Cosmic ray diffusion near the Bohm limit in the Cassiopeia A supernova remnant

Supernova remnants (SNRs) are believed to be the primary location of the acceleration of Galactic cosmic rays, via diffusive shock (Fermi) acceleration. Despite considerable theoretical work the precise details are still unknown, in part because of the difficulty in directly observing nucleons that are accelerated to TeV energies in, and affect the structure of, the SNR shocks. However, for the last ten years, X-ray observatories ASCA, and more recently Chandra, XMM-Newton, and Suzaku have made it possible to image the synchrotron emission at keV energies produced by cosmic-ray electrons accelerated in the SNR shocks. In this article, we describe a spatially-resolved spectroscopic analysis of Chandra observations of the Galactic SNR Cassiopeia A to map the cutoff frequencies of electrons accelerated in the forward shock. We set upper limits on the electron diffusion coefficient and find locations where particles appear to be accelerated nearly as fast as theoretically possible (the Bohm limit).Comment: 18 pages, 5 figures. Accepted for publication in Nature Physics (DOI below), final version available week of August 28, 2006 at http://www.nature.com/nphy

High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer:the randomized phase III NeoTN trial

Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution (p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23–1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III (n = 35; HR 0.16; 95% CI 0.03–0.75), but not stage II (n = 86; HR 1.00; 95% CI 0.30–3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24–87%), 71% (95% CI 48–100%) and 88% (95% CI 74–100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069

PCB-containing wood floor finish is a likely source of elevated PCBs in residents' blood, household air and dust: a case study of exposure

© 2008 Rudel et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Coherence Potentials Encode Simple Human Sensorimotor Behavior

Recent work has shown that large amplitude negative periods in the local field potential (nLFPs) are able to spread in saltatory manner across large distances in the cortex without distortion in their temporal structure forming ‘coherence potentials’. Here we analysed subdural electrocorticographic (ECoG) signals recorded at 59 sites in the sensorimotor cortex in the left hemisphere of a human subject performing a simple visuomotor task (fist clenching and foot dorsiflexion) to understand how coherence potentials arising in the recordings relate to sensorimotor behavior. In all behaviors we found a particular coherence potential (i.e. a cascade of a particular nLFP wave pattern) arose consistently across all trials with temporal specificity. During contrateral fist clenching, but not the foot dorsiflexion or ipsilateral fist clenching, the coherence potential most frequently originated in the hand representation area in the somatosensory cortex during the anticipation and planning periods of the trial, moving to other regions during the actual motor behavior. While these ‘expert’ sites participated more consistently, other sites participated only a small fraction of the time. Furthermore, the timing of the coherence potential at the hand representation area after onset of the cue predicted the timing of motor behavior. We present the hypothesis that coherence potentials encode information relevant for behavior and are generated by the ‘expert’ sites that subsequently broadcast to other sites as a means of ‘sharing knowledge’

Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines

The field of tumor vaccination is currently undergoing a shift in focus, from individualized tailor-made vaccines to more generally applicable vaccine formulations. Although primarily predicated by financial and logistic considerations, stemming from a growing awareness that clinical development for wide-scale application can only be achieved through backing from major pharmaceutical companies, these new approaches are also supported by a growing knowledge of the intricacies and minutiae of antigen presentation and effector T-cell activation. Here, the development of whole-cell tumor and dendritic cell (DC)-based vaccines from an individualized autologous set-up to a more widely applicable allogeneic approach will be discussed as reflected by translational studies carried out over the past two decades at our laboratories and clinics in the vrije universiteit medical center (VUmc) in Amsterdam, The Netherlands

Expansion and Characterization of Human Melanoma Tumor-Infiltrating Lymphocytes (TILs)

Various immunotherapeutic strategies for cancer are aimed at augmenting the T cell response against tumor cells. Adoptive cell therapy (ACT), where T cells are manipulated ex vivo and subsequently re-infused in an autologous manner, has been performed using T cells from various sources. Some of the highest clinical response rates for metastatic melanoma have been reported in trials using tumor-infiltrating lymphocytes (TILs). These protocols still have room for improvement and furthermore are currently only performed at a limited number of institutions. The goal of this work was to develop TILs as a therapeutic product at our institution.TILs from 40 melanoma tissue specimens were expanded and characterized. Under optimized culture conditions, 72% of specimens yielded rapidly proliferating TILs as defined as at least one culture reaching ≥3×10(7) TILs within 4 weeks. Flow cytometric analyses showed that cultures were predominantly CD3+ T cells, with highly variable CD4+:CD8+ T cell ratios. In total, 148 independent bulk TIL cultures were assayed for tumor reactivity. Thirty-four percent (50/148) exhibited tumor reactivity based on IFN-γ production and/or cytotoxic activity. Thirteen percent (19/148) showed specific cytotoxic activity but not IFN-γ production and only 1% (2/148) showed specific IFN-γ production but not cytotoxic activity. Further expansion of TILs using a 14-day "rapid expansion protocol" (REP) is required to induce a 500- to 2000-fold expansion of TILs in order to generate sufficient numbers of cells for current ACT protocols. Thirty-eight consecutive test REPs were performed with an average 1865-fold expansion (+/- 1034-fold) after 14 days.TILs generally expanded efficiently and tumor reactivity could be detected in vitro. These preclinical data from melanoma TILs lay the groundwork for clinical trials of ACT

Motor skill learning in the middle-aged: limited development of motor chunks and explicit sequence knowledge

The present study examined whether middle-aged participants, like young adults, learn movement patterns by preparing and executing integrated sequence representations (i.e., motor chunks) that eliminate the need for external guidance of individual movements. Twenty-four middle-aged participants (aged 55–62) practiced two fixed key press sequences, one including three and one including six key presses in the discrete sequence production task. Their performance was compared with that of 24 young adults (aged 18–28). In the middle-aged participants motor chunks as well as explicit sequence knowledge appeared to be less developed than in the young adults. This held especially with respect to the unstructured 6-key sequences in which most middle-aged did not develop independence of the key-specific stimuli and learning seems to have been based on associative learning. These results are in line with the notion that sequence learning involves several mechanisms and that aging affects the relative contribution of these mechanisms

The “conscious pilot”—dendritic synchrony moves through the brain to mediate consciousness

Cognitive brain functions including sensory processing and control of behavior are understood as “neurocomputation” in axonal–dendritic synaptic networks of “integrate-and-fire” neurons. Cognitive neurocomputation with consciousness is accompanied by 30- to 90-Hz gamma synchrony electroencephalography (EEG), and non-conscious neurocomputation is not. Gamma synchrony EEG derives largely from neuronal groups linked by dendritic–dendritic gap junctions, forming transient syncytia (“dendritic webs”) in input/integration layers oriented sideways to axonal–dendritic neurocomputational flow. As gap junctions open and close, a gamma-synchronized dendritic web can rapidly change topology and move through the brain as a spatiotemporal envelope performing collective integration and volitional choices correlating with consciousness. The “conscious pilot” is a metaphorical description for a mobile gamma-synchronized dendritic web as vehicle for a conscious agent/pilot which experiences and assumes control of otherwise non-conscious auto-pilot neurocomputation

Strong Neurophilosophy and the Matter of Bat Consciousness: A case study

In “What is it like to be boring and myopic?” Kathleen Akins offers an interesting, empirically driven, argument for thinking that there is nothing that it is like to be a bat. She suggests that bats are “boring” in the sense that they are governed by behavioral scripts and simple, non-representational, control loops, and are best characterized as biological automatons. Her approach has been well received by philosophers sympathetic to empirically informed philosophy of mind. But, despite its influence, her work has not met with any critical appraisal. It is argued that a reconsideration of the empirical results shows that bats are not boring automatons, driven by short input-output loops, instincts, and reflexes. Grounds are provided for thinking that bats satisfy a range of philosophically and scientifically interesting elaborations of the general idea that consciousness is best understood in terms of representational functions. A more complete examination of bat sensory capabilities suggests there is something that it is like after all. The discussion of bats is also used to develop an objection to strongly neurophilosophical approaches to animal consciousness