fenestrated capillaries in the maintenance of blood composition.
PMCID: PMC3525343  PMID: 23237953
18.  Anaplastic Carcinoma of the Pancreas Mimicking Submucosal Gastric Tumor: A Case Report of a Rare Tumor 
Case Reports in Medicine  2013;2013:523237.
Anaplastic carcinoma of the pancreas (ACP) is a rare neoplasm of the pancreas. ACPs are aggressive neoplasms with a poorer prognosis than poorly differentiated ductal adenocarcinomas of the pancreas. The 3-year survival rate of patients with ACP is less than 3%, with a life expectancy of 10 to 20 months. We describe here a 64-year-old man with ACP mimicking a submucosal gastric tumor. The patient was found to have a giant mass mimicking a submucosal tumor. Total gastrectomy with splenectomy and partial resection of the tail of the pancreas were performed. The pathological diagnosis was ACP, with immunohistological findings showing pleomorphic-type ACP. Because the surgery was noncurative, the patient received adjuvant chemotherapy with paclitaxel but died of peritoneal dissemination and multiple liver metastases 4 months after surgery.
PMCID: PMC3870639  PMID: 24382965
19.  Functional Roles of D2-Lys317 and the Interacting Chloride Ion in the Water Oxidation Reaction of Photosystem II As Revealed by Fourier Transform Infrared Analysis 
Biochemistry  2013;52(28):4748-4757.
Photosynthetic water oxidation in plants and cyanobacteria is catalyzed by a Mn4CaO5 cluster within the photosystem II (PSII) protein complex. Two Cl– ions bound near the Mn4CaO5 cluster act as indispensable cofactors, but their functional roles remain to be clarified. We have investigated the role of the Cl– ion interacting with D2-K317 (designated Cl-1) by Fourier transform infrared spectroscopy (FTIR) analysis of the D2-K317R mutant of Synechocystis sp. PCC 6803 in combination with Cl–/NO3– replacement. The D2-K317R mutation perturbed the bands in the regions of the COO– stretching and backbone amide vibrations in the FTIR difference spectrum upon the S1 → S2 transition. In addition, this mutation altered the 15N isotope-edited NO3– bands in the spectrum of NO3–-treated PSII. These results provide the first experimental evidence that the Cl-1 site is coupled with the Mn4CaO5 cluster and its interaction is affected by the S1 → S2 transition. It was also shown that a negative band at 1748 cm–1 arising from COOH group(s) was altered to a positive intensity by the D2-K317R mutation as well as by NO3– treatment, suggesting that the Cl-1 site affects the pKa of COOH/COO– group(s) near the Mn4CaO5 cluster in a common hydrogen bond network. Together with the observation that the efficiency of the S3 → S0 transition significantly decreased in the core complexes of D2-K317R upon moderate dehydration, it is suggested that D2-K317 and Cl-1 are involved in a proton transfer pathway from the Mn4CaO5 cluster to the lumen, which functions in the S3 → S0 transition.
PMCID: PMC3777104  PMID: 23786399
20.  B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer 
Cancer research  2012;72(18):4765-4776.
Both the PI3K→Akt→mTOR and MAPK signaling pathways are often deregulated in prostate tumors with poor prognosis. Here we describe a new genetically-engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and ERK1/2 MAP kinase signaling is activated by inducible expression of a BRAFV600E oncogene. These tissue-specific compound mutant mice develop lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow and lungs where they form overt metastases in ~30% of the cases. Activation of PI3K→Akt→mTOR and MAPK signaling pathways in these prostate tumors cooperate to upregulate c-Myc. Accordingly, therapeutic treatments with Rapamycin and PD0325901 to target these pathways, respectively, attenuate c-Myc levels and reduce tumor and metastatic burden. Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K→Akt→mTOR and ERK1/2 MAPK signaling pathways.
PMCID: PMC3445712  PMID: 22836754
Akt/mTOR signaling; MAP kinase signaling; genetically engineered mouse models; Braf; Myc
21.  TRAF6 Is Essential for Maintenance of Regulatory T Cells That Suppress Th2 Type Autoimmunity 
PLoS ONE  2013;8(9):e74639.
Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 + Tregs into Rag2-/- mice revealed that TRAF6-deficient Tregs converted into Foxp3- cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3+ to Foxp3- (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.
PMCID: PMC3772853  PMID: 24058613
22.  Clinical Experience of Bronchoscopy-Guided Radiofrequency Ablation for Peripheral-Type Lung Cancer 
We have developed a new internal cooled electrode for radiofrequency ablation (RFA) (Japan Application no. 2006-88228) suitable for forceps channel bronchoscopy. Here, we present our clinical experience with bronchoscopy-guided RFA under computed tomography (CT) monitoring for patients with peripheral-type non-small-cell lung cancer (NSCLC). Bronchoscopy-guided RFA was performed in two patients (80 and 70 years old) with NSCLC, who had no lymph node involvement and distant metastases (T1N0M0), but not indicated for surgery because of other complications, such as advanced age, poor pulmonary function, and refusal of thoracic surgery. The locations of the tumors were right S2 and left S3, respectively. Although the tumors showed ground-glass opacity (GGO) with solid components in both cases, radiographic findings changed to reduced mass-like shadow and remained stable for 4 and 3.5 years after bronchoscopy-guided RFA. As the former case developed progressive disease on chest CT, bronchoscopy-guided RFA was repeated in the same lesion, resulting in no change for the subsequent 1 year. There were no adverse reactions during the procedures. Thus, bronchoscopy-guided RFA is a safe and feasible procedure that represents a potentially useful therapeutic tool in local control in medically inoperable patients with stage I NSCLC.
PMCID: PMC3784239  PMID: 24106625
23.  Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model 
Cancer research  2012;72(17):4483-4493.
While the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer and, therefore, remains fatal. In this study, we investigate a new therapeutic approach for treatment of castration-resistant prostate cancer, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting castration-resistant prostate cancer in preclinical studies in vivo using a refined genetically-engineered mouse model of the disease. The efficacy of the combination treatment contrasts with their limited efficacy as single agents, since delivery of MK-2206 or MK-8669 individually had a modest impact in vivo on the overall tumor phenotype. In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus (MK-8669) are due in part to limiting the mTORC2-feedback activation of Akt. Moreover, the effects of these drugs are mediated by inhibition of cellular proliferation via the retinoblastoma (RB) pathway. Our findings suggest that dual targeting the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of castration-resistant prostate cancer, particularly for patients with deregulated RB pathway activity.
PMCID: PMC3432676  PMID: 22815528
Akt/mTOR signaling; castration-resistant prostate cancer; genetically engineered mouse models; preclinical analyses; Pten; RB
24.  Experimental Evidence of Persistent Androgen-Receptor-Dependency in Castration-Resistant Prostate Cancer 
In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent sublines derived from originally androgen-dependent LNCaP prostate cancer cells overexpress the AR and PSA, for which silencing the AR gene suppresses cellular proliferation. The overexpression of the AR confers androgen-independent growth ability on androgen-dependent prostate cancer cells. Some patient-derived prostate cancer xenograft lines also acquire castration-resistant growth ability secreting PSA. More recent publications have shown that the AR activated in CRPC cells regulates distinct gene sets from that in androgen-dependent status. This concept provides very important insights in the development of novel anti-prostate cancer drugs such as new generation anti-androgens and CYP17 inhibitors.
PMCID: PMC3759876  PMID: 23896594
prostate cancer; castration resistant; androgen receptor; molecular target
25.  Symptomatic cervical disc herniation in teenagers: two case reports 
The development of a symptomatic herniated cervical disc before the age of 20 is extremely rare. Sporadically reported cases of patients with cervical disc herniation under the age of 20 usually have had underlying disease.
Case presentation
Case 1: A 19-year-old Asian man visited our clinic and presented with progressive pain in his upper left scapula and weakness of the left deltoid and biceps brachii muscles. C5 radiculopathy by soft disc herniation at C4-C5 without calcification was diagnosed. Microsurgical posterior foraminotomy was performed and he recovered completely eight weeks after the surgery.
Case 2: A 15-year-old Asian man presented with difficulty in lifting his arm and neck pain on the right side. Neurological examination showed weakness of the right deltoid and biceps brachii muscles. A magnetic resonance imaging scan demonstrated a herniated intervertebral disc in the right C4-C5 foramen. The patient was treated conservatively and put under observation only, and had completely recovered eight weeks after admission.
Although extremely rare, symptomatic cervical disc herniations may occur even in the younger population under the age of 20 without any trauma or underlying disease. Favorable outcomes can be achieved by conventional treatments for cervical disc herniation.
PMCID: PMC3599747  PMID: 23402661

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