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Biomedicines, Volume 7, Issue 1 (March 2019)

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Cover Story (view full-size image) Multiple mechanisms can explain MS progression. First, an inflammatory phenomenon compartmentalized [...] Read more.
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Open AccessReview
Zebrafish Larvae as a Behavioral Model in Neuropharmacology
Biomedicines 2019, 7(1), 23; https://doi.org/10.3390/biomedicines7010023
Received: 12 February 2019 / Revised: 22 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Zebrafish larvae show a clear and distinct pattern of swimming in response to light and dark conditions, following the development of a swim bladder at 4 days post fertilization. This swimming behavior is increasingly employed in the screening of neuroactive drugs. The recent [...] Read more.
Zebrafish larvae show a clear and distinct pattern of swimming in response to light and dark conditions, following the development of a swim bladder at 4 days post fertilization. This swimming behavior is increasingly employed in the screening of neuroactive drugs. The recent emergence of high-throughput techniques for the automatic tracking of zebrafish larvae has further allowed an objective and efficient way of finding subtle behavioral changes that could go unnoticed during manual observations. This review highlights the use of zebrafish larvae as a high-throughput behavioral model for the screening of neuroactive compounds. We describe, in brief, the behavior repertoire of zebrafish larvae. Then, we focus on the utilization of light-dark locomotion test in identifying and screening of neuroactive compounds. Full article
(This article belongs to the Special Issue Zebrafish Models for Development and Disease)
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Open AccessReview
Assessment and Impact of Cognitive Impairment in Multiple Sclerosis: An Overview
Biomedicines 2019, 7(1), 22; https://doi.org/10.3390/biomedicines7010022
Received: 11 January 2019 / Revised: 13 March 2019 / Accepted: 14 March 2019 / Published: 19 March 2019
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Abstract
Cognitive impairment affects 40–60% of patients with multiple sclerosis. It may be present early in the course of the disease and has an impact on a patient’s employability, social interactions, and quality of life. In the last three decades, an increasing interest in [...] Read more.
Cognitive impairment affects 40–60% of patients with multiple sclerosis. It may be present early in the course of the disease and has an impact on a patient’s employability, social interactions, and quality of life. In the last three decades, an increasing interest in diagnosis and management of cognitive impairment has arisen. Neuropsychological assessment and neuroimaging studies focusing on cognitive impairment are now being incorporated as primary outcomes in clinical trials. However, there are still key uncertainties concerning the underlying mechanisms of damage, neural basis, sensitivity and validity of neuropsychological tests, and efficacy of pharmacological and non-pharmacological interventions. The present article aimed to present an overview of the assessment, neural correlates, and impact of cognitive impairment in multiple sclerosis. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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Open AccessArticle
Calcium Carbonate Nanoparticles Can Activate the Epithelial–Mesenchymal Transition in an Experimental Gastric Cancer Model
Biomedicines 2019, 7(1), 21; https://doi.org/10.3390/biomedicines7010021
Received: 14 February 2019 / Revised: 14 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
Previously, we have shown the possibility of intramucosal gastric carcinoma induction by the intragastric administration of a mixture of formaldehyde and hydrogen peroxide in rats. In this study, we report a sizable increase in carcinogenic properties of the mixture when a suspension containing [...] Read more.
Previously, we have shown the possibility of intramucosal gastric carcinoma induction by the intragastric administration of a mixture of formaldehyde and hydrogen peroxide in rats. In this study, we report a sizable increase in carcinogenic properties of the mixture when a suspension containing calcium carbonate nanoparticles was added to it. This technique allowed us to reduce both the number of the carcinogen administrations from twelve to two and the time to the cancer induction from six to four months. Although the induced tumors were represented by the intramucosal carcinomas, they were characterized by the extensive invasion of individual tumor cells and their clusters into the muscle layer and serosa as well as into the omentum and blood vessels. Considering that the invasive tumor cells were positive for vimentin, Snail and TGF-β2, we concluded that their invasion was the result of the activation of epithelial–mesenchymal transition (EMT) mechanisms. Thus, taking into account the data obtained, it can be assumed that under the conditions of inflammation or carcinogenesis, the calcium carbonate nanoparticles may affect the activation of EMT mechanisms. Full article
(This article belongs to the Special Issue Gastric Cancer Research: From Basic Science to the Clinic)
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Open AccessReview
Monoclonal Antibodies in Multiple Sclerosis: Present and Future
Biomedicines 2019, 7(1), 20; https://doi.org/10.3390/biomedicines7010020
Received: 9 February 2019 / Revised: 11 March 2019 / Accepted: 11 March 2019 / Published: 14 March 2019
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Abstract
The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do [...] Read more.
The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do their activities of daily living. Thankfully, the development of novel disease modifying therapies continues to increase. Monoclonal antibodies (MABs) have become a mainstay of MS treatment and they are likely to continue to be developed for the treatment of this disease. Specifically, MABs have proven to be some of the most efficacious treatments at reducing relapses and the inflammation in MS patients, including the first treatment for primary progressive MS and are being explored as reparative/remyelinating agents as well. These relatively new treatments will be reviewed here to help evaluate their efficacy, adverse events, immunogenicity, and benefit-risk ratios in the treatment of the diverse spectrum of MS. The focus will be on MABs that are currently approved or may be approved in the near future. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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Open AccessReview
Current Knowledge of IL-6 Cytokine Family Members in Acute and Chronic Kidney Disease
Biomedicines 2019, 7(1), 19; https://doi.org/10.3390/biomedicines7010019
Received: 22 February 2019 / Revised: 8 March 2019 / Accepted: 10 March 2019 / Published: 13 March 2019
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Abstract
Healthy kidneys are important for the efficient regulation of metabolism. However, there is an ever increasing population of patients suffering from both acute and chronic kidney diseases that disrupt this homeostasis. This review will explore the emerging roles that interleukin 6 (IL-6) cytokine [...] Read more.
Healthy kidneys are important for the efficient regulation of metabolism. However, there is an ever increasing population of patients suffering from both acute and chronic kidney diseases that disrupt this homeostasis. This review will explore the emerging roles that interleukin 6 (IL-6) cytokine family members play in the pathogenesis of kidney disease. The IL-6 family of cytokines are involved in a diverse range of physiological functions. In relation to kidney disease, their involvement is no less diverse. Evidence from both preclinical and clinical sources show that IL-6 cytokine family members can play either a deleterious or protective role in response to kidney disease. This appears to be dependent on the type of kidney disease in question or the specific cytokine. Current attempts to use or target IL-6 cytokine family members as therapies of kidney diseases will be highlighted throughout this review. Finally, the involvement of IL-6 cytokine family members in kidney disease will be presented in the context of three regularly overlapping conditions: obesity, hypertension and diabetes. Full article
(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)
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Open AccessReview
Daclizumab: Mechanisms of Action, Therapeutic Efficacy, Adverse Events and Its Uncovering the Potential Role of Innate Immune System Recruitment as a Treatment Strategy for Relapsing Multiple Sclerosis
Biomedicines 2019, 7(1), 18; https://doi.org/10.3390/biomedicines7010018
Received: 22 January 2019 / Revised: 6 March 2019 / Accepted: 6 March 2019 / Published: 11 March 2019
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Abstract
Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces [...] Read more.
Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces IL-2 consumption by effector T cells, it increases IL-2 bioavailability allowing for greater interaction with the intermediate-affinity IL-2R, and therefore drives the expansion of CD56bright natural killer (NK) cells. Furthermore, there appears to be a direct correlation between CD56bright NK cell expansion and DAC HYP efficacy in reducing relapses and MRI evidence of disease activity in patients with RMS in phase II and phase III double-blind, placebo- and active comparator-controlled trials. Therapeutic efficacy was maintained during open-label extension studies. However, treatment was associated with an increased risk of rare adverse events, including cutaneous inflammation, autoimmune hepatitis, central nervous system Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) syndrome, and autoimmune Glial Fibrillary Acidic Protein (GFAP) alpha immunoglobulin-associated encephalitis. As a result, DAC HYP was removed from clinical use in 2018. The lingering importance of DAC is that its use led to a deeper understanding of the underappreciated role of innate immunity in the potential treatment of autoimmune disease. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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Open AccessReview
Therapeutic Targeting Strategies of Cancer Stem Cells in Gastrointestinal Malignancies
Biomedicines 2019, 7(1), 17; https://doi.org/10.3390/biomedicines7010017
Received: 28 January 2019 / Revised: 4 March 2019 / Accepted: 9 March 2019 / Published: 10 March 2019
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Abstract
Cancer stem cells (CSCs) are thought to be a distinct population of cells within a tumor mass that are capable of asymmetric division and known to have chemoresistant characteristics. The description and identification of CSC models in cancer growth and recurrence has inspired [...] Read more.
Cancer stem cells (CSCs) are thought to be a distinct population of cells within a tumor mass that are capable of asymmetric division and known to have chemoresistant characteristics. The description and identification of CSC models in cancer growth and recurrence has inspired the design of novel treatment strategies to overcome treatment resistance by targeting both CSCs and non-CSC tumor cells. Several cellular signaling pathways have been described as playing a role in the induction and maintenance of stemness in CSCs, such as the Wnt/β-catenin, Notch, STAT3, and Hedgehog pathways. In this review, we aim to review some of the ongoing CSC therapeutic targeting strategies in gastrointestinal malignancies. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
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Open AccessReview
Alcohol Interaction with Cocaine, Methamphetamine, Opioids, Nicotine, Cannabis, and γ-Hydroxybutyric Acid
Biomedicines 2019, 7(1), 16; https://doi.org/10.3390/biomedicines7010016
Received: 9 January 2019 / Revised: 21 February 2019 / Accepted: 27 February 2019 / Published: 7 March 2019
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Abstract
Millions of people around the world drink alcoholic beverages to cope with the stress of modern lifestyle. Although moderate alcohol drinking may have some relaxing and euphoric effects, uncontrolled drinking exacerbates the problems associated with alcohol abuse that are exploding in quantity and [...] Read more.
Millions of people around the world drink alcoholic beverages to cope with the stress of modern lifestyle. Although moderate alcohol drinking may have some relaxing and euphoric effects, uncontrolled drinking exacerbates the problems associated with alcohol abuse that are exploding in quantity and intensity in the United States and around the world. Recently, mixing of alcohol with other drugs of abuse (such as opioids, cocaine, methamphetamine, nicotine, cannabis, and γ-hydroxybutyric acid) and medications has become an emerging trend, exacerbating the public health concerns. Mixing of alcohol with other drugs may additively or synergistically augment the seriousness of the adverse effects such as the withdrawal symptoms, cardiovascular disorders, liver damage, reproductive abnormalities, and behavioral abnormalities. Despite the seriousness of the situation, possible mechanisms underlying the interactions is not yet understood. This has been one of the key hindrances in developing effective treatments. Therefore, the aim of this article is to review the consequences of alcohol’s interaction with other drugs and decipher the underlying mechanisms. Full article
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Open AccessReview
On Zebrafish Disease Models and Matters of the Heart
Biomedicines 2019, 7(1), 15; https://doi.org/10.3390/biomedicines7010015
Received: 25 January 2019 / Revised: 23 February 2019 / Accepted: 26 February 2019 / Published: 28 February 2019
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Abstract
Coronary artery disease (CAD) is the leading form of cardiovascular disease (CVD), which is the primary cause of mortality worldwide. It is a complex disease with genetic and environmental risk factor contributions. Reports in human and mammalian models elucidate age-associated changes in cardiac [...] Read more.
Coronary artery disease (CAD) is the leading form of cardiovascular disease (CVD), which is the primary cause of mortality worldwide. It is a complex disease with genetic and environmental risk factor contributions. Reports in human and mammalian models elucidate age-associated changes in cardiac function. The diverse mechanisms involved in cardiac diseases remain at the center of the research interest to identify novel strategies for prevention and therapy. Zebrafish (Danio rerio) have emerged as a valuable vertebrate model to study cardiovascular development over the last few decades. The facile genetic manipulation via forward and reverse genetic approaches combined with noninvasive, high-resolution imaging and phenotype-based screening has provided new insights to molecular pathways that orchestrate cardiac development. Zebrafish can recapitulate human cardiac pathophysiology due to gene and regulatory pathways conservation, similar heart rate and cardiac morphology and function. Thus, generations of zebrafish models utilize the functional analysis of genes involved in CAD, which are derived from large-scale human population analysis. Here, we highlight recent studies conducted on cardiovascular research focusing on the benefits of the combination of genome-wide association studies (GWAS) with functional genomic analysis in zebrafish. We further summarize the knowledge obtained from zebrafish studies that have demonstrated the architecture of the fundamental mechanisms underlying heart development, homeostasis and regeneration at the cellular and molecular levels. Full article
(This article belongs to the Special Issue Zebrafish Models for Development and Disease)
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Open AccessReview
Mechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis
Biomedicines 2019, 7(1), 14; https://doi.org/10.3390/biomedicines7010014
Received: 29 January 2019 / Revised: 14 February 2019 / Accepted: 18 February 2019 / Published: 20 February 2019
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Abstract
Multiple Sclerosis (MS) is a major cause of neurological disability, which increases predominantly during disease progression as a result of cortical and grey matter structures involvement. The gradual accumulation of disability characteristic of the disease seems to also result from a different set [...] Read more.
Multiple Sclerosis (MS) is a major cause of neurological disability, which increases predominantly during disease progression as a result of cortical and grey matter structures involvement. The gradual accumulation of disability characteristic of the disease seems to also result from a different set of mechanisms, including in particular immune reactions confined to the Central Nervous System such as: (a) B-cell dysregulation, (b) CD8+ T cells causing demyelination or axonal/neuronal damage, and (c) microglial cell activation associated with neuritic transection found in cortical demyelinating lesions. Other potential drivers of neurodegeneration are generation of oxygen and nitrogen reactive species, and mitochondrial damage, inducing impaired energy production, and intra-axonal accumulation of Ca2+, which in turn activates a variety of catabolic enzymes ultimately leading to progressive proteolytic degradation of cytoskeleton proteins. Loss of axon energy provided by oligodendrocytes determines further axonal degeneration and neuronal loss. Clearly, these different mechanisms are not mutually exclusive and could act in combination. Given the multifactorial pathophysiology of progressive MS, many potential therapeutic targets could be investigated in the future. This remains however, an objective that has yet to be undertaken. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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Open AccessArticle
The TLR3 Agonist Poly Inosinic:Cytidylic Acid Significantly Augments the Therapeutic Activity of an Anti-CD7 Immunotoxin for Human T-Cell Leukaemia
Biomedicines 2019, 7(1), 13; https://doi.org/10.3390/biomedicines7010013
Received: 15 January 2019 / Revised: 7 February 2019 / Accepted: 12 February 2019 / Published: 16 February 2019
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Abstract
We have previously shown that antibody-dependent cellular cytotoxicity (ADCC) cooperates with immunotoxin (IT)-mediated killing of human leukaemia cells in an severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukaemia (SCID-HSB-2 mice), but not in an equivalent non-obese diabetic (NOD)/SCID mouse [...] Read more.
We have previously shown that antibody-dependent cellular cytotoxicity (ADCC) cooperates with immunotoxin (IT)-mediated killing of human leukaemia cells in an severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukaemia (SCID-HSB-2 mice), but not in an equivalent non-obese diabetic (NOD)/SCID mouse model. In these earlier studies, we reasoned that diminished ADCC due to the functional deficit in natural killer (NK) cell activity in NOD/SCID mice resulted in a failure of effective perforin/granzyme-mediated cytotoxicity necessary for the delivery of the augmentative effect. Poly-inosinic-cytidylic acid [poly (I:C)] is a synthetic dsRNA toll-like receptor 3 (TLR3) agonist that possesses a number of biological properties that includes the in vivo activation of NK cells. We show here that intravenous (i.v.) injection of SCID mice with [poly (I:C)] results in characteristic time-related changes in serum interleukin 2 (IL-2), IL-12, and interferon γ (INFγ) cytokine levels that are consistent with TLR3 driven activation of SCID mouse NK cells. Concomitantly, there are changes in the expression levels of CD2, CD16/32 (FcγRII/RIII), CD161 (NK1.1), and F4/80 in the bulk splenocyte population. These observed changes correlate with an increase in the in vitro lytic capabilities of putative NK cells from within the splenocyte population of [poly (I:C)] treated SCID mice. We demonstrate that the in vivo activation of NK cells with [poly (I:C)] in SCID mice bearing disseminated human T-cell leukaemia xenografts resulted in a significant improvement in the therapeutic activity exerted by an intact murine monoclonal antibody against human CD7. This was also seen for a saporin-based immunotoxin constructed with the same intact antibody (HB2-SAPORIN), but not with an F(ab’)2 derivative of the same antibody or of an IT constructed with the same F(ab’)2 HB2 antibody derivative. This study further demonstrates the previously reported reinforcing role of ADCC for the therapeutic activity of IT in an SCID mouse model of human T-ALL and the potential to significantly boost this further with [poly (I:C)]. Our study provides the rationale to justify the exploration of the clinical utility of IT based therapeutics in combination with TLR3 agonists, such as [poly (I:C)], for the treatment of haematological, and possibly other, malignancies. Full article
(This article belongs to the Special Issue Immunotoxins: Future Advances and Directions)
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Open AccessPerspective
Bioactive Titanium Surfaces: Interactions of Eukaryotic and Prokaryotic Cells of Nano Devices Applied to Dental Practice
Biomedicines 2019, 7(1), 12; https://doi.org/10.3390/biomedicines7010012
Received: 12 January 2019 / Revised: 28 January 2019 / Accepted: 11 February 2019 / Published: 12 February 2019
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Abstract
Background: In recent years, many advances have been made in the fields of bioengineering and biotechnology. Many methods have been proposed for the in vitro study of anatomical structures and alloplastic structures. Many steps forward have been made in the field of prosthetics [...] Read more.
Background: In recent years, many advances have been made in the fields of bioengineering and biotechnology. Many methods have been proposed for the in vitro study of anatomical structures and alloplastic structures. Many steps forward have been made in the field of prosthetics and grafts and one of the most debated problems lies in the biomimetics and biocompatibility of the materials used. The contact surfaces between alloplastic material and fabric are under study, and this has meant that the surfaces were significantly improved. To ensure a good contact surface with the cells of our body and be able to respond to an attack by a biofilm or prevent the formation, this is the true gold standard. In the dental field, the study of the surfaces of contact with the bone tissue of the implants is the most debated, starting from the first concepts of osteointegration. Method: The study searched MEDLINE databases from January 2008 to November 2018. We considered all the studies that talk about nanosurface and the biological response of the latter, considering only avant-garde works in this field. Results: The ultimate aim of this study is to point out all the progress made in the field of bioengineering and biotechnologies about nanosurface. Surface studies allow you to have alloplastic materials that integrate better with our body and allow more predictable rehabilitations. Particularly in the field of dental implantology the study of surfaces has allowed us to make huge steps forward in times of rehabilitation. Overcoming this obstacle linked to the time of osseointegration, however, today the real problem seems to be linked to the “pathologies of these surfaces”, or the possible infiltration, and formation of a biofilm, difficult to eliminate, being the implant surface, inert. Conclusions: The results of the present investigation demonstrated how nanotechnologies contribute substantially to the development of new materials in the biomedical field, being able to perform a large number of tests on the surface to advance research. Thanks to 3D technology and to the reconstructions of both the anatomical structures and eventually the alloplastic structures used in rehabilitation it is possible to consider all the mechanical characteristics too. Recent published papers highlighted how the close interaction between cells and the biomaterial applied to the human body is the main objective in the final integration of the device placed to manage pathologies or for rehabilitation after a surgical tumor is removed. Full article
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Open AccessReview
Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights
Biomedicines 2019, 7(1), 11; https://doi.org/10.3390/biomedicines7010011
Received: 3 January 2019 / Revised: 20 January 2019 / Accepted: 24 January 2019 / Published: 5 February 2019
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Abstract
Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded [...] Read more.
Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program. Full article
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Open AccessReply
Reply to the Comment on: Subrat Khanal et al. The Repertoire of Adenovirus in Human Disease: The Innocuous to the Deadly. Biomedicines 2018, 6, 30
Biomedicines 2019, 7(1), 10; https://doi.org/10.3390/biomedicines7010010
Received: 11 January 2019 / Accepted: 29 January 2019 / Published: 2 February 2019
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Abstract
We would like to thank Dr [...] Full article
(This article belongs to the Special Issue Adenoviruses: From Virus to Medicine)
Open AccessEditorial
Acknowledgement to Reviewers of Biomedicines in 2018
Published: 24 January 2019
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Abstract
Rigorous peer-review is the corner-stone of high-quality academic publishing [...] Full article
Open AccessComment
Comment on Khanal et al. The Repertoire of Adenovirus in Human Disease: The Innocuous to the Deadly. Biomedicines 2018, 6, 30
Received: 12 December 2018 / Accepted: 17 January 2019 / Published: 22 January 2019
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Abstract
In their comprehensive review on adenoviruses, Khanal et al. omitted obesity as a disease caused by adenovirus 36 (Adv36). Animal studies have shown that experimental infection with Adv36 causes increased adiposity, and human association studies have shown that prior infection with Adv36 is [...] Read more.
In their comprehensive review on adenoviruses, Khanal et al. omitted obesity as a disease caused by adenovirus 36 (Adv36). Animal studies have shown that experimental infection with Adv36 causes increased adiposity, and human association studies have shown that prior infection with Adv36 is correlated with greater body weight in humans in multiple countries of the world. Full article
(This article belongs to the Special Issue Adenoviruses: From Virus to Medicine)
Open AccessArticle
Umbilical Cord Blood Mesenchymal Stem Cells as an Infertility Treatment for Chemotherapy Induced Premature Ovarian Insufficiency
Received: 29 October 2018 / Revised: 6 January 2019 / Accepted: 14 January 2019 / Published: 18 January 2019
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Abstract
Background: Premature ovarian insufficiency (POI) is a challenging disease, with limited treatment options at the moment. Umbilical cord blood mesenchymal stem cells (UCMSCs) have demonstrated promising regenerative abilities in several diseases including POI. Materials and Method: A pre-clinical murine case versus vehicle control [...] Read more.
Background: Premature ovarian insufficiency (POI) is a challenging disease, with limited treatment options at the moment. Umbilical cord blood mesenchymal stem cells (UCMSCs) have demonstrated promising regenerative abilities in several diseases including POI. Materials and Method: A pre-clinical murine case versus vehicle control randomized study. Two experiments ran in parallel in each of the three groups. The first was to prove the ability of UCMSCs in restoring ovarian functions. The second was to prove improved fertility. A total of 36 mice were randomly assigned; 6 mice into each of 3 groups for two experiments. Group 1 (control), group 2 (sham chemotherapy), group 3 (stem cells). Results: In the first experiment, post-UCMSCs treatment (group 3) showed signs of restored ovarian function in the form of increased ovarian weight and estrogen-dependent organs (liver, uterus), increased follicular number, and a significant decrease in FSH serum levels (p < 0.05) compared to group 2, and anti-Mullerian hormone (AMH) serum levels increased (p < 0.05) in group 3 versus group 2. Immuno-histochemistry analysis demonstrated a higher expression of AMH, follicle stimulating hormone receptor (FSHR) and Inhibin A in the growing follicles of group 3 versus group 2. In the second experiment, post-UCMSCs treatment (group 3) pregnancy rates were higher than group 2, however, they were still lower than group 1. Conclusion: We demonstrated the ability of UCMSCs to restore fertility in female cancer survivors with POI and as another source of stem cells with therapeutic potentials. Full article
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Open AccessReview
Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies
Received: 20 November 2018 / Revised: 26 December 2018 / Accepted: 3 January 2019 / Published: 5 January 2019
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Abstract
Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used [...] Read more.
Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile. Full article
(This article belongs to the Special Issue Immunotoxins: Future Advances and Directions)
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Open AccessReview
Hypothalamic-Pituitary-Ovarian Axis Disorders Impacting Female Fertility
Received: 1 December 2018 / Revised: 24 December 2018 / Accepted: 26 December 2018 / Published: 4 January 2019
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Abstract
The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling female reproduction. HPO axis dysfunction leading to ovulation disorders can be classified into three categories defined by the World Health Organization (WHO). Group I ovulation disorders involve hypothalamic failure characterized as hypogonadotropic hypogonadism. [...] Read more.
The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling female reproduction. HPO axis dysfunction leading to ovulation disorders can be classified into three categories defined by the World Health Organization (WHO). Group I ovulation disorders involve hypothalamic failure characterized as hypogonadotropic hypogonadism. Group II disorders display a eugonadal state commonly associated with a wide range of endocrinopathies. Finally, group III constitutes hypergonadotropic hypogonadism secondary to depleted ovarian function. Optimal evaluation and management of these disorders is based on a careful analysis tailored to each patient. This article reviews ovulation disorders based on pathophysiologic mechanisms, evaluation principles, and currently available management options. Full article
Open AccessArticle
α-Ketoglutaric Acid-Modified Carbonate Apatite Enhances Cellular Uptake and Cytotoxicity of a Raf-Kinase Inhibitor in Breast Cancer Cells through Inhibition of MAPK and PI-3 Kinase Pathways
Received: 13 November 2018 / Revised: 16 December 2018 / Accepted: 18 December 2018 / Published: 3 January 2019
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Abstract
AZ628 is a hydrophobic Raf-kinase inhibitor (rapidly accelerated fibrosarcoma) currently in clinical trial of various cancer. The physicochemical properties of hydrophobic drugs that affect the drug-particle interactions and cause aggregation of drugs and particles might be the key aspect to impede effective drug [...] Read more.
AZ628 is a hydrophobic Raf-kinase inhibitor (rapidly accelerated fibrosarcoma) currently in clinical trial of various cancer. The physicochemical properties of hydrophobic drugs that affect the drug-particle interactions and cause aggregation of drugs and particles might be the key aspect to impede effective drug delivery. Retaining smaller particle size is the prerequisite to overcome the opsonization and improve cytotoxicity in the targeted region. Carbonate apatite (CA), an attractive biodegradable vector, has been used to carry both hydrophilic and hydrophobic drugs and release the payloads inside the cells following endocytosis. We incorporated AZ628 into CA and also modified it with α-ketoglutaric acid (α-KA) for reducing particle growth kinetics and increasing total surface area to improve the delivery of AZ628 by enhancing cellular uptake by breast cancer cells. AZ628-loaded nanoparticles of CA and α-KA-modified CA (α-KAMCA) were synthesized and evaluated in MCF-7 and 4T1 cell lines by measuring cytotoxicity and cellular uptake analysis. HPLC (high-performance liquid chromatography) assay was performed to quantify the binding affinity of the nanocarriers towards the drug. Western blot analysis was done to see the activation and expression levels of Akt, MAPK (mitogen-activated protein kinase) pathways and Caspase-3. Zetasizer was used to measure the particle size along with the surface charge. α-KAMCA showed almost 88% encapsulation efficacy for AZ628 with around 21% enhanced cellular uptake of the drug in two different breast cancer cell lines. These findings suggest that α-KAMCA could be a promising therapeutic tool to carry AZ628 for breast cancer treatment. Full article
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Open AccessEditorial
Special Issue: Cancer Biomarkers and Targets in Digestive Organs
Received: 29 November 2018 / Revised: 24 December 2018 / Accepted: 27 December 2018 / Published: 2 January 2019
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Abstract
The identification and development of cancer biomarkers and targets have greatly accelerated progress towards precision medicine in oncology. [...] Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
Open AccessReview
Premature Ovarian Insufficiency: Procreative Management and Preventive Strategies
Received: 30 November 2018 / Revised: 22 December 2018 / Accepted: 24 December 2018 / Published: 28 December 2018
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Abstract
Premature ovarian insufficiency (POI) is the loss of normal hormonal and reproductive function of ovaries in women before age 40 as the result of premature depletion of oocytes. The incidence of POI increases with age in reproductive-aged women, and it is highest in [...] Read more.
Premature ovarian insufficiency (POI) is the loss of normal hormonal and reproductive function of ovaries in women before age 40 as the result of premature depletion of oocytes. The incidence of POI increases with age in reproductive-aged women, and it is highest in women by the age of 40 years. Reproductive function and the ability to have children is a defining factor in quality of life for many women. There are several methods of fertility preservation available to women with POI. Procreative management and preventive strategies for women with or at risk for POI are reviewed. Full article
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Open AccessReview
Immunotoxins Targeting B cell Malignancy—Progress and Problems With Immunogenicity
Received: 28 November 2018 / Revised: 17 December 2018 / Accepted: 19 December 2018 / Published: 21 December 2018
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Abstract
Few immunotoxins or targeted toxins have become mainline cancer therapies. Still immunotoxins continue to be of major interest and subject of research and development as alternative therapies for drug resistant cancer. A major matter of concern continues to be immunogenicity exemplified by the [...] Read more.
Few immunotoxins or targeted toxins have become mainline cancer therapies. Still immunotoxins continue to be of major interest and subject of research and development as alternative therapies for drug resistant cancer. A major matter of concern continues to be immunogenicity exemplified by the anti-toxin response of the treated patient. Since some of our most effective toxins are bacterial in nature and bacterial proteins are highly immunogenic, this review describes some efforts to address this pressing issue. Full article
(This article belongs to the Special Issue Immunotoxins: Future Advances and Directions)
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