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Background: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5‐fluorouracil (5‐FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5‐FU with Lut in PDACs. Methods and Results: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5‐FU. The xenograft tumors of DPYD‐overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA‐seq analysis of the DPYD‐overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity—MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5‐FU on DPYD‐overexpressing xenograft tumors and PDAC of Pdx1‐Cre; LSL‐KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5‐FU nor Lut showed significant inhibitory effects; however, the combined administration of 5‐FU and Lut exhibited a significant tumor‐suppressive effect in both the xenograft tumors and KPPC models. Conclusion: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5‐FU resistance, in PDACs. The combination therapy of Lut and 5‐FU holds the potential for enhanced efficacy against PDACs. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a cancer with a poor prognosis due to difficulties in diagnosis and limited treatment options, highlighting the urgent need for new targeted therapies. In a clinical setting, we found that leukotriene levels in bile were higher than in serum. Immunohistochemical analysis of surgically resected samples also revealed that CysLT receptor 1 (CysLTR1) was more highly expressed in CCA than in normal bile duct tissue, prompting us to investigate leukotriene as a potential therapeutic target in CCA. In vitro studies using CCA cell lines expressing CysLTR1 showed that leukotriene D4, a major ligand of CysLTR1, promoted cell proliferation, with increased phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Additionally, treatment with two clinically available anti-allergic drugs—zileuton, an inhibitor of CysLT formation, and montelukast, a CysLTR1 inhibitor—had inhibitory effects on cell proliferation and migratory capacity, accompanied by the reduced phosphorylation of AKT and ERK1/2. Furthermore, the simultaneous administration of both drugs synergistically enhanced the inhibitory effect on cell proliferation. Our study suggests that use of these drugs may represent a novel approach to treat CCA through drug repositioning. [ABSTRACT FROM AUTHOR]

More than 100 different herpes simplex virus 1 (HSV‐1) genes belong to three major classes, and their expression is coordinately regulated and sequentially ordered in a cascade. This complex HSV‐1 gene expression is thought to be regulated by various viral and host cellular proteins. A host cellular protein, Myb‐binding protein 1A (MYBBP1A), has been reported to be associated with HSV‐1 viral genomes in conjunction with viral and cellular proteins critical for DNA replication, repair, and transcription within infected cells. However, the role(s) of MYBBP1A in HSV‐1 infections remains unclear. In this study, we examined the effects of MYBBP1A depletion on HSV‐1 infection and found that MYBBP1A depletion significantly reduced HSV‐1 replication, as well as the accumulation of several viral proteins. These results suggest that MYBBP1A is an important host cellular factor that contributes to HSV‐1 replication, plausibly by promoting viral gene expression. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX‐LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX‐LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target. [ABSTRACT FROM AUTHOR]

Herpes simplex virus-1 (HSV-1) is the most common cause of sporadic viral encephalitis, which can be lethal or result in severe neurological defects even with antiviral therapy. While HSV-1 causes encephalitis in spite of HSV-1-specific humoral and cellular immunity, the mechanism by which HSV-1 evades the immune system in the central nervous system (CNS) remains unknown. Here we describe a strategy by which HSV-1 avoids immune targeting in the CNS. The HSV-1 UL13 kinase promotes evasion of HSV-1-specific [CD8.sup.+] T cell accumulation in infection sites by downregulating expression of the [CD8.sup.+] T cell attractant chemokine CXCL9 in the CNS of infected mice, leading to increased HSV-1 mortality due to encephalitis. Direct injection of CXCL9 into the CNS infection site enhanced HSV-1-specific [CD8.sup.+] T cell accumulation, leading to marked improvements in the survival of infected mice. This previously uncharacterized strategy for HSV-1 evasion of [CD8.sup.+] T cell accumulation in the CNS has important implications for understanding the pathogenesis and clinical treatment of HSV-1 encephalitis., Introduction HSV-1 is generally associated with various mucocutaneous diseases, such as herpes labialis, genital herpes, herpetic whitlow, and keratitis (1). Also, HSV-1 is the most common cause of sporadic viral [...]

Wild‐type herpes simplex virus (HSV) strains infrequently mediate cell–cell fusion in cell cultures and barely induce large multinucleated cells. In this study, we established a system to quantify infrequent cell–cell fusion induced by wild‐type HSV strains. The established system clarified that the HSV‐1 envelope glycoprotein B and its N‐glycosylation at asparagine at position 141 were required for efficient cell–cell fusion. This study provides a link between cell–cell fusion induced by wild‐type HSV‐1 and viral pathogenesis in vivo. [ABSTRACT FROM AUTHOR]

Background: Endoscopic transpapillary gallbladder drainage (ETGBD) has been reported as an alternative procedure for acute cholecystitis but remains a challenging procedure. Aims: To elucidate the efficacy of a strategic approach for ETGBD that utilizes a four-step classification system and the optional use of 'Three-pillar' assistance with the following devices: cholangioscopy (SpyGlass DS, SG), a flex-type guidewire (Flex-GW), and a 3-Fr microcatheter (3-Fr Micro). Methods: A total of 115 patients undergoing ETGBD were studied retrospectively. Characteristics and technical outcomes were compared between conventional ETGBD technique (Classical ETGBD, N = 50) and strategic ETGBD with optional Three-pillar assistance (Strategic ETGBD, N = 65). Results: SG-assistance (15/65, 23.1%) was as an excellent troubleshooter in Category 1 (failure to identify the cystic duct [CD] orifice) and Category 2 (failure to advance the GW across the CD takeoff due to unfavorable angle). Flex-GW (19/65, 29.2%) worked for Category 3b (failure of GW access to the GB due to multiple tortuosities). 3-Fr Micro (11/65, 16.9%) was effective for Category 3a (failure of GW access to the GB due to CD obstruction) and Category 4 (failure of drainage stent insertion to the GB). The overall technical success rate was significantly higher for Strategic ETGBD (63/65, 96.9%) compared with Classical ETGBD (36/50, 72.0%) (p = 0.0001). Conclusions: Strategic ETGBD, which includes the Three-pillar assistance options of SG in the initial steps, Flex-GW for tortuous CD, and 3-Fr Micro for stenotic CD, achieved a significantly higher success rate than for Classical ETGBD. [ABSTRACT FROM AUTHOR]

Sampling of bile juice during endoscopic retrograde cholangiopancreatography (ERCP) has potential benefit of being amenable to the identification of novel biomarkers in liquid biopsy. This study reports the results of a global investigation of exosomal microRNAs (miRNAs) in bile to identify potential biomarkers for biliary tract cancers (BTCs). Eighty‐eight bile samples collected during ERCP (45 BTC and 43 noncancer control samples) were enrolled in this study. Eleven BTC samples and nine control samples were assigned as the discovery set. Exosomes in bile and serum samples were collected using a glass membrane column with size‐controlled macroporous glass (MPG), and exosomal miRNA expression profiles were evaluated using comprehensive miRNA microarray analysis (3D‐Gene). For validation, exosomal miRNA in the bile samples of 34 BTCs and 34 controls were comprehensively evaluated using 3D‐Gene. In the discovery set, eight exosomal miRNAs in bile were identified as significant aberrant expression markers, while no miRNA with aberrant expression in serum was identified. In a comparison of the discovery and validation sets, miR‐451a and miR‐3619‐3p were identified as reproducible upregulated markers, and the combination of the two bile miRNAs showed an excellent area under the curve (0.819) value for diagnosing BTCs. In addition, high miR‐3619‐3p expression in bile reflects poorer prognosis of BTCs (hazard ratio = 2.89). The MPG‐extracted exosomal miRNAs in bile aspirated during ERCP provide a convenient new approach for diagnosing biliary diseases. Bile‐derived miRNA analysis with miR‐451a and miR‐3619‐3p represents a potentially valuable diagnostic strategy for identifying BTCs as well as a predictive indicator of BTC prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Brush cytology remains the primary method used worldwide for diagnosing malignant biliary strictures, despite its low sensitivity. Although the endoscopic scraper, the simplicity of which is comparable to that of a conventional brush, has been used mainly in Japan, it has yet to gain popularity on a global scale. The purpose of this study was to evaluate the diagnostic performance of the endoscopic scraper by comparing diagnostic yields and the number of collected cells using quantitative digital image analysis. Our study revealed that the endoscopic scraper and cell block method achieved higher sensitivity than the brush with the cell block method, and showed that the number of cells on the cell block sections obtained by the endoscopic scraper were significantly higher than those obtained using the brush. Given its ease of use and high sample acquisition capability, the endoscopic scraper could replace brush cytology for diagnosing malignant biliary strictures. Histological evidence is essential for diagnosing malignant biliary strictures. However, conventional brush cytology remains the primary method used worldwide, despite its low diagnostic sensitivity and accuracy, as it is technically easy, rapid, and cost-effective. The aim of this study was to evaluate the diagnostic performance of a recently introduced endoscopic scraper, the simplicity of which is comparable to that of a conventional brush, by comparing diagnostic yields and the number of collected cells. The sensitivity of the endoscopic scraper when using the cell block technique was significantly higher than when using brush cytology or a brush with the cell block technique (53.6% vs. 30.9%, p < 0.001; 53.6% vs. 31.6%, p = 0.024, respectively). Quantitative digital image analysis of cell block sections revealed that the median number of cells obtained with the endoscopic scraper was significantly higher than when using the brush (1917 vs. 1014 cells, p = 0.042). Furthermore, seven cases (8.3%; 7/84) were diagnosed by immunohistochemical analysis of the cell block section obtained from the endoscopic scraper. Given its simplicity and greater capacity for sample acquisition, use of the endoscopic scraper in conjunction with the cell block technique could replace brush cytology for the histological diagnosis of malignant biliary strictures. [ABSTRACT FROM AUTHOR]

With the development of newer devices and technical innovations, pancreaticobiliary endoscopy is expanding to assume more advanced therapeutic roles. As with other devices, slimmed‐down "3‐Fr microcatheters" are considered to be opening new windows toward entirely new therapeutic techniques for various purposes. Our practical experience with a total of 34 consecutive patients in whom 3‐Fr microcatheters were applied during pancreaticobiliary endoscopic procedures clarified the potential roles of this instrument in pancreaticobiliary endoscopy. The major benefits of 3‐Fr microcatheters involve their slimness and flexibility. Applications of 3‐Fr microcatheters could be categorized into three groups according to the characteristics of usage: (1) utilization as a cannulation catheter for peroral digital cholangioscopy (n = 15); (2) selective advancement through deep flexures or severely stenotic ducts (n = 11); or (3) two‐devices‐in‐one‐channel technique (n = 8). The microcatheter worked successfully for cannulation of cholangioscopy in all but one case (14/15, 93.3%). For selective advancement, the microcatheter worked for troubleshooting in 9 of 11 cases (81.8%). With the two‐devices‐in‐one‐channel technique, the microcatheter proved satisfactory in all cases (8/8, 100%). In total, the microcatheter was successfully maneuvered in 31 of 34 cases (91.1%), following the failure of procedures using conventional endoscopic techniques. In terms of adverse events, cystic duct injury was only observed in two cases (5.8%), who recovered under conservative observation, because its slimness could minimize the damage. We believe that 3‐Fr microcatheters offer effective and safe salvage troubleshooting during various endoscopic pancreaticobiliary procedures that face troublesome situations with conventional strategies. [ABSTRACT FROM AUTHOR]

The 5-year survival rate of pancreatic ductal carcinoma (PDAC) patients is <10% despite progress in clinical medicine. Strategies to prevent the development of PDAC are urgently required. The flavonoids Luteolin (Lut) and hesperetin (Hes) may be cancer-chemopreventive, but effects on pancreatic carcinogenesis in vivo have not been studied. Here, the chemopreventive effects of Lut and Hes on pancreatic carcinogenesis are assessed in the BOP-induced hamster PDAC model. Lut but not Hes suppressed proliferation of pancreatic intraepithelial neoplasia (PanIN) and reduced the incidence and multiplicity of PDAC in this model. Lut also inhibited the proliferation of hamster and human pancreatic cancer cells in vitro. Multi-blot and microarray assays revealed decreased phosphorylated STAT3 (pSTAT3) and dihydropyrimidine dehydrogenase (DPYD) on Lut exposure. To explore the relationship between DPYD and STAT3 activity, the former was silenced by RNAi or overexpressed using expression vectors, and the latter was inactivated by small molecule inhibitors or stimulated by IL6 in human PDAC cells. DPYD knock-down decreased, and overexpression increased, pSTAT3 and cell proliferation. DPYD expression was decreased by inactivation of STAT3 and increased by its activation. The frequency of pSTAT3-positive cells and DPYD expression was significantly correlated and was decreased in parallel by Lut in the hamster PDAC model. Finally, immunohistochemical analysis in 73 cases of human PDAC demonstrated that DPYD expression was positively correlated with the Ki-67 labeling index, and high expression was associated with poor prognosis. These results indicate that Lut is a promising chemopreventive agent for PDAC, targeting a novel STAT3-DPYD pathway. [ABSTRACT FROM AUTHOR]

Peritoneal dissemination and malignant ascites in pancreatic ductal adenocarcinoma (PDAC) patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates the progression of various cancers. Based on the increasing evidence showing that LPA is abundant in malignant ascites, we focused on autotaxin (ATX), which is a secreted enzyme that is important for the production of LPA. This study aimed to elucidate the importance of the ATX‐LPA axis in malignant ascites in PDAC and to determine whether ATX works as a molecular target for treating peritoneal dissemination. In a PDAC peritoneal dissemination mouse model, the amount of ATX was significantly higher in ascites than in serum. An in vitro study using two PDAC cell lines, AsPC‐1 and PANC‐1, showed that ATX‐LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF‐8380. An in vivo study showed that PF‐8380 suppressed peritoneal dissemination and decreased malignant ascites, and these results were validated by the biological analysis as well as the in vitro study. Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC. [ABSTRACT FROM AUTHOR]

Background and aims: The revised Atlanta classification is widely used for the evaluation of acute pancreatitis (AP) severity. However, this classification cannot be used within 48 hours of AP onset. The aim of this study was to investigate the predictive factors of mortality in patients with AP on admission. Methods: We evaluated the association between AP mortality and clinical parameters at the time of admission in patients with AP from April 2013 to December 2017 at one university hospital and one tertiary care referral center. Results: A total of 203 consecutive patients were enrolled. Nine patients (4.4%) died despite multidisciplinary treatment. In a multivariable analysis, hematocrit ≥ 40% (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01–1.13; P = 0.021), blood urea nitrogen (BUN) ≥ 40 mg/dL (OR, 1.26; 95% CI, 1.11–1.42; P < 0.001), base excess < -3.0 mmol/L (OR, 1.15; 95% CI, 1.04–1.26; P = 0.004), and inflammation extending to the rectovesical excavation (OR, 1.19; 95% CI, 1.10–1.30; P < 0.001) on admission were significantly associated with mortality. Conclusion: Among the imaging findings, inflammation extending to the rectovesical excavation was the only independent predictive factor for mortality in AP. This simple finding, obtained on computed tomography without contrast agent on admission, might be a promising prognostic factor for AP. [ABSTRACT FROM AUTHOR]