State representation learning with recurrent capsule networks

Unsupervised learning of compact and relevant state representations has beenproved very useful at solving complex reinforcement learning tasks Ha and Schmid-huber (2018). In this paper, we propose a recurrent capsule network Hinton et al.(2011) that learns such representations by trying to predict the future observationsin an agent’s trajector

Flatland: a Lightweight First-Person 2-D Environment for Reinforcement Learning

Flatlandis a simple, lightweight environment for fastprototyping and testing of reinforcement learning agents. It is oflower complexity compared to similar 3D platforms (e.g. Deep-Mind Lab or VizDoom), but emulates physical properties of thereal world, such as continuity, multi-modal partially-observablestates with first-person view and coherent physics. We proposeto use it as an intermediary benchmark for problems related toLifelong Learning.Flatlandis highly customizable and offers awide range of task difficulty to extensively evaluate the propertiesof artificial agents. We experiment with three reinforcementlearning baseline agents and show that they can rapidly solvea navigation task inFlatland. A video of an agent acting inFlatlandis available here: https://youtu.be/I5y6Y2ZypdA

Flatland: a Lightweight First-Person 2-D Environment for Reinforcement Learning

Flatlandis a simple, lightweight environment for fastprototyping and testing of reinforcement learning agents. It is oflower complexity compared to similar 3D platforms (e.g. Deep-Mind Lab or VizDoom), but emulates physical properties of thereal world, such as continuity, multi-modal partially-observablestates with first-person view and coherent physics. We proposeto use it as an intermediary benchmark for problems related toLifelong Learning.Flatlandis highly customizable and offers awide range of task difficulty to extensively evaluate the propertiesof artificial agents. We experiment with three reinforcementlearning baseline agents and show that they can rapidly solvea navigation task inFlatland. A video of an agent acting inFlatlandis available here: https://youtu.be/I5y6Y2ZypdA

A textile platform using mechanically reinforced hydrogel fibres towards engineering tendon niche

INTRODUCTION: Tendon injuries can result from tendon overuse or trauma, resulting in substantial pain and disability. Given that natural or surgical repair of tendons lead to a poor outcome in terms of mechanical properties and functionality, there is a great need for tissue engineering strategies. Textile platforms enable the generation of biomimetic constructs [1]. Therefore, the main goal of this study is the development of cell-laden hybrid hydrogel fibers reinforced with a mechanically robust core fiber and their assembly into braided constructs towards replicating tendon mechanical properties and architecture. METHODS: To fabricate mechanically reinforced hydrogel fibres, a commercially available suture was coated using a cell-hydrogel mixture of methacryloyl gelatine (GelMA) and alginate. Composite fibres (CFs) were obtained by ionic crosslinking of alginate followed by photocrosslinking of GelMA. CFs were assembled using braiding technique and the mechanical properties of single fibres and braided constructs were evaluated. Different cells were encapsulated in the hydrogel layer, including MC-3T3, mesenchymal stem cells (MSCs) and human tendon-derived cells (TDCs). Cell viability and metabolic activity were evaluated by LIVE/DEAD staining and presto blue assay of metabolic activity. The expression of tendon-related markers and matrix deposition were also investigated. RESULTS: CFs were fabricated with a GelMA:alginate hydrogel layer and using multifilament twisted cotton or biodegradable suturing threads. The biocompatibility of this system was evaluated on encapsulated cells (Fig.1a). Cells (MC-3T3, MSCs and TDCs) were homogeneously distributed along the hydrogel layer, being viable up to 14 days in culture. In addition, TDCs were spreading inside the hydrogel after less than 48 h. Moreover, to further improve the mechanical properties of CFs, braided constructs were generated (Fig. 1b). Braiding CFs together enhanced their tensile strength and the process did not affect the viability of encapsulated cells.DISCUSSION & CONCLUSIONS: CFs were generated with a load bearing core and a hydrogel layer towards mimicking both mechanical properties and the matrix-rich microenvironment of tendon tissue. Accordingly, cell behaviour can be further modulated by modifying the hydrogel composition or, ultimately, through the addition of bioactive cues. Finally, braiding CFs together allows tuning the mechanical properties of developed constructs to match those of native tendon tissues.Fundação para a Ciência e a Tecnologia in the framework of FCT-POPH-FSE, the PhD grant SFRH/BD/96593/2013 of R.C-

Baseline characteristics and treatment pattern of type 2 diabetes patients in Jordan: analysis from the DISCOVER patient population

Introduction: Jordan has limited published data on T2DM and its treatment patterns. This analysis of the DISCOVER study, focusing on Jordan, is aimed at describing the characteristics of patients and treatment patterns according to the real-world setting in T2DM patients initiating a second-line antidiabetic treatment Methods: The DISCOVER study is an ongoing, multi-country, multicenter, observational, prospective, and longitudinal cohort study. The baseline data of patients’ characteristics, clinical and laboratory variables, micro- and macro-complications, and treatment choices were captured on a standardized case report form. Results: Two hundred and seventy-one patients were enrolled from 13 different clinical sites in Jordan. Sixty percent of the patients were male. The participants overall mean age was 53.8 ± 11.3 years with a mean BMI 30.8 ± 5.0 kg/m 2. The mean duration of T2DM was almost 6 years and the mean documented HbA1c and fasting plasma glucose were e 8.4% ± 1.6 and 180.9 ± 63.7 mg/dL, respectively, at the initiation of second-line antidiabetic treatment. Almost 25% of the participants were reported to be either current smokers or ex-smokers. More than 40% of patients had comorbidities such as hypertension or dyslipidemia. Diabetes related microvascular and macrovascular complications were documented in 10.3% and 12.5% of patients, respectively. Metformin (MET) alone was used as a first-line therapy in almost one-half of the patients and in combination with sulfonylurea (SU) in approximately one-third of the patients. The most commonly used second-line therapy was the combination of MET and dipeptidyl peptidase-4 inhibitors (DPP-4i) with 29.9% followed by the triple therapy of MET, SU, and DPP-4i with 28%. Conclusion: A substantial number of patients were young with uncontrolled diabetes and at high risk for micro- and macrovascular complications. Therefore, a comprehensive management with early treatment intensification and risk factors modifications are required to achieve target goals

A Concerted HIF-1α/MT1-MMP Signalling Axis Regulates the Expression of the 3BP2 Adaptor Protein in Hypoxic Mesenchymal Stromal Cells

Increased plasticity, migratory and immunosuppressive abilities characterize mesenchymal stromal cells (MSC) which enable them to be active participants in the development of hypoxic solid tumours. Our understanding of the oncogenic adaptation of MSC to hypoxia however lacks the identification and characterization of specific biomarkers. In this study, we assessed the hypoxic regulation of 3BP2/SH3BP2 (Abl SH3-binding protein 2), an immune response adaptor/scaffold protein which regulates leukocyte differentiation and motility. Gene silencing of 3BP2 abrogated MSC migration in response to hypoxic cues and generation of MSC stably expressing the transcription factor hypoxia inducible factor 1alpha (HIF-1α) resulted in increased endogenous 3BP2 expression as well as cell migration. Analysis of the 3BP2 promoter sequence revealed only one potential HIF-1α binding site within the human but none in the murine sequence. An alternate early signalling cascade that regulated 3BP2 expression was found to involve membrane type-1 matrix metalloproteinase (MT1-MMP) transcriptional regulation which gene silencing abrogated 3BP2 expression in response to hypoxia. Collectively, we provide evidence for a concerted HIF-1α/MT1-MMP signalling axis that explains the induction of adaptor protein 3BP2 and which may link protein binding partners together and stimulate oncogenic MSC migration. These mechanistic observations support the potential for malignant transformation of MSC within hypoxic tumour stroma and may contribute to evasion of the immune system by a tumour

The lectin concanavalin-A signals MT1-MMP catalytic independent induction of COX-2 through an IKKγ/NF-κB-dependent pathway

The lectin from Canavalia ensiformis (Concanavalin-A, ConA), one of the most abundant lectins known, enables one to mimic biological lectin/carbohydrate interactions that regulate extracellular matrix protein recognition. As such, ConA is known to induce membrane type-1 matrix metalloproteinase (MT1-MMP) which expression is increased in brain cancer. Given that MT1-MMP correlated to high expression of cyclooxygenase (COX)-2 in gliomas with increasing histological grade, we specifically assessed the early proinflammatory cellular signaling processes triggered by ConA in the regulation of COX-2. We found that treatment with ConA or direct overexpression of a recombinant MT1-MMP resulted in the induction of COX-2 expression. This increase in COX-2 was correlated with a concomitant decrease in phosphorylated AKT suggestive of cell death induction, and was independent of MT1-MMP’s catalytic function. ConA- and MT1-MMP-mediated intracellular signaling of COX-2 was also confirmed in wild-type and in Nuclear Factor-kappaB (NF-κB) p65−/− mutant mouse embryonic fibroblasts (MEF), but was abrogated in NF-κB1 (p50)−/− and in I kappaB kinase (IKK) γ−/− mutant MEF cells. Collectively, our results highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of COX-2. That signaling pathway could account for the inflammatory balance responsible for the therapy resistance phenotype of glioblastoma cells, and prompts for the design of new therapeutic strategies that target cell surface carbohydrate structures and MT1-MMP-mediated signaling. Concise summary Concanavalin-A (ConA) mimics biological lectin/carbohydrate interactions that regulate the proinflammatory phenotype of cancer cells through yet undefined signaling. Here we highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of cyclooxygenase-2, and that could be responsible for the therapy resistance phenotype of glioblastoma cells

Resveratrol Targeting of Carcinogen-Induced Brain Endothelial Cell Inflammation Biomarkers MMP-9 and COX-2 is Sirt1-Independent

The occurrence of a functional relationship between the release of metalloproteinases (MMPs) and the expression of cyclooxygenase (COX)-2, two inducible pro-inflammatory biomarkers with important pro-angiogenic effects, has recently been inferred. While brain endothelial cells play an essential role as structural and functional components of the blood-brain barrier (BBB), increased BBB breakdown is thought to be linked to neuroinflammation. Chemopreventive mechanisms targeting both MMPs and COX-2 however remain poorly investigated. In this study, we evaluated the pharmacological targeting of Sirt1 by the diet-derived and antiinflammatory polyphenol resveratrol. Total RNA, cell lysates, and conditioned culture media from human brain microvascular endothelial cells (HBMEC) were analyzed using qRT-PCR, immunoblotting, and zymography respectively. Tissue scan microarray analysis of grade I–IV brain tumours cDNA revealed increased gene expression of Sirt-1 from grade I–III but surprisingly not in grade IV brain tumours. HBMEC were treated with a combination of resveratrol and phorbol 12-myristate 13-acetate (PMA), a carcinogen known to increase MMP-9 and COX-2 through NF-κB. We found that resveratrol efficiently reversed the PMA-induced MMP-9 secretion and COX-2 expression. Gene silencing of Sirt1, a critical modulator of angiogenesis and putative target of resveratrol, did not lead to significant reversal of MMP-9 and COX-2 inhibition. Decreased resveratrol inhibitory potential of carcinogen-induced IκB phosphorylation in siSirt1-transfected HBMEC was however observed. Our results suggest that resveratrol may prevent BBB disruption during neuroinflammation by inhibiting MMP-9 and COX-2 and act as a pharmacological NF-κB signal transduction inhibitor independent of Sirt1

Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery.

BACKGROUND: Nanomedicine offers an excellent opportunity to tackle treatment-refractory malignancies by enhancing the delivery of therapeutics to the tumor site. High endothelial venules (HEVs) are found primarily in lymph nodes or formed de novo in peripheral tissues during inflammatory responses. They express peripheral node addressin (PNAd), which is recognized by the monoclonal antibody MECA79. METHODS: Here, we demonstrated that HEVs form de novo in human pancreatic ductal adenocarcinoma (PDAC). We engineered MECA79 coated nanoparticles (MECA79-NPs) that recognize these ectopic HEVs in PDAC. FINDINGS: The trafficking of MECA79-NPs following intravenous delivery to human PDAC implanted in a humanized mouse model was more robust than non-conjugated NPs. Treatment with MECA79-Taxol-NPs augmented the delivery of Paclitaxel (Taxol) to the tumor site and significantly reduced the tumor size. This effect was associated with a higher apoptosis rate of PDAC cells and reduced vascularization within the tumor. INTERPRETATION: Targeting the HEVs of PDAC using MECA79-NPs could lay the ground for the localized delivery of a wide variety of drugs including chemotherapeutic agents. FUND: National Institutes of Health (NIH) grants: T32-EB016652 (B·B.), NIH Cancer Core Grant CA034196 (L.D.S.), National Institute of Allergy and Infectious Diseases grants R01-AI126596 and R01-HL141815 (R.A.)

miR451 and AMPK Mutual Antagonism in Glioma Cell Migration and Proliferation: A Mathematical Model

Glioblastoma multiforme (GBM) is the most common and the most aggressive type of brain cancer; the median survival time from the time of diagnosis is approximately one year. GBM is characterized by the hallmarks of rapid proliferation and aggressive invasion. miR-451 is known to play a key role in glioblastoma by modulating the balance of active proliferation and invasion in response to metabolic stress in the microenvironment. The present paper develops a mathematical model of GBM evolution which focuses on the relative balance of growth and invasion. In the present work we represent the miR-451/AMPK pathway by a simple model and show how the effects of glucose on cells need to be “refined” by taking into account the recent history of glucose variations. The simulations show how variations in glucose significantly affect the level of miR-451 and, in turn, cell migration. The model predicts that oscillations in the levels of glucose increase the growth of the primary tumor. The model also suggests that drugs which upregulate miR-451, or block other components of the CAB39/AMPK pathway, will slow down glioma cell migration. The model provides an explanation for the growth-invasion cycling patterns of glioma cells in response to high/low glucose uptake in microenvironment in vitro, and suggests new targets for drugs, associated with miR-451 upregulation