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Targeting PI3K/mTOR signaling in cancer

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192441 Year: Pages: 93 DOI: 10.3389/978-2-88919-244-1 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Biology --- Medicine (General) --- Oncology
Added to DOAB on : 2015-11-16 15:44:59
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The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway integrates signals from growth factors with nutrient signals and other conditions and controls multiple cell responses, including proliferation, survival and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer. Somatic or inherited mutations frequently occur in tumor suppressor genes (PTEN, TSC1/2, LKB1) and oncogenes (PIK3CA, PIK3R1, AKT) in the PI3K/mTOR pathway. The fact that the PI3K/mTOR pathway is deregulated in a large number of human malignancies, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. Rapamycin and its analogs targeting mTOR are effective in many preclinical cancer models. Although rapalogs are approved for the treatment of some cancers, their efficacy in clinical trials remains the subject of debate. Due to the complexity of the PI3K/mTOR signaling pathway, developing an effective anti-cancer therapy remains a challenge. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments.

Preclinical and clinical issues in Alzheimer's disease drug research and development

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194339 Year: Pages: 100 DOI: 10.3389/978-2-88919-433-9 Language: English
Publisher: Frontiers Media SA
Subject: Therapeutics --- Science (General)
Added to DOAB on : 2016-01-19 14:05:46
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Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss, inability to perform the activities of daily living and mood disorders. According to the so-called “amyloid cascade hypothesis”, amyloid-ß- peptide (Aß), produced by beta- and gamma- secretase-mediated cleavages of the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of AD. Aß was also shown to contribute to AD pathology by stimulating the hyperphosphorylation of tau which is responsible for the formation of neurofibrillary tangles. However, the “amyloid cascade hypothesis” was challenged by other theories which lend support to the idea that Aß is not causative but can be considered as an “innocent bystander” in AD. Although preclinical research generated impressive lines of evidence about the several intracellular mechanism(s) whose impairment leads to the onset and progression of AD, clinical research aimed at the development of new drugs capable of preventing or delaying the onset of neuronal damage in AD patients has produced limited results. The drugs currently available for the treatment of AD are acetylcholinesterase inhibitors (AChEI) and the NMDA glutamate receptor antagonist memantine. The AChEI increase acetylcholine levels in the synaptic cleft, which are reduced because of the progressive damage of cholinergic neurons in cognitive brain areas (e.g. amygdala, hippocampus, and frontal cortex), whereas memantine is used to prevent/reduce calcium-dependent excitotoxic neuronal cell death. Both classes of drugs have been shown to improve symptoms related to cognitive decline, but their effects are confined largely to patients with mild to moderate AD, in particular during the first year or so of treatment. An alternative to this symptomatic treatments involves the use of drugs that intervene in the pathogenesis of the disease. Recently, monoclonal antibodies against Aß were proposed as novel agents capable to remove Aß from the brain thus preventing neuronal damage. The research topic focuses on the preclinical and clinical evidence about the several factors that contribute to the pathogenesis of AD as well as the potential therapeutic role of new classes of drugs still under preclinical or clinical development.

Data-Based Radiation Oncology - Design of Clinical Trials

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889454389 Year: Pages: 109 DOI: 10.3389/978-2-88945-438-9 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Oncology
Added to DOAB on : 2018-11-16 17:17:57
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In radiation oncology as in many other specialties clinical trials are essential to investigate new therapy approaches. Usually, preparation for a prospective clinical trial is extremely time consuming until ethics approval is obtained. To test a new treatment usually many years pass before it can be implemented in the routine care. During that time, already new interventions emerge, new drugs appear on the market, technical & physical innovations are being implemented, novel biology driven concepts are translated into clinical approaches while we are still investigating the ones from years ago. Another problem is associated with molecular diagnostics and the growing amount of tumor specific biomarkers which allows for a better stratification of patient subgroups. On the other side, this may result in a much longer time for patient recruiting and consequently in larger multicenter trials. Moreover, all of the relevant data must be readily available for treatment decision making, treatment as well as follow-up, and ultimately for trial evaluation. This challenges even more for agreed standards in data acquisition, quality and management. How could we change the way currently clinical trials are performed in a way they are safe and ethically justifiable and speed up the initiation process, so we can provide new and better treatments faster for our patients?Further, while we rely on various quantitative information handling distributed, large heterogeneous amounts of data efficiently is very important. Thus data management becomes a strong focus. A good infrastructure helps to plan, tailor and conduct clinical trials in a way they are easy and quickly analyzable.In this research topic we want to discuss new ideas for intelligent trial designs and concepts for data management.

Paradigm changes are required in HIV vaccine research

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197279 Year: Pages: 74 DOI: 10.3389/978-2-88919-727-9 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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In his 1962 book "The Structure of Scientific Revolutions", Thomas Kuhn famously argued that researchers in every field of scientific enquiry always operate under a set of presuppositions known as paradigms that are rarely explicitly stated. In the field of HIV vaccine research, several prevailing paradigms led scientists for many years to pursue unfruitful lines of investigations that impeded significant progress. The uncritical acceptance of reigning paradigms makes scientists reluctant to abandon their mistaken assumptions even when they obtain results that are not consistent with the paradigms. The following five paradigms which disregard the degeneracy of the immune system were particularly harmful. 1) There is a primary and intrinsic epitope specific for each B cell receptor and for the corresponding monoclonal antibody.In reality, there is no single, intrinsic or "real" epitope for any antibody but only a diverse group of potential ligands. 2) Reactions with monoclonal antibodies are more specific than the combined reactivity of polyclonal antibodies. In reality, a polyclonal antiserum has greater specificity for a multiepitopic protein because different antibodies in the antiserum recognize separate epitopes on the same protein, giving rise to an additive specificity effect. By focusing vaccine design on single epitope-Mab pairs, the beneficial neutralizing synergy that occurs with polyclonal antibody responses is overlooked. 3) The HIV epitope identified by solving the crystallographic structure of a broadly neutralizing Mab – HIV Env complex should be able, when used as immunogen, to elicit antibodies endowed with the same neutralizing capacity as the Mab. Since every anti HIV bnMab is polyspecific, the single epitope identified in the complex is not necessarily the one that elicited the bnMab. Since hypermutated Mabs used in crystallographic studies differ from their germline-like receptor version present before somatic hypermutation, the identified epitope will not be an effective vaccine immunogen. 4) Effective vaccine immunogenicity can be predicted from the antigenic binding capacity of viral epitopes. Most fragments of a viral antigen can induce antibodies that react with the immunogen, but this is irrelevant for vaccination since these antibodies rarely recognize the cognate, intact antigen and even more rarely neutralize the infectivity of the viral pathogen that harbors the antigen. 5) The rational design of vaccine immunogens using reverse vaccinology is superior to the trial-and-error screening of vaccine candidates able to induce protective immunity. One epitope can be designed to increase its structural complementarity to one particular bnMab, but such antigen design is only masquerading as immunogen design because it is assumed that antigenic reactivity necessarily entails the immunogenic capacity to elicit neutralizing antibodies. When HIV Env epitopes, engineered to react with a bnMab are used to select from human donors rare memory B cells secreting bnAbs, this represents antigen design and not immunogen design. The aim of this Research Topic is to replace previous misleading paradigms by novel ones that better fit our current understanding of immunological specificity and will help HIV vaccine development.

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