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Objectives: To investigate the heterogeneous transmission patterns of Middle East respiratory syndrome (MERS) in the Republic of Korea, with a particular focus on epidemiological characteristics of superspreaders., Design: Retrospective epidemiological analysis., Setting: Multiple healthcare facilities of secondary and tertiary care centres in an urban setting., Participants: A total of 185 laboratory-confirmed cases with partially known dates of illness onset and most likely sources of infection., Primary and Secondary Outcome Measures: Superspreaders were identified using the transmission tree. The reproduction number, that is, the average number of secondary cases produced by a single primary case, was estimated as a function of time and according to different types of hosts., Results: A total of five superspreaders were identified. The reproduction number throughout the course of the outbreak was estimated at 1.0 due to reconstruction of the transmission tree, while the variance of secondary cases generated by a primary case was 52.1. All of the superspreaders involved in this outbreak appeared to have generated a substantial number of contacts in multiple healthcare facilities (association: p<0.01), generating on average 4.0 (0.0-8.6) and 28.6 (0.0-63.9) secondary cases among patients who visited multiple healthcare facilities and others. The time-dependent reproduction numbers declined substantially below the value of 1 on and after 13 June 2015., Conclusions: Superspreaders who visited multiple facilities drove the epidemic by generating a disproportionate number of secondary cases. Our findings underscore the need to limit the contacts in healthcare settings. Contact tracing efforts could assist early laboratory testing and diagnosis of suspected cases., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Glucagon-like peptide 1 (GLP-1) induces insulin secretion and proliferation of pancreatic β-cells, and inhibits their apoptosis through the GLP-1 receptor (GLP-1R), thus providing a foundation for using GLP-1-based therapies for the treatment of type 2 diabetes. However, doubts have emerged regarding the drug safety of these therapies. We investigated the potential role of GLP-1R in pancreatic ductal adenocarcinoma (PDAC). GLP-1R expression was semi-quantitatively evaluated by immunohistochemistry in 48 PDAC samples, and its correlations with clinicopathological features were investigated. CFPAC-1 cells were used for GLP-1R knockdown to evaluate its effects on cell proliferation, migration and invasion. GLP-1R expression was positive in 23 tumors and negative in 25 tumors. No correlations were found between GLP-1R expression status and clinicopathological characteristics. Furthermore, GLP-1R expression status did not affect the patient prognosis (P=0.74). The majority of lymph node metastases (11 of 15 samples examined; 73%) were positive for GLP-1R expression. Immunoreactivity for GLP-1R was also noted in sites of perineural and lymphovascular invasion. GLP-1R knockdown significantly reduced the proliferation, migration and invasion of CFPAC-1 cells (P<0.05). In conclusion, although GLP-1R is not an independent prognostic factor in PDAC patients, it appears to have some implications for PDAC metastatic ability.

Objectives: A large cluster of the Middle East respiratory syndrome (MERS) linked to healthcare setting occurred from May to July 2015 in the Republic of Korea. The present study aimed to estimate the case fatality ratio (CFR) by appropriately taking into account the time delay from illness onset to death. We then compare our estimate against previously published values of the CFR for MERS, i.e., 20% and 40%., Methods: Dates of illness onset and death of the MERS outbreak in the Republic of Korea were extracted from secondary data sources. Using the known distribution of time from illness onset to death and an integral equation model, we estimated the delay-adjusted risk of MERS death for the South Korean cluster., Results: Our most up-to-date estimate of CFR for the MERS outbreak in South Korea was estimated at 20.0% (95% confidence intervals (CI): 14.6, 26.2). During the course of the outbreak, estimate of the CFR in real time appeared to have decreased and become significantly lower than 40%., Conclusions: The risk of MERS death in Korea was consistent with published CFR. The estimate decreased with time perhaps due to time-dependent increase in case ascertainment. Crude ratio of cumulative deaths to cases underestimates the actual risk of MERS death because of time delay from illness onset to death., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: As a strategy to diagnose early-stage pancreatic ductal adenocarcinoma (PDAC) is urgently needed, we aimed to clarify characteristics of early-stage PDAC., Methods: We retrospectively reviewed medical records of 299 consecutive patients who underwent R0 or R1 surgical resection for PDAC between 1994 and 2013 and compared clinical characteristics between patients with early-stage (stages 0-I by Japanese General Rules for Pancreatic Cancer) and advanced-stage (stages II-IV) disease. Diagnostic processes were also analyzed., Results: Twenty-four patients (8%) had early-stage PDAC (stage 0: 11; stage I: 13). Univariate and multivariate analyses showed that presence or history of intraductal papillary mucinous neoplasm (P < 0.01), history of pancreatitis (P < 0.01), and presence or history of extrapancreatic malignancies (P = 0.01) independently predicted detection of early-stage PDAC. Cytological examination during endoscopic retrograde pancreatography cytology was ∼65% sensitive in preoperative diagnosis of early-stage PDAC, whereas other imaging modalities were only 29% to 38% sensitive; 9 of 24 early-stage PDACs were diagnosed by endoscopic retrograde pancreatography cytology alone., Conclusions: Endoscopic retrograde pancreatography cytology for patients with intraductal papillary mucinous neoplasm or pancreatitis may help diagnose early-stage PDAC. Surveillance of extrapancreatic malignancies might also provide opportunities to detect early-stage PDAC as a second malignancy.

Background: An outbreak of the Middle East respiratory syndrome (MERS), comprising 185 cases linked to healthcare facilities, occurred in the Republic of Korea from May to July 2015. Owing to the nosocomial nature of the outbreak, it is particularly important to gain a better understanding of the epidemiological determinants characterizing the risk of MERS death in order to predict the heterogeneous risk of death in medical settings., Methods: We have devised a novel statistical model that identifies the risk of MERS death during the outbreak in real time. While accounting for the time delay from illness onset to death, risk factors for death were identified using a linear predictor tied to a logit model. We employ this approach to (1) quantify the risks of death and (2) characterize the temporal evolution of the case fatality ratio (CFR) as case ascertainment greatly improved during the course of the outbreak., Results: Senior persons aged 60 years or over were found to be 9.3 times (95% confidence interval (CI), 5.3-16.9) more likely to die compared to younger MERS cases. Patients under treatment were at a 7.8-fold (95% CI, 4.0-16.7) significantly higher risk of death compared to other MERS cases. The CFR among patients aged 60 years or older under treatment was estimated at 48.2% (95% CI, 35.2-61.3) as of July 31, 2015, while the CFR among other cases was estimated to lie below 15%. From June 6, 2015, onwards, the CFR declined 0.3-fold (95% CI, 0.1-1.1) compared to the earlier epidemic period, which may perhaps reflect enhanced case ascertainment following major contact tracing efforts., Conclusions: The risk of MERS death was significantly associated with older age as well as treatment for underlying diseases after explicitly adjusting for the delay between illness onset and death. Because MERS outbreaks are greatly amplified in the healthcare setting, enhanced infection control practices in medical facilities should strive to shield risk groups from MERS exposure.

Objectives: A rubella epidemic occurred in Japan from 2012-14, involving more than 15,000 cases. The present study aimed to estimate the immunizing effect of the epidemic, analyzing seroepidemiological data that were collected over time and age., Methods: Annual nationwide cross-sectional surveys were conducted from July to September, collecting serum from at least 5,400 individuals. The proportions seropositive were estimated before (2012), during (2013) and after (2014) the epidemic., Results: While the cases were mainly seen among men aged from 30-49 years, no significant increase was observed in the proportion seropositive in the corresponding age group. Even after the epidemic, age-standardized proportion seropositive of the total population remained 79.3% (95% confidence interval (CI): 75.2, 83.4) and that among males was as small as 76.7% (95% CI: 73.8, 79.6)., Conclusions: Susceptible pockets remain in Japan, exposing the country to risk of additional rubella epidemics., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The cell surface protein Transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors, and its expression on tumor cells is implicated in cancer cell metastasis and patient prognosis. The role of TM4SF1 in malignant tumors remains poorly understood, particularly in pancreatic cancer. We performed immunohistochemical staining to analyze the expression of TM4SF1 in resected pancreatic tissues and investigated the correlation between TM4SF1 expression and prognosis. The function of TM4SF1 in the invasion and migration of pancreatic cancer cells was analyzed in vitro using an RNA interference technique. In pancreatic cancer tissues, TM4SF1 expression was detected in cancer cells, and patients with high tumor levels of TM4SF1 showed longer survival times than those with low TM4SF1 levels (P=0.0332). In vitro, reduced TM4SF1 expression enhanced the migration (P<0.05) and invasion (P<0.05) of pancreatic cancer cells partially via decreased E-cadherin expression. TM4SF1 protein levels were also reduced after TGF-β1-induced epithelial-mesenchymal transition (EMT).TM4SF1 expression is associated with better prognosis in pancreatic cancer. Loss of TM4SF1 contributes to the invasion and migration of pancreatic cancer cells.

Background: At present, there is no standard of treatment using systemic high-dose corticosteroids in cases of pregnant women with Vogt-Koyanagi-Harada (VKH) disease. Although high-dose systemic corticosteroid treatment is often used for VKH disease during pregnancy, it also poses a risk to the fetus., Findings: A 29-year-old woman in the 34th week of pregnancy experienced bilateral metamorphopsia. She had been receiving 5 mg of prednisolone daily for the past 8 years as treatment for rheumatoid arthritis. In order to prevent progression of bilateral serous retinal detachment caused by VKH disease, we recommended the use of high-dose systemic corticosteroids but the patient refused. Thus, we administered only topical ophthalmic betamethasone for mild anterior uveitis. Surprisingly, however, the bilateral bullous retinal detachment healed in just 19 days after the onset of symptoms. A healthy baby was born 1 month later, and sunset glow fundus was subsequently observed without any recurrence of uveitis., Conclusions: We report a case in which bilateral subretinal fluid caused by VKH disease in a young woman during late pregnancy resolved without high-dose corticosteroid treatment. Pregnancy may have had a beneficial effect on uveitis activity caused by VKH disease. To our knowledge, this report describes the shortest healing period for bilateral bullous retinal detachment in a pregnant woman with VKH disease.

Background: Invasive cases of extramammary Paget's disease have a poor prognosis, owing to its rapid progression and resistance to irradiation and chemotherapy. Morton et al. introduced a technique to identify sentinel lymph nodes by local injection of vital dyes and reported its benefit for managing the progress of malignant melanoma., Objectives: Since the rate of lymph node metastasis of extramammary Paget's disease is not uncommon (reported from 8.5% to 26%), this study tested the hypothesis that sentinel lymph node biopsy would be useful to detect lymph node metastasis in the clinically early stage of extramammary Paget's disease., Materials & Methods: Eighteen patients with primary extramammary Paget's disease were enrolled in the study. The precise location of sentinel lymph nodes was visualized using either intraoperative patent blue dye injection or indocyanine green dye injection in combination with a hand-held gamma-detecting probe after a 99mTc phytate injection., Results: Of the 18 patients, sentinel lymph node metastasis was identified in 2 (Cases 2 and 15) of the 2 patients with deep invasion and in 1 (Case 12) of the 7 patients with minimal dermal invasion, however, it was absent in 9 patients who had been categorized into the intraepidermal group., Conclusion: This study demonstrates that extramammary Paget's disease possibly causes metastasis via regional lymphatic systems to which the lesion belongs, even in the early stages of no nodule or tumor formation, and that sentinel lymph node biopsy is useful to detect lymph node metastasis.

Objective: The aims of this study were to investigate the GNAS mutational status in pancreatic intraductal papillary mucinous neoplasm (IPMN) with and without distinct pancreatic ductal adenocarcinoma (PDAC) and to evaluate the significance of GNAS analysis using duodenal fluid (DF) in patients with IPMN., Methods: The clinicopathologic features of 110 patients with IPMN including 16 with distinct PDAC were reviewed. The GNAS status in the IPMN tissue and 23 DF specimens was assessed by sensitive mutation scanning methods., Results: The GNAS mutation rate in IPMN with distinct PDAC was significantly lower than that in IPMN without PDAC (4/16, 25%, vs 61/94, 65%; P = 0.0047). By multivariate analysis, GNAS wild-type and gastric type IPMNs were significantly associated with distinct PDAC. Of 45 GNAS wild-type IPMNs, 10 (43%) of 23 gastric type IPMNs had distinct PDAC, whereas only 2 (9%) of 22 non-gastric type IPMNs had distinct PDAC (P = 0.017). The GNAS status in DF was consistent with that in tissue in 21 (91%) of 23 patients., Conclusions: Distinct PDACs frequently develop in the pancreas with gastric type IPMN without GNAS mutations. Duodenal fluid DNA test would predict the GNAS status of IPMN, whereas the detection of the gastric subtype using noninvasive test remains to be determined.

Improvement in child nutritional status is one of the major health priorities in Timor-Leste. A qualitative study was conducted in Aileu District, adjacent to the capital of Timor-Leste, Dili, in September 2010 to determine the possible risk factors associated with the high prevalence of child malnutrition. In-depth interviews were conducted to 32 guardians of children aged younger than 5 years. It was observed that early termination of exclusive breast-feeding and a short lactation period along with an unsanitary living environment were associated with the nutritional status of children in the study area. Although previous surveys have reported poor food security conditions in the country, no statements from the subjects supported this contention. The identified possible risk factors for child malnutrition were closely linked to each other and were mostly modifiable., (© 2013 APJPH.)

Background: Main duct intraductal papillary mucinous neoplasms (MD-IPMNs) may occur in 1 or multiple segments of the pancreatic duct. Unlike multifocal branch duct (BD)-IPMNs, the clonality of multisegmental MD-IPMNs remains unclear. GNAS mutations are common and specific for IPMNs, and mutational assessment might be useful to determine the clonality of IPMNs as well as to detect high-risk IPMN with distinct ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]). Our aim was to clarify clonality using GNAS status in multisegmental MD-IPMNs., Methods: We retrospectively reviewed the medical records of 70 patients with MD-IPMN. Histologic subtypes and KRAS/GNAS mutations were investigated, and the clonal relationships among multisegmental MD-IPMNs were assessed. Mutational analysis was performed using high-resolution melting analysis and subsequent Sanger/pyrosequencing., Results: Thirteen patients had multiple synchronous and/or metachronous lesions. Seven of these 13 patients had multiple MD-IPMNs; 3 had multiple MD-IPMNs and distinct BD-IPMNs; 1 had multiple MD-IPMNs and a distinct PDAC; 1 had a solitary MD-IPMN, BD-IPMN, and PDAC; and 1 had a solitary MD-IPMN and PDAC. KRAS/GNAS mutations were consistent in 10 of 11 multisegmental MD-IPMNs, whereas MD-IPMNs, BD-IPMNs, and PDACs tended to show different mutational patterns. The frequency of malignant IPMNs was significantly higher in the multisegment cohort; malignant IPMNs constituted 90% (9/10) of the multiple cohort and 56% (32/57) of the solitary cohort (P = .04). Mutant GNAS was more frequently observed in the intestinal subtype (94%) than the others., Conclusion: MD-IPMNs can be characterized by monoclonal skip progression. Close attention should be paid to the possible presence of skip areas during or after partial pancreatectomy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (P<0.0001), high histological cellular grade (P<0.0001), and adverse outcome (P<0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-β), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-β signaling using recombinant soluble human TGF-β receptor type II and TGF-β-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-β from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.

A 47-year-old woman with a 2-year history of rheumatoid arthritis (RA) undergoing methotrexate treatment developed a perforated ulcer in the ileum for which she underwent emergency surgery. A histological analysis of the extirpated specimen presented a possible Epstein-Barr virus (EBV) infection in the ulcerative lesion without a feature of lymphoproliferative disorder. Interestingly, the patient's serological tests with a paired serum diagnosed a primary EBV infection. The present case emphasizes the importance of being aware of severe enteritis as a possibility for patients with RA, for an accurate diagnosis.

Asia has recorded the fastest economic growth in the world. However, some countries are still struggling with economic stagnation and poverty. Even in the emerging countries, there are economic disparities between urban and rural areas within a country. Reflecting the situations, nutritional issues in Asia came to be the antithetical situation of excess and insufficiency. The rate of overweight and obesity keeps increasing, especially in emerging countries. Meanwhile, underweight is still a critical problem in the region. Although the importance of nutrition is well recognized for social and economic development, it is difficult to identify the immediate outcome of nutrition interventions. Evidence-based decision-making is an important element of quality health care and efficiency and effectiveness are always key words. Along with enhanced attention to accountability and transparency of budget use in health services, attention to the economic evaluation of nutrition interventions has increased in recent years. In this symposium, we will review the current situation of nutritional issues and economic evaluation of nutrition interventions in Asia through experience of an international organization, the basis and trends for health care economics, and also efforts have been made in an Asian country. Discussion will be made about efficient and effective ways to evaluate projects/programmes for nutrition improvement.

Background: Micro RNAs (miRNAs) are small noncoding RNAs that have gained attention as key molecules in the malignant characteristics of cancers, and several recent investigations also have identified some miRNAs as potential key regulators to inhibit the malignant characteristics of tumors. MiRNA-373 (miR-373) has recently been reported to induce E-cadherin, which is a key regulator of epithelial-mesenchymal transition (EMT). However, the role of miR-373 in the characteristics of cancer cells is not still well known., Methods: We investigated the expression levels of miR-373 in pancreatic cancer cell lines and its effect on the invasiveness of pancreatic cancer by using in vitro and in vivo models. We also analyzed the expression of miR-373 using formalin-fixed paraffin-embedded (n = 152) and microdissected frozen (n = 57) samples from pancreatic tissues., Results: The levels of miR-373 expression were low in pancreatic cancer cell lines. In formalin-fixed paraffin-embedded and microdissected frozen samples, miR-373 expression was significantly down-regulated in pancreatic cancer compared with that in healthy pancreas (P < 0.001 and P = 0.005, respectively). We also found that reexpression of miR-373 repressed transforming growth factor-β-induced EMT, leading to inhibition of invasiveness of cancer cells. Furthermore, reexpression of miR-373 significantly inhibited peritoneal dissemination in vivo (P < 0.001)., Conclusions: MiR-373 is down-regulated in pancreatic cancer, and its reexpression represses the invasiveness of pancreatic cancer cells.

Background: Routine endoscopic retrograde pancreatography (ERP) for pancreatic juice cytology (PJC) during management of intraductal papillary mucinous neoplasm (IPMN) is not recommended in the international consensus guidelines 2012. The aim of the present study was to investigate the roles of PJC in relation to the new stratification of clinical findings in the consensus guidelines 2012., Methods: Medical records of 70 consecutive patients who underwent preoperative PJC, subsequent pancreatectomy, and a pathological diagnosis of IPMN were reviewed. Diagnostic ability of PJC to detect malignant lesions was calculated by the stratification of clinical findings., Results: Forty patients had malignant lesions, including 29 with malignant IPMN, 10 with concomitant pancreatic adenocarcinoma, and one with both. Accuracies of PJC in all 70 patients and in 59 patients with IPMN alone were 77 and 80 %, respectively. The sensitivity and accuracy of PJC in patients with "worrisome features" were 100 and 94 %, respectively. Eight of 11 patients with concomitant pancreatic adenocarcinoma had non-malignant IPMN without risk factors, and 3 significant lesions could be diagnosed only by ERP/PJC. In addition, the management plan based on imaging study changed from observation to resection in two patients who had the single "worrisome feature" of branch duct IPMN and positive PJC results. As a result, PJC altered the management plan in 5 patients., Conclusions: Pancreatic juice cytology potentially has important roles to determine the adequate treatment choice in patients with IPMNs with "worrisome features," and to detect significant lesions that could not be detected by other imaging modalities.

Objectives: The 2012 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas stratified patients into 2 clinical categories, "high-risk stigmata" and "worrisome features," and recommended different therapeutic strategies for these groups. The aim of this study was to elucidate the significance of these categories in terms of predicting malignant IPMNs., Methods: The medical records of 100 consecutive patients who underwent pancreatectomy for IPMNs were retrospectively reviewed. Seventy patients with branch duct IPMNs (BD-IPMNs) were stratified into 3 groups. The relationships between the number of predictive factors and histopathologic grade were investigated., Results: The prevalence rates of malignant IPMN, invasive carcinoma, and lymph node metastasis in the high-risk group were 80%, 55%, and 20%, respectively, with these percentages significantly increasing in a stepwise manner according to the number of predictive factors. In contrast, there was no significant correlation between the number of worrisome features and grade of malignancy in patients stratified as having worrisome BD-IPMNs., Conclusions: The number of high-risk stigmata correlated significantly with the grade of malignancy of BD-IPMNs. The presence of at least 1 high-risk stigma in patients with BD-IPMNs indicates a need for pancreatectomy with lymphadenectomy.

Varicose veins (VV) in legs are commonly observed in the general global population. However, the prevalence of and risk factors for VV in Japan are not clear. This study aimed at clarifying the risk factors for VV in traditional rural areas of Shimane prefecture. Subjects (113 men and 205 women aged ≥45 years) were recruited from health examinations in those areas in 2012. VV were defined as a reflux of blood in the great and/or small saphenous vein and incompetent perforating veins detected by ultrasonography. Risk factors for VV were analyzed using logistic regression models that included various parameters. We also investigated the possible interaction between standing at work and overweight and calculated the synergistic index. VV were found in 20.1% of the subjects (12.4% of men and 24.4% of women). The previously known risk factors of prolonged upright standing posture during work, higher body mass index (BMI), female sex, and age were also significant factors for VV. There was a significant combined effect of overweight (BMI ≥25) and prolonged upright standing posture at work [adjusted odds ratio = 3.42; 95% confidence interval (CI), 1.07-10.89], although the synergistic effect was not significant [synergistic index = 1.3; 95% CI, 0.2-8.7]. The prevalence of VV in the traditional rural area of Shimane prefecture was comparable to that reported previously in European countries. Our results confirm that exposure to both prolonged standing at work and overweight exacerbate VV development. This finding is useful to develop strategies for VV prevention., (© 2014 Japanese Dermatological Association.)

Purpose: In patients with pancreatic ductal carcinoma (PDAC), EUS-FNA carries a risk of cancer seeding. To avoid this risk, we attempted to obtain preoperative cytological confirmation of adenocarcinoma by ERCP. The aim of this study was to assess the validity of our diagnostic strategy., Methods: The medical records of 124 consecutive patients who were investigated for potentially resectable PDAC were retrospectively reviewed, and the ability to detect adenocarcinoma by ERCP was evaluated., Results: ERCP was performed in 115 patients, 69 of whom had positive cytology results. Thirty-four patients underwent EUS-FNA, 29 of whom had positive cytology results. A total of 98 patients (79 %), therefore, had preoperative cytological confirmation of adenocarcinoma, which was more frequent in patients with lesions of the head of the pancreas than in those with lesions of the body or tail of the pancreas. The postoperative pathological diagnosis demonstrated malignant pancreatic neoplasms in 122 patients (98 %), including 111 with PDAC. EUS-FNA did not affect the rate of postoperative peritoneal dissemination., Conclusions: Our strategy using ERCP as the initial diagnostic modality for obtaining cytological confirmation of potentially resectable PDAC seems to be adequate, yielding a high rate of positive cytology, especially in cases with tumors of the head of the pancreas.

Background: CD166, also known as activated leukocyte cell adhesion molecule (ALCAM), is expressed by various cells in several tissues including cancer. However, the role of CD166 in malignant tumors is controversial, especially in pancreatic cancer. This study aimed to clarify the role and significance of CD166 expression in pancreatic cancer., Methods: We performed immunohistochemistry and flow cytometry to analyze the expression of CD166 in surgical pancreatic tissues and pancreatic cancer cell lines. The differences between isolated CD166+ and CD166- pancreatic cancer cells were analyzed by invasion and migration assays, and in mouse xenograft models. We also performed quantitative RT-PCR and microarray analyses to evaluate the expression levels of CD166 and related genes in cultured cells., Results: Immunohistochemistry revealed high expression of CD166 in pancreatic cancer tissues (12.2%; 12/98) compared with that in normal pancreas controls (0%; 0/17) (p = 0.0435). Flow cytometry indicated that CD166 was expressed in 33.8-70.2% of cells in surgical pancreatic tissues and 0-99.5% of pancreatic cancer cell lines. Invasion and migration assays demonstrated that CD166- pancreatic cancer cells showed stronger invasive and migratory activities than those of CD166+ cancer cells (p<0.05). On the other hand, CD166+ Panc-1 cells showed a significantly stronger colony formation activity than that of CD166- Panc-1 cells (p<0.05). In vivo analysis revealed that CD166+ cells elicited significantly greater tumor growth than that of CD166- cells (p<0.05) in both subcutaneous and orthotopic mouse tumor models. mRNA expression of the epithelial-mesenchymal transition activator Zeb1 was over-expressed in CD166- cells (p<0.001). Microarray analysis showed that TSPAN8 and BST2 were over-expressed in CD166+ cells, while BMP7 and Col6A1 were over-expressed in CD166- cells., Conclusions: CD166+ pancreatic cancer cells are strongly tumorigenic, while CD166- pancreatic cancer cells exhibit comparatively stronger invasive and migratory activities. These findings suggest that CD166 expression is related to different functions in pancreatic cancer cells.

Aim: In this study, we evaluated the effect of divalent metal cations on zinc uptake via mouse Zrt/Irt-like protein 1 (mZIP1), a ubiquitously expressed zinc transporter, which plays a role in maintenance of cellular zinc homeostasis, using HEK293T cells overexpressing it., Main Methods: mZIP1 cDNA, which was cloned from mouse microglia, was transfected into HEK293T cells by a lipofection method, and its functional expression was confirmed by Western blotting and immunocytochemical analyses, and (65)Zn ((65)ZnCl2) uptake., Key Findings: (65)Zn uptake by mZIP1 cDNA-transfected cells time-dependently increased compared with that by mock cells, indicating functional expression of mZIP1. mZIP1-mediated (65)Zn uptake showed clear saturable kinetics consisting of a single component with a Michaelis constant of 5.88 μM. FeCl2 and NiCl2 competitively inhibited the (65)Zn uptake, the inhibition constants (Ki) being estimated to be 0.92 and 28.6 μM, respectively. In addition, CoCl2 and CdCl2 showed non-competitive inhibition of mZIP1-mediated (65)Zn uptake, the Ki values being 219 and 32.5 μM, respectively. On the other hand, CuCl2 also significantly decreased the uptake, but the inhibition mode could not evaluate because of its low solubility, while MnCl2 and MgCl2 had no effect on (65)Zn uptake via mZIP1., Significance: Iron, nickel, cobalt and cadmium act as inhibitors of mZIP1, the affinity order being iron>zinc>nickel=cadmium>cobalt, and copper might also act as an inhibitor, while manganese and magnesium are not recognized by mZIP1. These findings provide valuable information as to the contribution of mZIP1 to total cellular zinc transport., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A thickened, enhanced cyst wall on imaging examinations is one of the "worrisome features" described in the consensus guidelines for management of intraductal papillary mucinous neoplasm of the pancreas (IPMN). Podoplanin (PDPN) expression by cancer-associated fibroblasts is known to be an indicator of poor prognosis in some types of cancer. We performed immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in IPMN lesions and determined the pathological wall thickness by measuring the thinnest and thickest α-SMA-positive parts of the wall of the largest cyst in each case, and the mean of these two values was recorded as the wall thickness. The thickness of the pathological wall increased with progression from IPMN with low-grade dysplasia to IPMN with an invasive carcinoma. The pathological wall was thicker in IPMN with main duct involvement, nongastric-type IPMN, and IPMN with mural nodules. We also stained for PDPN and assessed the thickness of cyst wall staining as for α-SMA. The thickness of the PDPN-positive cyst wall varied in a pattern similar to the thickness of the α-SMA-positive pathological cyst wall. PDPN-positive stromal fibroblasts in the invasive component of IPMN-IC were evaluated as a ratio to α-SMA-positive fibroblasts. A high ratio (>50 %) of PDPN-positive stromal fibroblasts was a predictor of poor outcome. PDPN expression in the cyst wall correlates with the progression of IPMN. PDPN may be a significant prognostic marker of IPMN-IC.

Background & Objectives: The present study aimed to systematically quantify the well known risk of severe dengue during secondary infection in literature and to understand how epidemiological mechanisms of enhancement during the secondary infection influence the empirically estimated risk of severe dengue by means of mathematical modeling., Methods: Two conditional risks of severe dengue, i.e. symptomatic illness and dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), given secondary infection were explored based on systematically searched prospective studies. A two-strain epidemiological model was employed to simulate the transmission dynamics of dengue and to identify the relevant data gaps in empirical observations., Results: Using the variance-based weighting, the pooled relative risk (RR) of symptomatic illness during secondary infection was estimated at 9.4 [95% confidence interval (CI): 6.1-14.4], and similarly, RR of DHF/DSS was estimated to be 23.7 (95% CI: 15.3-36.9). A variation in the RR of DHF/DSS was observed among prospective studies. Using the mathematical modeling technique, we identified the duration of cross-protective immunity as an important modulator of the time-dependent behaviour of the RR of severe dengue. Different epidemiological mechanisms of enhancement during secondary infection yielded different RR of severe dengue., Interpretation & Conclusion: Optimal design of prospective cohort study for dengue should be considered, accounting for the time-dependence in the RR during the course of dengue epidemic. It is critical to statistically infer the duration of cross-protective immunity and clarify how the enhancement influences the epidemiological dynamics during secondary infection.

Myofibroblasts in the stroma of pancreatic cancers promote tumor proliferation, invasion and metastasis by increasing extracellular matrix and secretion of several growth factors. In contrast, the role of myofibroblasts at peritoneally disseminated sites of pancreatic cancer has not yet been determined. This study was designed to assess the role of myofibroblasts at peritoneally disseminated sites of pancreatic cancer. Three primary cultures of human peritoneal myofibroblasts (hPMFs) were established from disseminated sites of pancreatic cancer and their interactions with the SUIT-2 and CAPAN-1 human pancreatic cancer cell lines were analyzed in vitro. Using a model in BALB/c nu/nu mice, we compared the dissemination ability of intraperitoneally implanted pancreatic cancer cells, with and without hPMFs, and examined the presence of green fluorescent protein (GFP)-labeled hPMFs at peritoneally disseminated sites in mice. hPMFs significantly promoted the migration and invasion of pancreatic cancer cells (P<0.05), while the cancer cells significantly promoted the migration and invasion of hPMFs (P<0.05). In vivo, the number of peritoneally disseminated nodules, more than 3 mm in size, was significantly greater in mice implanted with cancer cells plus hPMFs compared to mice implanted with cancer cells alone, with GFP-labeled hPMFs surviving in the peritoneal cavity of the former. hPMFs promote the peritoneal dissemination of pancreatic cancer. The cancer-stromal cell interaction in the peritoneal cavity may be a new therapeutic target to prevent the dissemination of pancreatic cancer.

We examined associations between optic nerve head structural parameters and glaucomatous visual field indices. The study population included patients with glaucomatous optic neuropathy who were evaluated at Aichi Medical University, Nagakute, Aichi, Japan, from October 2010 to January 2011. A total of 57 eyes from 33 patients were assessed. We measured visual field using a Humphrey field analyzer, peripapillary retinal nerve fiber layer thickness (RNFL-T), and Bruch's membrane opening-minimum rim width (BMO-MRW) using spectral domain optical coherence tomography, and rim area with referring three-dimensional photography. Spearman's rank correlation coefficients were calculated between the threshold of visual sensitivity or total deviation of visual field and the following five optic nerve head structural parameters: RNFL-T length, BMO-MRW length, rim area, and calculated RNFL-T and BMO-MRW volumes (each length multiplied by rim area). The Akaike information criterion was calculated to determine which structural parameter was the best predictor of each visual field index. Threshold of visual sensitivity had correlation coefficients of 0.23 with global sector of RNFL-T, 0.32 with BMO-MRW, 0.14 with rim area, 0.21 with RNFL-T volume, and 0.26 with BMO-MRW volume. The correlation coefficients for each parameter with total deviation of visual field were 0.22, 0.33, 0.28, 0.36, and 0.37, respectively. The Akaike information criterion of BMO-MRW showed the smallest values in analyses of both threshold of visual sensitivity and total deviation. The present results show that RNFL-T volume and BMO-MRW volume were more strongly correlated with total deviation than BMO-MRW, but BMO-MRW appeared to be the best predictor of the two glaucomatous visual field indices.

The synthesis of influenza virus mRNA is primed by capped (m(7)GpppNm-) short RNAs that are cleaved from RNA polymerase II transcripts by a virally encoded endonuclease. This cap-dependent endonuclease activity called "cap-snatching" may provide a unique target for novel anti-viral agents. To screen candidate inhibitors, it is essential to establish a method for producing efficiently a capped RNA substrate and a convenient assay for the cap-snatching activity. A 3'-biotinylated short RNA was prepared by in vitro transcription, purified by C18 reverse-phase column chromatography, and subjected to a capping reaction involving three recombinant capping enzymes. This capped RNA was shown to be an efficient substrate for the cap-snatching assay. Cap-snatching activity was then measured with the novel pull-down assay developed in this study, which is based on the streptavidin-biotin interaction. A known inhibitor for the cap-snatching reaction was evaluated by the pull-down assay, demonstrating the efficacy of the established screening system., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Defects in glucose uptake by the skeletal muscle cause diseases linked to metabolic disturbance such as type 2 diabetes. The molecular mechanism determining glucose disposal in the skeletal muscle in response to cellular stimuli including insulin, however, remains largely unknown. The hypoxia-inducible factor-1α (HIF-1α) is a transcription factor operating in the cellular adaptive response to hypoxic conditions. Recent studies have uncovered pleiotropic actions of HIF-1α in the homeostatic response to various cellular stimuli, including insulin under normoxic conditions. Thus we hypothesized HIF-1α is involved in the regulation of glucose metabolism stimulated by insulin in the skeletal muscle. To this end, we generated C2C12 myocytes in which HIF-1α is knocked down by short-hairpin RNA and examined the intracellular signaling cascade and glucose uptake subsequent to insulin stimulation. Knockdown of HIF-1α expression in the skeletal muscle cells resulted in abrogation of insulin-stimulated glucose uptake associated with impaired mobilization of glucose transporter 4 (GLUT4) to the plasma membrane. Such defect seemed to be caused by reduced phosphorylation of the protein kinase B substrate of 160 kDa (AS160). AS160 phosphorylation and GLUT4 translocation by AMP-activated protein kinase activation were abrogated as well. In addition, expression of the constitutively active mutant of HIF-1α (CA-HIF-1α) or upregulation of endogenous HIF-1α in C2C12 cells shows AS160 phosphorylation comparable to the insulin-stimulated level even in the absence of insulin. Accordingly GLUT4 translocation was increased in the cells expressing CA-HIF1α. Taken together, HIF-1α is a determinant for GLUT4-mediated glucose uptake in the skeletal muscle cells thus as a possible target to alleviate impaired glucose metabolism in, e.g., type 2 diabetes.

Background: Mucinous cystic neoplasms (MCN) of the pancreas frequently develop in the distal pancreases of young women. Laparoscopic surgery can enhance cosmetic benefits and ease of surgery. This study assessed the feasibility of laparoscopic surgery for MCN., Methods: The medical records of 21 patients pathologically diagnosed with benign MCN after laparoscopic resection were reviewed. Clinical data were compared in the 11 patients with tumors ≥ 45 mm (large tumor group) and the 10 patients with tumors < 45 mm (small tumor group)., Results: Laparoscopic resection was completed in all patients, including distal pancreatectomy with (n = 9) and without (n = 11) spleen preservation and enucleation for pancreatic head lesion (n = 1). Operation time, blood loss, postoperative morbidity, and hospital stay were similar in the two groups. Spleen-preserving pancreatectomy could be more frequently completed in the small MCN group (P = 0.02). No recurrence was observed during a median follow-up period of 12 months., Conclusions: Laparoscopic surgery can be completed in all patients with benign MCN, even those with large tumors, and patients with small MCN can get the additional benefit of spleen preservation., (© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objectives: Aberrant expression of several microRNAs (miRs) has been reported in various neoplasms including intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. MicroRNA-196a (miR-196a) is up-regulated in Barrett esophagus (characterized by intestinal metaplasia) and in colorectal cancer; this relationship between intestinal characteristics and miR-196a might also be applicable to intestinal-type IPMNs. The aim of this study was to evaluate whether intestinal-type IPMNs can be discriminated from non-intestinal-type IPMNs by the expression level of miR-196a in tissue and pancreatic juice samples., Methods: Thirty-seven formalin-fixed paraffin-embedded tissue samples (including 3 of normal pancreatic ducts) and 36 pancreatic juice samples were obtained. The expression level of miR-196a measured by quantitative reverse transcription-polymerase chain reaction assays was compared between intestinal-type and non-intestinal-type IPMNs., Results: MicroRNA-196a expression in intestinal-type IPMN tissue samples (n = 18) was significantly higher than that of non-intestinal-type IPMNs (n = 16) (P < 0.001). Similarly, miR-196a expression in pancreatic juice samples of intestinal-type IPMNs (n = 6) was significantly higher than that of non-intestinal-type IPMNs (n = 30) (P = 0.008), and the sensitivity and specificity for prediction of intestinal-type IPMNs using pancreatic juice samples were both 83%., Conclusions: Elevated expression of miR-196a in pancreatic juice samples is predictive of intestinal-type IPMNs.

Objectives: Gemcitabine resistance (GR) is one of the critical issues for therapy for pancreatic cancer, but the mechanism still remains unclear. Our aim was to increase the understanding of GR by metabolic profiling approach., Methods: To establish GR cells, 2 human pancreatic cancer cell lines, SUIT-2 and CAPAN-1, were exposed to increasing concentration of gemcitabine. Both parental and chemoresistant cells obtained by this treatment were subjected to metabolic profiling based on liquid chromatography-mass spectrometry., Results: Multivariate statistical analyses, both principal component analysis and orthogonal partial least squares discriminant analysis, distinguished metabolic signature of responsiveness and resistance to gemcitabine in both SUIT-2 and CAPAN-1 cells. Among significantly different (P < 0.005) metabolite peaks between parental and GR cells, we identified metabolites related to several metabolic pathways such as amino acid, nucleotide, energy, cofactor, and vitamin pathways. Decreases in glutamine and proline levels as well as increases in aspartate, hydroxyproline, creatine, and creatinine levels were observed in chemoresistant cells from both cell lines., Conclusions: These results suggest that metabolic profiling can isolate distinct features of pancreatic cancer in the metabolome of gemcitabine-sensitive and GR cells. These findings may contribute to the biomarker discovery and an enhanced understanding of GR in pancreatic cancer.

Objectives: To clarify the recurrence pattern after resection of main duct intraductal papillary mucinous neoplasms (MD-IPMNs) using molecular analyses and determine the most adequate treatment strategy., Background: The most appropriate resection line for MD-IPMNs remains an unresolved issue., Methods: Medical records of 56 patients with pancreatectomy were retrospectively reviewed. Histological subtypes and Kras/GNAS mutations were assessed in patients with recurrence in the remnant pancreas., Results: Forty-nine patients underwent partial pancreatectomy and 7 underwent total pancreatectomy. Thirty-six patients (64%) had malignant MD-IPMNs. Recurrence was observed in 7 of 49 patients (14%), including 6 with malignant IPMNs and 1 with pancreatic ductal adenocarcinoma, all of whom underwent remnant pancreatectomy. The cumulative disease-specific survival rate of patients with pancreatic recurrence was greater than that of patients with extrapancreatic recurrence (P < 0.001). Although the pancreatic margin status at the initial operation did not affect the pancreatic recurrence rate, all 4 recurrent IPMNs examined had histological subtypes and Kras/GNAS mutations identical to those of the initial lesions. Four patients experienced recurrence in the remnant pancreas or systemic recurrence after resection of high-grade dysplasia of MD-IPMN. Three of the 56 patients had concomitant pancreatic ductal adenocarcinomas and MD-IPMNs., Conclusions: One-step total pancreatectomy can be avoided, and remnant total pancreatectomy would lead to favorable outcomes even in patients with pancreatic recurrence, some cases of which seem to involve residual lesions. Postoperative surveillance of high-grade dysplasia should be performed as if malignant, and close attention should be paid to the occurrence of concomitant pancreatic ductal adenocarcinomas in patients with MD-IPMNs.

Background: There has been a variation in published opinions toward the effectiveness of school closure which is implemented reactively when substantial influenza transmissions are seen at schools. Parameterizing an age-structured epidemic model using published estimates of the pandemic H1N1-2009 and accounting for the cost effectiveness, we examined if the timing and length of school closure could be optimized., Methods: Age-structured renewal equation was employed to describe the epidemic dynamics of an influenza pandemic. School closure was assumed to take place only once during the course of the pandemic, abruptly reducing child-to-child transmission for a fixed length of time and also influencing the transmission between children and adults. Public health effectiveness was measured by reduction in the cumulative incidence, and cost effectiveness was also examined by calculating the incremental cost effectiveness ratio and adopting a threshold of 1.0 × 10⁷ Japanese Yen/life-year., Results: School closure at the epidemic peak appeared to yield the largest reduction in the final size, while the time of epidemic peak was shown to depend on the transmissibility. As the length of school closure was extended, we observed larger reduction in the cumulative incidence. Nevertheless, the cost effectiveness analysis showed that the cost of our school closure scenario with the parameters derived from H1N1-2009 was not justifiable. If the risk of death is three times or greater than that of H1N1-2009, the school closure could be regarded as cost effective., Conclusions: There is no fixed timing and duration of school closure that can be recommended as universal guideline for different types of influenza viruses. The effectiveness of school closure depends on the transmission dynamics of a particular influenza virus strain, especially the virulence (i.e. the infection fatality risk).

Frozen human tissues are necessary for research purposes, but tissue banking methods have not changed for more than a decade. Many institutions use cryovial tubes or plastic molds with an optimal cutting temperature compound. However, these methods are associated with several problems, such as samples sticking to one another and the need for a larger storing space. We established an efficient tissue freezing and storing procedure ("tissue tablet method") applicable to both molecular analysis and frozen tissue microarray. Tissue samples were chopped into tiny fragments and embedded into tablet-shaped frozen optimal cutting temperature compound using our original tissue-freezing plate. These tablets can be sectioned and stored in cryovial tubes. We compared the tissue quality of tablet-shaped samples with that of conventional optimal cutting temperature blocks and found no significant difference between them. Tissue microarray is a key method to utilize tissue-banking specimens. However, most tissue microarrays require the coring out of cylindrically shaped tissues from formalin-fixed, paraffin-embedded tissue blocks. Antigenic changes and mRNA degradation are frequently observed with formalin-fixed, paraffin-embedded samples. Therefore, we have applied tablet-shaped samples to construct frozen tissue microarrays with our original mounting base. Constructed tissue microarray sections showed good morphology without obvious artifact and good immunohistochemistry and in situ hybridization results. These results suggest that the quality of arrayed samples was sufficiently appropriate for research purposes. In conclusion, the tissue tablet method and frozen tissue microarray procedure can save time, provides easy tissue handling and processing, and satisfies the demands of research methodologies and tissue banking., (© 2013.)

A 21-day-old female neonate weighing 3.2 kg was scheduled for surgical excision of a maxillary tumor under general anesthesia. The lesion was present since birth, with gradual enlargement since then. Preoperatively, the lesion measured 25 mm in diameter, although it was not known whether it was benign or malignant. The oral surgeon anticipated that the surgery would require 30 minutes for completion and would involve minimal bleeding. Hence, blood products were not prepared preoperatively. A good intravenous access was secured before induction of general anesthesia, which was achieved with IV thiopental. When it was ascertained that the patient could be easily ventilated by a bag and mask, rocuronium bromide was administered, together with inhalation of sevoflurane. However, the glottis could not be completely visualized on laryngoscopy for tracheal intubation with Cormack and Lehane scores of grade III. Hence, after discussion with the surgeon, we inserted a flexible laryngeal mask for airway management. During the surgery, unexpected massive hemorrhage occurred after incision of the tumor, followed by a severe drop in blood pressure. The amount of blood loss was 100 cc. For this catastrophic hypovolemia, we urgently transfused red cell concentrate (RCC). The surgical procedure lasted for 27 minutes and at the end of the surgery we successfully intubated the patient's trachea with a spiral tube using a guide wire and bronchofiber. After adequate blood transfusion to restore the patient's blood volume, a nasogastric tube was inserted and the patient was extubated in a fully awake state with establishment of adequate spontaneous breathing. Postoperatively, histopathologic examination revealed that the tumor was a jawbone medullary hemangioma.

Objectives: Glucagon-like peptide 1 (GLP-1) interacts with its specific high-affinity receptor, glucagon-like peptide 1 receptor (GLP-1R), and induces cellular growth and inhibition of apoptosis in pancreatic β cells. The aim of this study was to investigate the significance of GLP-1R expression in pancreatic neuroendocrine tumors (PNETs)., Methods: Glucagon-like peptide 1 receptor expression was semiquantitatively evaluated by immunohistochemical staining in 50 resected PNETs, and the correlation between the GLP-1R expression and clinicopathologic features was investigated., Results: There were 23 PNETs with positive expression and 27 PNETs with negative expression of GLP-1R. Positive expression of GLP-1R was more frequently observed in insulinoma than in gastrinoma and nonfunctioning tumor (P < 0.05). Although expression status of GLP-1R did not affect the prognosis of the patients with PNETs (P = 0.82), most of the metastatic sites such as lymph node and liver showed positive staining for GLP-1R (8 of 11 PNETs, 73%)., Conclusions: Glucagon-like peptide 1 receptor would be a diagnostic marker of insulinoma and might become a molecular target for treatment of metastatic PNETs and hormonal regulation of insulin.

Background: Interactions between cancer cells and surrounding cancer-associated fibroblasts (CAFs) play an important role in cancer progression. Invasive ductal carcinoma (IDC) of the pancreas is characterized by abundant fibrous connective tissue called desmoplasia. Podoplanin (PDPN) is a lymphatic vessel marker (D2-40), and expression of PDPN by stromal CAFs has been reported to be a prognostic indicator in various types of cancer., Methods: Expression of PDPN in pancreatic IDCs was assessed by immunohistochemical examination in 105 patients who underwent pancreatic resection. Primary CAFs were established from pancreatic cancer tissue obtained by surgery. Quantitative reverse transcription-polymerase chain reaction and flow cytometric analysis were performed to investigate PDPN expression in CAFs. We sorted CAFs according to PDPN expression, and analyzed the functional differences between PDPN+ CAFs and PDPN- CAFs using indirect co-culture with pancreatic cancer cell lines. We also investigated the culture conditions to regulate PDPN expression in CAFs., Results: PDPN expression in stromal fibroblasts was associated with lymphatic vessel invasion (P = 0.0461), vascular invasion (P = 0.0101), tumor size ≥ 3 cm (P = 0.0038), histological grade (P = 0.0344), Union for International Cancer Control classification T stage (P = 0.029), and shorter survival time (P < 0.0001). Primary CAFs showed heterogeneous PDPN expression in vitro. Moreover, migration and invasion of pancreatic cancer cell lines (PANC-1 and SUIT-2) were associated with PDPN expression in CAFs (P < 0.01) and expression of CD10, matrix metalloproteinase (MMP) 2, and MMP3. In cultured CAFs, PDPN positivity changed over time under several conditions including co-culture with cancer cells, different culture media, and addition of growth factor., Conclusions: PDPN-expressing CAFs enhance the progression of pancreatic IDC, and a high ratio of PDPN-expressing CAFs is an independent predictor of poor outcome. Understanding the regulation of the tumor microenvironment is an important step towards developing new therapeutic strategies.

Objectives: CD105 expression correlates with prognosis for several cancers. However, its significance in pancreatic cancer is unclear., Methods: We analyzed CD105 expression in resected pancreatic cancer tissue and pancreatic cancer cell lines, compared the properties of CD105(+) and CD105(-) cells using quantitative RT-PCR and migration assays, and evaluated the relationship between CD105(+) cells and pancreatic stellate cells (PSCs)., Results: Immunohistochemistry showed that the frequency of CD105 expression was higher in pancreatic cancer than that in normal tissue(8% vs 0%, respectively). In flow cytometry, CD105 was expressed in pancreatic cancer cells, whereas weak CD105 expression was detected in normal pancreatic ductal epithelial cells. Quantitative RT-PCR showed that E-cadherin mRNA expression was suppressed and vimentin mRNA was overexpressed in CD105(+) cells (P < 0.05). Migration of CD105(+) cancer cells was strongly enhanced (more than that of CD105(+) cells) in coculture with PSCs (P < 0.05). CD105 expression did not correlate to clinicopathologic characteristics or the Kaplan-Meier survival analysis., Conclusions: Suppression of an epithelial marker and over expression of a mesenchymal marker suggest that epithelial-mesenchymal transition is induced in CD105(+) pancreatic cancer cells. CD105(+) pancreatic cancer cell migration is strongly enhanced by PSCs, suggesting that these cells play a role in the pancreatic cancer microenvironment.

Gradients of topographic cues play essential roles in the organization of sensory systems by guiding axonal growth cones. Little is known about whether there are additional mechanisms for precise topographic mapping of synaptic connections. Whereas the C. elegans DA8 and DA9 neurons have similar axonal trajectories, their synapses are positioned in distinct but adjacent domains in the anterior-posterior axis. We found that two Wnts, LIN-44 and EGL-20, are responsible for this spatial organization of synapses. Both Wnts form putative posterior-high, anterior-low gradients. The posteriorly expressed LIN-44 inhibits synapse formation in both DA9 and DA8, and creates a synapse-free domain on both axons via LIN-17 /Frizzled. EGL-20, a more anteriorly expressed Wnt, inhibits synapse formation through MIG-1/Frizzled, which is expressed in DA8 but not in DA9. The Wnt-Frizzled specificity and selective Frizzled expression dictate the stereotyped, topographic positioning of synapses between these two neurons., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

mRNA capping is the first cotranscriptional modification of mRNA in the nucleus. In Saccharomyces cerevisiae, the first two steps of mRNA capping are catalyzed by the RNA triphosphatase Cet1p and the RNA guanylyltransferase Ceg1p. Cet1p and Ceg1p interact to form a mRNA capping enzyme complex and the guanylyltransferase activity of Ceg1p is stimulated by binding with Cet1p. The Cet1p-Ceg1p complex needs to be transported into the nucleus, where mRNA capping occurs. However, the molecular mechanism of nuclear transport of the Cet1p-Ceg1p complex is not known. Here, we show that Cet1p is responsible and that the Cet1p-Ceg1p interaction is essential for the nuclear localization of the Cet1p-Ceg1p complex. The results indicate that the Cet1p-Ceg1p interaction is important not only for the activation of Ceg1p, but also for nuclear import of the complex.

Improving poor outcomes in patients with pancreatic cancer requires a greater understanding of the biological mechanisms contributing to radioresistance. We, therefore, sought to identify genes involved in the radioresistance of pancreatic cancer cells. Two pancreatic cancer cell lines, CFPAC-1 and Capan-1, were repeatedly exposed to radiation, establishing two radioresistant cell lines. Gene expression profiling using cDNA microarrays was performed to identify genes responsible for radioresistance. The levels of expression of mRNAs encoded by selected genes and their correlation with radiation dose resulting in 50% survival rate were analyzed in pancreatic cancer cell lines. The radiation dose resulting in a 50% survival rate was significantly higher in irradiated (IR) compared to parental CFPAC-1 cells (8.31 ± 0.85 Gy vs. 2.14 ± 0.04 Gy, P<0.0001), but was lower in IR compared with parental Capan-1 cells (2.66 ± 0.24 Gy vs. 2.25 ± 0.03 Gy, P=0.04). cDNA microarray analysis identified 4 genes, including S100 calcium binding protein A4 (S100A4), overexpressed and 23 genes underexpressed in the IR compared with the parental cell lines. The levels of S100A4 mRNA expression were correlated with radiation dose resulting in a 50% survival rate (Pearson's test, R2=0.81, P=0.0025). S100A4 mRNA expression may predict radioresistance of pancreatic cancer cells and may play an important role in the poor response of pancreatic cancer cells to radiation therapy.

Ten patients aged 75 years or more with advanced or metastatic gastric cancer were prescribed S-1 plus docetaxel (DOC) combination therapy. None of the patients showed complete response, but 2 showed partial response and 4 showed stable disease. Grade 3 or 4 toxicities occurred in 3 patients. Three patients with performance status (PS) 1 achieved partial response or stable disease and were free of Grade 3 or 4 toxicities, whereas the response and occurrence of adverse events in 7 patients with PS 2 varied widely. In these patients, an investigation of the relationship between response to treatment and the Vulnerable Elders Survey (VES-13) score showed that VES-13 scores were higher in the non-response group than in the other patients and in patients who experienced adverse events than in those who did not. These findings suggest that VES-13 could be a useful screening tool for predicting response and the occurrence of adverse events in elderly patients undergoing combined S-1 plus DOC therapy for advanced or metastatic gastric cancer.

Background: Improvement in the prognosis of patients with pancreatic cancer, novel effective screening and diagnostic strategies and treatments are needed. Recent advances in the understanding of pancreatic carcinogenesis and tumor microenvironment have allowed identification of biomarkers for screening, diagnosis and prediction of cancer treatments, including novel therapies targeting specific cancer or stromal cell subpopulations. Personalized therapy in pancreatic cancer is also promising as several drugs such as S1, capecitabine and gemcitabine reportedly have significant therapeutic effects. Predictive markers are thus needed to select patients most likely to benefit from therapies based on gemcitabine or other drugs., Summary: We review the clinical significance of promising screening, diagnostic, predictive and prognostic biomarkers based on genetic and epigenetic alterations and microRNA abnormalities in pancreatic cancer. We also review new types of biomarkers based on stromal cells, such as pancreatic stellate cells, in the microenvironment of pancreatic cancer.

Purpose: To measure choroidal thickness in healthy pregnant women using enhanced depth imaging optical coherence tomography (EDI-OCT) and compare the measurements with those of healthy non-pregnant women., Methods: Choroidal thickness was measured at the fovea and at 3 mm superior, inferior, temporal, and nasal to the fovea using EDI-OCT in both healthy pregnant and non-pregnant women., Results: The mean choroidal thickness in pregnant women was 275 ± 84 μm at the subfoveal and 307 ± 89, 277 ± 89, 274 ± 74, and 159 ± 60 μm at 3 mm superior, inferior, temporal, and nasal to the fovea, respectively. In comparison, the mean choroidal thickness in non-pregnant women was 273 ± 92 μm at the subfoveal and 301 ± 73, 290 ± 76, 293 ± 77, and 149 ± 55 μm at 3 mm superior, inferior, temporal, and nasal to the fovea, respectively. No significant statistical differences were found for choroidal thickness between the pregnant and non-pregnant women at any of the measurement points., Conclusions: The results of this study demonstrate that the choroidal thickness was not significantly different between healthy pregnant and non-pregnant women.

Background: Pancreatic cancer is associated with a devastating prognosis, partially because of its aggressive metastatic ability. Identification of prognostic markers of metastasis would be useful in the clinical management of postoperative patients with pancreatic cancer. Mal, T-cell differentiation protein 2 (MAL2) has been identified as a molecule predictive of metastases; the clinical relevance of MAL2 in pancreatic cancer is unknown., Methods: Orthotopic human pancreatic cancer xenografts from the pancreatic cancer cell line SUIT-2 were established in nude mice. Only liver metastasis was harvested and cultured. These metastatic cycles were repeated 5 times to establish a highly metastatic cell line, termed metastatic SUIT-2 (MS). We investigated proliferation and motility of MS cells compared with those of the parent SUIT-2. Microarray analysis was performed to investigate differences in gene expression. We also performed immunohistochemical analysis of 89 formalin-fixed, paraffin-embedded human pancreatic cancer tissue samples to investigate the clinical significance of MAL2 expression., Results: MS cells showed a greater metastatic rate after orthotopic implantation than parental SUIT-2. MS cells had increased motility but decreased proliferation compared with parental SUIT-2. Microarray analyses showed that 26 genes were significantly upregulated (>10-fold) in MS cells compared with parental SUIT-2, particularly MAL2 expression. Immunohistochemical analysis showed that high expression of MAL2 was associated with a lesser survival of postoperative patients (P = .03) and a high rate of distant metastasis (P = .008)., Conclusion: We characterized a newly established pancreatic cancer cell line with highly metastatic potential. MAL2 is a promising predictive marker for distant metastasis and short survival in patients with resected pancreatic cancer., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Context: There are few studies regarding the surveillance period and interval of resected or observed branch duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in terms of early detection of concomitant pancreatic ductal adenocarcinoma. Despite a strict surveillance protocol, some patients are diagnosed with metastatic distinct ductal adenocarcinoma after resection of IPMN., Case Report: We herein report a patient with unresectable pancreatic ductal adenocarcinoma that developed in the remnant pancreas 18 months after resection of branch duct IPMN. Although the patient was surveyed every 6 months after the operation and imaging studies at 6 and 12 months postoperatively demonstrated no evidence of recurrence, invasive ductal adenocarcinoma with liver metastasis appeared 18 months after the operation. The patient subsequently underwent chemotherapy; however, he died 9 months after the diagnosis of metachronous pancreatic ductal adenocarcinoma., Conclusions: In some patients with branch duct IPMNs, 6-month surveillance seems to be insufficient to detect resectable concomitant pancreatic ductal adenocarcinoma. Therefore, identification of high-risk patients who require surveillance at shorter intervals is urgently needed.