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At least 1,351 records · Page 75Linked to original sources
PubMed1995

[The flab method of intraoperative radiotherapy].

PURPOSE: Improvement of the relapse rate by locally increasing the tumor dose. METHODS: To increase the dose in the tumor bed a method for intraoperative radiation therapy has been developed. The radiation is applied using a high-dose-rate afterloading system. Flexible plastic flabs are used as applicators. Each flab contains tubes for the alterloading source. The size of the applicator is chosen to correspond to the size of the target volume. In the dosage system we use the dwell times at all source positions are equal. The dwell time has been precalculated to give the reference dose at the reference position which is located at the surface of the flab in the center of the target volume. RESULTS: The dose distributions around the flab have been calculated as a function of the thickness of the flab. If the source is not placed on a regular grid within the applicator due to a non ideal positioning of the tubes within the applicator, the dose distribution is not altered too much, if the positioning error is not larger than +/- 2 mm. The influence of a curvature of the flab has been evaluated and methods to decrease the dose at critical organs are discussed. CONCLUSION: The flab methods for IORT is safe and easy and has been demonstrated for more than 150 cases. This method allows the increase in tumor dose even in regions which are not easily treated by electron IORT due to the rigid electron applicators. Because of the rapid dose fall off, the flab method can only be used for flat target volumes like the tumor bed.

Humans↗
PubMed1994

Tyrosine kinase-dependent activation of human NK cell functions upon stimulation through a 58-kDa surface antigen selectively expressed on discrete subsets of NK cells and T lymphocytes.

We have raised a mAb, termed HP-3E4 (IgM), by immunizing BALB/c mice against human IL2-activated NK cells. The HP-3E4 mAb recognized in different donors variable proportions (< 2-70%) of either fresh or activated NK cells. A small population of T cells (alpha/beta and gamma/delta) appeared HP-3E4+ in PBL. No reactivity was detected on other leukocytes and a panel of cell lines from different lineages. By immunohistochemical staining of different tissues, few HP-3E4+ cells were detected only in lymphoid organs. Analysis of CD56+CD16+CD3- clones (n = 167) from unrelated donors (n = 6), showed that the Ag was stably expressed on 8 to 70%, moreover it was detected on some gamma/delta + T cell clones, whereas all CD3+ alpha/beta +(CD4+ and CD8+) clones analyzed (n = 90) were HP-3E4-. As assessed by SDS-PAGE analysis, the HP-3E4 mAb immunoprecipitated a 58-kDa surface structure. When compared with two mAbs (GL183 and EB6) previously reported to bind also a clonally distributed 54- to 58-kDa Ag, the HP-3E4 mAb appeared to recognize a distinct epitope, thus allowing to further define NK cell subsets. Stimulation of IL2-activated NK cells with the mAb triggered TNF-alpha and IFN-gamma production, which was enhanced by using the mAb attached to plastic or in the presence of suboptimal concentrations of phorbol esters. Although the HP-3E4 mAb did not significantly modify NK cell-mediated cytotoxicity against different targets, with the exception of the Hmy-C1R cell line, it activated BLT esterase secretion. Remarkably, the HP-3E4 mAb triggered phosphoinositide turnover and an early increase of [Ca2+]i, as well as tyrosine phosphorylation of several cellular substrates including CD3 zeta; inhibition of tyrosine kinase activity with genistein hampered the HP-3E4-mediated stimulation of cytokine production. Our data provide further support for the structural diversity of a 58-kDa surface Ag, whose expression is restricted to discrete NK and T cell subsets. Moreover, the results support the fact that the molecule plays an active role in regulating NK cell functions through signal transduction mechanisms comparable to those triggered via Fc gamma RIII.

Antibodies, Monoclonal↗
PubMed1994

Expression and function of CD7 molecule on human natural killer cells.

The CD7 molecule, one of the earliest T-lymphocyte Ag expressed during ontogeny, has recently been demonstrated to facilitate activation of T cells and to preferentially activate TCR-gamma/delta + subset of T cells. The CD7 Ag is also expressed on human NK cells, but its function has not been determined. In this study, expression and function of CD7 Ag on highly enriched NK cells (94 +/- 3% mean +/- SD, n = 12) obtained by negative selection from peripheral blood of normal donors were investigated. The CD7 Ag was found to be expressed at a significantly (p < 0.002) higher level on fresh NK cells than on IL-2-activated, NK cells. CD7 on human NK cells was found to be a signal-transducing molecule with a rapid increase in cytoplasmic free calcium observed on binding of anti-CD7 mAb to the surface of NK cells. Cross-linking of CD7 induced expression of surface activation molecules such as CD25, CD71, HLA-DR, CD69, and CD54. Activation by anti-CD7 mAb cross-linked to plastic or through goat anti-mouse Ig also induced a variety of NK cell functions: it stimulated secretion of IFN-gamma, led to proliferation of NK cells, as measured by [3H]thymidine incorporation, and significantly enhanced cytotoxicity of NK cells against K562 targets (p < 0.03). However, CD7 on NK cells did not seem to transduce a lytic signal, because it neither mediated redirected killing of Fc gamma R+ murine mastocytoma P815 cells nor triggered lysis of a hybridoma expressing the antibody in a membrane-bound form. CD7 molecules appeared to have a regulatory role in adhesion of NK cells to fibronectin, because cross-linking of CD7 on resting NK cells significantly augmented their adhesion to fibronectin-coated plastic surfaces. However, this induced adhesion was not associated with increased expression of beta 1-integrins on NK cells. Thus, CD7-mediated signals appear to augment function of adhesion molecules on NK cells, which may be involved in NK cell activation by providing both anchorage and costimulatory triggering.

Antigens, CD↗
PubMed2004

Learned regulation of spatially localized brain activation using real-time fMRI.

It is not currently known whether subjects can learn to voluntarily control activation in localized regions of their own brain using neuroimaging. Here, we show that subjects were able to learn enhanced voluntary control over task-specific activation in a chosen target region, the somatomotor cortex. During an imagined manual action task, subjects were provided with continuous direction regarding their cognitive processes. Subjects received feedback information about their current level of activation in a target region of interest (ROI) derived using real-time functional magnetic resonance imaging (rtfMRI), and they received automatically-adjusted instructions for the level of activation to achieve. Information was provided both as continously upated graphs and using a simple virtual reality interface that provided an image analog of the level of activation. Through training, subjects achieved an enhancement in their control over brain activation that was anatomically specific to the target ROI, the somatomotor cortex. The enhancement took place when rtfMRI-based training was provided, but not in a control group that received similar training without rtfMRI information, showing that the effect was not due to conventional, practice-based neural plasticity alone. Following training, using cognitive processes alone subjects could volitionally induce fMRI activation in the somatomotor cortex that was comparable in magnitude to the activation observed during actual movement. The trained subjects increased fMRI activation without muscle tensing, and were able to continue to control brain activation even when real-time fMRI information was no longer provided. These results show that rtfMRI information can be used to direct cognitive processes, and that subjects are able to learn volitionally regulate activation in an anatomically-targeted brain region, surpassing the task-driven activation present before training.

Arousal↗
PubMed1989

Improved coupling of ultrasound hyperthermia applicators to patients.

Coupling ultrasound (US) hyperthermia (HT) applicators to patients requires an acoustical medium conforming to both applicator and patient that allows for rapid, reproducible set-up for each treatment and prevents drift or misalignment of the applicator during treatments. We describe a technique that uses a commercially available immobilization foam to create a rigid, conforming foam block that kinematically positions the US applicator over the tumor area. The central volume of the foam block is removed and filled with a plastic bag of degassed water or with US gel during treatments. We also describe a technique for positioning surface and interstitial thermometry sensors in alignment with individual elements of a multi-element US applicator. Using these techniques, relative movement between patient and applicator is minimized, correct thermometry sensor location relative to each US element is confirmed, and efficient transmission of the acoustical power into the target volume is assured. These techniques are particularly important when using multi-element applicators with complex temperature-power control algorithms.

Humans↗
PubMed2000

Regeneration as an application of gastropod neural plasticity.

Gastropod research is providing many insights into mechanisms of neural regeneration. These observations were made possible by the pioneering work of individuals who described the nervous systems of gastropods, mapped prominent neurons and determined their roles and connections, and developed the techniques for culturing them. This information has allowed questions about injury responses, target selection, and pathway cues to be explored at the level of individually identified neurons. Because of gastropod studies, more is known about axon sealing, growth cone formation and behavior, signals that travel from the site of axotomy to the soma, and the second messengers that are activated there. The responses in neurons and non-neuronal cells during neural development and injury are coordinated by chemical messenger systems that are highly conserved, including neurotransmitters, cytokines, and neurotrophins. The nervous system is modified in learning paradigms by some of the same messenger systems activated by injury, because learning and injury both challenge neurons to change. The conservation of basic mechanisms that coordinate neuronal plasticity allows us to approach basic questions in relatively simple nervous systems with reasonable confidence that the findings will be relevant for other nervous systems, including possible applications to the mammalian nervous system.

Animals↗
PubMed2004

Emerging targets for the pharmacology of learning and memory.

Learning and memory are dynamic processes associated with modifications in morphology, biochemistry and physiology of the nervous system, that can be analysed at different levels of biological organization. Within this context, changes correlated with cognitive processes are identifiable at distinct cellular and molecular loci of the nervous system. Synaptic plasticity represents an experience-dependent alteration of neuronal properties that subserve learning and memory, and for which a neuronal network can be considered as a candidate for being part of an engram. Multiple molecular systems at various levels of the signal transduction cascade, such as those involving receptors, second messengers and gene expression, may be linked to synaptic remodelling during cognitive processes. After a brief overview of the various facets of memory and the higher levels of cerebral organization (with special attention to the hippocampus), this review is devoted to the presentation of some novel potential therapeutic targets within the signal transduction cascade that might be considered for rational pharmacological intervention to improve learning and memory in both diseased and healthy individuals.

Animals↗
PubMed2003

Retinal remodeling triggered by photoreceptor degenerations.

Many photoreceptor degenerations initially affect rods, secondarily leading to cone death. It has long been assumed that the surviving neural retina is largely resistant to this sensory deafferentation. New evidence from fast retinal degenerations reveals that subtle plasticities in neuronal form and connectivity emerge early in disease. By screening mature natural, transgenic, and knockout retinal degeneration models with computational molecular phenotyping, we have found an extended late phase of negative remodeling that radically changes retinal structure. Three major transformations emerge: 1) Müller cell hypertrophy and elaboration of a distal glial seal between retina and the choroid/retinal pigmented epithelium; 2) apparent neuronal migration along glial surfaces to ectopic sites; and 3) rewiring through evolution of complex neurite fascicles, new synaptic foci in the remnant inner nuclear layer, and new connections throughout the retina. Although some neurons die, survivors express molecular signatures characteristic of normal bipolar, amacrine, and ganglion cells. Remodeling in human and rodent retinas is independent of the initial molecular targets of retinal degenerations, including defects in the retinal pigmented epithelium, rhodopsin, or downstream phototransduction elements. Although remodeling may constrain therapeutic intervals for molecular, cellular, or bionic rescue, it suggests that the neural retina may be more plastic than previously believed.

Aging↗
PubMed1984

Adaptive modification of the vestibulo-ocular reflex by mental effort in darkness.

The vestibulo-ocular reflex (VOR) can be suppressed in darkness if a subject tries to imagine that he looks at a head fixed target. This mental suppression of VOR was used to induce adaptive changes in VOR gain during 3 h of active head oscillations in complete darkness. VOR gain changes were tested by asking the subject to look at a visual target; then passively or actively the head was turned in darkness while the subject "fixated" the same target. Corrective saccades occurring at the end of the movement when lights were turned on give an elegant measure of VOR gain. Three hours of training induced in 3 subjects a mean of 10.9% and 11.4% decrease of VOR gain for passive and active conditions, respectively. This demonstrates that reflex adaptation can be obtained without external cues, and probably with only an internal reconstruction of target and eye movement.

Adaptation, Physiological↗
PubMed1992

Supraspinal fiber outgrowth and apparent synaptic remodelling across transected-reconstructed feline spinal cord.

Following complete transection of the spinal cord at T9, 12 cats were separated into two groups: Group 1 received a collagen matrix (CM) treated with a neuroactive agent or with saline to bridge the spinal cord stumps and an omental transposition which was placed on the dorsal surface of the matrix; Group 2 received spinal cord transection only. Two cats received no spinal cord transection. After 90 days, all animals were killed and their brains and spinal cords were removed for immunohistochemical examination. Two weeks prior to sacrifice, spinal cord blood flows (SCBF) were measured and the retrograde axonal tracer Fluoro-Gold was injected below the transection site. Results show that omental transposition to the CM bridge in Group 1 animals increased SCBF an average 59% (assessed by clamping the omental blood supply to the cord). Examination of the brain 90 days after cord transection revealed Fluoro-Gold accumulation in the cytoplasm and processes of neurons located in the brainstem, midbrain, and diencephalic region which are known to contribute pathways to the spinal cord. Immunohistochemical staining with antibodies against the catecholamine synthesizing enzymes tyrosine hydroxylase and dopamine-B-hydroxylase, indicated that only Group I treated cats developed dense bundles of dopaminergic and noradrenergic fibers within the CM bridge and distal spinal cord tissue. These fibers were seen to extend 90 mm below the transection site. In addition, the synaptogenic marker synaptophysin (SYN) was observed in association with dopaminergic and noradrenergic fibers distal to the collagen matrix bridge, an indication that synaptic remodelling (regeneration) by previously denervated supraspinal axons may have occurred. Immunostaining for glial fibrillary acidic protein (GFAP) showed little to none reactive astrocytosis near the transection site of cats treated with the CM and omentum transposition (Group 1). No catecholaminergic fibers or SYN expression below the transection site were observed in Group 2 treated cats. Group 2 treated cats also showed dense immunostaining of GFAP near the transection site indicating significant astrocytic proliferation. These findings indicate that following complete spinal cord transection in cats and reconstruction with a treated collagen matrix and omental transposition, disconnected supraspinal fibers have the ability to regenerate for long anatomic distances and seemingly engage in synaptic remodelling with distal target tissue.

Animals↗
PubMed2006

Altered chloride homeostasis in neurological disorders: a new target.

Other than modifying either neurotransmitter release or receptor expression and/or properties, one way to modulate gamma-aminobutyric acid (GABA)A and glycine receptor-mediated signalling is to alter the transmembrane gradient for chloride ions. Because intracellular chloride concentration is low in neurons, and the reversal potential for chloride currents is close to the resting membrane potential, small changes in intracellular chloride concentration can dramatically affect the strength and even polarity of GABA/glycine-mediated transmission. It now appears that chloride homeostasis is actively regulated in the adult brain and affected by endogenous neuromodulators such as brain-derived neurotrophic factor. Modulating chloride gradients even emerges as a mechanism by which microglia can control neuronal excitability. These findings, together with the observation of altered chloride homeostasis in several neurological disorders, point to new targets for therapeutic agents.

Animals↗
PubMed1986

Maintenance of transient occipitospinal axons in the rat.

A developmentally transient occipitospinal projection arising from the visual association cortex persists if a fetal tectum is transplanted to the spinal cord at birth and at the same time, the host tectum is removed. The pathway is not sustained if the transplant is placed in the cord without a tectal lesion or if the tectum alone is damaged. Thus the tectal transplant promotes the survival of normally transient occipitospinal axons as long as another regular target of these axons is removed.

Animals↗
PubMed1995

Long-term regulation of short-term plasticity: a postsynaptic influence on presynaptic transmitter release.

The dynamics of presynaptic transmitter release are often matched to the physiological properties and function of the postsynaptic cell. Evidence in organisms as diverse as the cricket central nervous system and the cat spinal cord suggests that retrograde signaling is essential for matching presynaptic release properties to the postsynaptic cell. The cricket central nervous system is favorably organized for analysis of synaptic function in the central nervous system. Several lines of independent evidence suggest that it is possible to reliably estimate the size of single quantal release events at the sensory to interneuron synapses of the cricket. A quantal analysis suggests that a retrograde influence on the probability of presynaptic release is responsible for matching presynaptic dynamic properties to postsynaptic targets. This retrograde interaction is hypothesized to be a long-term modification on the basal probability of presynaptic release.

Animals↗
PubMed1998

Plasticity of Drosophila paired function.

The Drosophila Paired (Prd) transcription factor has homeodomain (HD) and paired domain (PD) DNA-binding activities required for in vivo function. Correspondingly, Prd activation of late even-skipped (eve) expression occurs through a conserved target sequence (PTE) with HD and PD half sites, both of which are required for activation. To investigate the relationship between the HD and PD, and their roles in conferring specificity to Prd function, we tested altered versions of the Prd protein and of the PTE target site using in vivo assays in embryos. We found that function through PTE was constrained by the targeting specifications of both the HD and PD as well as the spatial relationship between these two domains. PTE function was also constrained by the spacing between the target half sites for the PD and HD, although surprisingly, late eve activation was retained when PTE was replaced by in vitro optimized binding sites for either the PD alone or for an HD dimer. In contrast to late eve regulation, other Prd targets tolerated more changes in the Prd protein, suggesting that their target sequences may be qualitatively different from PTE.

Animals↗
PubMedDate not supplied

Physical characterization of neutron beams produced by protons and deuterons of various energies bombarding beryllium and lithium targets of several thicknesses.

Protons of 35 and 65 MeV and deuterons of 35 MeV were used to bombard beryllium and lithium targets of various thicknesses. Four types of experiments were conducted in order to characterize the neutron fields. They were (1) central axis depth-dose measurements in a water phantom, (2) dose buildup at small depths in tissue-equivalent plastic, (3) microdosimetric measurements and LET distributions, and (4) neutron yields and energy spectra at an angle of 0 deg. The results generally show that (a) the central axis depth doses for the 35 and 65 MeV particles roughly approximate those of 60Co and 4-MeV bremsstrahlung photons, respectively, (B) the neutron dose buildups are more rapid than those of the above-mentioned photon sources, (C) the microdosimetric spectra show differences which are consistent with the measured neutron energy spectra, and (D) P-Li compared to p-Be neutron spectra have larger high-energy particle flux for similar target and beam configurations.

Beryllium↗
PubMed1998

Competition for neurotrophic factors: mathematical analysis.

Neurotrophic factors, particularly the neurotrophin gene family of neurotrophic factors, are implicated in activity-dependent anatomical plasticity in the visual cortex and at the neuromuscular junction. Accumulating evidence implicates neurotrophic factors as possible mediators of activity-dependent competition between afferents, leading to the segregation of afferents' arbors on the target space. We present a biologically plausible mathematical model of competition for neurotrophic factors. We show that the model leads to anatomical segregation, provided that the levels of neurotrophic factors released in an activity-independent manner, or the levels available by exogenous infusion, are below a critical value, which we derive. Above this critical value, afferent segregation breaks down. We also show that the model segregates afferents even in the presence of very highly correlated patterns of afferent activity. The model is therefore ideally suited for application to the development of ocular dominance columns in the kitten visual cortex.

Afferent Pathways↗
PubMed1993

IL2-R alpha chain inhibitory factor (p29) produced by HIV-infected macrophages: cell target and mode of action.

We recently reported that HIV-infected adherent cells spontaneously produce a 29-kDa protein (p29), most probably of nonviral origin, which inhibits expression of the IL2R alpha chain on activated normal T cells. Studying the mode of action of this molecule, we observed that monocyte depletion of normal PBMC either by plastic adherence or by complement-mediated cytotoxicity using macrophage-specific monoclonal antibodies abrogated the inhibitory effect of p29. The biological activity of p29 in adherent cell-depleted PBMC could be restored either with rIL1 or with as little as 10(5) autologous adherent cells/ml. Moreover, p29 could not inhibit IL1 biologic activity, nor its binding to IL1 receptor. In addition, p29 could not inhibit the production of IL1 and TNF alpha by normal adherent cells. Positive and negative cell sorting of normal T cells as well as two-color immunofluorescence studies revealed that CD8+ subsets are the main cell targets of p29, which also mediated an impaired generation of alloantigen-specific CTL. Conversely, only a slight inhibitory activity could be detected in highly purified CD4+ cells. Our findings suggest that HIV-induced production of p29 inhibitory factor by adherent cells may be involved in mechanisms responsible for some of the impaired cytotoxic functions observed in AIDS patients.

CD8 Antigens↗
PubMed2024

Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.

Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.

Brain Neoplasms↗