Deep Chandra observations of Pictor A Hardcastle, M. J; Lenc, E; Birkinshaw, M ...
Monthly notices of the Royal Astronomical Society,
02/2016, Letnik:
455, Številka:
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We report on deep Chandra observations of the nearby broad-line radio galaxy Pictor A, which we combine with new Australia Telescope Compact Array (ATCA) observations. The new X-ray data have a ...factor of 4 more exposure than observations previously presented and span a 15 yr time baseline, allowing a detailed study of the spatial, temporal and spectral properties of the AGN, jet, hotspot and lobes. We present evidence for further time variation of the jet, though the flare that we reported in previous work remains the most significantly detected time-varying feature. We also confirm previous tentative evidence for a faint counterjet. Based on the radio through X-ray spectrum of the jet and its detailed spatial structure, and on the properties of the counterjet, we argue that inverse-Compton models can be conclusively rejected, and propose that the X-ray emission from the jet is synchrotron emission from particles accelerated in the boundary layer of a relativistic jet. For the first time, we find evidence that the bright western hotspot is also time-varying in X-rays, and we connect this to the small-scale structure in the hotspot seen in high-resolution radio observations. The new data allow us to confirm that the spectrum of the lobes is in good agreement with the predictions of an inverse-Compton model and we show that the data favour models in which the filaments seen in the radio images are predominantly the result of spatial variation of magnetic fields in the presence of a relatively uniform electron distribution.
Ewing's sarcoma, a highly malignant tumor of children, adolescents, and young adults, often responds to local excision plus a now-standard four-drug regimen of chemotherapy. This study shows that ...standard chemotherapy alternating with courses of ifosfamide plus etoposide significantly improves survival in patients with nonmetastatic disease at the time of diagnosis, but not in those with metastatic disease.
Ewing's sarcoma is a highly malignant tumor of bone that occurs in children, adolescents, and young adults. When treated with local control measures only (surgery or radiation therapy), the disease has an extremely high fatality rate.
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The use of adjuvant chemotherapy, which began in the early 1970s, resulted in a marked improvement in the outcome. Since the first Intergroup Ewing's Sarcoma Study demonstrated improved outcomes with the inclusion of doxorubicin, nearly every chemotherapy protocol for Ewing's sarcoma has been based on four drugs: doxorubicin, cyclophosphamide, vincristine, and dactinomycin.
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In the early 1980s, treatment with ifosfamide, with or without etoposide, . . .
Characterization of the properties of complex biomaterials using microrheological techniques has the promise of providing fundamental insights into their biomechanical functions; however, precise ...interpretations of such measurements are hindered by inadequate characterization of the interactions between tracers and the networks they probe. We here show that colloid surface chemistry can profoundly affect multiple particle tracking measurements of networks of fibrin, entangled F-actin solutions, and networks of cross-linked F-actin. We present a simple protocol to render the surface of colloidal probe particles protein-resistant by grafting short amine-terminated methoxy-poly(ethylene glycol) to the surface of carboxylated microspheres. We demonstrate that these poly(ethylene glycol)-coated tracers adsorb significantly less protein than particles coated with bovine serum albumin or unmodified probe particles. We establish that varying particle surface chemistry selectively tunes the sensitivity of the particles to different physical properties of their microenvironments. Specifically, particles that are weakly bound to a heterogeneous network are sensitive to changes in network stiffness, whereas protein-resistant tracers measure changes in the viscosity of the fluid and in the network microstructure. We demonstrate experimentally that two-particle microrheology analysis significantly reduces differences arising from tracer surface chemistry, indicating that modifications of network properties near the particle do not introduce large-scale heterogeneities. Our results establish that controlling colloid-protein interactions is crucial to the successful application of multiple particle tracking techniques to reconstituted protein networks, cytoplasm, and cells.
Human germ cell tumors (GCTs) may have variable histology and clinical behavior, depending on factors such as sex of the patient, age at clinical diagnosis, and anatomical site of the tumor. Some ...types of GCT, i.e., the seminomas/germinomas/dysgerminomas and embryonal carcinomas (the stem cell component of nonseminomas), have pluripotent potential, which is demonstrated by their capacity to differentiate into somatic and/or extraembryonic elements. Although embryonal carcinoma cells are intrinsically pluripotent, seminoma/germinoma/dysgerminoma cells, as well as their precursor carcinoma in situ/gonadoblastoma cells, have the phenotype of early germ cells that can be activated to pluripotency. The other types of GCT (teratomas and yolk sac tumors of infants and newborn, dermoid cyst of the ovary, and spermatocytic seminoma of elderly) are composed of (fully) differentiated tissues and lack the appearance of undifferentiated and pluripotent stem cells. OCT3/4, a transcription factor also known as OTF3 and POU5F1, is involved in regulation of pluripotency during normal development and is detectable in embryonic stem and germ cells. We analyzed the presence of POU5F1 in GCT and other tumor types using immunohistochemistry. The protein was consistently detected in carcinoma in situ/gonadoblastoma, seminomas/germinoma/dysgerminoma, and embryonal carcinoma but not in the various types of differentiated nonseminomas. Multitumor tissue microarray analysis covering >100 different tumor categories and 3600 individual cancers verified that POU5F1 expression is specific for particular subtypes of GCT of adults. No protein was observed in GCT of newborn and infants, spermatocytic seminomas, and the various tumors of nongerm cell origin. In addition, no difference in staining pattern was found in chemosensitive and chemoresistant GCT of adults. These results indicate preservation of the link between POU5F1 and pluripotency, as reported during normal development, after malignant transformation. Therefore, POU5F1 immunohistochemistry is an informative diagnostic tool for pluripotent GCT and offers new insights into the histological heterogeneity of this cancer.
Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ...ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids. Subsequent administration of the LC-LBFs to beagle dogs resulted in reasonable correlation between concentrations of CP-532,623 measured in the aqueous phase of the in vitro digest after 30 min digestion and in vivo exposure (AUC); however, the LC-LBFs required greater in vitro drug solubilization to elicit similar in vivo exposure when compared to previous studies with MC-LBF. Although post digestion solubilization was enhanced in LC-LBF compared to MC-LBF, equilibrium solubility studies of CP-532,623 in the aqueous phase isolated from blank lipid digestion experiments revealed that equilibrium solubility was also higher, and therefore supersaturation lower. A revised correlation based on supersaturation in the digest aqueous phase and drug absorption was therefore generated. A single, linear correlation was evident for both LC- and MC-LBF containing Kolliphor RH 40, but this did not extend to formulations based on other surfactants. The data suggest that solubilization and supersaturation are significant drivers of drug absorption in vivo, and that across formulations with similar formulation composition good correlation is evident between in vitro and in vivo measures. However, across dissimilar formulations, solubilization and supersaturation alone are not sufficient to explain drug exposure and other factors also likely play a role.
One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and ...etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes.
Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days.
Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms.
Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.
We report results from XMM-Newton observations of 13 X-ray bright BL Lacertae objects, selected from the Einstein Slew Survey sample (SSS). The survey was designed to look for evidence of departures ...of the X-ray spectra from a simple power-law shape (i.e., curvature and/or line features) and to find objects worthy of deeper study. Our data are generally well fit by power-law models, with three cases having hard ( < 2; dN/dE 8 E super(-)) spectra that indicate synchrotron peaks at E 5 keV. Previous data had suggested a presence of absorption features in the X-ray spectra of some BL Lac objects. In contrast, none of these spectra show convincing examples of line features in either absorption or emission, suggesting that such features are rare among BL Lac objects, or, more likely, are artifacts caused by instrumental effects. We find significant evidence for intrinsic curvature steepening by d/d(log E) = 0.4 c 0.15 in 14 of the 17 X-ray spectra. This cannot be explained satisfactorily via excess absorption, since the curvature is essentially constant from 0.5-6 keV, an observation that is inconsistent with the modest amounts of absorption that would be required. We use the XMM-Newton Optical Monitor data with concurrent radio monitoring to derive broadband spectral energy distributions and peak frequency estimates. From these, we examine models of synchrotron emission and model the spectral curvature we see as the result of episodic particle acceleration.
Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 ...on chromosome 19p13, which encodes the α1 subunit of a P/Q‐type voltage‐gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo‐ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.
We present a comprehensive multi-band spectral and polarimetric study of the jet of 3C 264 (NGC 3862). Included in this study are three Hubble Space Telescope (HST) optical and ultraviolet ...polarimetry data sets, along with new and archival Very Large Array radio imaging and polarimetry, a re-analysis of numerous HST broadband data sets from the near infrared to the far ultraviolet, and a Chandra ACIS-S observation. We investigate similarities and differences between optical and radio polarimetry, in both degree of polarization and projected magnetic field direction. We also examine the broadband spectral energy distribution of both the nucleus and jet of 3C 264, from the radio through the X-rays. From this, we place constraints on the physics of the 3C 264 system, the jet and its dynamics. We find significant curvature of the spectrum from the near-IR to ultraviolet, and synchrotron breaks steeper than 0.5, a situation also encountered in the jet of M87. This likely indicates velocity and/or magnetic field gradients and more efficient particle acceleration localized in the faster/higher magnetic field parts of the flow. The magnetic field structure of the 3C 264 jet is remarkably smooth; however, we do find complex magnetic field structure that is correlated with changes in the optical spectrum. We find that the X-ray emission is due to the synchrotron process; we model the jet spectrum and discuss mechanisms for accelerating particles to the needed energies, together with implications for the orientation of the jet under a possible spine-sheath model.
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