Search results: Found 4

Listing 1 - 4 of 4
Sort by
Ways to improve tumor uptake and penetration of drugs into solid tumors

Authors: --- ---
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193509 Year: Pages: 129 DOI: 10.3389/978-2-88919-350-9 Language: English
Publisher: Frontiers Media SA
Subject: Oncology --- Medicine (General) --- Therapeutics --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
License:

Loading...
Export citation

Choose an application

Abstract

The main scope of this topic is to give an update on pharmacologic and non-pharmacologic approaches to enhance uptake and penetration of cancer drugs into tumors. Inadequate accumulation of drugs in tumors has emerged over the last decade as one of the main problems underlying therapeutic failure and drug resistance in the treatment of cancer. Insufficient drug uptake and penetration is causally related to the abnormal tumor architecture. Thus, poor vascularization, increased resistance to blood flow and impaired blood supply represent a first obstacle to the delivery of antitumor drugs to tumor tissue. Decreased or even inverted transvascular pressure gradients compromise convective delivery of drugs. Eventually, an abnormal extracellular matrix offers increased frictional resistance to tumor drug penetration. Abnormal tumor architecture also changes the biology of tumor cells, which contributes to drug resistance through several different mechanisms. The variability in vessel location and structure can make many areas of the tumor hypoxic, which causes the tumor cells to become quiescent and thereby resistant to many antitumor drugs. In addition, the abnormally long distance of part of the tumor cell population from blood vessels provides a challenge to delivering cancer drugs to these cells. We have recently proposed additional mechanisms of tumor drug resistance, which are also related to abnormal tumor architecture. First, increased interstitial fluid pressure can by itself induce drug resistance through the induction of resistance-promoting paracrine factors. Second, the interaction of drug molecules with vessel- proximal tumor cell layers may also induce the release of these factors, which can spread throughout the cancer, and induce drug resistance in tumor cells distant from blood vessels. As can be seen, abnormal tumor architecture, inadequate drug accumulation and tumor drug resistance are tightly linked phenomena, suggesting the need to normalize the tumor architecture, including blood vessels, and/or increase the accumulation of cancer drugs in tumors in order to increase therapeutic effects. Indeed, several classes of drugs (that we refer to as promoter drugs) have been described, that promote tumor uptake and penetration of antitumor drugs, including those that are vasoactive, modify the barrier function of tumor vessels, debulk tumor cells, and overcome intercellular and stromal barriers. In addition, also non-pharmacologic approaches have been described that enhance tumor accumulation of effector drugs (e.g. convection-enhanced delivery, hyperthermia, etc.). Some drugs that have already received regulatory approval (e.g. the anti-VEGF antibody bevacizumab) exert antitumor effects at least in part through normalization of the tumor vasculature and enhancement of the accumulation of effector drugs. Other drugs, acting through different mechanisms of action, are now in clinical development (e.g. NGR-TNF in phase II/III studies) and others are about to enter clinical investigation (e.g. JO-1).

Inhibitory Function in Auditory Processing

Authors: --- ---
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196678 Year: Pages: 231 DOI: 10.3389/978-2-88919-667-8 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2016-08-16 10:34:25
License:

Loading...
Export citation

Choose an application

Abstract

There seems little doubt that from the earliest evolutionary beginnings, inhibition has been a fundamental feature of neuronal circuits - even the simplest life forms sense and interact with their environment, orienting or approaching positive stimuli while avoiding aversive stimuli. This requires internal signals that both drive and suppress behavior. Traditional descriptions of inhibition sometimes limit its role to the suppression of action potential generation. This view fails to capture the vast breadth of inhibitory function now known to exist in neural circuits. A modern perspective on inhibitory signaling comprises a multitude of mechanisms. For example, inhibition can act via a shunting mechanism to speed the membrane time constant and reduce synaptic integration time. It can act via G-protein coupled receptors to initiate second messenger cascades that influence synaptic strength. Inhibition contributes to rhythm generation and can even activate ion channels that mediate inward currents to drive action potential generation. Inhibition also appears to play a role in shaping the properties of neural circuitry over longer time scales. Experience-dependent synaptic plasticity in developing and mature neural circuits underlies behavioral memory and has been intensively studied over the past decade. At excitatory synapses, adjustments of synaptic efficacy are regulated predominantly by changes in the number and function of postsynaptic glutamate receptors. There is, however, increasing evidence for inhibitory modulation of target neuron excitability playing key roles in experience-dependent plasticity. One reason for our limited knowledge about plasticity at inhibitory synapses is that in most circuits, neurons receive convergent inputs from disparate sources. This problem can be overcome by investigating inhibitory circuits in a system with well-defined inhibitory nuclei and projections, each with a known computational function. Compared to other sensory systems, the auditory system has evolved a large number of subthalamic nuclei each devoted to processing distinct features of sound stimuli. This information once extracted is then re-assembled to form the percept the acoustic world around us. The well-understood function of many of these auditory nuclei has enhanced our understanding of inhibition's role in shaping their responses from easily distinguished inhibitory inputs. In particular, neurons devoted to processing the location of sound sources receive a complement of discrete inputs for which in vivo activity and function are well understood. Investigation of these areas has led to significant advances in understanding the development, physiology, and mechanistic underpinnings of inhibition that apply broadly to neuroscience. In this series of papers, we provide an authoritative resource for those interested in exploring the variety of inhibitory circuits and their function in auditory processing. We present original research and focused reviews touching on development, plasticity, anatomy, and evolution of inhibitory circuitry. We hope our readers will find these papers valuable and inspirational to their own research endeavors.

Ontogeny and Phylogeny of Brain Barrier Mechanisms

Authors: --- ---
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889198108 Year: Pages: 358 DOI: 10.3389/978-2-88919-810-8 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-01-19 14:05:46
License:

Loading...
Export citation

Choose an application

Abstract

The brain functions within an internal environment that is determined and controlled by morphological structures and cellular mechanisms present at interfaces between the brain and the rest of the body. In vertebrates these interfaces are across cerebral blood vessels (blood-brain barrier) choroid plexuses (blood-cerebrospinal fluid barrier) and pia-arachnoid. There is a CSF-brain barrier in the neuroepithelium lining the ventricular system that is only present in embryos. There is now substantial evidence that many brain barrier mechanisms develop early and that in some cases they are functionally more active and even more specialized compared to adult barriers. Therefore barriers in developing brain should be viewed as adapted appropriately for the growing brain and not, as is still widely believed, immature. Considerable advances in our understanding of these barrier mechanisms have come from studies of the developing brain and invertebrates. A striking aspect, to be highlighted in this special edition, is that many of the molecular mechanisms in these very diverse species are similar despite differences in the cellular composition of the interfaces. This Frontiers Topic comprises articles in three sections: Original studies, Reviews and Myths & Misconceptions. Original articles provide new information on molecular and cellular barrier mechanisms in developing brains of primates, including human embryos (Brøchner et al., Ek et al., Errede et al.), rodents (Bauer et al., Liddelow, Strazielle & Ghersi-Egea, Saunders et al., Whish et al.), chick (Bueno et al.) and zebrafish (Henson et al.) as well as studies in drosophila (Hindle & Bainton, De Salvo et al., Limmer et al.). The Reviews section includes evolutionary perspectives of the blood-brain and blood-CSF barriers (Bueno et al., Bill & Korzh). There are also detailed reviews of the current state of understanding of different interfaces and their functional mechanisms in developing brain (Bauer et al., Strazielle & Gjersi-Egea, Liddelow, Richardson et al., Errede et al., Henson et al., Brøchner et al.) and in invertebrates (Hindle & Bainton, De Salvo et al., Limmer et al). Different aspects of the relationship between properties of the internal environment of the brain and its development are discussed. (Stolp & Molnar, Johansson, Prasongchean et al.). A neglected area, namely barriers over the surface of the brain during development is also covered (Brøchner et al.). Clinically related perspectives on barrier disruption in neonatal stroke are provided by Kratzer et al. and other aspects of dysfunction by Morretti et al. and by Palmeta et al. on the continuing problem of bilirubin toxicity. Progress in this field is hampered by many prevailing myths about barrier function, combined with methodologies that are not always appropriately selected or interpreted. These are covered in the Misconceptions, Myths and Methods section, including historical aspects and discussion of the paracellular pathway, a central dogma of epithelial and endothelial biology (Saunders et al.) and a review of markers used to define brain barrier integrity in development and in pathological conditions (Saunders et al.). Use of inappropriate markers has caused considerable confusion and unreliable interpretation in many published studies. Torbett et al. deal with the complexities of the new field of applying proteomics to understanding blood-brain barrier properties as do Huntley at al. with respect to applying modern high throughput gene expression methods (Huntley et al.). The Editorial summarizes the contributions from all authors. This includes mention of some the main unanswered but answerable questions in the field and what the impediments to progress may be.

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias

Author:
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196470 Year: Pages: 141 DOI: 10.3389/978-2-88919-647-0 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Physiology
Added to DOAB on : 2016-08-16 10:34:25
License:

Loading...
Export citation

Choose an application

Abstract

The effective management of cardiac arrhythmias, either of atrial or of ventricular origin, remains a major challenge. Sudden cardiac death due to ventricular tachyarrhythmias remains the leading cause of death in industrialized countries while atrial fibrillation is the most common rhythm disorder; an arrhythmia that’s prevalence is increasing and accounts for nearly one quarter of ischemic stokes the elderly population. Yet, despite the enormity of the problem, effective therapeutic interventions remain elusive. In fact, several initially promising antiarrhythmic agents were found to increase rather than decrease mortality in patients recovering from myocardial infarction. The question then is what went wrong, why have these interventions proven to be so ineffective? An obvious answer is the drugs were designed to attack the wrong therapeutic target. Clearly, targeting single ion channels (using either isolated ion channels or single myocytes preparations) has proven to be less than effective. What then is the appropriate target? It is well established that cardiac electrical properties can vary substantially between single cells and intact preparations. One obvious example is the observation that action potential duration is much longer in isolated cells as compared to multi-cellular preparations or intact hearts. Due to the low electrical resistance between adjacent myocytes, the cells act in coordinated fashion producing “electrotonic interdependence” between neighboring cells. Myocardial infarction and/or acute ischemia provoke profound changes in the passive electrical properties of cardiac muscle. In particular, electrotonic uncoupling of the myocytes disrupts the coordinated activation and repolarization of cardiac tissue. The resulting compensatory changes in ionic currents decrease cardiac electrical stability increasing the risk for life-threatening changes in the cardiac rhythm. Thus, the electrical properties of myocardial cells must be considered as a unit rather than in isolation. It is the purpose of this Research Topic to evaluate the largely neglected relationship between changes in passive electrical properties of cardiac muscle and arrhythmia formation.

Listing 1 - 4 of 4
Sort by
Narrow your search

Publisher

Frontiers Media SA (4)


License

CC by (4)


Language

english (4)


Year
From To Submit

2016 (1)

2015 (2)

2014 (1)