Open AccessArticle
Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition
Biomedicines 2017, 5(2), 17; doi:10.3390/biomedicines5020017 -
Abstract
Virgin coconut oil (VCO) has been the subject of several studies which have aimed to alleviate Alzheimer’s disease (AD) pathology, focusing on in vitro antioxidant and acetylcholinesterase (AChE) inhibitory activities. Here, we studied an underutilized and lesser-valued part of the coconut tree, specifically
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Virgin coconut oil (VCO) has been the subject of several studies which have aimed to alleviate Alzheimer’s disease (AD) pathology, focusing on in vitro antioxidant and acetylcholinesterase (AChE) inhibitory activities. Here, we studied an underutilized and lesser-valued part of the coconut tree, specifically the leaves, using in vitro and in vivo approaches. Coconut leaf extract (CLE) was screened for antioxidant and AChE inhibitory properties in vitro and therapeutic effects in two strains of transgenic Caenorhabditis elegans expressing amyloid-β1–42 (Aβ1-42) in muscle cells. CLE demonstrated free radical scavenging activity with an EC50 that is 79-fold less compared to ascorbic acid, and an AChE inhibitory activity that is 131-fold less compared to Rivastigmine. Surprisingly, in spite of its low antioxidant activity and AChE inhibition, CLE reduced Aβ deposits by 30.31% in CL2006 in a dose-independent manner, and reduced the percentage of paralyzed nematodes at the lowest concentration of CLE (159.38 μg/mL), compared to dH2O/vehicle (control). Phytochemical analysis detected glycosides, anthocyanins, and hydrolyzable tannins in CLE, some of which are known to be anti-amyloidogenic. Taken together, these findings suggest that CLE metabolites alternatively decrease AB1–42 aggregation and paralysis prevalence independently of free radical scavenging and AChE inhibition, and this warrants further investigation on the bioactive compounds of CLE. Full article
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Open AccessArticle
Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia
Biomedicines 2017, 5(2), 16; doi:10.3390/biomedicines5020016 -
Abstract
Fibromyalgia (FM) is a complex, multi-symptom condition that predominantly affects women. The majority of those affected are unlikely to gain significant symptomatic control from the few treatments that are approved for FM. In this 10-week, single-blind, crossover trial we tested the immune effects
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Fibromyalgia (FM) is a complex, multi-symptom condition that predominantly affects women. The majority of those affected are unlikely to gain significant symptomatic control from the few treatments that are approved for FM. In this 10-week, single-blind, crossover trial we tested the immune effects of eight weeks of oral administration of low-dose naltrexone (LDN). We enrolled eight women with an average age of 46 years, symptom severity of 62 out of 100, and symptom duration of 14 years. We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF). We also found a 15% reduction of FM-associated pain and an 18% reduction in overall symptoms. The findings of this pilot trial suggest that LDN treatment in fibromyalgia is associated with a reduction of several key pro-inflammatory cytokines and symptoms. The potential role of LDN as an atypical anti-inflammatory medication should be explored further. Full article
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Open AccessReview
Modulation of NMDA Receptor Activity in Fibromyalgia
Biomedicines 2017, 5(2), 15; doi:10.3390/biomedicines5020015 -
Abstract
Activation of the N-methyl-d-aspartate receptor (NMDAR) results in increased sensitivity of spinal cord and brain pathways that process sensory information, particularly those which relate to pain. The NMDAR shows increased activity in fibromyalgia and hence modulation of the NMDAR is
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Activation of the N-methyl-d-aspartate receptor (NMDAR) results in increased sensitivity of spinal cord and brain pathways that process sensory information, particularly those which relate to pain. The NMDAR shows increased activity in fibromyalgia and hence modulation of the NMDAR is a target for therapeutic intervention. A literature review of interventions impacting on the NMDAR shows a number of drugs to be active on the NMDAR mechanism in fibromyalgia patients, with variable clinical effects. Low-dose intravenous ketamine and oral memantine both show clinically useful benefit in fibromyalgia. However, consideration of side-effects, logistics and cost need to be factored into management decisions regarding use of these drugs in this clinical setting. Overall benefits with current NMDAR antagonists appear modest and there is a need for better strategy trials to clarify optimal dose schedules and to delineate potential longer–term adverse events. Further investigation of the role of the NMDAR in fibromyalgia and the effect of other molecules that modulate this receptor appear important to enhance treatment targets in fibromyalgia. Full article
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Open AccessFeature PaperReview
Glycosylated Triterpenoids as Endosomal Escape Enhancers in Targeted Tumor Therapies
Biomedicines 2017, 5(2), 14; doi:10.3390/biomedicines5020014 -
Abstract
Protein-based targeted toxins play an increasingly important role in targeted tumor therapies. In spite of their high intrinsic toxicity, their efficacy in animal models is low. A major reason for this is the limited entry of the toxin into the cytosol of the
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Protein-based targeted toxins play an increasingly important role in targeted tumor therapies. In spite of their high intrinsic toxicity, their efficacy in animal models is low. A major reason for this is the limited entry of the toxin into the cytosol of the target cell, which is required to mediate the fatal effect. Target receptor bound and internalized toxins are mostly either recycled back to the cell surface or lysosomally degraded. This might explain why no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date although more than 500 targeted toxins have been developed within the last decades. To overcome the problem of insufficient endosomal escape, a number of strategies that make use of diverse chemicals, cell-penetrating or fusogenic peptides, and light-induced techniques were designed to weaken the membrane integrity of endosomes. This review focuses on glycosylated triterpenoids as endosomal escape enhancers and throws light on their structure, the mechanism of action, and on their efficacy in cell culture and animal models. Obstacles, challenges, opportunities, and future prospects are discussed. Full article
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Open AccessArticle
HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation
Biomedicines 2017, 5(2), 13; doi:10.3390/biomedicines5020013 -
Abstract
Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with
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Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with ATG. Homozygosity for human leukocyte antigen (HLA)-C group 1 killer-cell immunoglobulin-like receptor ligands (KIR-L), i.e. C1/1 KIR-L status, was recently shown to be a risk factor for severe aGVHD. Congruously, we have previously reported favorable outcomes in C1/1 recipients after ATG-based transplants in a monocentric analysis. Here, within an extended cohort, we test the hypothesis that incorporation of ATG for GVHD prophylaxis may improve survival particularly in HSCT recipients with at least one C1 KIR-ligand. Retrospectively, 775 consecutive allogeneic (excluding haploidentical) HSCTs were analyzed, including peripheral blood and bone marrow grafts for adults with hematological diseases at two Austrian HSCT centers. ATG-Fresenius/Grafalon, Thymoglobuline, and alemtuzumab were applied in 256, 87, and 7 transplants, respectively (subsequently summarized as “ATG”), while 425 HSCT were performed without ATG. Median follow-up of surviving patients is 48 months. Adjusted for age, disease-risk, HLA-match, donor and graft type, sex match, cytomegalovirus serostatus, conditioning intensity, and type of post-grafting GVHD prophylaxis, Cox regression analysis of the entire cohort (n = 775) revealed a significant association of ATG with decreased non-relapse mortality (NRM) (risk ratio (RR), 0.57; p = 0.001), and overall mortality (RR, 0.71; p = 0.014). Upon stratification for HLA-C KIR-L, the greatest benefit for ATG emerged in C1/1 recipients (n = 291), by reduction of non-relapse (RR, 0.34; p = 0.0002) and overall mortality (RR, 0.50; p = 0.003). Less pronounced, ATG decreased NRM (RR, 0.60; p = 0.036) in HLA-C group 1/2 recipients (n = 364), without significantly influencing overall mortality (RR, 0.70; p = 0.065). After exclusion of higher-dose ATG-based transplants, serotherapy significantly improved both NRM (RR, 0.54; p = 0.019; n = 322) and overall mortality (RR, 0.60; p = 0.018) in C1/2 recipients as well. In both, C1/1 (RR, 1.70; p = 0.10) and particularly in C1/2 recipients (RR, 0.94; p = 0.81), there was no statistically significant impact of ATG on relapse incidence. By contrast, in C2/2 recipients (n = 121), ATG neither reduced NRM (RR, 1.10; p = 0.82) nor overall mortality (RR, 1.50; p = 0.17), but increased the risk for relapse (RR, 4.38; p = 0.02). These retrospective findings suggest ATG may provide a survival benefit in recipients with at least one C1 group KIR-L, by reducing NRM without significantly increasing the relapse risk. Full article
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Open AccessArticle
Novel Computerized Method for Measurement of Retinal Vessel Diameters
Biomedicines 2017, 5(2), 12; doi:10.3390/biomedicines5020012 -
Abstract
Several clinical studies reveal the relationship between alterations in the topologies of the human retinal blood vessel, the outcrop and the disease evolution, such as diabetic retinopathy, hypertensive retinopathy, and macular degeneration. Indeed, the detection of these vascular changes always has gaps. In
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Several clinical studies reveal the relationship between alterations in the topologies of the human retinal blood vessel, the outcrop and the disease evolution, such as diabetic retinopathy, hypertensive retinopathy, and macular degeneration. Indeed, the detection of these vascular changes always has gaps. In addition, the manual steps are slow, which may be subjected to a bias of the perceiver. However, we can overcome these troubles using computer algorithms that are quicker and more accurate. This paper presents and investigates a novel method for measuring the blood vessel diameter in the retinal image. The proposed method is based on a thresholding segmentation and thinning step, followed by the characteristic point determination step by the Douglas-Peucker algorithm. Thereafter, it uses the active contours to detect vessel contour. Finally, Heron’s Formula is applied to assure the calculation of vessel diameter. The obtained results for six sample images showed that the proposed method generated less errors compared to other techniques, which confirms the high performance of the proposed method. Full article
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Open AccessReview
Viroimmunotherapy for Colorectal Cancer: Clinical Studies
Biomedicines 2017, 5(1), 11; doi:10.3390/biomedicines5010011 -
Abstract
Colorectal cancer is a leading cause of cancer incidence and death. Therapies for those with unresectable or recurrent disease are not considered curative at present. More effective and less toxic therapies are desperately needed. Historically, the immune system was thought to be an
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Colorectal cancer is a leading cause of cancer incidence and death. Therapies for those with unresectable or recurrent disease are not considered curative at present. More effective and less toxic therapies are desperately needed. Historically, the immune system was thought to be an enemy to oncolytic viral therapy. Thinking that oncolysis would be the only mechanism for cell death, oncolytic virologists theorized that immune clearance was a detriment to oncolysis. Recent advances in our understanding of the tumor microenvironment, and the interplay of tumor survival and a patient’s immune system have called into question our understanding of both arenas. It remains unclear what combination of restrictions or enhancements of innate and/or cell-mediated immunity can yield the highest likelihood of viral efficacy. This article reviews the variety of mechanisms explored for viruses such as immunotherapy for colorectal cancer. Full article
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Open AccessFeature PaperReview
The Continued Promise and Many Disappointments of Oncolytic Virotherapy in Gastrointestinal Malignancies
Biomedicines 2017, 5(1), 10; doi:10.3390/biomedicines5010010 -
Abstract
Oncolytic virotherapy represents a novel therapeutic strategy in the treatment of gastrointestinal malignancies. Oncolytic viruses, including genetically engineered and naturally occurring viruses, can selectively replicate in and induce tumor cell apoptosis without harming normal tissues, thus offering a promising tool in the armamentarium
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Oncolytic virotherapy represents a novel therapeutic strategy in the treatment of gastrointestinal malignancies. Oncolytic viruses, including genetically engineered and naturally occurring viruses, can selectively replicate in and induce tumor cell apoptosis without harming normal tissues, thus offering a promising tool in the armamentarium for cancer therapy. While this approach has garnered much interest over the past several decades, there has not been significant headway across various tumor types. The recent approval of talimogene laherparepvec, a second-generation oncolytic herpes simplex virus type-1, for the treatment of metastatic melanoma, confirms the therapeutic potential of oncolytic viral therapy. Herein, we will highlight and review the role of oncolytic viral therapy in gastrointestinal malignancies while discussing its limitations and potential alternative mechanisms to improve its treatment efficacy. Full article
Open AccessReview
Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation
Biomedicines 2017, 5(1), 9; doi:10.3390/biomedicines5010009 -
Abstract
Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or
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Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such “high-resolution” detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields. Full article
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Open AccessReview
Oncolytic Vesicular Stomatitis Virus as a Viro-Immunotherapy: Defeating Cancer with a “Hammer” and “Anvil”
Biomedicines 2017, 5(1), 8; doi:10.3390/biomedicines5010008 -
Abstract
Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor. Vesicular stomatitis virus (VSV), a negative-strand RNA
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Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor. Vesicular stomatitis virus (VSV), a negative-strand RNA virus, is under intense development as an oncolytic virus due to a variety of favorable properties, including its rapid replication kinetics, inherent tumor specificity, and its potential to elicit a broad range of immunomodulatory responses to break immune tolerance in the tumor microenvironment. Based on this powerful platform, a multitude of strategies have been applied to further improve the immune-stimulating potential of VSV and synergize these responses with the direct oncolytic effect. These strategies include: 1. modification of endogenous virus genes to stimulate interferon induction; 2. virus-mediated expression of cytokines or immune-stimulatory molecules to enhance anti-tumor immune responses; 3. vaccination approaches to stimulate adaptive immune responses against a tumor antigen; 4. combination with adoptive immune cell therapy for potentially synergistic therapeutic responses. A summary of these approaches will be presented in this review. Full article
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Open AccessCommunication
Nano-Magnetic Resonance Imaging (Nano-MRI) Gives Personalized Medicine a New Perspective
Biomedicines 2017, 5(1), 7; doi:10.3390/biomedicines5010007 -
Abstract
This paper reviews some of the major and most recent advances in nanoscale-magnetic resonance imaging (nano-MRI) for personalized medicine (PM). Nano-MRI may drastically expand the capabilities of the traditional magnetic resonance images (MRI), down to the nanometer scale and possibly, in the near
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This paper reviews some of the major and most recent advances in nanoscale-magnetic resonance imaging (nano-MRI) for personalized medicine (PM). Nano-MRI may drastically expand the capabilities of the traditional magnetic resonance images (MRI), down to the nanometer scale and possibly, in the near future, at the atomic scale. Nano-MRI is potentially able to observe structures which cannot be seen using today’s molecular imaging, with sensitivities of many billions of times better than MRI as currently used in hospitals, for example. The paper briefly reports on the foremost research themes in nano-MRI. Full article
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Open AccessEditorial
Acknowledgement to Reviewers of Biomedicines in 2016
Biomedicines 2017, 5(1), 6; doi:10.3390/biomedicines5010006 -
Abstract The editors of Biomedicines would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.[...] Full article
Open AccessReview
Targeting Autophagy for Oncolytic Immunotherapy
Biomedicines 2017, 5(1), 5; doi:10.3390/biomedicines5010005 -
Abstract
Oncolytic viruses (OVs) are capable of exerting anti-cancer effects by a variety of mechanisms, including immune-mediated tumor cell death, highlighting their potential use in immunotherapy. Several adaptation mechanisms such as autophagy contribute to OV-mediated anti-tumor properties. Autophagy regulates immunogenic signaling during cancer therapy
[...] Read more.
Oncolytic viruses (OVs) are capable of exerting anti-cancer effects by a variety of mechanisms, including immune-mediated tumor cell death, highlighting their potential use in immunotherapy. Several adaptation mechanisms such as autophagy contribute to OV-mediated anti-tumor properties. Autophagy regulates immunogenic signaling during cancer therapy which can be utilized to design therapeutic combinations using approaches that either induce or block autophagy to potentiate the therapeutic efficacy of OVs. In this article, we review the complicated interplay between autophagy, cancer, immunity, and OV, summarize recent progress in the contribution of OV-perturbed autophagy to oncolytic immunity, and discuss the challenges in targeting autophagy to enhance oncolytic immunotherapy. Full article
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Open AccessReview
The Current Use of Stem Cells in Bladder Tissue Regeneration and Bioengineering
Biomedicines 2017, 5(1), 4; doi:10.3390/biomedicines5010004 -
Abstract
Many pathological processes including neurogenic bladder and malignancy necessitate bladder reconstruction, which is currently performed using intestinal tissue. The use of intestinal tissue, however, subjects patients to metabolic abnormalities, bladder stones, and other long-term sequelae, raising the need for a source of safe
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Many pathological processes including neurogenic bladder and malignancy necessitate bladder reconstruction, which is currently performed using intestinal tissue. The use of intestinal tissue, however, subjects patients to metabolic abnormalities, bladder stones, and other long-term sequelae, raising the need for a source of safe and reliable bladder tissue. Advancements in stem cell biology have catapulted stem cells to the center of many current tissue regeneration and bioengineering strategies. This review presents the recent advancements in the use of stem cells in bladder tissue bioengineering. Full article
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Open AccessReview
Aptamer Technology: Adjunct Therapy for Malaria
Biomedicines 2017, 5(1), 1; doi:10.3390/biomedicines5010001 -
Abstract
Malaria is a life-threatening parasitic infection occurring in the endemic areas, primarily in children under the age of five, pregnant women, and patients with human immunodeficiency virus and acquired immunodeficiency syndrome (HIV)/(AIDS) as well as non-immune individuals. The cytoadherence of infected erythrocytes (IEs)
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Malaria is a life-threatening parasitic infection occurring in the endemic areas, primarily in children under the age of five, pregnant women, and patients with human immunodeficiency virus and acquired immunodeficiency syndrome (HIV)/(AIDS) as well as non-immune individuals. The cytoadherence of infected erythrocytes (IEs) to the host endothelial surface receptor is a known factor that contributes to the increased prevalence of severe malaria cases due to the accumulation of IEs, mainly in the brain and other vital organs. Therefore, further study is needed to discover a new potential anti-adhesive drug to treat severe malaria thus reducing its mortality rate. In this review, we discuss how the aptamer technology could be applied in the development of a new adjunct therapy for current malaria treatment. Full article
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Open AccessFeature PaperReview
Viroimmunotherapy of Thoracic Cancers
Biomedicines 2017, 5(1), 2; doi:10.3390/biomedicines5010002 -
Abstract
Thoracic cancers, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and malignant pleural mesothelioma (MM), cause the highest rate of cancer mortality worldwide. Most of these deaths are as a result of NSCLC; however, prognoses for the other two diseases
[...] Read more.
Thoracic cancers, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and malignant pleural mesothelioma (MM), cause the highest rate of cancer mortality worldwide. Most of these deaths are as a result of NSCLC; however, prognoses for the other two diseases remain as some of the poorest of any cancers. Recent advances in immunotherapy, specifically immune checkpoint inhibitors, have begun to help a small population of patients with advanced lung cancer. People who respond to these immune therapies generally have a durable response and many see dramatic decreases in their disease. However, response to immune therapies remains relatively low. Therefore, intense research is now underway to rationally develop combination therapies to expand the range of patients who will respond to and benefit from immune therapy. One promising approach is with oncolytic viruses. These oncolytic viruses (OVs) have been found to be selective for or have been engineered to preferentially infect and kill cancer cells. In pre-clinical models of different thoracic cancers, it has been found that these viruses can induce immunogenic cell death, increase the number of immune mediators brought into the tumor microenvironment and broaden the neoantigen-specific T cell response. We will review here the literature regarding the application of virotherapy toward augmenting immune responses in thoracic cancers. Full article
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Open AccessFeature PaperReview
Taking a Stab at Cancer; Oncolytic Virus-Mediated Anti-Cancer Vaccination Strategies
Biomedicines 2017, 5(1), 3; doi:10.3390/biomedicines5010003 -
Abstract
Vaccines have classically been used for disease prevention. Modern clinical vaccines are continuously being developed for both traditional use as well as for new applications. Typically thought of in terms of infectious disease control, vaccination approaches can alternatively be adapted as a cancer
[...] Read more.
Vaccines have classically been used for disease prevention. Modern clinical vaccines are continuously being developed for both traditional use as well as for new applications. Typically thought of in terms of infectious disease control, vaccination approaches can alternatively be adapted as a cancer therapy. Vaccines targeting cancer antigens can be used to induce anti-tumour immunity and have demonstrated therapeutic efficacy both pre-clinically and clinically. Various approaches now exist and further establish the tremendous potential and adaptability of anti-cancer vaccination. Classical strategies include ex vivo-loaded immune cells, RNA- or DNA-based vaccines and tumour cell lysates. Recent oncolytic virus development has resulted in a surge of novel viruses engineered to induce powerful tumour-specific immune responses. In addition to their use as cancer vaccines, oncolytic viruses have the added benefit of being directly cytolytic to cancer cells and thus promote antigen recognition within a highly immune-stimulating tumour microenvironment. While oncolytic viruses are perfectly equipped for efficient immunization, this complicates their use upon previous exposure. Indeed, the host’s anti-viral counter-attacks often impair multiple-dosing regimens. In this review we will focus on the use of oncolytic viruses for anti-tumour vaccination. We will explore different strategies as well as ways to circumvent some of their limitations. Full article
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Open AccessReview
Cellular and Molecular Preconditions for Retinal Pigment Epithelium (RPE) Natural Reprogramming during Retinal Regeneration in Urodela
Biomedicines 2016, 4(4), 28; doi:10.3390/biomedicines4040028 -
Abstract
Many regeneration processes in animals are based on the phenomenon of cell reprogramming followed by proliferation and differentiation in a different specialization direction. An insight into what makes natural (in vivo) cell reprogramming possible can help to solve a number of biomedical problems.
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Many regeneration processes in animals are based on the phenomenon of cell reprogramming followed by proliferation and differentiation in a different specialization direction. An insight into what makes natural (in vivo) cell reprogramming possible can help to solve a number of biomedical problems. In particular, the first problem is to reveal the intrinsic properties of the cells that are necessary and sufficient for reprogramming; the second, to evaluate these properties and, on this basis, to reveal potential endogenous sources for cell substitution in damaged tissues; and the third, to use the acquired data for developing approaches to in vitro cell reprogramming in order to obtain a cell reserve for damaged tissue repair. Normal cells of the retinal pigment epithelium (RPE) in newts (Urodela) can change their specialization and transform into retinal neurons and ganglion cells (i.e., actualize their retinogenic potential). Therefore, they can serve as a model that provides the possibility to identify factors of the initial competence of vertebrate cells for reprogramming in vivo. This review deals mainly with the endogenous properties of native newt RPE cells themselves and, to a lesser extent, with exogenous mechanisms regulating the process of reprogramming, which are actively discussed. Full article
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Open AccessReview
Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets
Biomedicines 2016, 4(4), 27; doi:10.3390/biomedicines4040027 -
Abstract
In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach
[...] Read more.
In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment. Full article
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Open AccessFeature PaperReview
Personalized Dosimetry for Radionuclide Therapy Using Molecular Imaging Tools
Biomedicines 2016, 4(4), 25; doi:10.3390/biomedicines4040025 -
Abstract
For treatment of systemic malignancies, when external radiation therapy is not applicable, radionuclide therapy can be an alternative. In this form of therapy, radionuclides are administered to the patient, often in a form where the radionuclide is labelled to a molecule that plays
[...] Read more.
For treatment of systemic malignancies, when external radiation therapy is not applicable, radionuclide therapy can be an alternative. In this form of therapy, radionuclides are administered to the patient, often in a form where the radionuclide is labelled to a molecule that plays the active part in the localization of the tumor. Since the aim is to impart lethal damage to tumor cells while maintaining possible side-effects to normal tissues at tolerable levels, a proper and accurate personalized dosimetry should be a pre-requisite. In radionuclide therapy, there is a need to measure the distribution of the radiopharmaceutical in vivo, as well as its re-distribution over time, in order estimate the total energy released in radioactive decays and subsequent charged-particle interactions, governing the absorbed dose to different organs and tumors. Measurements are usually performed by molecular imaging, more specifically planar and SPECT (Single-Photon Emission Computed Tomography) imaging, combined with CT. This review describes the different parts in the dosimetry chain of radionuclide therapy. Emphasis is given to molecular imaging tools and the requirements for determining absorbed doses from quantitative planar and SPECT images. As example solutions to the different problems that need to be addressed in such a dosimetric chain, we describe our tool, Lundadose, which is a set of methods that we have developed for personalized dosimetry. Full article
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