A Novel Fluorescent Gemcitabine Prodrug That Follows a Nucleoside Transporter-Independent Internalization and Bears Enhanced Therapeutic Efficacy With Respect to Gemcitabine.

The multiplexity of cancer has rendered it the second leading cause of mortality worldwide and theragnostic prodrugs have gained popularity in recent years as a means of treatment. Theragnostic prodrugs enable the simultaneous diagnosis and therapy of tumors via high-precision real-time drug release monitoring. Herein, we report the development of the small theragnostic prodrug GF, based on the nucleoside anticancer agent gemcitabine and the fluorescent dye 5(6)-carboxyfluorescein.

Hydrogel Membranes from Chitosan-Fish Gelatin-Glycerol for Biomedical Applications: Chondroitin Sulfate Incorporation Effect in Membrane Properties.

Chondroitin sulfate (ChS), chitosan (Chi), and fish gelatin (FG), which are byproducts of a fish-treatment small enterprise, were incorporated with glycerol (Gly) to obtain dense hydrogel membranes with reduced brittleness, candidates for dressing in wound healing applications. The mechanical properties of all samples were studied via Dynamic Mechanical Analysis (DMA) and tensile tests while their internal structure was characterized using Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray Diffraction (XRD) instruments. Their surface morphology was analyzed by ThermoGravimetric Analysis (TGA) method, while their water permeability was estimated via Water Vapor Transmission Rate (WVTR) measurements.

Culturing Human Pluripotent Stem Cells on Micropatterned Silicon Surfaces.

Human pluripotent stem cell culture conditions are constantly being optimized, thus providing insight to the environmental cues that affect cell choices. A wide variety of media, coating materials, and substrates is now available for use, serving different scientific needs. Factors such as material stiffness, roughness, and topography are being recognized to contribute or even direct the acquisition of specific phenotypes.

Translational control in neurovascular brain development.

The human brain carries out complex tasks and higher functions and is crucial for organismal survival, as it senses both intrinsic and extrinsic environments. Proper brain development relies on the orchestrated development of different precursor cells, which will give rise to the plethora of mature brain cell-types. Within this process, neuronal cells develop closely to and in coordination with vascular cells (endothelial cells (ECs), pericytes) in a bilateral communication process that relies on neuronal activity, attractive or repulsive guidance cues for both cell types and on tight-regulation of gene expression.

Embryonic stem cells are devoid of macropinocytosis, a trafficking pathway for activin A in differentiated cells.

Ligand-receptor complexes formed at the plasma membrane are internalised via various endocytic pathways that influence the ultimate signalling output by regulating the selection of interaction partners by the complex along the trafficking route. We report that, in differentiated cells, activin A-receptor complexes are internalised via clathrin-mediated endocytosis (CME) and macropinocytosis (MP), whereas in human embryonic stem cells (hESCs) internalisation occurs via CME. We further show that hESCs are devoid of MP, which becomes functional upon differentiation towards endothelial cells through mesoderm mediators.

Development of novel GnRH and Tat based luminescent probes with enhanced cellular uptake and bioimaging profile.

There is a clear need to develop photostable chromophores for bioimaging with respect to the classically utilized green fluorescent dye fluorescein. Along these lines, we utilized a phosphorescent carboxy-substituted ruthenium(ii) polypyridyl [Ru(bipy)2(mcb)]2+ (bipy = 2,2'-bipyridyl and mcb = 4-carboxy-4'-methyl-2,2'-bipyridyl) complex. We developed two luminescent peptide conjugates of the cell-penetrating peptide Tat48-60 consisting of either [Ru(bipy)2(mcb)]2+ or 5(6)-carboxyfluorescein (5(6)-FAM) tethered on the Lys50 of the peptide through amide bond.

Combined transcriptomic and phosphoproteomic analysis of BMP4 signaling in human embryonic stem cells.

Human embryonic stem cells (hESCs) are an invaluable tool in the fields of embryology and regenerative medicine. Activin A and BMP4 are well-characterised growth factors implicated in pluripotency and differentiation. In the current study, hESCs are cultured in a modified version of mTeSR1, where low concentrations of ActivinA substitute for TGFβ.

Development of programmable gemcitabine-GnRH pro-drugs bearing linker controllable "click" oxime bond tethers and preclinical evaluation against prostate cancer.

Peptide-drug conjugates (PDCs) are gaining considerable attention as anti-neoplastic agents. However, their development is often laborious and time-consuming. Herein, we have developed and preclinically evaluated three PDCs with gemcitabine as the anticancer cytotoxic unit and D-Lys-GnRH (gonadotropin-releasing hormone; GnRH) as the cancer-targeting unit.

Tissue Engineering Using Vascular Organoids From Human Pluripotent Stem Cell Derived Mural Cell Phenotypes.

Diffusion is a limiting factor in regenerating large tissues (100-200 μm) due to reduced nutrient supply and waste removal leading to low viability of the regenerating cells as neovascularization of the implant by the host is a slow process. Thus, generating prevascularized tissue engineered constructs, in which endothelial (ECs) and mural (MCs) cells, such as smooth muscle cells (SMCs), and pericytes (PCs), are preassembled into functional vessels capable of rapidly connecting to the host vasculature could overcome this obstacle. Toward this purpose, using feeder-free and low serum conditions, we developed a simple, efficient and rapid approach to induce the differentiation of human pluripotent stem cells-hPSCs (human embryonic stem cells and human induced pluripotent stem cells) to defined SMC populations (contractile and synthetic hPSC-SMCs) by extensively characterizing the cellular phenotype (expression of CD44, CD73, CD105, NG2, PDGFRβ, and contractile proteins) and function of hPSC-SMCs.

Integrating primary and secondary care to optimize hepatitis C treatment: development and evaluation of a multidisciplinary educational Masterclass series.

Background: It is increasingly being recognized that the elimination of HCV requires a multidisciplinary approach and effective cooperation between primary and secondary care.

Objectives: As part of a project (HepCare Europe) to integrate primary and secondary care for patients at risk of or infected with HCV, we developed a multidisciplinary educational Masterclass series for healthcare professionals (HCPs) working in primary care in Dublin and Bucharest. This article aims to describe and evaluate the series and examine how this model might be implemented into practice.

The seroprevalence of untreated chronic hepatitis C virus (HCV) infection and associated risk factors in male Irish prisoners: a cross-sectional study, 2017.

IntroductionData on chronic hepatitis C (HCV) infection prevalence in European prisons are incomplete and impact the public health opportunity that incarceration provides.AimsWe aimed to estimate the seroprevalence of untreated chronic HCV infection and to identify associated risk factors in an Irish male prison.MethodsWe conducted a cross-sectional study involving a researcher-administered questionnaire, review of medical records and HCV serology.

Using the Teacher IRAP (T-IRAP) interactive computerized programme to teach complex flexible relational responding with children with diagnosed autism spectrum disorder.

The research used an alternating-treatments design to compare relational responding for five children with diagnosed autism spectrum disorder (ASD) in two teaching conditions. Both conditions used applied behavior analysis; one was usual tabletop teaching (TT), and one was an interactive computerized teaching program, the Teacher-Implicit Relational Assessment Programme (T-IRAP; Kilroe, Murphy, Barnes-Holmes, & Barnes-Holmes, (2), 60-80, 2014). Relational skills targeted were coordination (same/different), with nonarbitrary and arbitrary stimuli.

'HepCheck Dublin': an intensified hepatitis C screening programme in a homeless population demonstrates the need for alternative models of care.

Background: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease worldwide. Prevalence of HCV in homeless populations ranges from 3.9 to 36.

Barriers and facilitators to hepatitis C (HCV) screening and treatment-a description of prisoners' perspective.

Background: Hepatitis C virus (HCV) infection is a global epidemic with an estimated 71 million people infected worldwide. People who inject drugs (PWID) are overrepresented in prison populations globally and have higher levels of HCV infection than the general population. Despite increased access to primary health care while in prison, many HCV infected prisoners do not engage with screening or treatment.

Assessing implicit and explicit dementia stigma in young adults and care-workers.

This aim of this study was to assess implicit and self-reported stigma towards people with dementia in young adults with no contact or experience ( = 23), and in care-workers ( = 17 professional dementia care-workers). Data were analysed to determine whether stigma was related to self-reported levels of depression, anxiety, stress and professional burnout. Forty participants completed the Implicit Relational Assessment Procedure and Dementia Attitudes Scale.

Exploring Patient Characteristics and Barriers to Hepatitis C Treatment in Patients on Opioid Substitution Treatment Attending a Community Based Fibro-scanning Clinic.

Background And Objectives: Hepatitis C virus (HCV) infection is a major public health issue. There is substandard uptake in HCV assessment and treatment among people who inject drugs (PWID). Community fibroscanning is used to assess disease severity and target treatment.

Generation of human induced pluripotent stem cells in defined, feeder-free conditions.

Herein, we describe a modified protocol for the generation of human induced pluripotent stem cells (hiPS) and expansion under defined, serum free and feeder free conditions. These cells exhibit a high level of plasticity towards various differentiation pathways both in vitro and in vivo. Ultimately, hiPS-derived lines achieved high standards of three dimensional differentiations on biomaterial scaffolds and promoted in vivo regeneration of complex organs, such as Anterior Cruciate Ligament (in swine ACL-rupture models) and other tissues as well.

Prospective, Double-Blind, Randomized Study to Evaluate Single-Injection Adductor Canal Nerve Block Versus Femoral Nerve Block: Postoperative Functional Outcomes After Total Knee Arthroplasty.

Background And Objectives: Despite multiple clinical trials comparing the adductor canal block (ACB) with femoral nerve block (FNB) for total knee arthroplasty, none looked at the aforementioned nerve blocks from early functional results to up to 6 months after surgery.

Methods: For this prospective, double-blind, randomized, single-center trial, we enrolled 98 patients set to undergo total knee arthroplasty. The patients were randomized, with 93 patients included in the intention-to-treat analysis.

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis.

Endocytosis plays a crucial role in receptor signalling. VEGFR2 (also known as KDR) and its ligand VEGFA are fundamental in neovascularisation. However, our understanding of the role of endocytosis in VEGFR2 signalling remains limited.

Generation of stem cell-based bioartificial anterior cruciate ligament (ACL) grafts for effective ACL rupture repair.

In the present study, we combined stem cell technology with a non-absorbable biomaterial for the reconstruction of the ruptured ACL. Towards this purpose, multipotential stromal cells derived either from subcutaneous human adipose tissue (hAT-MSCs) or from induced pluripotent stem cells (iPSCs) generated from human foreskin fibroblasts (hiPSC-MSCs) were cultured on the biomaterial for 21days in vitro to generate a 3D bioartifical ACL graft. Stem cell differentiation towards bone and ligament at the ends and central part of the biomaterial was selectively induced using either BMP-2/FGF-2 or TGF-β/FGF-2 combinations, respectively.

Proteome Changes during Transition from Human Embryonic to Vascular Progenitor Cells.

Human embryonic stem cells (hESCs) are promising in regenerative medicine (RM) due to their differentiation plasticity and proliferation potential. However, a major challenge in RM is the generation of a vascular system to support nutrient flow to newly synthesized tissues. Here we refined an existing method to generate tight vessels by differentiating hESCs in CD34(+) vascular progenitor cells using chemically defined media and growth conditions.

Cognitive deficits in transgenic and knock-in HTT mice parallel those in Huntington's disease.

Background: Huntington's disease (HD) is characterized not only by severe motor deficits but also by early cognitive dysfunction that significantly increases the burden of the disease for patients and caregivers. Considerable efforts have concentrated, therefore, on the assessment of cognitive deficits in some HD mouse models. However, many of these models that exhibit cognitive deficits also have contemporaneous serious motor deficits, confounding interpretation of cognitive decline.

VEGF signaling, mTOR complexes, and the endoplasmic reticulum: Towards a role of metabolic sensing in the regulation of angiogenesis.

Vascular endothelial growth factor (VEGF) activates unfolded protein response sensors in the endoplasmic reticulum through phospholipase C gamma (PLCγ)-mediated crosstalk with mammalian target of rapamycin complex 1 (mTORC1). Activation of transcription factor 6 (ATF6) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) activate mTORC2, ensuring maximal endothelial cell survival and angiogenic activity through phosphorylation of AKT on Ser473. As mTORC1 is a metabolic sensor, metabolic signals may be integrated with signals from VEGF in the regulation of angiogenesis.

VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates IRE1α, ATF6, and PERK cascades, leading to a transcriptional/translational response known as unfolded protein response (UPR). Here we show that VEGF activates UPR mediators through a PLCγ-mediated crosstalk with the mTORC1 complex without accumulation of unfolded proteins in the ER. Activation of ATF6 and PERK contributes to the survival effect of VEGF on endothelial cells (ECs) by positively regulating mTORC2-mediated phosphorylation of AKT on Ser473, which is required for full activity of AKT.