Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death

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Prevalence of Clinical and Neuroimaging Markers in Cerebral Amyloid Angiopathy: A Systematic Review and Meta-Analysis

BACKGROUND: Limited data exist regarding the prevalence of clinical and neuroimaging manifestations among patients diagnosed with cerebral amyloid angiopathy (CAA). We sought to determine the prevalence of clinical phenotypes and radiological markers in patients with CAA. METHODS: Systematic review and meta-analysis of studies including patients with CAA was conducted to primarily assess the prevalence of clinical phenotypes and neuroimaging markers as available in the included studies. Sensitivity analyses were performed based on the (1) retrospective or prospective study design and (2) probable or unspecified CAA status. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using the Cochran Q and I2 statistics. RESULTS: We identified 12 prospective and 34 retrospective studies including 7159 patients with CAA. The pooled prevalence rates were cerebral microbleeds (52% [95% CI, 43%-60%]; I2=93%), cortical superficial siderosis (49% [95% CI, 38%-59%]; I2=95%), dementia or mild cognitive impairment (50% [95% CI, 35%-65%]; I2=97%), intracerebral hemorrhage (ICH; 44% [95% CI, 27%-61%]; I2=98%), transient focal neurological episodes (48%; 10 studies [95% CI, 29%-67%]; I2=97%), lacunar infarcts (30% [95% CI, 25%-36%]; I2=78%), high grades of perivascular spaces located in centrum semiovale (56% [95% CI, 44%-67%]; I2=88%) and basal ganglia (21% [95% CI, 2%-51%]; I2=98%), and white matter hyperintensities with moderate or severe Fazekas score (53% [95% CI, 40%-65%]; I2=91%). The only neuroimaging marker that was associated with higher odds of recurrent ICH was cortical superficial siderosis (odds ratio, 1.57 [95% CI, 1.01-2.46]; I2=47%). Sensitivity analyses demonstrated a higher prevalence of ICH (53% versus 16%; P=0.03) and transient focal neurological episodes (57% versus 17%; P=0.03) among retrospective studies compared with prospective studies. No difference was documented between the prevalence rates based on the CAA status. CONCLUSIONS: Approximately one-half of hospital-based cohort of CAA patients was observed to have cerebral microbleeds, cortical superficial siderosis, mild cognitive impairment, dementia, ICH, or transient focal neurological episodes. Cortical superficial siderosis was the only neuroimaging marker that was associated with higher odds of ICH recurrence. Future population-based studies among well-defined CAA cohorts are warranted to corroborate our findings

Re: "Comparison of antipseudomonal betalactams for febrile neutropenia empiric therapy: systematic review and network metaanalysis" by Horita et al

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The Unusual Monomer Recognition of Guanine-Containing Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine

DB1255 is a symmetrical diamidinophenyl-dithiophene that exhibits cellular activity by binding to DNA and inhibiting binding of ERG, an ETS family transcription factor that is commonly overexpressed or translocated in leukemia and prostate cancer [Nhili, R., Peixoto, P., Depauw, S., Flajollet, S., Dezitter, X., Munde, M. M., Ismail, M. A., Kumar, A., Farahat, A. A., Stephens, C. E., Duterque-Coquillaud, M., Wilson, W. D., Boykin, D. W., and David-Cordonnier, M. H. (2013) Nucleic Acids Res. 41, 125−138]. Because transcription factor inhibition is complex but is an attractive area for anticancer and antiparasitic drug development, we have evaluated the DNA interactions of additional derivatives of DB1255 to gain an improved understanding of the biophysical chemistry of complex function and inhibition. DNase I footprinting, biosensor surface plasmon resonance, and circular dichroism experiments show that DB1255 has an unusual and strong monomer binding mode in minor groove sites that contain a single GC base pair flanked by AT base pairs, for example, 5′-ATGAT-3′. Closely related derivatives, such as compounds with the thiophene replaced with furan or selenophane, bind very weakly to GC-containing sequences and do not have biological activity. DB1255 is selective for the ATGAT site; however, a similar sequence, 5′-ATGAC-3′, binds DB1255 more weakly and does not produce a footprint. Molecular docking studies show that the two thiophene sulfur atoms form strong, bifurcated hydrogen bond-type interactions with the G-N-H sequence that extends into the minor groove while the amidines form hydrogen bonds to the flanking AT base pairs. The central dithiophene unit of DB1255 thus forms an excellent, but unexpected, single-GC base pair recognition module in a monomer minor groove complex

Evidence for a Rad18-Independent Frameshift Mutagenesis Pathway in Human Cell-Free Extracts

Bypass of replication blocks by specialized DNA polymerases is crucial for cell survival but may promote mutagenesis and genome instability. To gain insight into mutagenic sub-pathways that coexist in mammalian cells, we examined N-2-acetylaminofluorene (AAF)-induced frameshift mutagenesis by means of SV40-based shuttle vectors containing a single adduct. We found that in mammalian cells, as previously observed in E. coli, modification of the third guanine of two target sequences, 5'-GGG-3' (3G) and 5'-GGCGCC-3' (NarI site), induces –1 and –2 frameshift mutations, respectively. Using an in vitro assay for translesion synthesis, we investigated the biochemical control of these events. We showed that Pol eta, but neither Pol iota nor Pol zeta, plays a major role in the frameshift bypass of the AAF adduct located in the 3G sequence. By complementing PCNA-depleted extracts with either a wild-type or a non-ubiquitinatable form of PCNA, we found that this Pol eta-mediated pathway requires Rad18 and ubiquitination of PCNA. In contrast, when the AAF adduct is located within the NarI site, TLS is only partially dependent upon Pol eta and Rad18, unravelling the existence of alternative pathways that concurrently bypass this lesion

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Malten, a new synthetic molecule showing in vitro antiproliferative activity against tumour cells and induction of complex DNA structural alterations

Background: Hydroxypyrones represent several classes of molecules known for their high synthetic versatility. This family of molecules shows several interesting pharmaceutical activities and is considered as a promising source of new anti neoplastic compounds. Methods: In the quest to identify new potential anti cancer agents, a new maltol (3-hydroxy-2-methyl-4-pyrone)-derived molecule, named malten (N,N′-bis((3-hydroxy-4-pyron-2-yl)methyl)-N,N′-dimethylethylendiamine), has been synthesised and analysed at both biological and molecular levels for its antiproliferative activity in eight tumour cell lines. Results: Malten exposure led to a dose-dependent reduction in cell survival in all the neoplastic models studied. Sublethal concentrations of malten induce profound cell cycle changes, particularly affecting the S and/or G2-M phases, whereas exposure to lethal doses causes the induction of programmed cell death (apopotosis). The molecular response to malten was also investigated in two biological models: JURKAT and U937 cells. It showed the modulation of genes having key roles in cell cycle progression and apoptosis. Finally, as part of the effort to clarify the action mechanism, we showed that malten is able to impair DNA electrophoretic mobility and drastically reduce both PCR amplificability and fragmentation susceptibility of DNA. Conclusion: Taken together, these results show that malten may exert its antiproliferative activity through the induction of complex DNA structural modifications. This evidence, together with the high synthetic versatility of maltol-derived compounds, makes malten an interesting molecular scaffold for the future design of new potential anticancer agents

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented