Changes in the secretory profile of NSCLC-associated fibroblasts after ablative radiotherapy: potential impact on angiogenesis and tumor growth

In the context of radiotherapy, collateral effects of ablative ionizing radiation (AIR) on stromal components of tumors remains understudied. In this work, cancer-associated fibroblasts (CAFs) isolated from freshly resected human lung tumors were exposed to AIR (1x18Gy) and analyzed for their release of paracrine factors. Inflammatory mediators and regulators of angiogenesis and tumor growth were analyzed by multiplex protein assays in conditioned medium (CM) from irradiated and non-irradiated CAFs. Additionally, the profile of secreted proteins was examined by proteomics. In functional assays, effects of CAF-CM on proliferative and migratory capacity of lung tumor cells (H-520/H-522) and endothelial cells (HUVECs), and on the tube-forming capacity of endothelial cells was assessed. Our data show that exposure of CAFs to ablative doses of ionizing radiation results in a) down-regulated release of angiogenic factors SDF-1, angiopoietin and thrombospondin-2; b) up-regulated release of growth factor bFGF from most donors, and c) unaffected expression-levels of HGF and inflammatory mediators IL-6, IL-8, IL-1ƒÒ and TNF-£. Conditioned medium from irradiated and control CAFs did not affect differently the proliferative or migratory capacity of tumor cells (H-520/H-522), whereas migratory capacity of endothelial HUVEC cells was partially reduced in the presence of irradiated CAF conditioned medium. Overall we conclude that AIR mediates a transformation on the secretory profile of CAFs that could influence the behavior of other cells in the tumor tissue and hence guide to some extent therapeutic outcomes. The downstream consequences of the changes observed in this study merits further investigations

Proton tracking in a high-granularity Digital Tracking Calorimeter for proton CT purposes

Radiation therapy with protons as of today utilizes information from x-ray CT in order to estimate the proton stopping power of the traversed tissue in a patient. The conversion from x-ray attenuation to proton stopping power in tissue introduces range uncertainties of the order of 2-3% of the range, uncertainties that are contributing to an increase of the necessary planning margins added to the target volume in a patient. Imaging methods and modalities, such as Dual Energy CT and proton CT, have come into consideration in the pursuit of obtaining an as good as possible estimate of the proton stopping power. In this study, a Digital Tracking Calorimeter is benchmarked for proof-of-concept for proton CT purposes. The Digital Tracking Calorimeteris applied for reconstruction of the tracks and energies of individual high energy protons. The presented prototype forms the basis for a proton CT system using a single technology for tracking and calorimetry. This advantage simplifies the setup and reduces the cost of a proton CT system assembly, and it is a unique feature of the Digital Tracking Calorimeter. Data from the AGORFIRM beamline at KVI-CART in Groningen in the Netherlands and Monte Carlo simulation results are used to in order to develop a tracking algorithm for the estimation of the residual ranges of a high number of concurrent proton tracks. The range of the individual protons can at present be estimated with a resolution of 4%. The readout system for this prototype is able to handle an effective proton frequency of 1 MHz by using 500 concurrent proton tracks in each readout frame, which is at the high end range of present similar prototypes. A future further optimized prototype will enable a high-speed and more accurate determination of the ranges of individual protons in a therapeutic beam.Comment: 21 pages, 8 figure

Dielectronic Recombination of Argon-Like Ions

We present a theoretical investigation of dielectronic recombination (DR) of Ar-like ions that sheds new light on the behavior of the rate coefficient at low-temperatures where these ions form in photoionized plasmas. We provide results for the total and partial Maxwellian-averaged DR rate coefficients from the initial ground level of K II -- Zn XIII ions. It is expected that these new results will advance the accuracy of the ionization balance for Ar-like M-shell ions and pave the way towards a detailed modeling of astrophysically relevant X-ray absorption features. We utilize the AUTOSTRUCTURE computer code to obtain the accurate core-excitation thresholds in target ions and carry out multiconfiguration Breit-Pauli (MCBP) calculations of the DR cross section in the independent-processes, isolated-resonance, distorted-wave (IPIRDW) approximation. Our results mediate the complete absence of direct DR calculations for certain Ar-like ions and question the reliability of the existing empirical rate formulas, often inferred from renormalized data within this isoelectronic sequence

The Density of Coronal Plasma in Active Stellar Coronae

We have analyzed high-resolution X-ray spectra of a sample of 22 active stars observed with the High Energy Transmission Grating Spectrometer on {\em Chandra} in order to investigate their coronal plasma density. Densities where investigated using the lines of the He-like ions O VII, Mg XI, and Si XIII. While Si XIII lines in all stars of the sample are compatible with the low-density limit, Mg XI lines betray the presence of high plasma densities ($> 10^{12}$ cm$^{-3}$) for most of the sources with higher X-ray luminosity ($> 10^{30}$ erg/s); stars with higher $L_X$ and $L_X/L_{bol}$ tend to have higher densities at high temperatures. Ratios of O VII lines yield much lower densities of a few $10^{10}$ cm$^{-3}$, indicating that the ``hot'' and ``cool'' plasma resides in physically different structures. Our findings imply remarkably compact coronal structures, especially for the hotter plasma emitting the Mg XI lines characterized by coronal surface filling factor, $f_{MgXI}$, ranging from $10^{-4}$ to $10^{-1}$, while we find $f_{OVII}$ values from a few $10^{-3}$ up to $\sim 1$ for the cooler plasma emitting the O VII lines. We find that $f_{OVII}$ approaches unity at the same stellar surface X-ray flux level as solar active regions, suggesting that these stars become completely covered by active regions. At the same surface flux level, $f_{MgXI}$ is seen to increase more sharply with increasing surface flux. These results appear to support earlier suggestions that hot $10^7$ K plasma in active coronae arises from flaring activity, and that this flaring activity increases markedly once the stellar surface becomes covered with active regions.Comment: 53 pages, 19 figures, accepted for publication in Astrophysical Journal. A version of the paper with higher quality figures is available from http://www.astropa.unipa.it/Library/preprint.htm

Microtubules in Bacteria: Ancient Tubulins Build a Five-Protofilament Homolog of the Eukaryotic Cytoskeleton

Microtubules play crucial roles in cytokinesis, transport, and motility, and are therefore superb targets for anti-cancer drugs. All tubulins evolved from a common ancestor they share with the distantly related bacterial cell division protein FtsZ, but while eukaryotic tubulins evolved into highly conserved microtubule-forming heterodimers, bacterial FtsZ presumably continued to function as single homopolymeric protofilaments as it does today. Microtubules have not previously been found in bacteria, and we lack insight into their evolution from the tubulin/FtsZ ancestor. Using electron cryomicroscopy, here we show that the tubulin homologs BtubA and BtubB form microtubules in bacteria and suggest these be referred to as “bacterial microtubules” (bMTs). bMTs share important features with their eukaryotic counterparts, such as straight protofilaments and similar protofilament interactions. bMTs are composed of only five protofilaments, however, instead of the 13 typical in eukaryotes. These and other results suggest that rather than being derived from modern eukaryotic tubulin, BtubA and BtubB arose from early tubulin intermediates that formed small microtubules. Since we show that bacterial microtubules can be produced in abundance in vitro without chaperones, they should be useful tools for tubulin research and drug screening

One-pot Selective Formylation and Claisen Rearrangement on Calix[4]arenes

A versatile synthon with formyl and allyl groups at the upper rim of calix[4]arene has been synthesized in two steps. Selective formylation of 25,27-diallyloxy-26,28-dihydroxycalix[4]arene, along with the Claisen rearrangement of the allyl groups, was achieved by reaction with hexamethylenetetraamine (hexamine) in glacial acetic acid. A control reaction of the dipropyl analogue shows that the selective formylation takes place independently of the Claisen rearrangement. The crystal structure of the dimethylacetal derivative of 5,17-diformyl-11,23-diallylcalix[4]arene is reported

The IceCube Neutrino Observatory: Instrumentation and Online Systems

The IceCube Neutrino Observatory is a cubic-kilometer-scale high-energy neutrino detector built into the ice at the South Pole. Construction of IceCube, the largest neutrino detector built to date, was completed in 2011 and enabled the discovery of high-energy astrophysical neutrinos. We describe here the design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and our methodology for drilling and deployment. We also describe the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis. Due to a rigorous pre-deployment protocol, 98.4% of the DOMs in the deep ice are operating and collecting data. IceCube routinely achieves a detector uptime of 99% by emphasizing software stability and monitoring. Detector operations have been stable since construction was completed, and the detector is expected to operate at least until the end of the next decade.Comment: 83 pages, 50 figures; updated with minor changes from journal review and proofin