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Today, 12 Ιουλίου 2016, 3:55:54 μμ
Systemic Lupus Erythematosus: Correlation Between Immunodysregulation and Clinical Manifestations
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Systemic Lupus Erythematosus is considered a prototype of an autoimmune disorder. The greatly compromise immune system reflects in a global loss of self-tolerance and an array of autoantibodies which are the hallmark of the disease. Diagnosis and clinical management are a challenge to physicians owing its complex clinical course. Specific correlation between immunodysregulation and the clinical manifestations have been studied and we intended in this paper to review recent studies, highlighting new discoveries in this matter.
Dendritic Cells in Colorectal Cancer and a Potential for their Use in Therapeutic Approaches
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Multiple pathogenic mechanisms contribute to the development of colorectal cancer. This tumor is characterized by high chemoresistance and low immunogenicity due to the effective mechanisms of immunosuppression. Dendritic cells (DCs) play a key role in recognition of tumor antigens and induction of T-cell-primed anticancer response. However, in cancer microenvironment, the function of tumor-infiltrating DCs becomes impaired and switched from the immunostimulation to the immunosuppression. Colorectal cancer cells express anti-inflammatory cytokines such as IL-10 and TGF-β that could affect DC phenotype and support tumor escape from the immune surveillance. As a result, tumor-associated DCs display numerous defects in antigen-presenting capacity and have an altered pattern of expression of immune costimulatory molecules towards the immunoregulatory phenotype. Indeed, understanding of mechanisms, such as how tumor could impair activity of DCs, would help in the development of new DC-based vaccines against colorectal cancer.
The Structure-Function Relationships of Complement Receptor Type 2 (CR2; CD21)
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Human complement receptor type 2 (CR2; CD21) is a surface-associated glycoprotein which binds to a variety of endogenous ligands, including the complement component C3 fragments iC3b, C3dg and C3d, the low-affinity IgE receptor CD23, and the type I cytokine, interferon-alpha. CR2 links the innate complement-mediated immune response to pathogens and foreign antigens with the adaptive immune response by binding to C3d that is covalently attached to targets, and which results in a cell signalling phenomenon that lowers the threshold for B cell activation. Variations or deletions of the CR2 gene in humans, or the Cr2 gene in mice associate with a variety of autoimmune and inflammatory conditions. A number of infectious agents including Epstein-Barr virus (EBV), Human Immunodeficiency Virus (HIV) and prions also bind to CR2 either directly or indirectly by means of C3d-targeted immune complexes. </p><p> In this review we discuss the interactions that CR2 undertakes with its best characterized ligands C3d, CD23 and the EBV gp350/220 envelope protein. To date only a single physiologically relevant complex of CR2 with one of its ligands, C3d, has been elucidated. By contrast, the interactions with CD23 and EBV gp350/220, while being important from physiologic and disease-associated standpoints, respectively, are only incompletely understood. A detailed knowledge of the structure-function relationships that CR2 undergoes with its ligands is necessary to understand the implications of using recombinant CR2 in therapeutic or imaging agents, or alternatively targeting CR2 to down-regulate the antibody mediated immune response in cases of autoimmunity. </p><p>
Current Understanding of HSP90 as a Novel Therapeutic Target: An Emerging Approach for the Treatment of Cancer
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Heat Shock Protein 90 (HSP90) is a ubiquitous molecular chaperone that is considered to be the most abundantly expressed protein in various human cancers such as breast, lung, colon, prostate, leukemia and skin. The master regulator, HSP90 plays a pivotal role in the conformational stabilization, maturation and activity of its various labile oncogenic client proteins such as p53, ErbB2, Bcr-Abl, Akt, Her-2, Cdk4, Cdk6, Raf-1 and v-Src in altered cells. Hence, making a guaranteed attempt to inhibit such a master regulator for cancer therapy appears to be a potential approach for combinatorial inhibition of numerous oncogenic signaling pathways simultaneously. Considerable efforts are being under way to develop novel molecular targets and its inhibitors that may block key signaling pathways involved in the process of tumorigenesis and metastasis. In this regards, HSP90 has acquired immense interest as a potent anticancer drug-target due to its key functional link with multiple signaling pathways involved in the process of cell proliferation and cell survival. Notably, geldanamycin and its derivatives (17-AAG, 17-DMAG) have shown quite encouraging results in inhibiting HSP90 function in several cancers and currently almost 17 drug candidates known to be target HSP90 are being under clinical trials either as single agents or combinatorial therapy. Hence, this review is an attempt to get new insight into novel drug target therapy by focusing on recent advances made in understanding HSP90 chaperone structure-function relationships, identification of new HSP90 client proteins and, more importantly, on the advancements of HSP90 targeted therapy based on various existing and emerging classical inhibitors.
Progress of Synthesis and Separation of Regioisomerically Pure 5(6)-Substituted Rhodamine
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Regioisomerically pure 5(6)-substituted rhodamine is an outstanding molecular platform for functional probes and a very useful material for fluorescent labels. However, 5(6)-substituted rhodamine is difficult to be synthesized by general methods, which limits the application of the dye. This review highlights the progress regarding the methods for the synthesis and separation of regioisomerically pure 5(6)-substituted rhodamine, which are categorized by the four different protocols for acquiring 5(6)-substituted rhodamine. The advantages and disadvantages of each protocol are also discussed.
Modelling DNA Repair Pathways: Recent Advances and Future Directions
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Background: A major class of chemotherapy drugs targets the genome of cancer cells. These DNA damaging agents induce damage to the DNA helix, resulting in the programmed death of cancer cells. An overactivated DNA repair mechanism in cancer cells can reduce the efficacy of these drugs, thereby eliminating their therapeutic benefit and developing an acquired resistance to these otherwise effective drugs. A promising approach to enhance the therapeutic window of DNA damaging agents is to target the DNA repair pathways causing this type of resistance. Methods: Computational approaches have been applied successfully to study many of these DNA repair mechanisms at different scales and focusing on various aspects. The ultimate goal of these studies has been to identify the key players in developing resistance to DNA damaging agents and to design regulators for their activities. This review covers the most important and recent computational efforts toward this goal. This includes modelling the mechanisms involved in DNA repair and identifying novel pharmacological inhibitors for their activities. Results: We focus here mainly on the pathways associated with an acquired drug resistance to DNA damaging agents, concentrating on the recent advances in modelling the key mechanisms and foreseeing the future directions in this field. Conclusion: We hope that this short, yet comprehensive review can help in discovering novel strategies to overcome the resistance effects inherent in various cancer treatments.
Immunotherapy and Hormone-therapy in Metastatic Breast Cancer: A Review and an Update
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Historically, antiestrogen is the first targeted therapy used in breast cancer treatment. In fact, its rationale lies in the molecular pathways elucidated by basic research. In estrogen receptor (ER)-alpha positive metastatic breast cancer patients, hormone-therapy remains the first option of treatment. While tamoxifen concomitant with suppression of ovarian function with luteinizing hormone releasing hormone (LHRH) agonists is the standard first line treatment in premenopausal, third generation aromatase inhibitors (AIs) are the first line standard hormone therapy in postmenopausal. However, the development of acquired resistance during antiestrogen therapy continues to be a central clinical problem. This review provides an update on the antiestrogen action and report on immunological treatment of the advanced disease by some cytokines. Interleukin-2, interleukin-12 and interferons used alone or in combination demonstrated an anti-tumor action directly and/or through synergism with antiestrogens. A rationale for the addition of interferon-beta and interleukin-2 to antiestrogens is described. Furthermore, we summarize and interpret the clinical and laboratory data of a recent long-term hormone- immunotherapy study in metastatic endocrine dependent breast cancer patients. Prospective randomized trials are necessary to confirm some recent promising results based on an immunological approach in addition to antiestrogens to overcome or delay acquired hormone resistance.
Predictive Efficacy Biomarkers of Programmed Cell Death 1/Programmed Cell Death 1 Ligand Blockade Therapy
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Inhibitors of immune check-point molecule, programmed cell death 1 (PD-1) and its ligand, programmed cell death ligand 1 (PD-L1) have attracted much attention in cancer immunotherapy recently due to their durable antitumor effects in various malignances, especially the advanced ones. Unfortunately, only a fraction of patients with advanced tumors could benefit from anti-PD-1/PD-L1 therapy, while others still worsened. The key to this point is that there are no efficient biomarkers for screening anti-PD-1/PD-L1-sensitive patients. In this review, we aim at summarizing the latest advances of anti-PD-1/PDL1 immunotherapy and the potential predictive efficacy biomarkers to provide evidences for identifying anti-PD-1/PDL1- sensitive patients. The present article also includes the patent review coverage on this topic.
Nature and Nurture in the Early-Life Origins of Metabolic Syndrome
Today, 12 Ιουλίου 2016, 3:55:55 μμ
The combination of genetic background together with food excess and lack of exercise has become the cornerstone of metabolic disorders associated to lifestyle. The scenario is furthermore reinforced by their interaction with other environmental factors (stress, sleeping patterns, education, culture, rural versus urban locations, and xenobiotics, among others) inducing epigenetic changes in the exposed individuals. The immediate consequence is the development of further alterations like obesity and metabolic syndrome, and other adverse health conditions (type-2 diabetes, cardiovascular diseases, cancer, reproductive, immune and neurological disorders). Thus, having in mind the impact of the metabolic syndrome on the worldwide public health, the present review affords the relative roles and the interrelationships of nature (genetic predisposition to metabolic syndrome) and nurture (lifestyle and environmental effects causing epigenetic changes), on the establishment of the metabolic disorders in women; disorders that may evolve to metabolic syndrome prior or during pregnancy and may be transmitted to their descendants.
Lentiviral Delivery of Proteins for Genome Engineering
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Viruses have evolved to traverse cellular barriers and travel to the nucleus by mechanisms that involve active transport through the cytoplasm and viral quirks to resist cellular restriction factors and innate immune responses. Virus-derived vector systems exploit the capacity of viruses to ferry genetic information into cells, and now - more than three decades after the discovery of HIV - lentiviral vectors based on HIV-1 have become instrumental in biomedical research and gene therapies that require genomic insertion of transgenes. By now, the efficacy of lentiviral gene delivery to stem cells, cells of the immune system including T cells, hepatic cells, and many other therapeutically relevant cell types is well established. Along with nucleic acids, HIV-1 virions carry the enzymatic tools that are essential for early steps of infection. Such capacity to package enzymes, even proteins of nonviral origin, has unveiled new ways of exploiting cellular intrusion of HIV-1. Based on early findings demonstrating the packaging of heterologous proteins into virus particles as part of the Gag and GagPol polypeptides, we have established lentiviral protein transduction for delivery of DNA transposases and designer nucleases. This strategy for delivering genome-engineering proteins facilitates high enzymatic activity within a short time frame and may potentially improve the safety of genome editing. Exploiting the full potential of lentiviral vectors, incorporation of foreign protein can be combined with the delivery of DNA transposons or a donor sequence for homology-directed repair in so-called ‘all-in-one’ lentiviral vectors. Here, we briefly describe intracellular restrictions that may affect lentiviral gene and protein delivery and review the current status of lentiviral particles as carriers of tool kits for genome engineering.
An Intelligent On-Line Inspection and Warning System Based on Infrared Image for Transformer Bushings
Today, 12 Ιουλίου 2016, 3:55:55 μμ
This paper presents an on-line inspection and warning system based on infrared image to detect the thermal fault of transformer bushings in the early stage. The network infrared thermal imager combined with the omnidirectional PTZ platform is the key device for the surveillance task. BRISK (Binary Robust Invariant Scalable Keypoints) algorithm is applied for the automatic object recognition and localization. In addition, the software based on B/S architecture is designed and realized for remote data transmission, so the remote users can acquire the real-time information through the private network. This system realizes the remote, real-time online monitoring and analyzing of transformer bushings, the comparison results validate the accuracy and efficiency of the recognition method, and the evaluations of the measured data verify the practicability of the system in the 110kV substation.
The Development of Protein Chips for High Throughput Screening (HTS) of Chemically Labeling Small Molecular Drugs
Today, 12 Ιουλίου 2016, 3:55:55 μμ
How to construct protein chips and chemically labeling drug molecules without disrupting structures for HTS is still a challenging area. There are two main obstacles, one is that human multitrans membrane receptors, which are major drug targets, exhibit distinct motifs, and fold structures, and they will collapse unfold without membrane support in vitro; another one is that there still lack effective chemical labeling method for small drugs for detection. Therefore, how to acquire high detecting sensitivity for small molecules and to immobilize membrane protein receptors in native conformation with uniform direction on the chip, need to be solved for drug HTS. This paper reviews drug HTS trends in recent years, proposed a new virion-chip model and a feasible C-H activation method for CY-5 labeling drugs. It is expected to provide a good platform for future drug HTS.
Bacterial Multidrug Efflux Pumps of the Major Facilitator Superfamily as Targets for Modulation
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Causative agents of infectious disease that are multidrug resistant bacterial pathogens represent a serious public health concern due to the increasingly difficult nature of achieving efficacious clinical treatments. Of the various acquired and intrinsic antimicrobial agent resistance determinants, integral-membrane multidrug efflux pumps of the major facilitator superfamily constitute a major mechanism of bacterial resistance. The major facilitator superfamily (MFS) encompasses thousands of known related secondary active and passive solute transporters, including multidrug efflux pumps, from bacteria to humans. This review article addresses recent developments involving the targeting by various modulators of bacterial multidrug efflux pumps from the major facilitator superfamily. It is currently of tremendous interest to modulate bacterial multidrug efflux pumps in order to eventually restore the clinical efficacy of therapeutic agents against recalcitrant bacterial infections. Such MFS multidrug efflux pumps are good targets for modulation.
Molecular Mechanisms Underlying Psychological Stress and Cancer
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy.
Preclinical Models of Multiple Sclerosis: Advantages and Limitations Towards Better Therapies
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) with an unknown etiology. MS complex pathophysiology—characterized by CNS inflammation, demyelination and axonal injury—has made its modeling in experimental systems particularly problematic. Moreover, the evidence that MS does not naturally occur in other species has further complicated MS preclinical studies. Through the years, several MS in vivo models have been developed. Experimental autoimmune encephalomyelitis (EAE) represents the most widely used MS experimental model and relies upon the autoimmune paradigm to explore MS neuropathology. Although EAE has been instrumental in understanding the molecular events which take place upon neuroinflammation, not all MS hallmarks can be efficiently shaped within this conceptual frameshift. Thus, alternative models of CNS demyelination have been characterized, either based on viral infection or neurotoxin administration. However imperfect, these models have greatly improved our knowledge of the immune system's function in health and disease. On the other side, their intrinsic distance from MS has often led to misinterpreting and overestimating the data gleaned from these experimental systems. In this review, each model will be discussed in the light of its potentiality to mimic MS and translate the most promising therapies to patients. In addition, we will address how new genomic technologies can help improve the existing models.
The Impact of CRISPR/Cas9-Based Genomic Engineering on Biomedical Research and Medicine
Today, 12 Ιουλίου 2016, 3:55:55 μμ
There has been prolonged and significant interest in manipulating the genome for a wide range of applications in biomedical research and medicine. An existing challenge in realizing this potential has been the inability to precisely edit specific DNA sequences. Past efforts to generate targeted double stranded DNA cleavage have fused DNA-targeting elements such as zinc fingers and DNA-binding proteins to endonucleases. However, these approaches are limited by both design complexity and inefficient, costineffective operation. The discovery of CRISPR/Cas9, a branch of the bacterial adaptive immune system, as a potential genomic editing tool holds the promise of facile targeted cleavage. Its novelty lies in its RNA-guided endonuclease activity, which enhances its efficiency, scalability, and ease of use. The only necessary components are a Cas9 endonuclease protein and an RNA molecule tailored to the gene of interest. This lowbarrier of adoption has facilitated a plethora of advances in just the past three years since its discovery. In this review, we will discuss the impact of CRISPR/Cas9 on biomedical research and its potential implications in medicine.
Biomarker-Guided Strategy for Treatment of Autism Spectrum Disorder (ASD)
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Autism spectrum disorder (ASD) is a complex, life-long neurodevelopmental disorder currently affecting an estimated 1 out of 68 among children aged 8 y in the United States. ASD has complex genetic and epigenetic features that lead to the phenotype and there is no single genetic marker for the diagnosis. Therefore, the diagnosis for ASD is phenotype- based with no validated or credible laboratory tests available. Evidence-based treatments for ASD are limited. There is no FDA approved medical therapy that addresses either core ASD symptoms or pathophysiological processes associated with ASD. We outline herein, several ASD-associated basic physiological pathways that can be regulated by the small molecule phytochemical sulforaphane, as an example of a druggable small molecule target for which much in vitro, pre-clinical, and clinical evidence already exists: (1) redox metabolism/oxidative stress, (2) mitochondrial dysfunction, (3) immune dysregulation/neuroinflammation, (4) febrile illness and the heat shock response, and (5) synaptic dysfunction. Furthermore, we identify the biomarkers that can be used to assess the functioning of these pathways as well as suggesting how these biomarkers could guide novel treatment strategies to correct these biochemical abnormalities in order to improve core and associated symptoms of ASD.
An Intelligent Three-dimensional Ultrasound Program for Rapidly Imaging of the Fetal Cranial Mid-sagittal Plane
Today, 12 Ιουλίου 2016, 3:55:55 μμ
This paper described a novel intelligent technique for rapid visualization of the fetal cranial mid-sagittal view to allow for the differentiation of fetal midline anomalies. Two hundred consecutive normal singleton pregnancies and twenty abnormal fetuses with cranial midline anomalies were imaged to display the mid-sagittal view using this new intelligent three-dimensional imaging program developed by our team. The cranial transverse plane was used as starting plane to acquire the threedimensional volumes and then scanned with this new program. The three-dimensional median planes were also evaluated by other two doctors. The reference landmarks of the mid-sagittal plane were that the falxs of fetal head on Plane A and Plane B were parallel to the X-axis and the reference dot was put on the falx. If one doctor thought it was not the median plane or the structure of corpus callosum or cerebellar vermis was not clearly visualized, the case was labelled as failed case. The cranial mid-sagittal view was successfully visualized in 190 normal cases (95%) and 18 abnormal cases (90%) by Smart MSP program. The failed 12 cases becuase the cerebral falxs of these fetuses were unable to be recognized by the program. In conclusion, this new intelligent three-dimensional program is a feasible method for quick visualization of fetal cranial mid-sagittal plane and may become a potential tool for routinely screening the fetal midline anomalies.
Structure-Function Relationships of Class D Carbapenemases
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Class D carbapenemases, also known as Carbapenem-Hydrolyzing class D β-Lactamases (CHDLs) are of increasingly high clinical relevance, as they have been found in various important human pathogens, such as Acinetobacter baumannii and Klebsiella pneumoniae and contribute to the evolution of these pathogens towards extensively or totally-drug resistance (XDR/TDR) phenotypes. Essentially two main groups of phylogenetically-related enzymes have been described: one including the acquired OXA-23, OXA-24/40, OXA-51 and OXA-58 enzymes mostly in Acinetobacter baumannii, and the other including the OXA-48-related variants, i.e. OXA-54, OXA-162, OXA-163 and OXA- 181. In this article, the biochemical and structural features of class D carbapenemases will be discussed. Furthermore, the mechanistic hypothesis based on recently obtained crystal structures of the native forms of class D carbapenemases and mutants thereof, in complex with relevant substrates or inhibitors, will be critically reviewed. Finally, the mechanism of inhibition by available inhibitors, some of which are currently in clinical development, will be discussed.
Natural Products Towards the Discovery of Potential Future Antithrombotic Drugs
Today, 12 Ιουλίου 2016, 3:55:55 μμ
Globally, thrombosis-associated disorders are one of the main contributors to fatalities. Besides genetic influences, there are some acquired and environmental risk factors dominating thrombotic diseases. Although standard regimens have been used for a long time, many side effects still occur which can be life threatening. Therefore, natural products are good alternatives. Although the quest for antithrombotic natural products came to light only since the end of last century, in the last two decades, a considerable number of natural products showing antithrombotic activities (antiplatelet, anticoagulant and fibrinolytic) with no or minimal side effects have been reported. In this review, several natural products used as antithrombotic agents including medicinal plants, vegetables, fruits, spices and edible mushrooms which have been discovered in the last 15 years and their target sites (thrombogenic components, factors and thrombotic pathways) are described. In addition, the side effects, limitations and interactions of standard regimens with natural products are also discussed. The active compounds could serve as potential sources for future research on antithrombotic drug development. As a future direction, more advanced researches (in quest of the target cofactor or component involved in antithrombotic pathways) are warranted for the development of potential natural antithrombotic medications (alone or combined with standard regimens) to ensure maximum safety and efficacy.
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