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The patient was a 71-year-old woman with aquaporin-4-antibody positive neuromyelitis optica (NMO), with no history of diabetes. On admission, although she showed an extremely elevated plasma glucose level (1,080 mg/dL), her hemoglobin A1c level was low (7.1%), which indicated the rapid progression of diabetes. She also showed ketoacidosis and had a human leukocyte antigen haplotype, DRB1*09:01-DQB1*03:03 associated with Fulminant type 1 diabetes (FT1D). Based on these results, the patient was diagnosed with FT1D. We herein describe the first reported case of a patient with FT1D with NMO, which raises the possibility that T-cell-mediated autoimmunity is involved in the pathogenesis of both FT1D and NMO.

Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.

Precise neuronal wiring is critical for the function of the nervous system and is ultimately determined at the level of individual synapses. Neurons integrate various intrinsic and extrinsic cues to form synapses onto their correct targets in a stereotyped manner. In the past decades, the nervous system of nematode (Caenorhabditis elegans) has provided the genetic platform to reveal the genetic and molecular mechanisms of synapse formation and specificity. In this review, we will summarize the recent discoveries in synapse formation and specificity in C. elegans.

Background: Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer-stromal interaction., Methods: Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor., Results: Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer-stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model., Conclusions: These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis.

Purpose: This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer., Methods: We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin-CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model., Results: CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK-MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model., Conclusions: CD110 promotes pancreatic cancer progression and it may serve as a predictive factor for liver metastasis.

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy., (© 2018 UICC.)

Influenza virus RNA polymerase has cap-dependent endonuclease activity that produces capped RNA fragments for priming viral mRNA synthesis. This enzymatic activity is essential for viral propagation, but it is not present in any host cellular enzyme, making it an attractive target for the development of anti-influenza drugs. Here, we isolated a novel inhibitor of cap-dependent endonuclease, named flupyranochromene, from the fermentation broth of the fungus Penicillium sp. f28743. Structural analysis revealed that this compound bears a putative pharmacophore that chelates divalent metal ion(s) present in the endonuclease active site in the PA subunit of the polymerase. Consistently, in vitro endonuclease assays showed that flupyranochromene exerts its inhibitory effects by blocking endonucleolytic cleavage by the PA subunit of viral RNA polymerase complex.

The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A large body of epidemiologic research has concentrated on the 1918 influenza pandemic, but more work is needed to understand spatial variation in pandemic mortality and its effects on natality. We collected and analyzed 35,151 death records from Arizona for 1915-1921 and 21,334 birth records from Maricopa county for 1915-1925. We estimated the number of excess deaths and births before, during, and after the pandemic period, and we found a significant decline in the number of births occurring 9-11 months after peak pandemic mortality. Moreover, excess mortality rates were highest in northern Arizona counties, where Native Americans were historically concentrated, suggesting a link between ethnic and/or sociodemographic factors and risk of pandemic-related death. The relationship between birth patterns and pandemic mortality risk should be further studied at different spatial scales and in different ethnic groups.

Our ability to sequence genomes has vastly surpassed our ability to interpret the genetic variation we discover. This presents a major challenge in the clinical setting, where the recent application of whole-exome and whole-genome sequencing has uncovered thousands of genetic variants of uncertain significance. Here, we present a strategy for targeted human gene replacement and phenomic characterization, based on CRISPR-Cas9 genome engineering in the genetic model organism Caenorhabditis elegans , that will facilitate assessment of the functional conservation of human genes and structure-function analysis of disease-associated variants with unprecedented precision. We validate our strategy by demonstrating that direct single-copy replacement of the C. elegans ortholog ( daf-18 ) with the critical human disease-associated gene phosphatase and tensin homolog ( PTEN ) is sufficient to rescue multiple phenotypic abnormalities caused by complete deletion of daf-18 , including complex chemosensory and mechanosensory impairments. In addition, we used our strategy to generate animals harboring a single copy of the known pathogenic lipid phosphatase inactive PTEN variant (PTEN-G129E), and showed that our automated in vivo phenotypic assays could accurately and efficiently classify this missense variant as loss of function. The integrated nature of the human transgenes allows for analysis of both homozygous and heterozygous variants and greatly facilitates high-throughput precision medicine drug screens. By combining genome engineering with rapid and automated phenotypic characterization, our strategy streamlines the identification of novel conserved gene functions in complex sensory and learning phenotypes that can be used as in vivo functional assays to decipher variants of uncertain significance., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

During development, neurons form synapses with their fate-determined targets. While we begin to elucidate the mechanisms by which extracellular ligand-receptor interactions enhance synapse specificity by inhibiting synaptogenesis, our knowledge about their intracellular mechanisms remains limited. Here we show that Rap2 GTPase ( rap-2 ) and its effector, TNIK ( mig-15 ), act genetically downstream of Plexin ( plx-1 ) to restrict presynaptic assembly and to form tiled synaptic innervation in C. elegans . Both constitutively GTP- and GDP-forms of rap-2 mutants exhibit synaptic tiling defects as plx-1 mutants, suggesting that cycling of the RAP-2 nucleotide state is critical for synapse inhibition. Consistently, PLX-1 suppresses local RAP-2 activity. Excessive ectopic synapse formation in mig-15 mutants causes a severe synaptic tiling defect. Conversely, overexpression of mig-15 strongly inhibited synapse formation, suggesting that mig-15 is a negative regulator of synapse formation. These results reveal that subcellular regulation of small GTPase activity by Plexin shapes proper synapse patterning in vivo., Competing Interests: XC, AS, AH, MK, EF, NW, BM, HM, KM No competing interests declared, (© 2018, Chen et al.)

Background/aim: Metabolomics is widely used for biomarker discovery, but conventional mass-spectrometry extraction procedures lose the spatial localization of metabolites. In this study, we directly analyzed breast carcinoma tissues embedded in frozen tissue microarrays (fTMAs) using MALDI mass-spectrometry imaging (MALDI-MSI)., Materials and Methods: A total of 119 breast tissues (84 carcinoma and 35 normal) were used. MSI data were extracted from each tissue., Results: Overall, 185 of 1,915 peaks which were commonly detected in 60% of target areas were subjected to further analysis. One hundred and fifty-two peaks of carcinoma showed significantly higher intensity than normal. Comparing metabolite profiles from carcinoma and normal tissues, energy charge (EC) and the sum of adenosine phosphate compound (AXP) indicated significantly higher intensities in cancerous tissues than normal. But comparisons of EC and AXP among lymph node metastasis, tumor size and tumor subtypes indicated no significant differences., Conclusion: Breast carcinoma tissues had higher EC and AXP values than normal. MALDI-MSI could be a tool for characterizing breast carcinoma., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruction and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A recent outbreak of measles in Okinawa Prefecture, Japan ended with 33 measles cases whose symptoms were masked because of insufficient protection against the disease (modified measles). Using quantitative modelling, we determined the transmission potential of measles by clinical presentation (classic vs modified measles). We found low ascertainment probabilities among modified measles cases, indicating that intensified public health interventions that specifically target this group should be implemented to better contain outbreaks with modified measles cases.

Purpose: Our understanding of the temporal dynamics and age-specific mortality patterns of the 1918-1921 influenza pandemic remains scarce due to lack of detailed respiratory mortality datasets in the United States and abroad., Methods: We manually retrieved individual death records from Arizona during 1915-1921 and applied time series models to estimate the age specific mortality burden of the 1918-1921 influenza pandemic. We estimated influenza-related excess mortality rates and mortality rate ratio increase over baseline based on pneumonia and influenza (P&I), respiratory, tuberculosis and all-cause death categories., Results: Based on our analysis of 35,151 individual mortality records from Arizona, we identified three successive pandemic waves in spring 1918, fall 1918-winter 1919 and winter 1920. The pandemic associated excess mortality rates per 10,000 population in Arizona was estimated at 83 for P&I, 86 for respiratory causes, 84 for all-causes and 9 for tuberculosis. Age-specific P&I and tuberculosis excess death rates were highest among 25- to 44-year-olds and individuals ≥65 years, respectively. The 25- to 44-year-olds and 5- to 14-year-olds had highest P&I and tuberculosis mortality impact respectively when considering the ratio over background mortality., Conclusions: The 1918-1921 influenza pandemic killed an estimated 0.8% of the Arizona population in three closely spaced consecutive waves. The mortality impact of the fall 1918 wave in Arizona lies in the upper range of previous estimates reported for other US settings and Europe, with a telltale age distribution of deaths concentrated among young adults. We identified a significant rise in tuberculosis-related mortality during the pandemic, lending support to the hypothesis that tuberculosis was a risk factor for severe pandemic infection. Our findings add to our current understanding of the mortality impact of this pandemic in the US and globally., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The adenomatous polyposis coli (APC) tumor suppressor has dual functions in Wnt/β-catenin signaling and accurate chromosome segregation and is frequently mutated in colorectal cancers. Although APC contributes to proper cell division, the underlying mechanisms remain poorly understood. Here we show that Caenorhabditis elegans APR-1/APC is an attenuator of the pulling forces acting on the mitotic spindle. During asymmetric cell division of the C. elegans zygote, a LIN-5/NuMA protein complex localizes dynein to the cell cortex to generate pulling forces on astral microtubules that position the mitotic spindle. We found that APR-1 localizes to the anterior cell cortex in a Par-aPKC polarity-dependent manner and suppresses anterior centrosome movements. Our combined cell biological and mathematical analyses support the conclusion that cortical APR-1 reduces force generation by stabilizing microtubule plus-ends at the cell cortex. Furthermore, APR-1 functions in coordination with LIN-5 phosphorylation to attenuate spindle-pulling forces. Our results document a physical basis for the attenuation of spindle-pulling force, which may be generally used in asymmetric cell division and, when disrupted, potentially contributes to division defects in cancer., Competing Interests: The authors declare no conflict of interest.

Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Objectives: Despite some progress made in the fight against malnutrition in Madagascar, hospitals' mortality due to severe acute malnutrition (SAM) remains high. This study explores the risk factors for SAM among children hospitalized with SAM in the Analamanga region of Madagascar., Methods: We conducted an interview based qualitative study of 14 mothers of under-five children with SAM admitted to the hospital's pediatric unit and living in the Analamanga region. Data were analyzed using thematic analysis method., Results: There were direct, intermediate and basic causes of malnutrition shared with other health care settings. Low health literacy such as limited knowledge and optimistic perception of malnutrition, and lack of health service information resulted in delayed hospital visit for care of SAM. Vulnerable working mothers do not benefit from available community support structure. Mothers are unable to practice what they learned because financial difficulties at the household level occupy their time., Conclusions and Global Health Implications: Consideration of vulnerable working mothers' access to existing health services and interventions to address health literacy are important to prevent SAM at the community level. Study findings would be of interest to practitioners and policy makers in the region and perhaps in other resource limited settings., Competing Interests: Conflicts of Interest: The authors declare no conflicts of interest associated with this study.

Background: Salinomycin has cytotoxic effects on various types of malignancy and induces autophagy. However, it has not been clarified whether autophagy induced by salinomycin treatment has a protective or cytotoxic role. We investigated whether salinomycin affects autophagy in pancreatic cancer cells and whether autophagy induced by salinomycin treatment has a protective or cytotoxic role in these cells., Methods: We investigated the effect of salinomycin using three pancreatic cancer cell lines. We investigated effect on proliferation and the CD133 positive fraction using flow cytometry. In addition, we monitored the change in autophagic activity after salinomycin treatment using fluorescent immunostaining, western blotting, and flow cytometry. Finally, knockdown of ATG5 or ATG7 by siRNA was used to investigate the impact of autophagy inhibition on sensitivity to salinomycin., Results: Salinomycin suppressed the proliferation of pancreatic cancer cells in a concentration dependent manner, and reduced the CD133 positive fraction. Salinomycin enhanced autophagy activity in these cells in a concentration dependent manner. Autophagy inhibition made pancreatic cancer cells more sensitive to salinomycin., Conclusions: Our data provide the first evidence indicating that autophagy induced by salinomycin have a protective role in pancreatic cancer cells. A new therapeutic strategy of combining salinomycin, autophagy inhibitors, and anticancer drugs could hold promise for pancreatic cancer treatment., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Objective: This study was performed to investigate longitudinal changes in the subfoveal choroidal thickness (SFCT) during pregnancy and after delivery., Patients and Methods: The SFCT was measured in the first and third trimesters, shortly after delivery, and 1 month after delivery in 25 eyes of 25 women. Enhanced depth imaging optical coherence tomography was used for measurement., Results: The mean SFCT was 347 μm ± 86 μm, 329 μm ± 81 μm, 333 μm ± 81 μm, and 330 μm ± 87 μm in the first and third trimesters, shortly after delivery, and 1 month after delivery, respectively. The SFCT in the first trimester was significantly greater than that in the third trimester, shortly after delivery, and 1 month after delivery., Conclusions: This study indicates that the SFCT is greater in the first trimester and decreases in the third trimester of pregnancy. The SFCT does not subsequently change until 1 month after delivery. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:816-821.]., (Copyright 2017, SLACK Incorporated.)

Purpose: Intraocular pressure (IOP) increases in patients in a steep Trendelenburg position during robotic-assisted laparoscopic radical prostatectomy (RALP). We hypothesized that a steep Trendelenburg position during RALP, an unusual systemic condition involving a transiently increased IOP, may induce ocular pathology that can be detected by detailed evaluations long after the surgery. This study aims to explore ocular structural and functional parameters in patients before and in the long term after the surgery., Patients and Methods: A comparative observational study was performed. A total of 44 eyes of 22 male patients scheduled for RALP at Aichi Medical University from August 2012 to July 2013 were included. Clinical parameters before and after RALP were compared. Perioperative IOP was measured immediately post-induction of anesthesia in the flat supine position (T1), immediately post-steep Trendelenburg position (T2), and prior to returning to a flat supine position while in a steep Trendelenburg position (T3). The thicknesses of the peripapillary retinal nerve fiber layer, ganglion cell complex (GCC), and central fovea were measured with spectral domain optical coherence tomography. Humphrey perimetry was performed before and at 3 and 6 months after surgery., Results: The average IOPs (mmHg) at each stage were T1=10.4, T2=21.7, and T3=29.6, and differed significantly. The mean visual acuity (logarithm of the minimal angle of resolution), IOP, mean deviation, and pattern standard deviation measured by the Humphrey field analyzer showed no statistically significant difference before and after surgery. The ganglion cell complex and retinal nerve fiber layer thicknesses measured at each location and the central fovea thicknesses measured before and after surgery did not differ significantly., Conclusion: No significant disorders in ocular structural and functional parameters were found until long after RALP., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objectives: Despite the verification of measles elimination, Japan experienced multiple generations of measles transmission following importation events in 2016. The purpose of the present study was to analyze the transmission dynamics of measles in Japan, 2016, estimating the transmission potential in the partially vaccinated population., Methods: All diagnosed measles cases were notified to the government, and the present study analyzed two pieces of datasets independently, i.e., the transmission tree of the largest outbreak in Osaka (n=49) and the final size distribution of all importation events (n=23 events). Branching process model was employed to estimate the effective reproduction number R v , and the analysis of transmission tree in Osaka enabled us to account for the timing of introducing contact tracing and case isolation., Results: Employing a negative binomial distribution for the offspring distribution, the model with time-dependent decline in R v due to interventions appeared to best fit to the transmission tree data with R v of 9.20 (95% CI (confidence interval): 2.08, 150.68) and the dispersion parameter 0.32 (95% CI: 0.07, 1.17) before interventions were introduced. The relative transmissibility in the presence of interventions from week 34 was estimated at 0.005. Analyzing the final size distribution, models for subcritical and supercritical processes fitted equally well to the observed data, and the estimated reproduction number from both models did not exclude the possibility that R v >1., Conclusions: Our results likely reflect the highly contagious nature of measles, indicating that Japan is at risk of observing multiple generations of measles transmission given imported cases. Considering that importation events may continue in the future, supplementary vaccination of adults needs to be considered., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Pancreatic cancer is characterized by increased hyperplasia of fibrotic tissue, termed desmoplasia, and lymph node metastasis is an independent prognostic factor in this disease. However, there are no reports focused on desmoplasia in pancreatic cancer lymph node metastases. The present study evaluated a range of factors and investigated their association with poor prognosis in pancreatic cancer cases with lymph node metastasis, including the degree of desmoplasia in lesions. To identify the poor prognostic factors associated with lymph node metastasis, the present study retrospectively reviewed the clinical data of 65 patients with lymph node metastases that underwent surgical pancreatic cancer resection between 2007 and 2012 at a single institution. The investigation focused on the degree of fibrosis in metastatic lesions in 216 lymph nodes, and investigated associations with prognosis or clinicopathological findings. The ratios of the fibrotic area in metastatic lymph node lesions were evaluated and classified into three categories, high (≥70%), moderate (10-70%) and low (<10%). Desmoplasia was not observed in cancer-free lymph nodes. The size of metastatic lymph node lesions was additionally measured, and a significant association between metastatic lesion size and the degree of desmoplasia was observed (P<0.001). The degree of desmoplasia was additionally associated with local extranodal invasion. In the analysis of 65 pancreatic cancer patients with metastatic lymph nodes, the presence of multiple metastatic lymph nodes with moderate or high desmoplasia was significantly associated with poor survival (high, P=0.0048; moderate/high, P=0.0075). Of several clinicopathological factors, the presence of multiple metastatic lymph nodes with high or moderate desmoplasia was associated with overall survival in univariate (P=0.0098) and multivariate (P=0.0466) analyses. The degree of desmoplasia in metastatic lymph nodes is associated with lesion size, and the presence of multiple metastatic lymph nodes with desmoplasia is an independent poor prognostic factor, suggesting that the desmoplasia may have an important role in the malignant progression of lymph node metastases.

A core principle of nervous system organization is the diversification of neuron classes into subclasses that share large sets of features but differ in select traits. We describe here a molecular mechanism necessary for motor neurons to acquire subclass-specific traits in the nematode Caenorhabditis elegans . Cholinergic motor neuron classes of the ventral nerve cord can be subdivided into subclasses along the anterior-posterior (A-P) axis based on synaptic connectivity patterns and molecular features. The conserved COE-type terminal selector UNC-3 not only controls the expression of traits shared by all members of a neuron class, but is also required for subclass-specific traits expressed along the A-P axis. UNC-3, which is not regionally restricted, requires region-specific cofactors in the form of Hox proteins to co-activate subclass-specific effector genes in post-mitotic motor neurons. This intersectional gene regulatory principle for neuronal subclass diversification may be conserved from nematodes to mice.

Purpose: The GEST study showed non-inferiority of S-1 but not superiority of gemcitabine plus S-1 (GS) to gemcitabine alone for overall survival with the data by the cut-off date of 31st July in 2010 for chemo-naïve patients with advanced pancreatic cancer. We considered it important to determine whether S-1 maintains non-inferiority after a long-term follow-up in the GEST study and to obtain a firm positive conclusion. In addition, it may be an interesting challenge to explore the efficacious profile of GS in the long-term follow-up study. Using the data from the follow-up period, background and efficacy in patients from Taiwan and Japan, as well as the rates of tumor shrinkage in locally advanced and metastatic patients (Waterfall plot) were also analyzed., Methods: The results of the primary analysis were reconfirmed, and subset analysis of overall survival and progression-free survival was performed based on the overall survival data updated by the cut-off date of 31st July in 2011., Results: The median follow-up period was 29.8 months, and 795 deaths occurred (95.6%). The median overall survival was 8.8 months for gemcitabine, 9.7 months for S-1 (hazard ratio [HR], 0.96; 97.5% confidence interval [CI], 0.79-1.17), and 9.9 months for GS (HR 0.91; 97.5% CI 0.75-1.11). In patients with performance status (PS) 0, the median overall survival was 9.8 months for gemcitabine, 10.9 months for S-1, and 10.5 months for GS. In patients with PS 1, the median overall survival was 6.2 months for gemcitabine, 6.3 months for S-1, and 9.6 months for GS., Conclusion: Our survey reconfirmed the non-inferiority of S-1 to gemcitabine and showed S-1 can be used as one of the standard treatment options for advanced pancreatic cancer., Trial Registration: ClinicalTrials.gov: NCT00498225.

Yeast capping enzymes differ greatly from those of mammalian, both structurally and mechanistically. Yeast-type capping enzyme repressors are therefore candidate antifungal drugs. The 5'-guanine-N7 cap structure of mRNAs are an essential feature of all eukaryotic organisms examined to date and is the first co-transcriptional modification of cellular pre-messenger RNA. Inhibitors of the RNA 5'-triphosphatase in yeast are likely to show fungicidal effects against pathogenic yeast such as Candida. We discovered a new RNA 5'-triphosphatase inhibitor, designated as the kribellosides, by screening metabolites from actinomycetes. Kribellosides belong to the alkyl glyceryl ethers. These novel compounds inhibit the activity of Cet1p (RNA 5'-triphosphatase) from Saccharomyces cerevisiae in vitro with IC 50 s of 5-8 μM and show antifungal activity with MICs ranging from 3.12 to 100 μg ml -1 against S. cerevisiae.

Background & Aims: Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor environment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. PSCs have morphologic and functional similarities to hepatic stellate cells, which undergo autophagy to promote fibrosis and tumor growth. We investigated whether autophagy activates PSCs, which promotes development of the tumor stroma and growth of pancreatic tumors in mice., Methods: We used immunofluorescence microscopy and immunohistochemistry to analyze pancreatic tumor specimens from 133 patients who underwent pancreatectomy in Japan from 2000 to 2009. PSCs were cultured from pancreatic tumor tissues or tissues of patients with chronic pancreatitis; these were analyzed by immunofluorescence microscopy, immunoblots, quantitative reverse transcription polymerase chain reaction, and in assays for invasiveness, proliferation, and lipid droplets. Autophagy was inhibited in PSCs by administration of chloroquine or transfection with small interfering RNAs. Proteins were knocked down in immortalized PSCs by expression of small hairpin RNAs. Cells were transplanted into pancreatic tails of nude mice, and tumor growth and metastasis were quantified., Results: Based on immunohistochemical analyses, autophagy was significantly associated with tumor T category (P = .018), histologic grade (P = .001), lymph node metastases (P < .001), stage (P = .009), perilymphatic invasion (P = .001), and perivascular invasion (P = .003). Autophagy of PSCs was associated with shorter survival times of patients with pancreatic cancer. PSC expression of microtubule-associated protein 1 light chain 3, a marker of autophagosomes, was associated with poor outcomes (shorter survival time, disease recurrence) for patients with pancreatic cancer (relative risk of shorter survival time, 1.56). Immunoblots showed that PSCs from pancreatic tumor samples expressed higher levels of markers of autophagy than PSCs from chronic pancreatitis samples. Inhibitors of autophagy increased the number of lipid droplets of PSCs, indicating a quiescent state of PSCs, and reduced their production of ECM molecules and interleukin 6, as well as their proliferation and invasiveness in culture. PSCs exposed to autophagy inhibitors formed smaller tumors in nude mice (P = .001) and fewer liver metastases (P = .018) with less peritoneal dissemination (P = .018) compared to PSCs not exposed to autophagy inhibitors., Conclusions: Autophagic PSCs produce ECM molecules and interleukin 6 and are associated with shorter survival times and disease recurrence in patients with pancreatic cancer. Inhibitors of PSC autophagy might reduce pancreatic tumor invasiveness by altering the tumor stroma., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: This study was performed to compare health-related quality of life (HRQOL) of gemcitabine plus S-1 (GS), S-1 alone and gemcitabine alone as first-line chemotherapy for locally advanced or metastatic pancreatic cancer in the GEST (Gemcitabine and TS-1 Trial) study and to assess the impacts of adverse events and tumour response on HRQOL., Methods: Patients were randomly assigned to receive gemcitabine alone (1000 mg/m 2 weekly for 3 of 4 weeks), S-1 alone (80, 100 or 120 mg/day twice daily for 4 of 6 weeks) or GS (gemcitabine at 1000 mg/m 2 weekly plus S-1 at 60, 80 or 100 mg/day twice daily for 2 of 3 weeks). HRQOL was assessed using the EuroQoL-5D (EQ-5D) questionnaire at baseline and weeks 6, 12, 24, 48 and 72. EQ-5D scores, quality-adjusted life months (QALMs), quality-adjusted progression-free months (QAPFMs) and time until definitive HRQOL deterioration (TUDD) were compared among the three groups. The impacts of adverse events and tumour response on EQ-5D scores were analysed., Results: Including EQ-5D scores after death as 0, the mean profile was significantly better in the GS than gemcitabine group (difference, 0.069; p=0.003), but not the S-1 group (difference, -0.011; p=0.613). The mean profiles until death were similar in the three groups. QALMs, QAPFMs and TUDD were significantly longer in the GS than gemcitabine group (p<0.001, p<0.001 and p=0.004, respectively), but not the S-1 group (p=0.563, p=0.741 and p=0.701, respectively). Fatigue, anorexia and tumour response were significantly associated with changes in EQ-5D scores., Conclusions: GS achieved better HRQOL than gemcitabine alone, resulting a good balance between overall survival and HRQOL benefits. S-1 alone provides HRQOL similar to that provided by gemcitabine alone. Preventing fatigue and anorexia and maintaining better response would improve HRQOL., Competing Interests: Competing interests: YH is contractually employed by J-CRSU. YO has a leadership position at Statcom and J-CRSU; has stock in Statcom; received honoraria from Sanofi, Shionogi, Taiho, Kowa, Chugai and Eisai; and received research funding from Eisai. TO received honoraria from Chugai, Pfizer Japan, Novartis, Taiho, Merck Serono, Eli Lilly Japan, Sumitomo Dainippon, Eisai, Bayer, Yakult, Nobelpharma, Nippon Kayaku, Baxter and Astellas; received rewards for an advisory role from Eli Lilly Japan, Sumitomo Dainippon, Taiho, Ono, Nippon Boehringer Ingelheim, Nano Carrier and Zeria; and received research funding from Chugai, Eli Lilly Japan, Eisai, Novartis, Shizuoka Industry, Takeda Bio Development Center, Yakult, Onco Therapy Science, Otsuka, Taiho, Sceti Medical Labo, Nippon Boehringer Ingelheim, Kowa, Kyowa Hakko Kirin, Merck Serono, Ono, Bayer, Pfizer Japan, AstraZeneca, Sumitomo Dainippon, Nobelpharma, Zeria and Glaxo Smith Kline. HU received honoraria from Taiho and Chugai and received research funding from Taiho, NanoCarrier and Baxalta Japan. TI received rewards for an advisory role from Taiho, Yakult, Baxalta and JCRO; served on the speakers’ bureau of Taiho, Yakult, Daiichi Sankyo, Eisai, Mochida and Fujifilm; and received research funding from Taiho, AstraZeneca, Glaxo Smith Kline, Nihon Zouki, Zeria and Merck Sereno. NB received honoraria from Taiho and Eli Lilly. JF received honoraria from Taiho, Yakult, Eli Lilly Japan, Chugai, Eisai, Ono, Daiichi Sankyo, Merck Serono, Bayer, Novartis, Sumitomo Dainippon, Mitsubishi Tanabe, MSD, AstraZeneca, Sawai, Mochida, Takeda, Pfizer and Astellas; received rewards for an advisory role from Taiho, Yakult, Fujifilm, Chugai, Kyowa Hakko Kirin, Otsuka, Zeria and J-Pharma; served on the speakers’ bureau of Taiho and Yakult; and received research funding from J-Pharma, Taiho, Sumitomo Dainippon, Janssen, Daiichi Sankyo, MSD, Yakult, Takeda, Chugai, Ono, Astellas, Zeria, Novartis, Nanocarrier, Shionogi, Onco Therapy Science, Eli Lilly Japan, Bayer, Bristol-Myers Squibb, Merck Serono, Kyowa Hakko Kirin, Eisai and Mochida. SO received honoraria from Eli Lilly, Taiho, Yakult, Otsuka and Sandoz; received rewards for an advisory role from Boehringer Ingelheim; and received research funding from AstraZeneca. ALC received rewards for an advisory role from Bayer, Eisai, Novartis and Merck KGaA. AS received honoraria from Taiho and received rewards for an advisory role from Taiho. MT received honoraria from Taiho and Eli Lilly and received research funding from Eli Lilly. All remaining authors have declared no conflict of interest.

Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.

We report a case of Trousseau syndrome associated with advanced rectalcancer. A 67-year-old man visited our hospital for right hemiparesis and gait disturbance. Head magnetic resonance imaging showed multiple cerebral infarctions. Abdominal computed tomography showed wallthickening of the rectum and colonoscopy showed type 2 circumferentialrectalcancer. Therefore, he was diagnosed with Trousseau syndrome. After anticoagulation therapy with heparin, an operation was performed. Thereafter, chemotherapy was continued and he has experienced no recurrence of cerebralinfarction.

Nowadays, small pulmonary nodules are easily detectable in patients with soft tissue sarcomas (STSs) because of highly improved computed tomography (CT) technologies. The purpose of this study was to determine the frequency and significance of the pulmonary nodules detected by CT in high-grade STS patients. 124 patients with high-grade STS were retrospectively reviewed. There were 72 males (57%) and 52 females (43%). Patients' average age was 61 years (median (quartiles) 66 years (48-75), range 8-94 years). Pulmonary nodules were detected in 49 (39.5%) of 124 patients by CT scanning at first presentation. Of 49 patients with nodules at first presentation, 34 (69.4%) had benign lesions, and 13 (26.5%) had metastatic nodules. One patient (2%) had primary lung cancer and the remaining one with one nodule could not be definitively diagnosed due to a short follow-up time. 30 patients (24.1%) of 124 patients developed pulmonary nodules during their clinical progression. Seven (23.3%) had benign lesions, whereas 21 (70%) had metastatic lesions. Primary lung cancer was detected in two patients (6.7%). The size and timing of detection of a pulmonary nodule significantly affected the final clinical diagnosisby multivariate analysis. We conclude that pulmonary nodules can be detected highly frequently in patients with high-grade STSs because of improved CT technologies. Careful follow-up is needed if nodules are detected after initial treatment or during the clinical course of the disease., Competing Interests: The authors have declared that no competing interests exist.

The interaction between the cancer cells and the peritoneal mesothelial cells (PMCs) plays an important role in the peritoneal dissemination in several types of cancer. However, the role of PMCs in the peritoneal dissemination of pancreatic cancer remains unclear. In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the PMCs in the formation of peritoneal dissemination in vitro and in vivo. The tumor-stromal interaction of PCCs and PMCs significantly enhanced their mobility and invasiveness and enhanced the proliferation and anoikis resistance of PCCs. In a 3D organotypic culture model of peritoneal dissemination, co-culture of PCCs and PMCs significantly increased the cells invading into the collagen gel layer compared with mono-culture of PCCs. PMCs pre-invaded into the collagen gel, remodeled collagen fibers, and increased parallel fiber orientation along the direction of cell invasion. In the tissues of peritoneal dissemination of the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+;Pdx-1-Cre) transgenic mouse, the monolayer of PMCs was preserved in tumor-free areas, whereas PMCs around the invasive front of peritoneal dissemination proliferated and invaded into the muscle layer. In vivo, intraperitoneal injection of PCCs with PMCs significantly promoted peritoneal dissemination compared with PCCs alone. The present data suggest that the cancer-associated PMCs have important promoting roles in the peritoneal dissemination of PCCs. Therapy targeting cancer-associated PMCs may improve the prognosis of patients with pancreatic cancer.

Background: Florida State has reported autochthonous transmission of Zika virus since late July 2016. Here we assessed the transmissibility associated with the outbreak and generated a short-term forecast., Methods: Time-dependent dynamics of imported cases reported in the state of Florida was approximated by a logistic growth equation. We estimated the reproduction number using the renewal equation in order to predict the incidence of local cases arising from both local and imported primary cases. Using a bootstrap method together with the logistic and renewal equations, a short-term forecast of local and imported cases was carried out., Results: The reproduction number was estimated at 0.16 (95 % Confidence Interval: 0.13, 0.19). Employing the logistic equation to capture a drastic decline in the number of imported cases expected through the course of 2016, together with the low estimate of the local reproduction number in Florida, the expected number of local reported cases was demonstrated to show an evident declining trend for the remainder of 2016., Conclusions: The risk of local transmission in the state of Florida is predicted to dramatically decline by the end of 2016.

Objectives: The aim of this study was to determine the characteristics of patients with pancreatic ductal adenocarcinoma younger than 40 years., Methods: Data from the Japan Pancreas Society's nationwide Pancreatic Cancer Registry were analyzed retrospectively. Clinicopathological characteristics were compared in patients who were grouped according to age, namely, younger than 40 years versus 40 years and older., Results: Of the 36 145 patients in the database, the younger group included 526 (1.5%) patients. A family history of pancreatic cancer was not more frequent in the younger group. The frequency of Union Internationale Contre le Cancer T4 and M1 were both significantly higher in younger patients, resulting in a higher percentage of patients with Union Internationale Contre le Cancer stage IV. Pancreatectomy was performed less frequently in the younger group, and R0 resection was also less frequent. The overall survival rate was significantly better in the older group, whereas in surgically resected patients, the overall survival and recurrence-free survival rates were not different between the 2 groups., Conclusions: Younger patients with pancreatic adenocarcinoma were more often diagnosed at advanced stages, and the overall survival rate was worse than that in older patients. Family genetic background and the prognoses of patients who underwent surgery were similar between the 2 groups.

Cancer-associated fibroblasts (CAFs) are heterogeneous cell populations that influence tumor initiation and progression. CD146 is a cell membrane protein whose expression has been implicated in multiple human cancers. CD146 expression is also detected in pancreatic cancer stroma; however, the role it plays in this context remains unclear. This study aimed to clarify the function and significance of CD146 expression in pancreatic cancer. We performed immunohistochemical staining to investigate the prevalence of CD146 expression in stromal fibroblasts in pancreatic cancer. We also examined the influence of CD146 on CAF-mediated tumor invasion and migration and CAF activation using CD146 small interfering RNA or overexpression plasmids in primary cultures of CAFs derived from pancreatic cancer tissues. CD146 expression in CAFs was associated with high-grade pancreatic intraepithelial neoplasia and low histological grade invasive ductal carcinoma of the pancreas, while patients with low CD146 expression had a poorer prognosis. Blocking CD146 expression in CAFs significantly enhanced tumor cell migration and invasion in a co-culture system. CD146 knockdown also promoted CAF activation, possibly by inducing the production of pro-tumorigenic factors through modulation of NF-κB activity. Consistently, overexpression of CD146 in CAFs inhibited migration and invasion of co-cultured cancer cells. Finally, CD146 expression in CAFs was reduced by interaction with cancer cells. Our findings suggest that decreased CD146 expression in CAFs promotes pancreatic cancer progression. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer-stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer-stromal interaction., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Ptosis incidence following cataract surgery is reduced with a recently developed phacoemulsification technique using a small incision. However, it remains uncertain whether an upper transconjunctival sclerocorneal incision can cause minor blepharoptosis. In the present prospective study, patients underwent cataract surgery with either an upper or temporal 2.4-mm transconjunctival sclerocorneal incision. We measured the marginal reflex distance 1 (MRD1) preoperatively and postoperatively, and compared these measurements between the two different incision types. Further we explored the risk factors of the postoperative MRD1 reduction., Methods: The study population included patients who underwent cataract surgery on both eyes at Aichi Medical University between October 2013 and September 2015. In each patient, one eye was operated using an upper 2.4-mm transconjunctival sclerocorneal incision, and the other with a temporal incision. We prespecified that an MRD1 difference of ≥0.5 mm between the pre- and post-surgical measurements indicated postoperative ptosis, which was a strict criterion. MRD1 was measured using digital photography, and we calculated the difference between the preoperative and postoperative MRD1 values. This change in MRD1 was compared between the groups with different incision locations. The change in MRD1 was analyzed by using the multivariate regression model including incision position (temporal or upper), preoperative MRD1, and preoperative distance between medial and lateral canthi., Results: We assessed data from a total of 34 patients. The mean change in MRD1 from pre-operation to post-operation measurements was -0.26 ± 0.93 with the temporal incision and -0.24 ± 0.86 with the upper incision. The mean difference in the change in MRD1 between the different two incision types was -0.02, with a 95 % CI of -0.24 to 0.20, establishing equivalence between these incision types. The multivariate regression analysis showed that the preoperative MRD1 was significantly associated with the reduction of MRD1 after surgery (p = 0.034)., Conclusions: Cataract surgery using upper and temporal 2.4-mm transconjunctival sclerocorneal incisions are clinically equivalent with regards to change in MRD1, and neither incision type caused critical postoperative ptosis. The longer preoperative MRD1 was significantly associated with the reduction of MRD1 after surgery., Trial Registration: Current Controlled Trials UMIN000022310 . Retrospectively registered 14 May 2016.

Objectives: To clarify the usefulness of molecular biomarkers for distinguishing invasive carcinoma derived from intraductal papillary mucinous neoplasms (IPMNs [Inv-IPMN]) from concomitant pancreatic ductal adenocarcinoma (PDAC)., Methods: Data from 19 patients with resected concomitant PDAC were retrospectively reviewed. KRAS/GNAS mutations and immunohistochemical (IHC) expression of p53 and p16/CDKN2A were assessed in both IPMN and distinct PDAC. As controls, KRAS/GNAS mutations and IHC labeling were assessed between invasive and noninvasive components in 1 lesion of 22 independent patients., Results: KRAS/GNAS mutation status of invasive and noninvasive components in Inv-IPMN was consistent in 18 (86%) of 21 patients. Conversely, mutational patterns in IPMN and distinct PDAC in the same pancreas differed from each other in 17 (89%) of 19. There were 10 (53%) and 8 (42%) of 19 patients who showed the same p53 and p16/CDKN2A staining between concomitant PDAC and distinct IPMN. In the Inv-IPMN cohort, 19 (86%) of 22 patients showed the same IHC expression pattern between the noninvasive and invasive components., Conclusions: It may be possible to distinguish Inv-IPMN from concomitant PDAC by assessing these molecular biomarkers. More precise distinction of Inv-IPMN and concomitant PDAC will lead to adequate recognition of the natural history of IPMNs and hence optimal management.

A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver.

Objectives: There has been a growing concern over Zika virus (ZIKV) infection, particularly since a probable link between ZIKV infection during pregnancy and microcephaly in the baby was identified. The present study aimed to estimate a theoretical risk of microcephaly during pregnancy with ZIKV infection in Northeastern Brazil in 2015., Methods: Temporal distributions of microcephaly, reported dengue-like illness and dengue seropositive in Brazil were extracted from secondary data sources. Using an integral equation model and a backcalculation technique, we estimated the risk of microcephaly during pregnancy with Zika virus infection., Results: If the fraction of Zika virus infections among a total of seronegative dengue-like illness cases is 30%, the risk of microcephaly following infection during the first trimester was estimated at 46.7% (95% CI: 9.1, 84.2), comparable to the risk of congenital rubella syndrome. However, the risk of microcephaly was shown to vary widely from 14.0% to 100%. The mean gestational age at delivery with microcephaly was estimated at 37.5 weeks (95% CI: 36.9, 39.3)., Conclusions: The time interval between peaks of reported dengue-like illness and microcephaly was consistent with cause-outcome relationship. Our modeling framework predicts that the incidence of microcephaly is expected to steadily decline in early 2016, Brazil., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To identify factors predicting the development of high-risk lesions in the remnant pancreas after surgery for intraductal papillary mucinous neoplasm (IPMN)., Background: IPMN has unique features, including multifocality, adenoma-carcinoma sequence, and the development of distinct pancreatic ductal adenocarcinoma (PDAC) in the same pancreas. Careful attention should, therefore, be paid to the metachronous occurrence of high-risk lesions, including high-grade dysplasia or invasive carcinoma (HGD/INV) of IPMN and concomitant PDAC in the remnant pancreas after partial pancreatectomy for IPMN., Methods: Clinicopathologic and surveillance data for 195 patients who underwent partial pancreatectomy for IPMN were reviewed retrospectively., Results: Thirteen patients exhibited metachronous development of high-risk lesions including 6 HGD/INV and 7 concomitant PDACs in the remnant pancreas. The 5- and 10-year cumulative incidences of metachronous high-risk lesions in the remnant pancreas were 7.8% and 11.8%, respectively. Twelve of 13 patients had high-risk lesions at the time of initial surgery, and 10 of the 13 IPMNs were located in the distal pancreas. The IPMN subtypes initially resected were gastric in 6 patients, intestinal in 5, and pancreatobililary in the remaining 2. Univariate and multiple regression analyses identified pathologic results of HGD/INV and IPMN located in the distal pancreas as independent predictive factors for metachronous HGD/INV of IPMN, and the pancreatobiliary subtype of IPMN and presence of concomitant PDAC for metachronous PDAC., Conclusions: Patients undergoing partial pancreatectomy for IPMN are at high risk of developing lesions requiring surgery in the remnant pancreas, and close, long-term surveillance should be considered in these patients.

The accumulation of protein aggregates is a common pathological hallmark of many neurodegenerative diseases. However, we do not fully understand how aggregates are formed or the complex network of chaperones, proteasomes and other regulatory factors involved in their clearance. Here, we report a chemically controllable fluorescent protein that enables us to rapidly produce small aggregates inside living cells on the order of seconds, as well as monitor the movement and coalescence of individual aggregates into larger structures. This method can be applied to diverse experimental systems, including live animals, and may prove valuable for understanding cellular responses and diseases associated with protein aggregates.

We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4weeks. Treatment was well tolerated without any adverse events above grade 3. Analysis of peripheral blood lymphocytes showed that the number of regulatory T cells dropped from baseline after administration of cyclophosphamide and confirmed that TAA-specific T cell responses were associated significantly with longer overall survival. This phase I clinical trial demonstrated safety and promising immune responses that correlated with vaccine-induced T-cell responses. Therefore, this approach warrants further clinical studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background. An international spread of Zika virus (ZIKV) infection has attracted global attention. ZIKV is conveyed by a mosquito vector, Aedes species, which also acts as the vector species of dengue and chikungunya viruses. Methods. Arrival time of ZIKV importation (i.e., the time at which the first imported case was diagnosed) in each imported country was collected from publicly available data sources. Employing a survival analysis model in which the hazard is an inverse function of the effective distance as informed by the airline transportation network data, and using dengue and chikungunya virus transmission data, risks of importation and local transmission were estimated. Results. A total of 78 countries with imported case(s) have been identified, with the arrival time ranging from 1 to 44 weeks since the first ZIKV was identified in Brazil, 2015. Whereas the risk of importation was well explained by the airline transportation network data, the risk of local transmission appeared to be best captured by additionally accounting for the presence of dengue and chikungunya viruses. Discussion. The risk of importation may be high given continued global travel of mildly infected travelers but, considering that the public health concerns over ZIKV infection stems from microcephaly, it is more important to focus on the risk of local and widespread transmission that could involve pregnant women. The predicted risk of local transmission was frequently seen in tropical and subtropical countries with dengue or chikungunya epidemic experience.

Objectives: Zika virus has spread internationally through countries in the South Pacific and Americas. The present study aimed to estimate the basic reproduction number, R0, of Zika virus infection as a measurement of the transmission potential, reanalyzing past epidemic data from the South Pacific., Methods: Incidence data from two epidemics, one on Yap Island, Federal State of Micronesia in 2007 and the other in French Polynesia in 2013-2014, were reanalyzed. R0 of Zika virus infection was estimated from the early exponential growth rate of these two epidemics., Results: The maximum likelihood estimate (MLE) of R0 for the Yap Island epidemic was in the order of 4.3-5.8 with broad uncertainty bounds due to the small sample size of confirmed and probable cases. The MLE of R0 for French Polynesia based on syndromic data ranged from 1.8 to 2.0 with narrow uncertainty bounds., Conclusions: The transmissibility of Zika virus infection appears to be comparable to those of dengue and chikungunya viruses. Considering that Aedes species are a shared vector, this finding indicates that Zika virus replication within the vector is perhaps comparable to dengue and chikungunya., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pancreatic stellate cells (PSCs) enhance the malignant behavior of pancreatic cancer by interacting with cancer cells and producing extracellular matrix (ECM). To date, several stroma-targeted therapies for pancreatic cancer have been attempted, but these therapies are still not in practical use. Integrins expressed in stromal cells are involved in fibrosis of several organs, as well as promoting tumor malignancy. We investigated whether CD51, also known as integrin αV, expressed in PSCs was associated with stromal formation of pancreatic cancer and enhancement of tumor malignancy. We also assessed the effects of suppression of CD51 in PSCs on pancreatic cancer. Immunohistochemistry for CD51 in resected pancreatic cancer tissues showed that high expression of CD51 in the tumor stroma was associated with lymph node metastasis (P=0.025), positive pathologic margin (P=0.025), and shorter patient survival times (P=0.043). Lentivirus-mediated short hairpin RNA knockdown of CD51 decreased the proliferation and migration of PSCs. Quantitative real-time polymerase chain reaction showed that expression levels of genes related with ECM and tumor-stromal interactions were decreased by CD51 knockdown in PSCs. In a co-implantation model of pancreatic cancer cells and PSCs, tumor growth in vivo was inhibited by CD51 knockdown in PSCs (P<0.05). We also found reduced tumor stroma and decreased proliferation of cancer cells in implanted cancer tissues with CD51-silenced PSCs (P<0.05). Our results showed that CD51 expression in pancreatic cancer stroma is associated with enhanced tumor malignancy and that CD51 may be a potential therapeutic target for pancreatic cancer.

Metastasis is the main cause of cancer-associated death, and metastasis of pancreatic cancer remains difficult to treat because of its aggressiveness. MicroRNAs (miRNAs) play crucial roles in the regulation of various human transcripts, and many miRNAs have been reported to correlate with cancer metastasis. We identified an anti-metastatic miRNA, miR-5100, by investigating differences in miRNA profiling between highly metastatic pancreatic cancer cells and their parental cells. Overexpression of miR-5100 inhibited colony formation (P<0.05), cell migration (P<0.0001) and invasion (P<0.0001) of pancreatic cancer cells. In addition, we identified a possible target of miR-5100, podocalyxin-like 1 (PODXL), and demonstrated miR-5100 directly binds to the 3' untranslated region of PODXL and post-transcriptionally regulates its expression in pancreatic cancer cells. Silencing PODXL resulted in diminished cell migration (P<0.0001) and invasion (P<0.05). We also clarified the close relationship between expression of PODXL in human pancreatic cancer specimens and liver metastasis (P=0.0003), and determined that post-operative survival was longer in the low-PODXL expression group than in the high-PODXL expression group (P<0.05). These results indicate that miR-5100 and PODXL have considerable therapeutic potential for anti-metastatic therapy and could be potential indicators for cancer metastases in patients with pancreatic cancer.