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The Treatment of Metastatic Non-small Cell Lung Cancer (NSCLC) in New Era of Personalised Medicine

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195435 Year: Pages: 140 DOI: 10.3389/978-2-88919-543-5 Language: English
Publisher: Frontiers Media SA
Subject: Oncology --- Medicine (General)
Added to DOAB on : 2016-01-19 14:05:46
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Lung cancer is the leading cause of cancer related mortality in Canada and USA. Majority of the patients present in advanced stage of the disease and of these only about 2% will be alive at 5 years. NSCLC is the most common form of lung cancer, accounting for approximately 87% of cases. Systemic chemotherapies have been used to treat metastatic NSCLC for decades, but the improvements of outcomes have reached a plateau. Recent advances in understanding signalling pathways for malignant cells, their interconections,the importance of various receptors and biomarkers and the interplay between various oncogenes have led to the development of targeted treatments that are improving both efficacy and safety of the treatments. Knowledge about the advantages of treatments with the targeted agents in metastatic NSCLC is growing rapidly. Combining various targeted agents or sequencing them properly will be important in the era of personalised medicine and overcoming development of the resistence to various targeted agents will be challenging. The importance of a team work,from the diagnosis through various treatments, to supportive care, from the interventional radiologists, pneumologists or surgeons, who have to obtain a satisfactory tumor tissue specimen, to pathologists, radiation and medical oncologists, to supportive care specialists, will be described in our publications. We will cover completely present and future approaches to personalised medicine in this rapidly evolving field of metastatic NSCLC.

Genetics and epigenetics of fetal alcohol spectrum disorders

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195732 Year: Pages: 114 DOI: 10.3389/978-2-88919-573-2 Language: English
Publisher: Frontiers Media SA
Subject: Biology --- Science (General) --- Genetics
Added to DOAB on : 2016-02-05 17:24:33
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Women drinking during pregnancy can result in Fetal Alcohol Spectrum Disorder (FASD), which may feature variable neurodevelopmental deficits, facial dysmorphology, growth retardation, and learning disabilities. Research suggests the human brain is precisely formed through an intrinsic, genetic-cellular expression that is carefully orchestrated by an epigenetic program. This program can be influenced by environmental inputs such as alcohol. Current research suggests the genetic and epigenetic elements of FASD are heavily intertwined and highly dependent on one another. As such, now is the time for investigators to combine genetic, genomic and epigenetic components of alcohol research into a centralized, accessible platform for discussion. Genetic analyses inform gene sets which may be vulnerable to alcohol exposure during early neurulation. Prenatal alcohol exposure indeed alters expression of gene subsets, including genes involved in neural specification, hematopoiesis, methylation, chromatin remodeling, histone variants, eye and heart development. Recently, quantitative genomic mapping has revealed loci (QTLs) that mediate alcohol-induced phenotypes identified between two alcohol-drinking mouse strains. One question to consider is (besides the role of dose and stage of alcohol exposure) why only 5% of drinking women deliver newborns diagnosed with FAS (Fetal Alcohol Syndrome)? Studies are ongoing to answer this question by characterizing genome-wide expression, allele-specific expression (ASE), gene polymorphisms (SNPs) and maternal genetic factors that influence alcohol vulnerability. Alcohol exposure during pregnancy, which can lead to FASD, has been used as a model to resolve the epigenetic pathway between environment and phenotype. Epigenetic mechanisms modify genetic outputs through alteration of 3D chromatin structure and accessibility of transcriptional machinery. Several laboratories have reported altered epigenetics, including DNA methylation and histone modification, in multiple models of FASD. During development DNA methylation is dynamic yet orchestrated in a precise spatiotemporal manner during neurulation and coincidental with neural differentiation. Alcohol can directly influence epigenetics through alterations of the methionine pathway and subsequent DNA or histone methylation/acetylation. Alcohol also alters noncoding RNA including miRNA and transposable elements (TEs). Evidence suggests that miRNA expression may mediate ethanol teratology, and TEs may be affected by alcohol through the alteration of DNA methylation at its regulatory region. In this manner, the epigenetic and genetic components of FASD are revealing themselves to be mechanistically intertwined. Can alcohol-induced epigenomic alterations be passed across generations? Early epidemiological studies have revealed infants with FASD-like features in the absence of maternal alcohol, where the fathers were alcoholics. Novel mechanisms for alcohol-induced phenotypes include altered sperm DNA methylation, hypomethylated paternal allele and heritable epimutations. These studies predict the heritability of alcohol-induced epigenetic abnormalities and gene functionality across generations. We opened a forum to researchers and investigators the field of FASD to discuss their insights, hypotheses, fresh data, past research, and future research themes embedded in this rising field of the genetics and epigenetics of FASD. This eBook is a product of the collective sharing and debate among researchers who have contributed or reviewed each subject.

Adult neurogenesis twenty years later: physiological function versus brain repair

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194940 Year: Pages: 120 DOI: 10.3389/978-2-88919-494-0 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2015-11-16 15:44:59
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The discovery that mammalian brains contain neural stem cells which perform adult neurogenesis - the production and integration of new neurons into mature neural circuits - has provided a fully new vision of neural plasticity. On a theoretical basis, this achievement opened new perspectives for therapeutic approaches in restorative and regenerative neurology. Nevertheless, in spite of striking advancement concerning the molecular and cellular mechanisms which allow and regulate the neurogenic process, its exploitation in mammals for brain repair strategies remains unsolved. In non-mammalian vertebrates, adult neurogenesis also contributes to brain repair/regeneration. In mammals, neural stem cells do respond to pathological conditions in the so called "reactive neurogenesis", yet without substantial regenerative outcome. Why, even in the presence of stem cells in the brain, we lack an effective reparative outcome in terms of regenerative neurology, and which factors hamper the attainment of this goal? Essentially, what remains unanswered is the question whether (and how) physiological functions of adult neurogenesis in mammals can be exploited for brain repair purposes.

Oxytocin's routes in social behavior: Into the 21st century

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196968 Year: Pages: 132 DOI: 10.3389/978-2-88919-696-8 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-04-07 11:22:02
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Our brain is endowed with an incredible capacity to be social, to trust, to cooperate, to be altruistic, to feel empathy and love. Nevertheless, the biological underpinnings of such behaviors remain partially hardwired. Seminal research in rodents has provided important insights on the identification of specific genes in modulating social behaviors, in particular, the arginine vasopressin receptor and the oxytocin receptor genes. These genes are involved in regulating a wide range of social behaviors, mother-infant interactions, social recognition, aggression and socio-sexual behavior. Remarkably, we now know that these genes contribute to social behavior in a broad range of species from voles to humans. Indeed, advances in human non-invasive neuroimaging techniques and genetics have enabled scientists to begin to elucidate the neurobiological basis of the complexity of human social behaviors using "pharmacological fMRI" and "imaging genetics". Over the past few years, there has been a strong interest focused on the role of oxytocin in modulating human social behaviors with translational relevance for understanding neuropsychiatric disorders, such as autism, schizophrenia and depression, in which deficits in social perception and social recognition are key phenotypes. The convergence of this interdisciplinary research is beginning to reveal the complex nature of oxytocin’s actions. For instance, the way that oxytocin does influence social functioning is highly related to individual differences in social experiences, but also to the inter-individual variability in the receptor distribution of this molecule in the brain. Remarkably, despite the increasing evidence that oxytocin has a key role in regulating human social behavior, we still lack of knowledge on the core mechanisms of action of this molecule. Understanding its fundamental actions is a crucial need in order to target optimal therapeutic strategies for human social disorders. The originality of this Research Topic stands on its translational focus on bridging the gap between fundamental knowledge acquired from oxytocin research in voles and monkeys and recent clinical investigations in humans. For instance, what are the key animal findings that can import further knowledge on the mechanisms of actions of this molecule in humans? What are the key experiences that can be performed in the animal model in order to answer significant science gaps in the treatment of neuropsychiatric disorders? Hence, within this Research Topic, we will review the current state of the field, identify where the gaps in knowledge are, and propose directions for future research. This issue will begin with a comparative review that examines the role of this peptide in diverse animal models, which highlights the adaptive value of oxytocin’s function across multiple species. Then, a series of reviews will examine the role of oxytocin in voles, primates, and humans with an eye toward revealing commonalities in the underlying brain circuits mediating oxytocin’s effects on social behavior. Next, there will be a translational review highlighting the evidence for oxytocin’s role in clinical applications in psychopathology. Hence, via the continuum of basic to translational research areas, we will try to address the important gaps in our understanding of the neurobiological routes of social cognition and the mechanisms of action of the neuropeptides that guide our behaviors and decisions.

Schizophrenia: A Consequence of Gene-Environment Interactions?

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195312 Year: Pages: 126 DOI: 10.3389/978-2-88919-531-2 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2015-12-10 11:59:06
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Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors (e.g. stress and cannabis use). In recent years, an increasing number of researchers worldwide have started investigating the ‘two-hit hypothesis’ of schizophrenia predicting that genetic and environmental risk factors interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. Eventually, it might help advance studies of the molecular pathways involved in this mental disorder and propose more specific molecular medicine. However, the complexity of this multi-factorial line of research has also caused difficulties in data interpretation and comparison. Our research topic is intended to cover past and current directions in research dedicated to the understanding and measurement of gene-environment interactions (GxE) in schizophrenia, the neurobiological and behavioural consequences of such interactions as well as the challenges and limitations one encounters when working on complex aetiological systems.

Mechanisms of antibiotic resistance

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195268 Year: Pages: 224 DOI: 10.3389/978-2-88919-526-8 Language: English
Publisher: Frontiers Media SA
Subject: Microbiology --- Science (General)
Added to DOAB on : 2015-12-10 11:59:06
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Antibiotics represent one of the most successful forms of therapy in medicine. But the efficiency of antibiotics is compromised by the growing number of antibiotic-resistant pathogens. Antibiotic resistance, which is implicated in elevated morbidity and mortality rates as well as in the increased treatment costs, is considered to be one of the major global public health threats (www.who.int/drugresistance/en/) and the magnitude of the problem recently prompted a number of international and national bodies to take actions to protect the public (http://ec.europa.eu/dgs/health_consumer/docs/road-map-amr_en.pdf: http://www.who.int/drugresistance/amr_global_action_plan/en/; http://www.whitehouse.gov/sites/default/files/docs/carb_national_strategy.pdf). Understanding the mechanisms by which bacteria successfully defend themselves against the antibiotic assault represent the main theme of this eBook published as a Research Topic in Frontiers in Microbiology, section of Antimicrobials, Resistance, and Chemotherapy. The articles in the eBook update the reader on various aspects and mechanisms of antibiotic resistance. A better understanding of these mechanisms should facilitate the development of means to potentiate the efficacy and increase the lifespan of antibiotics while minimizing the emergence of antibiotic resistance among pathogens.

Pattern recognition receptors and cancer

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196746 Year: Pages: 201 DOI: 10.3389/978-2-88919-674-6 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-08-16 10:34:25
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The group of pattern recognition receptors (PRRs) includes families of Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), and AIM-2-like receptors (ALRs). Conceptually, receptors constituting these families are united by two general features. Firstly, they directly recognize common antigen determinants of virtually all classes of pathogens (so-called pathogen-associated molecular patterns, or simply PAMPs) and initiate immune response against them via specific intracellular signaling pathways. Secondly, they recognize endogenous ligands (since they are usually released during cell stress, they are called damage-associated molecular patterns, DAMPs), and, hence, PRR-mediated immune response can be activated without an influence of infectious agents. So, pattern recognition receptors play the key role performing the innate and adaptive immune response. In addition, many PRRs have a number of other vital functions apart from participation in immune response realization. The fundamental character and diversity of PRR functions have led to amazingly rapid research in this field. Such investigations are very promising for medicine as immune system plays a key role in vast majority if not all human diseases, and the process of discovering the new aspects of the immune system functioning is rapidly ongoing. The role of Toll-like receptors in cancer was analyzed in certain reviews but the data are still scattered. This collection of reviews systematizes the key information in the field.

Towards translating research to clinical practice: Novel Strategies for Discovery and Validation of Biomarkers for Brain Injury

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193912 Year: Pages: 178 DOI: 10.3389/978-2-88919-391-2 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Neurology
Added to DOAB on : 2015-12-03 13:02:24
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Traumatic brain injury (TBI) is a major cause of death and disability and one of the greatest unmet needs in medicine and public health. TBI not only has devastating effects on patients and their relatives but results in huge direct and indirect costs to society. Although guidelines for the management of patients have been developed and more than 200 clinical trials have been conducted, they have resulted in few improvements in clinical outcomes and no effective therapies approved for TBI. It is now apparent that the heterogeneity of clinical TBI is underlain by molecular phenotypes more complex and interactive than initially conceived and current approaches to the characterization, management and outcome prediction of TBI are antiquated, unidimensional and inadequate to capture the interindividual pathophysiological heterogeneity. Recent advances in proteomics and biomarker development provide unparalleled opportunities for unraveling substantial injury-specific and patient-specific variability and refining disease characterization. The identification of novel, sensitive, objective tools, referred to as biomarkers, can revolutionize pathophysiological insights, enable targeted therapies and personalized approaches to clinical management. In this Research Topic, we present novel approaches that provide an infrastructure for discovery and validation of new biomarkers of acute brain injury. These techniques include refined mass spectrometry technology and high throughput immunoblot techniques. Output from these approaches can identify potential candidate biomarkers employing systems biology and data mining methods. In this Research Topic, we present novel approaches that provide an infrastructure for discovery and validation of new biomarkers of acute brain injury. These techniques include refined mass spectrometry technology and high throughput immunoblot techniques. Output from these approaches can identify potential candidate biomarkers employing systems biology and data mining methods. Finally, suggestions are provided for the way forward, with an emphasis on need for a multidimensional approach that integrate a panel of pathobiologically diverse biomarkers with clinical variables and imaging-based assessments to improve diagnosis and classification of TBI and to develop best clinical practice guidelines.

Multi-omic Data Integration

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196487 Year: Pages: 135 DOI: 10.3389/978-2-88919-648-7 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Biology --- Genetics
Added to DOAB on : 2016-08-16 10:34:25
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Stable, predictive biomarkers and interpretable disease signatures are seen as a significant step towards personalized medicine. In this perspective, integration of multi-omic data coming from genomics, transcriptomics, glycomics, proteomics, metabolomics is a powerful strategy to reconstruct and analyse complex multi-dimensional interactions, enabling deeper mechanistic and medical insight. At the same time, there is a rising concern that much of such different omic data –although often publicly and freely available- lie in databases and repositories underutilised or not used at all. Issues coming from lack of standardisation and shared biological identities are also well-known. From these considerations, a novel, pressing request arises from the life sciences to design methodologies and approaches that allow for these data to be interpreted as a whole, i.e. as intertwined molecular signatures containing genes, proteins, mRNAs and miRNAs, able to capture inter-layers connections and complexity. Papers discuss data integration approaches and methods of several types and extents, their application in understanding the pathogenesis of specific diseases or in identifying candidate biomarkers to exploit the full benefit of multi-omic datasets and their intrinsic information content. Topics of interest include, but are not limited to: • Methods for the integration of layered data, including, but not limited to, genomics, transcriptomics, glycomics, proteomics, metabolomics;• Application of multi-omic data integration approaches for diagnostic biomarker discovery in any field of the life sciences;• Innovative approaches for the analysis and the visualization of multi-omic datasets;• Methods and applications for systematic measurements from single/undivided samples (comprising genomic, transcriptomic, proteomic, metabolomic measurements, among others);• Multi-scale approaches for integrated dynamic modelling and simulation;• Implementation of applications, computational resources and repositories devoted to data integration including, but not limited to, data warehousing, database federation, semantic integration, service-oriented and/or wiki integration;• Issues related to the definition and implementation of standards, shared identities and semantics, with particular focus on the integration problem. Research papers, reviews and short communications on all topics related to the above issues were welcomed.

Phenotypic screening in the 21st century

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194698 Year: Pages: 67 DOI: 10.3389/978-2-88919-469-8 Language: English
Publisher: Frontiers Media SA
Subject: Therapeutics --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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In the genomic era of 1990s-2000s, pharmaceutical research moved to target-based drug discovery which enabled development of a number of small molecule drugs against a wide range of diseases. In many cases however, drugs that arose from genomics failed, questioning the validity of the targets and the suitability of target-based drug discovery as an optimal strategy for all disease states. For monogenic diseases, target-based approaches may be well-suited to the identification of novel therapies. Most diseases, however, are caused by a combination of several genetic and environmental factors and are likely to require simultaneous modulation of multiple molecular targets/pathways for successful treatment. For such diseases, reductionist approaches focusing on individual targets rather than biological networks are unlikely to succeed and new drug development strategies are required. In search of more successful approaches, the pharmaceutical industry is moving towards phenotypic screening beyond individual genes/targets. However, this requires rethinking of diseases and drug discovery approaches from a network and systems biology perspective. Since returning to the pre-genomics era of screening drug candidates in laborious animal models is not a feasible solution, the industry needs to evolve a new paradigm of phenotypic drug discovery within the context of systems biology. Such a paradigm must combine physiologically and disease relevant biological substrates with sufficient throughput, operational simplicity and statistical vigour. Biomarker strategies for translational medicine, as well as preclinical safety and selectivity assessments, would also need to be revised to adapt to the target agnostic style. This focused issue aims to discuss strategies, key concepts and technologies related to systems-based approaches in drug development. Design and implementation of innovative biological assays, featuring multiple target strategies, and rational drug design in the absence of target knowledge during the early drug discovery are illustrated with examples. Specific topics include: • The need for systems-based approaches in drug development • Phenotypic screening strategies • Compound libraries (natural product inspired compound collections) • Target deconvolution and identification • Target agnostic lead discovery and optimization • Multi-target approaches and decoding the phenotype (understanding biological interactions and multiscale systems modelling) • Translational aspects • Early evaluation of selectivity and safety in a target agnostic manner

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2015 (11)