Search

Extradomain-B Fibronectin (EDB-FN) is an oncomarker that can be visualized with magnetic resonance molecular imaging (MRMI) to detect pancreatic ductal adenocarcinoma (PDAC) metastasis. In this study, we sought to assess the expression of EDB-FN in clinical samples of PDAC and to evaluate MRMI of PDAC metastasis with an EDB-FN-specific gadolinium-based contrast agent (MT218) in an orthotopic KPC-GFP-Luc mouse model. EDB-FN expression was evaluated in PDAC tissue samples through immunohistochemistry. RNA-Seq data obtained from the GEPIA2 project was evaluated to demonstrate EDB-FN expression in large patient cohorts. FLASH-3D MRI at 3 T of the KPC-GFP-Luc metastasis model was performed following injection of MT218. Tumor enhancement in MR images was correlated to postmortem distribution of KPC-GFP-Luc tumors using fluorescent and bright-field cryo-imaging and anatomical landmarks. EDB-FN immunohistochemical staining scores of human metastatic tumor stroma, (2.17 ± 0.271), metastatic tumor parenchyma (2.08 ± 0.229), primary tumor stroma (1.61 ± 0.26), and primary tumor parenchyma (1.61 ± 0.12) were significantly (p

Purpose of the study: COVID-19 pandemic has severely hit the global economy. It has also had a huge impact on the tourism industry. The purpose of the study is to identify the possible initiatives to be taken to revive the tourism industry during or after the COVID-19 era. Methodology: A qualitative analysis of secondary data has been applied. NVivo 12 has been used for organizing, analyzing, and visualizing the data. Main Findings: It is found that government will have to play the most prominent role in the revival of the tourism sector through financial stimulus packages and subsidies. The use of marketing activities, promotional tools, and social media platforms will also aid in the recovery process. Initially, tourism activities can be restarted at domestic levels and in travel bubbles, motivating international tourists. Most importantly, maintaining hygiene and maintaining social distance will be the main tool to revive the tourism industry. Applications of this study: The findings of this study will enable the decision-makers of the hospitality and tourism industry to make a strategic recovery plan Covid-19 stricken tourism economy. The originality of this study: Although most of the industries are slowly turning around during the pandemic, the tourism industry is still struggling to survive. This study proposes several possible recovery plans in light of past epidemic experiences.

Well-defined boronic acid block copolymers were demonstrated to exhibit glucose-responsive disassembly at physiological pH. A boronic acid-containing acrylamide monomer with an electron-withdrawing substituent on the pendant phenylboronic acid moiety was polymerized by reversible addition–fragmentation chain transfer (RAFT) polymerization to yield a polymer with a boronic acid pKa = 8.2. Below this value, a block copolymer of this monomer with poly(N,N-dimethylacrylamide) self-assembled into aggregates. Addition of base to yield a pH > pKa or addition of glucose at pH = 7.4 resulted in aggregate dissociation that may prove promising for controlled delivery applications under physiological relevant conditions.

Highly efficient polymer-antibody conjugations were demonstrated via a tetrafluorophenyl active ester. A well-defined diblock copolymer was synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization with a temperature-responsive block, poly(N-isopropylacrylamide), and a block of N,N-dimethylacrylamide and 2,3,5,6-tetrafluorophenyl acrylate active ester. The polymer was conjugated to anti-p24 IgG antibody with about 100% efficiency in as little as 2 h at room temperature in a pH 10.8 buffer. The temperature-responsiveness of the polymer was conferred to the polymer–antibody conjugates after conjugation. The conjugates bound p24 antigen specifically and with binding efficiency comparable to native antibodies. Thus, the active ester diblock copolymer can facilitate the synthesis of temperature-responsive bioconjugates, which may be promising reagents for immunoassays, bioseparations, and specimen-enrichment applications.

Matrix factorization (MF) which is a Collaborative filtering (CF) based model, is widely used in the recommendation systems (RS). For our experiment, we collected data from a company's internal web site where curated contents are published and pushed to the employees. However, the size of the dataset is small and interaction data is also limited. We got a sparse matrix when we generated a user-item rating matrix. We have used Multi-Layer Perceptron (MLP) to calculate the rating scores from the implicit feedbacks. However, on this sparse dataset traditional content only or CF-only RSs do not work well. Here, we propose ahybrid RS that incorporates content similarity scores into an MLP-based MF-model. To integrate the content similarity scores into the MF, we have defined an objective function based on a regularization term. The experimental result shows that our proposed model demonstrates a better result than the traditional MF-based models.

Library Analytics is used to analyze the huge amount of data that is collected by most colleges and universities when the library website is browsed. It is really useful to assess and evaluate the usage of different types of library e-resource items such as books, journals etc. In this thesis work we have designed and implemented a multi-threaded Library Analytics system specifically for the Ryerson Library. We have analyzed the library usage data to generate different types of reports through a data visualization engine based on requirements from the librarian. Furthermore, we have paid special attention to the task of e-resource item clustering, which could better organize the resources and potentially be used to recommend interesting items to users. We have compared different clustering algorithms and found that association-rule based clustering is 20% more accurate than others and it also identifies the hidden relationships between different browsed articles.

The impact of AI on world economy and its various aspects can only be anticipated but not predicted. However, there are obvious aspects that our mind can expect. This chapter is an attempt to walk through the various impact of AIs in the world economy. The impact on the world economy and various aspects of it that AI will have can only be anticipated. The evolution of the world economy from the past up to what it is now; the substitutes and complements economists perceive an evolving technology to have. Can a wider acceptance of AI trigger geographical migration for humans? Such concerns are addressed in this chapter.

The user feedback data such as likes, dislikes, comments on movie trailers posted on YouTube can be a useful information source for movie recommender systems. In this paper, we study the effect of adding the feedback data on trailers as a type of the side information to the movie rating data. We propose a recommendation framework that can integrate the trailer and rating data adopting different integration strategies: integrating all the trailer data as movie features, using sentiment scores derived from the trailer comments as a rating matrix to integrate with the movie rating matrix and treating others as the movie features, or only integrating the sentiment score based rating matrix with the movie rating matrix. Our experiment shows that if we include the movie trailer data, recommendation accuracy is improved. We also find that the most accurate result is achieved if all the trailer feedback data is integrated as movie features. To design our system, we use both Matrix Factorization (MF) and Deep Neural Network (DNN) Models. We find that the DNN model performs better than the MF model.

This study demonstrates a novel application of nitrogen-doped carbon dots (NCDs) to enable the separation of different lengths of single-stranded DNA (ssDNA) by eletrokinetic means. Carbon dots have recently found widespread application in the fields of sensing, diagnostics, and healthcare due to their biocompatibility and low toxicity. In light of growing interest in the use of ssDNA aptamers over antibodies in the fields of biosensor development and drug delivery, it is important to establish a simple and effective method for aptamer separation. In this study, we employed NCDs as buffer additives in a capillary electrophoresis (CE)-based method, giving rise to the separation of FAM-labeled ssDNA samples ranging from 32 to 100 bases in length, with resolutions ranging from 1.30 – 1.77. In particular, we adopted a capillary transient isotachophoresis (ctITP) system with laser-induced fluorescence (LIF) detection, with both the separation and sample buffers modified by the addition of 30 μg/mL NCDs. These nanomaterials were prepared by a simple hydrothermal method from a mixture of citric acid and ethylenediamine. The NCDs themselves are highly fluorescent and photostable. As components in the background electrolyte, they did not interfere with the fluorescence emission of the FAM-labeled DNA samples. Under the conditions employed, no separation could be achieved in the absence of the NCDs nor with undoped CDs. The results show that NCDs function as buffer additives capable of enhancing electrokinetic-based separations of ssDNA, and hence, provide a new application for these carbon nanomaterials.

Pulmonary melioidosis is a bacterial disease with high morbidity and a mortality rate that can be as high as 40% in resource-poor regions of South Asia. This disease burden is linked to the pathogen's intrinsic antibiotic-resistance and protected intracellular localization in alveolar macrophages. Current treatment regimens require several antibiotics with multi-month oral and intravenous administrations that are difficult to implement in the developing world. Herein, we report that a macrophage-targeted polyciprofloxacin prodrug acts as a surprisingly effective pre-exposure prophylactic in highly lethal murine models of aerosolized human pulmonary melioidosis. A single dose of the polymeric prodrug maintained high lung drug levels and targeted an intracellular depot of ciprofloxacin to the alveolar macrophage compartment that was sustained over a period of 7 days above minimal inhibitory concentrations. This intracellular pharmacokinetic profile provided complete pre-exposure protection in a BSL-3 model with a drug-resistant, aerosolized clinical isolate of Burkholderia pseudomallei from Thailand. This total protection was achieved despite the bacteria's intrinsic resistance to ciprofloxacin and where an equivalent dose of pulmonary-administered ciprofloxacin was ineffective. For the first time, we demonstrate that targeting the intracellular macrophage compartment with extended antibiotic dosing can achieve pre-exposure prophylaxis in a model of pulmonary melioidosis. This fully synthetic and modular therapeutic platform could be an important therapeutic approach with new or re-purposed antibiotics for melioidosis prevention and treatment, especially as portable inhalation devices in high-risk, resource-poor settings.

The synthesis and characterization of a novel natural-synthetic hybrid material based on cellulose is reported. The reversible addition-fragmentation chain-transfer (RAFT) process was used to graft poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) onto a cellulosic substrate. The weight ratio was increased with an increase in monomer concentration, polymerization time and degree of polymerization (DP). We found that the addition of free chain-transfer agent has a pronounced effect on the weight ratio, chain length of grafted polymer, monomer conversion and homopolymer formation in solution. The cellulose-graft-poly(2-(dimethylamino)ethyl methacrylate) copolymers were characterized by gravimetry, elemental analysis, attenuated total reflectance Fourier transform infrared spectroscopy, scanning electron microscopy, thermal analysis and atomic force microscopy. The dithioester end-group present at the chain end of PDMAEMA was removed via aminolysis. The livingness of the process was utilized to block-copolymerize styrene from the grafted PDMAEMA chains. The hydrophilic/hydrophobic properties of the novel cellulose-g-(PDMAEMA-b-polystyrene) material were illustrated by contact-angle measurements.

Primaquine and tafenoquine are the two 8-aminoquinoline (8-AQ) antimalarial drugs approved for malarial radical cure - the elimination of liver stage hypnozoites after infection with Plasmodium vivax. A single oral dose of tafenoquine leads to high efficacy against intra-hepatocyte hypnozoites after efficient first pass liver uptake and metabolism. Unfortunately, both drugs cause hemolytic anemia in G6PD-deficient humans. This toxicity prevents their mass administration without G6PD testing given the approximately 400 million G6PD deficient people across malarial endemic regions of the world. We hypothesized that liver-targeted delivery of 8-AQ prodrugs could maximize liver exposure and minimize erythrocyte exposure to increase their therapeutic window. Primaquine and tafenoquine were first synthesized as prodrug vinyl monomers with self-immolative hydrolytic linkers or cathepsin-cleavable valine-citrulline peptide linkers. RAFT polymerization was exploited to copolymerize these prodrug monomers with hepatocyte-targeting GalNAc monomers. Pharmacokinetic studies of released drugs after intravenous administration showed that the liver-to-plasma AUC ratios could be significantly improved, compared to parent drug administered orally. Single doses of the liver-targeted, enzyme-cleavable tafenoquine polymer were found to be as efficacious as an equivalent dose of the oral parent drug in the P. berghei causal prophylaxis model. They also elicited significantly milder hemotoxicity in the humanized NOD/SCID mouse model engrafted with red blood cells from G6PD deficient donors. The clinical application is envisioned as a single subcutaneous administration, and the lead tafenoquine polymer also showed excellent bioavailability and liver-to-blood ratios exceeding the IV administered polymer. The liver-targeted tafenoquine polymers warrant further development as a single-dose therapeutic via the subcutaneous route with the potential for broader patient administration without a requirement for G6PD diagnosis.

Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafenamide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/106 cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications.

HIV and hepatitis B are two of the most prevalent viruses globally, and despite readily available preventive treatments unforgiving treatment regimens still exist, such as daily doses of medicine that are challenging to maintain especially in poorer countries. More advanced and longer-lasting delivery vehicles can potentially overcome this problem by reducing maintenance requirements and significantly increase access to medicine. Here, we designed a technology to control the delivery of an antiviral drug over a long timeframe via a nanofiber based delivery scaffold that is both easy to produce and use. An antiviral prodrug containing tenofovir alafenamide (TAF) was synthesized by initial conjugation to glycerol monomethacrylate followed by polymerization to form a diblock copolymer (pTAF) using reversible addition-fragmentation chain transfer (RAFT). In order to generate an efficient drug delivery system this copolymer was fabricated into an electrospun nanofiber (ESF) scaffold using blend electrospinning with poly(caprolactone) (PCL) as the carrier polymer. SEM images revealed that the pTAF-PCL ESFs were uniform with an average diameter of (787 ± 0.212 nm), while XPS analysis demonstrated that the pTAF was overrepresented at the surface of the ESFs. Additionally, the pTAF exhibited a sustained release profile over a 2 month period in human serum (HS), suggesting that these types of copolymer-based drugamers can be used in conjunction with electrospinning to produce long-lasting drug delivery systems.

We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases.

Engineered immune cells are an exciting therapeutic modality which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat tumors and their immune-suppressive environments. Here, a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering has been developed. Macrophage and T cell therapeutics are engineered to express a bioorthogonal single chain variable fragment receptor. The receptor binds a fluorescein ligand that directs cell loading with ligand-tagged polymeric prodrugs, termed “drugamers”. The fluorescein ligand facilitated stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporated prodrug monomers of the phosphoinositide-3-kinase inhibitor, PI-103. The extended release of PI-103 from the drugamer sustained anti-proliferative activity against a glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system was demonstrated by loading T cells with a second fluorescein-drugamer. This drugamer incorporated a small molecule trans-gene activator, CMP8, that switched-on a degron-tagged gene circuit to provide temporal regulation of engineered T cell protein expression. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both anti-tumor and transgene-activating small molecule prodrugs.

Introduction: Assessing the tumor vasculature in models of pancreatic tumors can improve the characterization of these models, which can then support the eventual assessments of anti-cancer treatments. In this study, we sought to relate hypoxia, vascular perfusion, and vascular patency using synergistic imaging methods. In vivo Multispectral Optoacoustic Tomography (MSOT; also known as photoacoustic imaging) can measure %sO2 a relative measurement of oxy- vs. deoxy-hemoglobin in tumors. In vivo Dynamic Contrast Enhanced (DCE) MSOT can measure vascular perfusion. CryoVizTM imaging, a serial-sectioning-and-block-face-imaging technique, provides high-resolution 3D microscopic color anatomy and sensitive fluorescence making it ideal for assessing vascular perfusion by imaging ICG uptake and vascular patency by imaging Dylight488 lectin uptake. Methods: We performed MSOT and CryoVizTM imaging with subcutaneous tumor mouse models of SU.86.86 and MIA PaCa-2 pancreatic cancer. We performed MSOT with 21% O2 and 100% O2 carrier gas, which measures %sO2 (% oxyhemoglobin/total hemoglobin) as a biomarker of hypoxia. We performed DCE MSOT with 50 nmol indocyanine green (ICG), which measures Kapp (uptake rate from blood to tumor tissue) - a biomarker of vascular perfusion. To assess microvessel patency, we injected Dylight488 lectin via retro-orbital injection into the mice 3 min before euthanasia to enable CryoVizTM visualization of functional blood vessels. Subsequently, mice were euthanized, embedded in optimal cutting temperature (OCT) gel and flash-frozen in liquid nitrogen, and then imaged on the CryoVizTM. We acquired brightfield color anatomy, Dylight488 lectin (visible) fluorescence (ex: 460-490 nm, em>510nm) and ICG (NIR) fluorescence images (ex: 747/11 nm, em: >790nm) with an in-plane resolution of 10.232µm and a section thickness of 40 µm. Results: The in vivo MSOT analysis indicated that the MIA PaCa-2 model was more hypoxic than the SU.86.86 model, based on lower %sO2 measurements with both carrier gases. The in vivo DCE MSOT analysis indicated that the MIA PaCa-2 model had greater vascular perfusion than SU.86.86, based on a higher Kapp value. CryoVizTM images showed higher levels of lectin and ICG fluorescence in MIA PaCa-2 as compared to SU.86.86, indicating greater vascular patency and perfusion in the former. A strong lectin signal was observed in the injection site (retro-orbital sinuses), and in the renal medulla. ICG was also found to be retained in the axillary lymph node in both MIA PaCa-2 and SU.86.86, and in the kidney/adrenal glands of the MIA PaCa-2 mouse. Conclusion: Together, these results confirmed that the MIA PACa-2 model had higher hypoxia, vascular perfusion, and vascular patency, demonstrating the relationship between hypoxia and angiogenesis. This study reveals the power of 3D CryoVizTM imaging as a gold standard validation tool in cancer imaging. Citation Format: Madhusudhana Gargesha, Shreya Goel, Bryan Scott, Mark D. Pagel, Debashish Roy. CryoVizTM and photoacoustic imaging for assessment of tumor vasculature in mouse models of pancreatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB239.

Poor prognosis for glioblastoma (GBM) is a consequence of the aggressive and infiltrative nature of gliomas where individual cells migrate away from the main tumor to distant sites, making complete surgical resection and treatment difficult. In this manuscript, we characterize an invasive pediatric glioma model and determine if nanoparticles linked to a peptide recognizing the GBM tumor biomarker PTPmu can specifically target both the main tumor and invasive cancer cells in adult and pediatric glioma models. Using both iron and lipid-based nanoparticles, we demonstrate by magnetic resonance imaging, optical imaging, histology, and iron quantification that PTPmu-targeted nanoparticles effectively label adult gliomas. Using PTPmu-targeted nanoparticles in a newly characterized orthotopic pediatric SJ-GBM2 model, we demonstrate individual tumor cell labeling both within the solid tumor margins and at invasive and dispersive sites.

Library Analytics is used to analyze the huge amount of data that is collected by most colleges and universities when the library electronic resources are browsed. In this research work, we have analyzed the library usage data to accomplish the task of e-resource item clustering. We have compared different clustering algorithms and found that association-rule (ARM) based clustering is more accurate than others and it also identifies the hidden relationships between articles which are content-wise not similar. We have also shown that items in the same cluster offer a good source for recommendation.

Pheochromocytoma is a catecholamine secreting neuroendocrine tumor arising from chromaffin cells in the adrenal medulla or extraadrenal paraganglia. The classic triad of symptoms consists of episodic headache, palpitations and diaphoresis. Pheochromocytomas can result in various cardiac manifestations including systemic hypertension, ventricular hypertrophy and congestive heart failure due to prolonged hypertension. They can also manifest with arrhythmias, myocarditis and dilated cardiomyopathy due to toxic exposure to catecholamines, or occasionally as acute coronary syndrome. Here, we describe a case who presented very similar to acute coronary syndrome with elevated cardiac biomarkers and was taken into catheterization lab. His coronaries were normal but he was incidentally detected to have suprarenal mass during angiography. He was finally diagnosed as having pheochromocytoma. Subsequently he was surgically treated and cured.

Mesenchymal stem or stromal cells (MSC) are under investigation as a potential immunotherapy. MSC are usually administered via intravenous infusion, after which they are trapped in the lungs and die and disappear within a day. The fate of MSC after their disappearance from the lungs is unknown and it is unclear how MSC realize their immunomodulatory effects in their short lifespan. We examined immunological mechanisms determining the fate of infused MSC and the immunomodulatory response associated with it. Tracking viable and dead human umbilical cord MSC (ucMSC) in mice using Qtracker beads (contained in viable cells) and Hoechst33342 (staining all cells) revealed that viable ucMSC were present in the lungs immediately after infusion. Twenty-four hours later, the majority of ucMSC were dead and found in the lungs and liver where they were contained in monocytic cells of predominantly non-classical Ly6C low phenotype. Monocytes containing ucMSC were also detected systemically. In vitro experiments confirmed that human CD14 ++ /CD16 - classical monocytes polarized toward a non-classical CD14 ++ CD16 + CD206 + phenotype after phagocytosis of ucMSC and expressed programmed death ligand-1 and IL-10, while TNF-α was reduced. ucMSC-primed monocytes induced Foxp3 + regulatory T cell formation in mixed lymphocyte reactions. These results demonstrate that infused MSC are rapidly phagocytosed by monocytes, which subsequently migrate from the lungs to other body sites. Phagocytosis of ucMSC induces phenotypical and functional changes in monocytes, which subsequently modulate cells of the adaptive immune system. It can be concluded that monocytes play a crucial role in mediating, distributing, and transferring the immunomodulatory effect of MSC. Stem Cells 2018;36:602–615.

Background Mesenchymal stromal cells (MSC) possess immunomodulatory properties and low immunogenicity, both crucial properties for their development into an effective cellular immunotherapy. They have shown benefit in clinical trials targeting liver diseases; however the efficacy of MSC therapy will benefit from improvement of the immunomodulatory and immunogenic properties of MSC. Methods MSC derived from human umbilical cords (ucMSC) were treated for 3 days in vitro with various inflammatory factors, interleukins, vitamins and serum deprivation. Their immunogenicity and immunomodulatory capacity were examined by gene-expression analysis, surface-marker expressions, IDO activity, PGE2 secretion and inhibition of T cell proliferation and IFNγ production. Furthermore, their activation of NK cell cytotoxicity was investigated via CD107a expression on NK cells. The immunomodulatory capacity, biodistribution and survival of pre-treated ucMSC were investigated in a CCl4-induced liver disease mouse model. In addition, capacity of pre-treated MSC to ameliorate liver inflammation was examined in an ex vivo liver inflammation co-culture model. Results IFN-γ and a multiple cytokine cocktail (MC) consisting of IFN-γ, TGFβ and retinoic acid upregulated the expression of immunomodulatory factor PD-L1 and IDO activity. Subsequently, both treatments enhanced the capacity of ucMSC to inhibit CD4 and CD8 T cell proliferation and IFN-γ production. The susceptibility of ucMSC for NK cell lysis was decreased by IFN-β, TGFβ and MC treatment. In vivo, no immunomodulation was observed by the ucMSC. Four hours after intravenous infusion in mice with CCl4-induced inflammatory liver injury, the majority of ucMSC were trapped in the lungs. Rapid clearance of ucMSC(VitB6), ucMSC(Starv + VitB6) and ucMSC(MC) and altered bio-distribution of ucMSC(TGFβ) compared to untreated ucMSC was observed. In the ex vivo co-culture system with inflammatory liver slices ucMSC(MC) showed significantly enhanced modulatory capacity compared to untreated ucMSC. Conclusions The present study demonstrates the responsiveness of ucMSC to in vitro optimisation treatment. The observed improvements in immunomodulatory capacity as well as immunogenicity after MC treatment may improve the efficacy of ucMSC as immunotherapy targeted towards liver inflammation. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0590-6) contains supplementary material, which is available to authorized users.

The macrostructures of synthetic polymers are essentially the complete molecular chain architectures, including the types and amounts of constituent short-range microstructures, such as the regio- and stereosequences of the inserted monomers, the amounts and sequences of monomers found in co-, ter-, and tetra-polymers, branching, inadvertent, and otherwise, etc. Currently, the best method for characterizing polymer microstructures uses high field, high resolution 13C-nuclear magnetic resonance (NMR) spectroscopy observed in solution. However, even 13C-NMR is incapable of determining the locations or positions of resident polymer microstructures, which are required to elucidate their complete macrostructures. The sequences of amino acid residues in proteins, or their primary structures, cannot be characterized by NMR or other short-range spectroscopic methods, but only by decoding the DNA used in their syntheses or, if available, X-ray analysis of their single crystals. Similarly, there are currently no experimental means to determine the sequences or locations of constituent microstructures along the chains of synthetic macromolecules. Thus, we are presently unable to determine their macrostructures. As protein tertiary and quaternary structures and their resulting ultimate functions are determined by their primary sequence of amino acids, so too are the behaviors and properties of synthetic polymers critically dependent on their macrostructures. We seek to raise the consciousness of both synthetic and physical polymer scientists and engineers to the importance of characterizing polymer macrostructures when attempting to develop structure–property relations. To help achieve this task, we suggest using the electrical birefringence or Kerr effects observed in their dilute solutions. The molar Kerr constants of polymer solutes contributing to the birefringence of their solutions, under the application of a strong electric field, are highly sensitive to both the types and locations of their constituent microstructures. As a consequence, we may begin to characterize the macrostructures of synthetic polymers by means of the Kerr effect. To simplify implementation of the Kerr effect to characterize polymer macrostructures, we suggest that NMR first be used to determine the types and amounts of constituent microstructures present. Subsequent comparison of observed Kerr effects with those predicted for different microstructural locations along the polymer chains can then be used to identify the most likely macrostructures. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 155–166