Cytomegalovirus (CMV) infection is a serious complication that may occur in the weeks or months following bone marrow transplantation. However, both Ganciclovir and the CMV infection itself can cause ...marrow toxicity, notably neutropenia, that may consequently expose these immunosuppressed patients to life-threatening bacterial and/or fungal infections. The aim of this retrospective study was to identify factors associated with the occurrence of grade III–IV neutropenia among patients receiving pre-emptive Ganciclovir therapy after allogeneic stem cell transplantation at our Institution. We identified 547 consecutive patients transplanted from January 2005 to June 2011 at our Institution. In all, 190 patients (35%) presented with CMV reactivation of whom 30 patients (5%) were excluded from the analysis because they already had neutropenia at the time of reactivation. Finally, 160 (29%) patients were analysed. According to multivariate analysis, at the time of treatment initiation, the risk factors significantly associated with a grade III–IV Ganciclovir-related neutropenia included a high viral load (hazard ratio (HR) = 2.68, 95% CI 1.25–5.737, p 0.01); an absolute neutrophil count >3000 was a protective factor (HR = 0.26, 95% CI 0.125–0.545, p <0001) whereas serum creatinine >2 mg/dL was associated with higher Ganciclovir-related neutropenia (HR = 2.4, 95% CI 1.11–5.17, p 0.002). This large analysis revealed three risk factors for Ganciclovir-related neutropenia among patients with CMV reactivation after allogeneic stem cell transplantation; prompt identification of patients at risk when antiviral therapy is started may allow clinicians to adopt adequate preventive measures, so reducing the morbidity and mortality associated with CMV reactivation.
The usual configuration of uniaxial whispering gallery mode resonators is a disk shaped geometry where the optic axis points along the symmetry axis, a so called z-cut resonator. Recently x-cut ...resonators, where the optic axis lies in the equatorial plane, became of interest as they enable extremely broadband second harmonic generation. In this paper we report on the properties of a more generalized system, the so called angle-cut resonator, where the optic axis exhibits an arbitrary angle against the symmetry axis. We show experimentally that the modal structure and quality factors are similar to common resonators but that the polarization properties differ quite significantly: due to the asymmetry the polarization depends on the equatorial position and is, in general, elliptical.
ABSTRACT We present simultaneous XMM-Newton and Nuclear Spectroscopic Telescope Array (NuSTAR) observations spanning 3-78 keV of the nearest radio galaxy, Centaurus A (Cen A). The accretion geometry ...around the central engine in Cen A is still debated, and we investigate possible configurations using detailed X-ray spectral modeling. NuSTAR imaged the central region of Cen A with subarcminute resolution at X-ray energies above 10 keV for the first time, but found no evidence for an extended source or other off-nuclear point sources. The XMM-Newton and NuSTAR spectra agree well and can be described with an absorbed power law with a photon index Γ = 1.815 0.005 and a fluorescent line in good agreement with literature values. The spectrum does not require a high-energy exponential rollover, with a constraint of Efold > 1 MeV. A thermal Comptonization continuum describes the data well, with parameters that agree with values measured by INTEGRAL, in particular an electron temperature kTe between 100-300 keV and seed photon input temperatures between 5 and 50 eV. We do not find evidence for reflection or a broad iron line and put stringent upper limits of R < 0.01 on the reflection fraction and accretion disk illumination. We use archival Chandra data to estimate the contribution from diffuse emission, extra-nuclear point sources, and the outer X-ray jet to the observed NuSTAR and XMM-Newton X-ray spectra and find the contribution to be negligible. We discuss different scenarios for the physical origin of the observed hard X-ray spectrum and conclude that the inner disk is replaced by an advection-dominated accretion flow or that the X-rays are dominated by synchrotron self-Compton emission from the inner regions of the radio jet or a combination thereof.
Objective
To evaluate the long‐term safety of rituximab in an observational cohort of patients with rheumatoid arthritis (RA) who had an inadequate response to ≥1 anti–tumor necrosis factor therapy ...in the US (SUNSTONE Study of the Safety of Rituxan in Patients With Rheumatoid Arthritis After an Inadequate Response to Previous Anti‐TNF Therapy registry).
Methods
In this prospective, observational cohort study, patients received rituximab according to their physician's standard practice and were evaluated at standard‐of‐care follow‐up visits at least every 6 months. The primary outcome was the incidence of protocol‐defined significant infections. Secondary outcomes included serious adverse events potentially associated with rituximab, cardiovascular or thrombotic events, seizures, deaths, and pregnancies. Post hoc analyses assessed outcomes by concomitant medication use.
Results
Overall, 989 patients (safety‐evaluable population) received ≥1 dose of rituximab, with a total follow‐up of 3,844 patient‐years (mean duration 3.9 years). In total, 341 significant infections occurred in 197 patients (19.9%). The incidence rates (95% confidence intervals 95% CIs) for significant infections, cardiovascular or thrombotic events, and seizures were 8.87 (95% CI 7.98–9.86), 1.95 (95% CI 1.56–2.45), and 0.18 (95% CI 0.09–0.38) per 100 patient‐years, respectively. The incidence of significant infections did not increase with time or with cumulative rituximab exposure. During the study, 64 patients died (crude mortality rate 1.66 per 100 patient‐years 95% CI 1.30–2.13). The most common causes of death were infections (n = 19), malignancy (n = 14), and cardiovascular events (n = 13). Eight pregnancies were reported in 7 patients.
Conclusion
In patients with RA treated with rituximab for up to 5 years, the rates of significant infections were stable over time and higher in patients who received long‐term systemic steroid treatment.
Purpose
Tumor cells thrive by adapting to the signals in their microenvironment. To adapt, cancer cells activate signaling and transcriptional programs and migrate to establish micro-niches, in ...response to signals from neighboring cells and non-cellular stromal factors. Understanding how the tumor microenvironment evolves during disease progression is crucial to deciphering the mechanisms underlying the functional behavior of cancer cells.
Methods
Multiplex immunohistochemistry, spatial analysis and histological dyes were used to identify and measure immune cell infiltration, cell signal activation and extracellular matrix deposition in low-grade, high-grade astrocytoma and glioblastoma.
Results
We show that lower grade astrocytoma tissue is largely devoid of infiltrating immune cells and extracellular matrix proteins, while high-grade astrocytoma exhibits abundant immune cell infiltration, activation, and extensive tissue remodeling. Spatial analysis shows that most T-cells are restricted to perivascular regions, but bone marrow-derived macrophages penetrate deep into neoplastic cell-rich regions. The tumor microenvironment is characterized by heterogeneous PI3K, MAPK and CREB signaling, with specific signaling profiles correlating with distinct pathological hallmarks, including angiogenesis, tumor cell density and regions where neoplastic cells border the extracellular matrix. Our results also show that tissue remodeling is important in regulating the architecture of the tumor microenvironment during tumor progression.
Conclusion
The tumor microenvironment in malignant astrocytoma, exhibits changes in cell composition, cell signaling activation and extracellular matrix deposition during disease development and that targeting the extracellular matrix, as well as cell signaling activation will be critical to designing personalized therapy.
Chronic inflammation‐related diseases are characterized by persistent leukocyte infiltration into the underlying tissue. The vascular endothelium plays a major role in this pathophysiological ...condition. Only few therapeutic strategies focus on the vascular endothelium as a major target for an anti‐inflammatory approach. In this study, we present the natural compound‐derived carbazole derivative C81 as chemical modulator interfering with leukocyte‐endothelial cell interactions. An in vivo assay employing intravital microscopy to monitor leukocyte trafficking after C81 treatment in postcapillary venules of a murine cremaster muscle was performed. Moreover, in vitro assays using HUVECs and monocytes were implemented. The impact of C81 on cell adhesion molecules and the NFκB signaling cascade was analyzed in vitro in endothelial cells. Effects of C81 on protein translation were determined by incorporation of a puromycin analog‐based approach and polysome profiling. We found that C81 significantly reduced TNF‐activated leukocyte trafficking in postcapillary venules. Similar results were obtained in vitro when C81 reduced leukocyte‐endothelial cell interactions by down‐regulating cell adhesion molecules. Focusing on the NFκB signaling cascade, we found that C81 reduced the activation on multiple levels of the cascade through promoted IκBα recovery by attenuation of IκBα ubiquitination and through reduced protein levels of TNFR1 caused by protein translation inhibition. We suggest that C81 might represent a promising lead compound for interfering with inflammation‐related processes in endothelial cells by down‐regulation of IκBα ubiquitination on the one hand and inhibition of translation on the other hand without exerting cytotoxic effects.
This study presents an educational performance assessment of Brazilian state‐level units using the technique for order preference by similarity to the ideal solution (TOPSIS). Although this technique ...is a well‐established multi‐criteria decision making (MCDM) model that can be applied across diverse areas, it has yet to be applied to an analysis of primary and secondary education. We assess how state‐level units in Brazil perform in terms of primary and secondary educational inputs and outputs during the period from 2013 to 2017. We handle epistemic uncertainty with regard to weight definition using maximal information entropy. Additionally, a Tobit regression approach on performance scores is developed. Results show that region of the country plays an important role in determining educational performance. Moreover, results indicate that gross domestic product (GDP) is positively related to education scores while infant mortality is negatively associated with educational performance.
The preparation of different uridine and uracil dimers Fahr, E; Fürst, G; Pastille, R
Zeitschrift für Naturforschung. Teil B, Chemie, Biochemie, Biophysik, Biologie und verwandte Gebiete
23, Številka:
10
Journal Article
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