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Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10-200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the "magic bullet"-both effective and safe-to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer., Competing Interests: The authors declare no conflict of interest.

In pulmonary arterial hypertension (PAH), excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) causes vascular medial thickening. Medial thickening is a histopathological hallmark of pulmonary vascular remodeling, the central disease process driving PAH progression. Pulmonary vascular remodeling causes stenosis and/or obstruction of small pulmonary arteries. This leads to increased pulmonary vascular resistance, elevated pulmonary arterial pressure, and ultimately right heart failure. To improve the survival of PAH patients, which remains at approximately 60% at 3 years after diagnosis, the development of novel PAH-targeted drugs is desired. To this end, a detailed understanding of the mechanisms underlying excessive PASMC proliferation and the medial thickening that ensues is necessary. However, a lack of in vitro models that recapitulate medial thickening impedes our deeper understanding of the pathogenetic mechanisms involved. In the present study, we applied 3-dimensional (3D) cell culture technology to develop a novel in vitro model of the pulmonary artery medial layer using human PAH patient-derived PASMCs. The addition of platelet-derived growth factor (PDGF)-BB, a mitogen known to promote excessive PASMC proliferation in PAH, resulted in increased thickness of the 3D-PAH media tissues. Conversely, administration of the PDGF receptor inhibitor imatinib or other clinical PAH drugs inhibited this medial thickening-inducing effect of PDGF-BB. Altogether, by using 3D cell culture technology, we report the generation of an in vitro model of medial thickening in PAH, which had hitherto not been successfully modeled in vitro . This model is potentially useful for assessing the ability of candidate PAH drugs to suppress medial thickening., (Copyright © 2020 Morii, Tanaka, Izushi, Nakao, Yamamoto, Matsubara, Kano and Ogawa.)

Pancreatic ductal adenocarcinoma (PDAC) is an often lethal disease characterized by a dense, fibrotic stroma. However, the lack of relevant preclinical models that recapitulate the characteristic histopathology of human PDAC in vitro impedes the development of novel therapies. The amount of stromal elements differ largely within and between patients, but in vitro models of human PDAC often do not account for this heterogeneity. Indeed, analyses of human PDAC histopathology revealed that the proportion of stroma ranged from 40 to 80% across patients. We, therefore, generated a novel 3D model of human PDAC, consisting of co-cultured human PDAC tumor cells and fibroblasts/pancreatic stellate cells, in which the proportion of fibrotic elements can be tuned across the clinically observed range. Using this model, we analyzed the signaling pathways involved in the differentiation of myofibroblasts, a characteristic subpopulation of fibroblasts seen in PDAC. We show that both YAP and SMAD2/3 in fibroblasts are required for myofibroblastic differentiation and that both shared and distinct signaling pathways regulate the nuclear localization of these factors during this process. Our novel model will be useful in promoting the understanding of the complex mechanisms by which the fibrotic stroma develops and how it might be therapeutically targeted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Oral anticoagulants use has increased rapidly, internationally. Here we look at risks and benefits, based on Japanese data, of therapy with low risk non-valvular atrial fibrillation patients., Objectives: Using a health insurance claims data set we assessed: (i) oral anticoagulants usage in Japan, and (ii) efficacy and safety of dabigatran compared with warfarin, in Japanese patients with non-valvular atrial fibrillation, aged 18-74 years., Methods: We identified 4380 non-valvular atrial fibrillation patients treated with anticoagulants between 1 January 2005, and 28 February 2014, and estimated the adjusted hazard ratio for stroke or systemic embolism, and any hemorrhagic event (Cox proportional hazards regression model with stabilized inverse probability treatment weighting)., Results: The data included 101 989 anticoagulant prescriptions for 4380 patients, of which direct oral anticoagulants increased to 40.0% of the total by the end of the study. After applying exclusion criteria, 1536 new non-valvular atrial fibrillation patients were identified, including 1071 treated with warfarin and 465 with dabigatran. Mean ages were 56.11 ± 9.70 years for warfarin, and 55.80 ± 9.65 years for dabigatran. The adjusted hazard ratio (95% confidence interval), comparing dabigatran with warfarin, was 0.48 (0.25-0.91) for stroke or systemic embolism, and 0.91 (0.60-1.39) for any hemorrhage including intracranial and gastrointestinal., Conclusions: Number of patients prescribed direct oral anticoagulants steadily increased, and incidence of all-cause bleeding related to dabigatran was similar to warfarin, in our study population of younger non-valvular atrial fibrillation patients. Dabigatran, compared with warfarin, generally reduced risk of all-cause stroke and systemic embolism., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns., Purpose: Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan., Methods: We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic., Results: Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs., Conclusions: According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.

Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Pancreatic cancer is known for its dismal prognosis despite efforts to improve therapeutic outcome. Recently, cancer nanomedicine, application of nanotechnology to cancer diagnosis and treatment, has gained interest for treatment of pancreatic cancer. The enhanced permeability and retention (EPR) effect that promotes selective accumulation of nanometer-sized molecules within tumors is the theoretical rationale of treatment. However, it is clear that EPR may be insufficient in pancreatic cancer as a result of stromal barriers within the tumor microenvironment (TME). These limit intratumoral accumulation of macromolecules. The TME and stromal barriers inside it consist of various stromal cell types which interact both with each other and with tumor cells. We are only beginning to understand the complexities of the stromal barriers within the TME and its functional consequences for nanomedicine. Understanding the complex crosstalk between barrier stromal cells is challenging because of the difficulty of modeling pancreatic cancer TME. Here we provide an overview of stromal barriers within the TME. We also describe the preclinical models, both in vivo and in vitro, developed to study them. We furthermore discuss the critical gaps in our understanding, and how we might formulate a better strategy for using nanomedicine against pancreatic cancer., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Angiogenesis is a multi-step process that culminates in vascular maturation whereby nascent vessels stabilize to become functional, and mural cells play an essential role in this process. Recent studies have shown that mural cells in tumors also promote and maintain vascular integrity, with wide-reaching clinical implications including the regulation of tumor growth, metastases, and drug delivery. Various regulatory signaling pathways have been hitherto implicated, but whether regulation of Fas-dependent apoptotic mechanisms is involved has not yet been fully investigated. We first compared endothelial FAS staining in human pancreatic ductal adenocarcinomas and colon carcinomas and show that the latter, characterized by lower mural cell coverage of tumor vasculature, demonstrated higher expression of FAS than the former. Next, in an in vitro coculture system of MS-1 and 10T1/2 cells as endothelial and mural cells respectively, we show that mural cells decreased endothelial Fas expression. Then, in an in vivo model in which C26 colon carcinoma cells were inoculated together with MS-1 cells alone or with the further addition of 10T1/2 cells, we demonstrate that mural cells prevented hemorrhage. Finally, knockdown of endothelial Fas sufficiently recapitulated the protection against hemorrhage seen with the addition of mural cells. These results together suggest that regulation of endothelial Fas signaling is involved in the promotion of vascular integrity by mural cells in tumors., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)