Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth

The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multi- forme (GBM) cell lines and primary culture models are reported. Dose–response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repop- ulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR func- tions. DP68-induced interstrand DNA cross-links were dem- onstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell–cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced anti- glioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collec- tively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DN

The Thermal Properties of Solar Flares Over Three Solar Cycles Using GOES X-ray Observations

Solar flare X-ray emission results from rapidly increasing temperatures and emission measures in flaring active region loops. To date, observations from the X-Ray Sensor (XRS) onboard the Geostationary Operational Environmental Satellite (GOES) have been used to derive these properties, but have been limited by a number of factors, including the lack of a consistent background subtraction method capable of being automatically applied to large numbers of flares. In this paper, we describe an automated temperature and emission measure-based background subtraction method (TEBBS), which builds on the methods of Bornmann (1990). Our algorithm ensures that the derived temperature is always greater than the instrumental limit and the pre-flare background temperature, and that the temperature and emission measure are increasing during the flare rise phase. Additionally, TEBBS utilizes the improved estimates of GOES temperatures and emission measures from White et al. (2005). TEBBS was successfully applied to over 50,000 solar flares occurring over nearly three solar cycles (1980-2007), and used to create an extensive catalog of the solar flare thermal properties. We confirm that the peak emission measure and total radiative losses scale with background subtracted GOES X-ray flux as power-laws, while the peak temperature scales logarithmically. As expected, the peak emission measure shows an increasing trend with peak temperature, although the total radiative losses do not. While these results are comparable to previous studies, we find that flares of a given GOES class have lower peak temperatures and higher peak emission measures than previously reported. The resulting TEBBS database of thermal flare plasma properties is publicly available on Solar Monitor (www.solarmonitor.org/TEBBS/) and will be available on Heliophysics Integrated Observatory (www.helio-vo.eu)

Exciton Footprint of Self-assembled AlGaAs Quantum Dots in Core-Shell Nanowires

Quantum-dot-in-nanowire systems constitute building blocks for advanced photonics and sensing applications. The electronic symmetry of the emitters impacts their function capabilities. Here, we study the fine structure of gallium-rich quantum dots nested in the shell of GaAs-AlGaAs core-shell nanowires. We used optical spectroscopy to resolve the splitting resulting from the exchange terms and extract the main parameters of the emitters. Our results indicate that the quantum dots can host neutral as well as charges excitonic complexes and that the excitons exhibit a slightly elongated footprint, with the main axis tilted with respect to the growth axis. GaAs-AlGaAs emitters in a nanowire are particularly promising for overcoming the limitations set by strain in other systems, with the benefit of being integrated in a versatile photonic structure

Drug resistance outcomes of long-term ART with tenofovir disoproxil fumarate in the absence of virological monitoring

Objectives: The resistance profiles of patients receiving long-term ART in sub-Saharan Africa have been poorly described. This study obtained a sensitive assessment of the resistance patterns associated with long-term tenofovir-based ART in a programmatic setting where virological monitoring is yet to become part of routine care. Methods: We studied subjects who, after a median of 4.2 years of ART, replaced zidovudine or stavudine with tenofovir disoproxil fumarate while continuing lamivudine and an NNRTI. Using deep sequencing, resistance-associated mutations (RAMs) were detected in stored samples collected at tenofovir introduction (T0) and after a median of 4.0 years (T1). Results: At T0, 19/87 (21.8%) subjects showed a detectable viral load and 8/87 (9.2%) had one or more major NNRTI RAMs, whereas 82/87 (94.3%) retained full tenofovir susceptibility. At T1, 79/87 (90.8%) subjects remained on NNRTI-based ART, 5/87 (5.7%) had introduced lopinavir/ritonavir due to immunological failure, and 3/87 (3.4%) had interrupted ART. Whilst 68/87 (78.2%) subjects maintained or achieved virological suppression between T0 and T1, a detectable viral load with NNRTI RAMs at T0 predicted lack of virological suppression at T1. Each treatment interruption, usually reflecting unavailability of the dispensary, doubled the risk of T1 viraemia. Tenofovir, lamivudine and efavirenz selected for K65R, K70E/T, L74I/V and Y115F, alongside M184V and multiple NNRTI RAMs; this resistance profile was accompanied by high viral loads and low CD4 cell counts. Conclusions: Viraemia on tenofovir, lamivudine and efavirenz led to complex resistance patterns with implications for continued drug activity and risk of onward transmission

Analysis by x-ray microtomography of a granular packing undergoing compaction

Several acquisitions of X-ray microtomography have been performed on a beads packing while it compacts under vertical vibrations. An image analysis allows to study the evolution of the packing structure during its progressive densification. In particular, the volume distribution of the pores reveals a large tail, compatible to an exponential law, which slowly reduces as the system gets more compact. This is quite consistent, for large pores, with the free volume theory. These results are also in very good agreement with those obtained by a previous numerical model of granular compaction.Comment: 4 pages, 4 figures. Latex (revtex4). to be published in Phys. Rev.

Treatment of Buruli Ulcer

BU has long been treated by surgical resection. During the last two decades, it has become increasingly clear that antimicrobial treatment, first, using a combination of streptomycin 15 mg/kg i.m. and rifampin 10 mg/kg p.o. for 8 weeks, results in relapse-free cure in lesions &lt;10 cm cross-sectional diameter. Recently, a large clinical trial from Ghana and Benin showed that fully oral treatment—rifampin 10 mg/kg combined with clarithromycin—extended release, 15 mg/kg, also for 8 weeks, was equally effective but less toxic; none of the close to 300 study participants needed surgical resection, and only four had split skin grafts; sequelae were negligible. The use of other antimicrobials including fluoroquinolones has been shown to be effective in cohort studies from Australia. The role of resection surgery was studied in Benin in patients with larger lesions. Compared to patients that were operated on at week 8, a delayed decision on surgery at week 14 appeared beneficial; delay resulted in significantly less patients being operated, with reduced in-hospital treatment, and no difference in healing rate or sequelae. Sequelae such as contractures due to scar formation around joints may need specialized care in dedicated centers. General medical care with adequate nutrition and proper wound care are critical; wound saline rinsing and cleaning, dressings with non-adhesive cover, and absorptive material with short-stretch compression are all important for speedy healing. Other topical treatments (nitric oxide crème; traditional herbal remedies; clay; phenytoin) have been little studied; heat treatment might be an option for those that cannot tolerate antimicrobial treatment, such as during pregnancy. Active, early case finding has been shown to be highly efficacious.</p

Treatment of Buruli Ulcer

BU has long been treated by surgical resection. During the last two decades, it has become increasingly clear that antimicrobial treatment, first, using a combination of streptomycin 15 mg/kg i.m. and rifampin 10 mg/kg p.o. for 8 weeks, results in relapse-free cure in lesions &lt;10 cm cross-sectional diameter. Recently, a large clinical trial from Ghana and Benin showed that fully oral treatment—rifampin 10 mg/kg combined with clarithromycin—extended release, 15 mg/kg, also for 8 weeks, was equally effective but less toxic; none of the close to 300 study participants needed surgical resection, and only four had split skin grafts; sequelae were negligible. The use of other antimicrobials including fluoroquinolones has been shown to be effective in cohort studies from Australia. The role of resection surgery was studied in Benin in patients with larger lesions. Compared to patients that were operated on at week 8, a delayed decision on surgery at week 14 appeared beneficial; delay resulted in significantly less patients being operated, with reduced in-hospital treatment, and no difference in healing rate or sequelae. Sequelae such as contractures due to scar formation around joints may need specialized care in dedicated centers. General medical care with adequate nutrition and proper wound care are critical; wound saline rinsing and cleaning, dressings with non-adhesive cover, and absorptive material with short-stretch compression are all important for speedy healing. Other topical treatments (nitric oxide crème; traditional herbal remedies; clay; phenytoin) have been little studied; heat treatment might be an option for those that cannot tolerate antimicrobial treatment, such as during pregnancy. Active, early case finding has been shown to be highly efficacious.</p