Pathology Division

Japan

Pathology Division

Japan

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Porter A.I.,U.S. Army | Erwin-Cohen R.A.,U.S. Army | Twenhafel N.,Pathology Division | Chance T.,Pathology Division | And 7 more authors.
Virology Journal | Year: 2017

Background: Licensed antiviral therapeutics and vaccines to protect against eastern equine encephalitis virus (EEEV) in humans currently do not exist. Animal models that faithfully recapitulate the clinical characteristics of human EEEV encephalitic disease, including fever, drowsiness, anorexia, and neurological signs such as seizures, are needed to satisfy requirements of the Food and Drug Administration (FDA) for clinical product licensing under the Animal Rule. Methods: In an effort to meet this requirement, we estimated the median lethal dose and described the pathogenesis of aerosolized EEEV in the common marmoset (Callithrix jacchus). Five marmosets were exposed to aerosolized EEEV FL93-939 in doses ranging from 2.4 × 101 PFU to 7.95 × 105 PFU. Results: The median lethal dose was estimated to be 2.05 × 102 PFU. Lethality was observed as early as day 4 post-exposure in the highest-dosed marmoset but animals at lower inhaled doses had a protracted disease course where humane study endpoint was not met until as late as day 19 post-exposure. Clinical signs were observed as early as 3 to 4 days post-exposure, including fever, ruffled fur, decreased grooming, and leukocytosis. Clinical signs increased in severity as disease progressed to include decreased body weight, subdued behavior, tremors, and lack of balance. Fever was observed as early as day 2-3 post-exposure in the highest dose groups and hypothermia was observed in several cases as animals became moribund. Infectious virus was found in several key tissues, including brain, liver, kidney, and several lymph nodes. Clinical hematology results included early neutrophilia, lymphopenia, and thrombocytopenia. Key pathological changes included meningoencephalitis and retinitis. Immunohistochemical staining for viral antigen was positive in the brain, retina, and lymph nodes. More intense and widespread IHC labeling occurred with increased aerosol dose. Conclusion: We have estimated the medial lethal dose of aerosolized EEEV and described the pathology of clinical disease in the marmoset model. The results demonstrate that the marmoset is an animal model suitable for emulation of human EEEV disease in the development of medical countermeasures. © 2017 The Author(s).


Xia A.,Pathology Division | Chai L.,Tangshan Workers Hospital
Chinese Journal of Clinical Oncology | Year: 2014

Objective: To investigate the expression and clinical significance of wild-type p53-induced phosphatase 1 (Wip1) in thyroid carcinoma and biological effect of siRNA-targeting Wipl on the thyroid carcinoma cell line.Methods: Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were performed to detect the expression of Wip1 in 73 specimens of thyroid carcinoma tissues and normal thyroid tissues (5 cm away from the margin of thyroid carcinoma), respectively. Wip1 siRNA was transiently transfected into the papillary thyroid carcinoma cell by using a liposome-mediated method and then detected by RT-PCR and Western blot. Methyl thiazolyl tetrazolium (MTT) assay and flow cytometry (FCM) were also conducted to observe cell proliferation, cell apoptosis, and cell cycle.Results: The positive rates of Wipl protein were 80.8% in thyroid carcinoma tissues and 9.6% in the normal tissues (X2=47.036, P<0.05). The relative mRNA contents of Wip1 were 0.665 ± 0.046 and 0.225 ± 0.039 in carcinoma and normal tissues, respectively; these results significantly differed between the two types (t=12.637, P<0.05). Significant correlation was not observed between Wip1 expression and other factors, such as patient's gender, age, and tumor size (P>0.05). However, significant correlations among Wip1 expression, lymph node metastasis, clinical stages and tumor differentiation (P<0.05) were observed. RT-PCR and Western blot results showed that K1 cell-transfected Wip1 siRNA exhibited a relatively lower expression than normal cells (t=17.039, t= 14.637, P<0.05). MTT assay results showed that the K1 cells transfected with Wipl siRNA showed a lower survival fraction, higher cell apoptosis, higher percentage of G0/G1 phases, and lower cell concentration in G2/M and S phases (P<0.05).Conclusion: Wip1 protein and mRNA were increased in thyroid carcinoma and are correlated with lymph node metastasis, clinical stages and tumor differentiation. Wip1 may be involved in proliferation. apoptosis. and cycle of thyroid cancer cells.


PubMed | National Institute of Allergy and Infectious Diseases, Defense Health Agency Veterinary Services, Uniformed Services University of the Health Sciences, U.S. Army and Pathology Division.
Type: Case Reports | Journal: The Journal of infectious diseases | Year: 2015

A 3.5-year-old adult female rhesus macaque (Macaca mulatta) manifested swelling of the left upper eyelid and conjunctiva and a decline in clinical condition 18 days following intramuscular challenge with Ebola virus (EBOV; Kikwit-1995), after apparent clinical recovery. Histologic lesions with strong EBOV antigen staining were noted in the left eye (scleritis, conjunctivitis, and peri-optic neuritis), brain (choriomeningoencephalitis), stomach, proximal duodenum, and pancreas. Spleen, liver, and adrenal glands, common targets for acute infection, appeared histologically normal with no evidence of EBOV immunoreactivity. These findings may provide important insight for understanding sequelae seen in West African survivors of Ebola virus disease.


Terashima T.,National Cancer Center Hospital | Terashima T.,Kanazawa University | Morizane C.,National Cancer Center Hospital | Hiraoka N.,National Cancer Center Research Institute | And 9 more authors.
Neuroendocrinology | Year: 2012

Background: The chemotherapy for small-cell lung carcinoma (SCLC) has been adopted for advanced extrapulmonary neuroendocrine carcinomas (EP-NECs). The aim of this study was to clarify the efficacy of standard SCLC regimens when used to treat EP-NECs and to compare the outcome with that for SCLC. Methods: We reviewed the medical records of 136 patients (41 with EP-NEC and 95 with SCLC) who were treated using a platinum-containing regimen for advanced disease between January 2000 and October 2008 at our hospital. Results: The primary site of the EP-NEC was the gastrointestinal tract in 18 patients (GI tract group); the liver, biliary tract or pancreas in 16 patients (HBP group), and other sites in 7 patients ('others' group). The response rate in the SCLC patients was 77.8%, and the response rate in the EP-NEC patients was 30.8% (37.5% in the GI tract group, 12.5% in the HBP group, and 57.1% in the 'others' group). The median survival time for the SCLC patients was 13.6 months, while that for the EP-NEC patients was 9.2 months (14.9 months in the GI tract group, 7.8 months in the HBP group, and 8.9 months in the 'others' group). A multivariate analysis demonstrated that a poor performance status, liver involvement, and the treatment regimen were independent unfavorable prognostic factors. Conclusion: The response rate and prognosis of the patients with advanced EP-NECs were worse than those of the patients with SCLC in this study. The Eastern Cooperative Oncology Group performance status, liver involvement, and treatment regimen had a larger impact on the prognosis than the primary tumor site, as demonstrated by multivariate analysis. Copyright © 2012 S. Karger AG, Basel.


Yoshida S.,Kinki University | Yoshida S.,Osaka Medical College | Matsumoto K.,Kinki University | Arao T.,Kinki University | And 5 more authors.
Anticancer Research | Year: 2013

Background: The gene amplification of ribosomal protein S6 kinase 1 and 2 (S6K1 and S6K2) and its clinical relevance in gastric cancer remain unclear. Materials and Methods: A comparative genomic hybridization analysis and DNA copy number assay were performed for nine cancer cell lines. The gene amplification of S6K1 and S6K2 were determined using a DNA copy number assay of 213 gastric cancer tissues. Results: S6K1 and S6K2 amplifications were observed in one and three cancer cell lines, respectively. No amplification of S6K1 was detected in the gastric cancer tissues, while S6K2 amplification was observed in 4.7% of the gastric carcinoma tissues. Patients with stage IV gastric cancer whose tumors exhibited amplification had a significantly shorter overall survival. Conclusion: S6K2 amplification was frequently observed in gastric cancer and was related to a poor prognosis. Our findings may provide novel insight into the dysregulation of mammalian target of rapamycin signaling by S6K2 amplification in gastric cancer. © 2013 Anticancer Research.


Ojima H.,Pathology Division | Yoshikawa D.,Cancer Genomics Project | Ino Y.,Pathology Division | Shimizu H.,Cancer Genomics Project | And 15 more authors.
Cancer Science | Year: 2010

The aim of this study was to establish new biliary tract carcinoma (BTC) cell lines and identify predictive biomarkers for the potential effectiveness of gemcitabine therapy. Surgical specimens of BTC were transplanted directly into immunodeficient mice to establish xenografts, then subjected to in vitro cell culture. The gemcitabine sensitivity of each cell line was determined and compared with the genome-wide gene expression profile. A new predictive biomarker candidate was validated using an additional cohort of gemcitabine-treated BTC cases. From 55 BTC cases, we established 19 xenografts and six new cell lines. Based on their gemcitabine sensitivity, 10 BTC cell lines (including six new and four publicly available ones) were clearly categorized into two groups, and MAGEH1 mRNA expression in the tumor cells showed a significant negative correlation with their sensitivity to gemcitabine. Immunohistochemically, MAGEH1 protein was detected in three (50%) out of six sensitive cell lines, and four (100%) out of four resistant cell lines. In the validation cohort of gemcitabine-treated recurrence cases, patients were categorized into "effective" and "non-effective" groups according to the RECIST guidelines for assessment of chemotherapeutic effects. MAGEH1 protein expression was detected in two (40%) out of five "effective" cases and all four (100%) "non-effective" cases. We have established a new BTC bioresource that covers a wide range of biological features, including drug sensitivity, and is linked with clinical information. Negative expression of MAGEH1 protein serves as a potential predictive marker for the effectiveness of gemcitabine therapy in BTC. © 2010 Japanese Cancer Association.

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