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BACKGROUND AND PURPOSE: Recent reports suggest an association between dural AVFs and cerebral venous thrombosis. We aimed to investigate the specific temporal and anatomic association between the 2 conditions. MATERIALS AND METHODS: A consecutive cohort of adult patients with dural AVFs was seen at Amsterdam University Medical Centers (2007-2020). An experienced neuroradiologist re-evaluated the presence and imaging characteristics of dural AVFs and cerebral venous thrombosis on all available imaging. The temporal (previous/concurrent/subsequent) and anatomic (same/adjacent/unrelated venous sinus or vein) association between dural AVFs and cerebral venous thrombosis was determined. RESULTS: Among 178 patients with dural AVFs, the mean age was 58.3 (SD, 13.2) years and 85 (48%) were women. Of 55 patients (31%) with cerebral venous thrombosis, 34 (62%) were women. Four patients (7%) had cerebral venous thrombosis before the development of a dural AVF, 33 (60%) had cerebral venous thrombosis at the time of dural AVF diagnosis (concurrent), and 18 (33%) developed cerebral venous thrombosis during follow-up after conservative treatment. The incidence rate of cerebral venous thrombosis after a dural AVF was 79 per 1000 person-years (95% CI, 50-124). In 45 (82%) patients with dural AVFs and cerebral venous thrombosis, the thrombosis was located in the same venous sinus as the dural AVF, whereas in 8 (15%) patients, thrombosis occurred in a venous sinus adjacent to the dural AVF. CONCLUSIONS: One-third of patients with a dural AVF in this study were diagnosed with cerebral venous thrombosis. In almost two-thirds of patients, cerebral venous thrombosis was diagnosed prior to or concurrent with the dural AVF. In 97% of patients, there was an anatomic association between the dural AVF and cerebral venous thrombosis. These data support the hypothesis of a bidirectional association between the 2 diseases.

Since the beginning of the COVID-19 pandemic, research has explored various aspects of face mask use. While most of the research explores their effectiveness to prevent the spread of the virus, a growing body of literature has found that using face masks also has social meaning. But what social meaning does it have, and how does this meaning express itself in people's practice? Based on 413 qualitative interviews with residents in five European countries (Austria, Belgium, Germany, Ireland, and Switzerland), we found that the meanings of face masks have changed drastically during the first months of the pandemic. While in spring 2020 people wearing them had to fear stigmatization, in autumn of 2020 not wearing masks was more likely to be stigmatized. Throughout the first year of the pandemic, we found that mask wearing had multiple and partly seemingly contradictory meanings for people. They were perceived as obstacles for non-verbal communication, but also a way to affirm friendships and maintain social contacts. They also signaled specific moral or political stances on the side of face mask wearers and non-wearers alike, expressed their belonging to certain communities, or articulated concern. In sum, our findings show how face masks serve as scripts for people to navigate their lives during the COVID-19 pandemic. We conclude that public and political discussions concerning face masks should include not only evidence on the epidemiological and infectiological effects of face masks, but also on their social meanings and their social effects. ispartof: FRONTIERS IN PUBLIC HEALTH vol:10 ispartof: location:Switzerland status: published

This study explores the different manifestations and navigations of uncertainty in the practice of diagnostic next-generation sequencing (NGS) testing. Drawing upon multi-sited fieldwork conducted at a large Centre for Human Genetics in Belgium, we analyse how uncertainty takes shape and is managed in the different steps of the diagnostic process: starting from the testing offer, to the analysis in the lab, the multidisciplinary team meetings (MDTs) and ending with the consultation with the patient. Building on interviews with genetic healthcare professionals and their patients and observations in consultations and MDTs, our empirical work underlines the duality of uncertainty as both burdensome and productive. Building on the existing literature on uncertainty in medicine and NGS, our analysis shows the ontological politics at play in the everyday uncertainty work in this CHG. We show how the, at times, contrasting ways of dealing with uncertainty lead to friction but also result in constructive negotiation and collaboration between actors, making use of multiple types of evidence and expertise. By not only minimising but also sustaining or inviting uncertainty, genetic healthcare professionals are able to advance the practices around NGS in a way that matches their multidisciplinary understandings, considerations and more normative stances.

ATP-citrate lyase (Acly) is the target of the new class low-density lipoprotein-cholesterol (LDL-C)-lowering drug bempedoic acid (BA). Acly is a key metabolic enzyme synthesizing acetyl-CoA as the building block of cholesterol and fatty acids. Treatment with BA lowers circulating lipid levels and reduces systemic inflammation, suggesting a dual benefit of this drug for atherosclerosis therapy. Recent studies have shown that targeting Acly in macrophages can attenuate inflammatory responses and decrease atherosclerotic plaque vulnerability. Therefore, it could be beneficial to extend the application of Acly inhibition from solely lipid-lowering by liver-specific inhibition to also targeting macrophages in atherosclerosis. Here, we outline the possibilities of targeting Acly and describe the future needs to translate these findings to the clinic.

Objective In native articular cartilage, chondrocytes are surrounded by a thin pericellular matrix (PCM) forming chondrons. The PCM is exclusively rich in type VI collagen. The retention of the PCM has a significant influence on the metabolic activity of the chondrocytes. Design This study investigated the influence of 2 hydrogels (hyaluronic acid [HA] and agarose) and 2 media compositions (basal and chondrogenic) on the preservation/maintenance and acceleration of PCM formation over a 21-day time course. Different combinations of chondrocytes, chondrons, and mesenchymal stem cells (MSCs) were studied. Results Both hydrogels preserved chondrons PCM from day 1 up to 21-day culture regardless of media composition. Type VI collagen immunostaining of the cultured chondrons appeared both dense and homogenous. The presence of MSCs did not influence this outcome. At day 1, type VI collagen was not present around chondrocytes alone or their co-culture with MSCs. In the HA hydrogel, type VI collagen was located within the PCM after 7 days in both mono- and co-cultures. In the agarose hydrogel, collagen VI was located within the PCM at 7 days (co-cultures) and 14 days (monocultures). In both hydrogel systems, chondrogenic media enhanced the production of key extracellular matrix components in both mono- and co-cultures in comparison to basal media (11.5% and 14% more in glycosaminoglycans and type II collagen for chondrocytes samples at day 21 culture samples, respectively). However, the media types did not enhance type VI collagen synthesis. Conclusion Altogether, a 3D chondrogenic hydrogel environment is the primary condition for maintenance and acceleration of PCM formation.

The accreting millisecond X-ray pulsar Swift J1756.9$-$2508 went into outburst in April 2018 and June 2019, 8.7 yr after the previous activity period. We investigated the temporal, timing and spectral properties of these two outbursts using data from NICER, XMM-Newton, NuSTAR, INTEGRAL, Swift and Insight-HXMT. The two outbursts exhibited similar broad-band spectra and X-ray pulse profiles. For the first time, we report the detection of the pulsed emission up to $\sim100$ keV observed by Insight-HXMT during the 2018 outburst. We also found the pulsation up to $\sim60$ keV observed by NICER and NuSTAR during the 2019 outburst. We performed a coherent timing analysis combining the data from two outbursts. The binary system is well described by a constant orbital period over a time span of $\sim12$ years. The time-averaged broad-band spectra are well fitted by an absorbed thermal Comptonization model in a slab geometry with the electron temperature $kT_{\rm e}=40$-50 keV, Thomson optical depth $\tau\sim 1.3$, blackbody seed photon temperature $kT_{\rm bb,seed}\sim $0.7-0.8 keV and hydrogen column density of $N_{\rm H}\sim 4.2\times10^{22}$ cm$^{-2}$. We searched the available data for type-I (thermonuclear) X-ray bursts, but found none, which is unsurprising given the estimated low peak accretion rate ($\approx0.05$ of the Eddington rate) and generally low expected burst rates for hydrogen-poor fuel. Based on the history of four outbursts to date, we estimate the long-term average accretion rate at roughly $5\times10^{-12}\ M_\odot\,{\rm yr}^{-1}$ for an assumed distance of 8 kpc. The expected mass transfer rate driven by gravitational radiation in the binary implies the source can be no closer than 4 kpc., Comment: Accepted for publication in A&A

BACKGROUND Multimorbidity is defined as the presence of two or more chronic diseases and associated comorbidities. There is a need to improve best practices around the provision of well-coordinated, person-centered care for persons with multimorbidities. Present health systems across the European Union (EU) focus on supporting a single-disease framework of care; the primary challenge is to create a patient-centric, integrated care ecosystem to understand and manage multimorbidity. ProACT is a large-scale project funded by the European Commission under the Horizon 2020 programme, that involved the design, development, and evaluation of a digital health platform to improve and advance home-based integrated care, and supported self-management, for older adults (aged ≥65 years) living with multimorbidity. OBJECTIVE This paper describes the trial implementation protocol of a proof-of-concept digital health platform (ProACT) in 2 EU member states (Ireland and Belgium) to support older persons with multimorbidities self-managing at home, supported by their care network (CN). METHODS Research was conducted across 2 EU member states, Ireland and Belgium. A 12-month action research trial design, divided into 3 evaluation cycles and lasting 3 months each, with a reflective redesign and development phase of 1 month after cycles 1 and 2 was conducted. Participants were 120 (60/120, 50% in Ireland and 60/120, 50% in Belgium) older persons with multimorbidities diagnosed with two or more of the following chronic conditions: diabetes, chronic obstructive pulmonary disease, chronic heart failure, and cardiovascular diseases. With permission from persons with multimorbidities, members of their CN were invited to participate in the study. Persons with multimorbidities were provided with ProACT technologies (tablet, devices, or sensors) to support them in self-managing their conditions. CN members also received access to an app to remotely support their persons with multimorbidity. Qualitative and quantitative feedback and evaluation data from persons with multimorbidity and CN participants were collected across four time points: baseline (T1), at the end of each 3-month action research cycle (T2 and T3), and in a final posttrial interview (T4). Thematic analysis was used to analyze the qualitative interview data. Quantitative data were analyzed via platform use statistics (to assess engagement) and standardized questionnaires (using descriptive and inferential statistics). This study is approved by the ethics committees of Ireland and Belgium. RESULTS The trial implementation phase for this 44-month (2016-2019) funded study was April 2018 to June 2019. The trial outcomes are at various stages of publication since 2021. CONCLUSIONS ProACT aims to co-design and develop a digital intervention with persons with multimorbidities and their CN, incorporating clinical guidelines with the state of the art in human-computer interaction, behavioral science, health psychology, and data analytic methods to deliver a digital health platform to advance self-management of multimorbidity at home, as part of a proactive, integrated model of supported person-centered care. INTERNATIONAL REGISTERED REPORT RR1-10.2196/22125

Simultaneous observations of PSR B0823+26 with ESA's XMM-Newton, the Giant Metrewave Radio Telescope and international stations of the Low Frequency Array revealed synchronous X-ray/radio switching between a radio-bright (B) mode and a radio-quiet (Q) mode. During the B mode we detected PSR B0823+26 in 0.2$-$2 keV X-rays and discovered pulsed emission with a broad sinusoidal pulse, lagging the radio main pulse by 0.208 $\pm$ 0.012 in phase, with high pulsed fraction of 70$-$80%. During the Q mode PSR B0823+26 was not detected in X-rays (2 $\sigma$ upper limit a factor ~9 below the B-mode flux). The total X-ray spectrum, pulse profile and pulsed fraction can globally be reproduced with a magnetized partially ionized hydrogen atmosphere model with three emission components: a primary small hot spot ($T$$\sim$3.6$\times10^6$ K, $R$$\sim$17 m), a larger cooler concentric ring ($T$$\sim$1.1$\times10^6$ K, $R$$\sim$280 m) and an antipodal hot spot ($T$$\sim$1.1$\times10^6 $ K, $R$$\sim$100 m), for the angle between the rotation axis and line of sight direction $\sim66^\circ$. The latter is in conflict with the radio derived value of $(84\pm0.7)^\circ$. The average X-ray flux within hours-long B-mode intervals varied by a factor $\pm$20%, possibly correlated with variations in the frequency and lengths of short radio nulls or short durations of weak emission. The correlated X-ray/radio moding of PSR B0823+26 is compared with the anti-correlated moding of PSR B0943+10, and the lack of X-ray moding of PSR B1822-09. We speculate that the X-ray/radio switches of PSR B0823+26 are due to variations in the rate of accretion of material from the interstellar medium through which it is passing., Comment: 16 pages, 11 figures

We report on simultaneous X-ray and radio observations of the radio-mode-switching pulsar PSR B1822-09 with ESA's XMM-Newton and the WSRT, GMRT and Lovell radio telescopes. PSR B1822-09 switches between a radio-bright and radio-quiet mode, and we discovered a relationship between the durations of its modes and a known underlying radio-modulation timescale within the modes. We discovered X-ray (energies 0.2-1.4 keV) pulsations with a broad sinusoidal pulse, slightly lagging the radio main pulse in phase by 0.094 +/- 0.017, with an energy-dependent pulsed fraction varying from ~0.15 at 0.3 keV to ~0.6 at 1 keV. No evidence is found for simultaneous X-ray and radio mode switching. The total X-ray spectrum consists of a cool component (T ~ 0.96 x 10^6 K, hot-spot radius R ~ 2.0 km) and a hot component (T ~ 2.2 x 10^6 K, R ~ 100 m). The hot component can be ascribed to the pulsed emission and the cool component to the unpulsed emission. The high-energy characteristics of PSR B1822-09 resemble those of middle-aged pulsars such as PSR B0656+14, PSR B1055-52 and Geminga, including an indication for pulsed high-energy gamma-ray emission in Fermi LAT data. Explanations for the high pulsed fraction seem to require different temperatures at the two poles of this orthogonal rotator, or magnetic anisotropic beaming effects in its strong magnetic field. In the X-ray skymap we found a harder source at only (5.1+/- 0.5 )arcsec from PSR B1822-09, which might be a pulsar wind nebula., Comment: 22 pages, 16 figures, MNRAS accepted

Contains fulltext : 171056.pdf (Publisher’s version ) (Open Access) BACKGROUND: Data on non-small-cell lung cancer (NSCLC) patients with non-classic epidermal growth factor receptor (EGFR) mutations are scarce, especially in non-Asian populations. The purpose of this study was to evaluate prevalence, clinical characteristics and outcome on EGFR-TKI treatment according to type of EGFR mutation in a Dutch cohort of NSCLC patients. METHODS: We retrospectively evaluated a cohort of 240 EGFR-mutated NSCLC patients. Data on demographics, clinical and tumour-related features, EGFR-TKI treatment and clinical outcome were collected and compared between patients with classic EGFR mutations, EGFR exon 20 insertions and other uncommon EGFR mutations. RESULTS: Classic EGFR mutations were detected in 186 patients (77.5%) and non-classic EGFR mutations in 54 patients (22.5%); 23 patients with an exon 20 insertion (9.6%) and 31 patients with an uncommon EGFR mutation (12.9%). Median progression-free survival (PFS) and overall survival (OS) on EGFR-TKI treatment were 2.9 and 9.7 months, respectively, for patients with an EGFR exon 20 insertion, and 6.4 and 20.2 months, respectively, for patients with an uncommon EGFR mutation. Patients with a double uncommon EGFR mutation that included G719X/L861Q/S768I had longer PFS and OS on EGFR-TKI treatment compared with patients with a single G719X/L861Q/S768I EGFR mutation (both P=0.02). CONCLUSIONS: In our Dutch cohort, prevalence and genotype distribution of non-classic EGFR mutations were in accordance with previously reported data. The PFS and OS on EGFR-TKI treatment in patients with an uncommon EGFR mutation were shorter compared with patients with classic EGFR mutations, but varied among different uncommon EGFR mutations. 9 p.

High ionisation lines in the soft X-ray band are generally associated to either interstellar hot gas along the line of sight or to photoionised gas intrinsic to the source. In the low-mass X-ray binary 4U 1820-30, the nature of these lines is not well understood. We characterised the ionised gas present along the line of sight towards the source producing the X-ray absorption lines of Mg XI, Ne IX, Fe XVII, O VII, and O VIII. We analysed all the observations available for this source in the XMM-Newton and Chandra archives, taken with the RGS, HETG, and LETG spectrometers. The high-resolution grating spectra have been accurately examined through a standard X-ray analysis based on the $C$-statistic and through the Bayesian parameter inference. We tested two physical models which describe a plasma in either collisional ionisation or photoionisation equilibrium. We adopted the Bayesian model comparison to statistically compare the different combinations of the models used for the analysis.} We found that the lines are consistent with hot gas in the interstellar medium rather than being associated with the intrinsic gas of the X-ray binary. Our best-fit model reveals the presence of a collisionally ionised plasma with a temperature of $T=(1.98\pm0.05)\times10^6 $ K. The photoionisation model fails to fit the Fe XVII line (which is detected with a significance of $6.5\sigma$) due to the low column density predicted by the model. Moreover, the low inclination of the binary system is likely the reason for the non-detection of ionised gas intrinsic to the source.}, Comment: 13 pages, 7 Figure, Accepted for publication in A&A

In the 1980s, professionals wanted to determine what the best method was for treating fractures of the mandibula. The emergence of osteosynthesis plates in the late 1960s, bringing with them the possibility of immediate functional restoration, had had a dramatic effect. This type of plate was most often placed by means of an extra-oral incision. A decade later, a system of smaller plates was introduced, which were placed intra-orally. A doctoral research project from 1991 investigated the advantages and disadvantages of the various methods of treating a mandibular fracture in order to determine which was most applicable. The importance of careful assessment on the basis of the type of fracture and the desired firmness of the osteosynthesis, described in the dissertation, is still decisive in conclusions concerning surgical treatment method and choice of material.In de jaren 80 van de vorige eeuw werd de behoefte gevoeld om uit te zoeken welke methode voor behandeling van fracturen van de mandibula de voorkeur genoot. De opkomst van osteosynthese­platen tegen het einde van de jaren 60, met de mogelijkheid van direct functieherstel, had een schokeffect gehad. Dit type platen werd overwegend via een extraorale incisie aangebracht. Een tiental jaren later werd een systeem van kleinere platen gepresenteerd, die via een intraorale benadering waren te plaatsen. Een promotie­onderzoek uit 1991 onderzocht de voor- en nadelen van de verschillende behandelingsmogelijkheden voor mandibulafracturen om een uitspraak te kunnen doen over de best toepasbare methode. Het in het proefschrift beschreven belang van zorgvuldige indicatiestelling op basis van type fractuur en de gewenste stevigheid van de osteosynthese is nog steeds bepalend bij de besluitvorming over chirurgische behandelmethode en materiaalkeuze.

IGR J17591−2342 is an accreting millisecond X-ray pulsar, discovered with INTEGRAL, which went into outburst around July 21, 2018. To better understand the physics acting in these systems during the outburst episode, we performed detailed temporal-, timing-, and spectral analyses across the 0.3–300 keV band using data from NICER,XMM-Newton,NuSTAR, and INTEGRAL. The hard X-ray 20–60 keV outburst profile covering ∼85 days is composed of four flares. Over the course of the maximum of the last flare, we discovered a type-I thermonuclear burst in INTEGRAL JEM-X data, posing constraints on the source distance. We derived a distance of 7.6 ± 0.7 kpc, adopting Eddington-limited photospheric radius expansion and assuming anisotropic emission. In the timing analysis, using all NICER 1–10 keV monitoring data, we observed a rather complex set of behaviours starting with a spin-up period (MJD 58345–58364), followed by a frequency drop (MJD 58364–58370), an episode of constant frequency (MJD 58370–58383), concluded by irregular behaviour till the end of the outburst. The 1–50 keV phase distributions of the pulsed emission, detected up to ∼120 keV using INTEGRAL ISGRI data, was decomposed in three Fourier harmonics showing that the pulsed fraction of the fundamental increases from ∼10% to ∼17% going from ∼1.5 to ∼4 keV, while the harder photons arrive earlier than the soft photons for energies ≲10 keV. The total emission spectrum of IGR J17591−2342 across the 0.3–150 keV band could adequately be fitted in terms of an absorbedCOMPPS model yielding as best fit parameters a column density ofNH = (2.09 ± 0.05) × 1022cm−2, a blackbody seed photon temperaturekTbb, seedof 0.64 ± 0.02 keV, electron temperaturekTe = 38.8 ± 1.2 keV and Thomson optical depthτT = 1.59 ± 0.04. The fit normalisation results in an emission area radius of 11.3 ± 0.5 km adopting a distance of 7.6 kpc. Finally, the results are discussed within the framework of accretion physics- and X-ray thermonuclear burst theory.

The 5′-hydroxymethyl metabolite of the penicillin based antibiotic flucloxacillin (FLX) is considered to be involved in bile duct damage occurring in a small number of patients. Because 5′-hydroxymethyl FLX is difficult to obtain by organic synthesis, biosynthesis using highly active and regioselective biocatalysts would be an alternative approach. By screening an in-house library of Cytochrome P450 (CYP) BM3 mutants, mutant M11 L437E was identified as a regioselective enzyme with relatively high activity in production of 5′-hydroxymethyl FLX as was confirmed by mass spectrometry and NMR. In contrast, incubation of M11 L437E and other mutants with oxacillin (OX, which differs from FLX by a lack of aromatic halogens) resulted in formation of two metabolites. In addition to 5′-hydroxymethyl OX we identified a product resulting from aromatic hydroxylation. In silico studies of both FLX and OX with three CYP BM3 mutants revealed substrate binding poses allowing for 5′-methyl hydroxylation, as well as binding poses with the aromatic moiety in the vicinity of the heme iron for which the corresponding product of aromatic hydroxylation was not observed for FLX. Supported by the (differences in) experimentally determined ratios of product formation for OX hydroxylation by M11 and its L437A variant and M11 L437E, Molecular Dynamics simulations suggest that the preference of mutant M11 L437E to bind FLX in its catalytically active pose over the other binding orientation contributes to its biocatalytic activity, highlighting the benefit of studying effects of active-site mutations on possible alternative enzyme-substrate binding poses in protein engineering.

Background: HER2 expression and amplification are observed in ~15% of tumour biopsies from patients with a sensitising EGFR mutation who develop EGFR TKI resistance. It is unknown whether HER2 targeting in this setting can result in tumour responses. Methods: A single arm phase II study was performed to study the safety and efficacy of trastuzumab and paclitaxel treatment in patients with a sensitising EGFR mutation who show HER2 expression in a tumour biopsy (IHC ≥ 1) after progression on EGFR TKI treatment. Trastuzumab (first dose 4 mg/kg, thereafter 2 mg/kg) and paclitaxel (60 mg/m2) were dosed weekly until disease progression or unacceptable toxicity. The primary end-point was tumour response rate according to RECIST v1.1. Results: Twenty-four patients were enrolled. Nine patients were exon 21 L858R positive and fifteen exon 19 del positive. Median HER2 IHC was 2+ (range 1–3). For 21 patients, gene copy number by in situ hybridisation could be calculated: 5 copies/nucleus (n = 9), 5–10 copies (n = 8), and >10 copies (n = 4). An objective response was observed in 11/24 (46%) patients. Highest response rates were seen for patients with 3+ HER2 IHC (12 patients, ORR 67%) or HER2 copy number ≥10 (4 patients, ORR 100%). Median tumour change in size was 42% decrease (range −100% to +53%). Median duration of response was 5.6 (95% confidence interval [CI], 3.8 to 7.3) months. Treatment toxicity was mild with four patients experiencing grade ≥3 toxicity, including fatigue, neuropathy, neutropaenia, urinary tract infection, and pneumonitis. Conclusions: Trastuzumab-paclitaxel induces objective tumour responses in 46% of EGFR TKI pretreated patients with an activating EGFR mutation and HER2 expression. The treatment was well tolerated. The relation between response rate and HER2 expression level and copy number suggests effective HER2 targeting by trastuzumab, although the combination with paclitaxel does not allow to determine the relative contribution of the individual drugs in terms of treatment efficacy.

Objectives: Development of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC)patients is associated with a poor prognosis. It has been suggested that LM-patients with epidermal growth factor receptor mutated (EGER+) NSCLC have a superior prognosis compared to EGFR-wild type NSCLC. Studies in EGFR+ NSCLC-patients with LM are scarce. We retrospectively evaluated a multiinstitutional cohort of EGER+ NSCLC-patients for LM to assess clinical outcome in relation to patient characteristics and treatment modalities.Material and methods: Medical records of advanced-stage EGFR+ NSCLC-patients (diagnosed between August 2000 and June 2014) from 11 Dutch hospitals were evaluated for LM as diagnosed by MRI and/or cytopathological liquor analysis. Data on patient characteristics, treatment and outcome were collected.Results: Thirty-two of 356 (9.0%) advanced-stage EGFR+ NSCLC-patients (median follow-up 21.0 months), were diagnosed with LM between 2006 and 2014. LM was diagnosed by MM (59.4%), liquor analysis (9.4%) or by both MRI and liquor analysis (31.3%). Median survival after LM-diagnosis was 3.1 months (95% Cl: 0.0-7.3). Six- and 12-month survival rates were 43.8% and 18.8%, respectively. Patients with performance status (PS) 0-1 at time of diagnosis of LM had a significantly higher chance to be alive after 6 months and had a significantly longer survival after diagnosis of LM compared to patients with PS >= 2. Age, treatment with high-dose EGFR-TKI, radiotherapy and whether LM was the only site of progressive disease did not influence survival after LM-diagnosis.Conclusion: Although median survival after LM-diagnosis in EGFR-mutated NSCLC-patients was poor, a substantial part of the patients had a prolonged survival of more than 6 months. PS of 0-1 at time of diagnosis of LM was associated with prolonged survival. No other patient- or treatment-related characteristics were identified. Further research is warranted to identify treatment strategies that improve survival in EGFR+ NSCLC-patients with LM. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

We report the detection of the pulsed signal of the radio-quiet magnetar-like pulsar PSR J1846-0258 in the high-energy \gr-ray data of the Fermi Large Area Telescope (Fermi LAT). We produced phase-coherent timing models exploiting RXTE PCA and Swift XRT monitoring data for the post- (magnetar-like) outburst period from 2007 August 28 to 2016 September 4, with independent verification using INTEGRAL ISGRI and Fermi GBM data. Phase-folding barycentric arrival times of selected Fermi LAT events from PSR J1846-0258, resulted in a 4.2 sigma detection (30--100 MeV) of a broad pulse consistent in shape and aligned in phase with the profiles that we measured with Swift XRT (2.5--10 keV), INTEGRAL ISGRI (20--150 keV) and Fermi GBM (20--300 keV). The pulsed flux (30--100 MeV) is (3.91 +/- 0.97)E-9 photons/(cm^2 s MeV). Declining significances of the INTEGRAL ISGRI 20--150 keV pulse profiles suggest fading of the pulsed hard X-ray emission during the post-outburst epochs. We revisited with greatly improved statistics the timing and spectral characteristics of PSR B1509-58 as measured with the Fermi LAT. The broad-band pulsed emission spectra (from 2 keV up to GeV energies) of PSR J1846-0258 and PSR B1509-58 can be accurately described with similarly curved shapes, with maximum luminosities at 3.5 +/- 1.1 MeV (PSR J1846-0258) and 2.23 +/- 0.11 MeV (PSR B1509-58). We discuss possible explanations for observational differences between Fermi LAT detected pulsars that reach maximum luminosities at GeV energies, like the second magnetar-like pulsar PSR J1119-6127, and pulsars with maximum luminosities at MeV energies, which might be due to geometric differences rather than exotic physics in high-B fields., 13 pages, 8 figures, accepted by MNRAS on 2017 November 30

Purpose: To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs) and to study resistance mechanisms in afatinib-resistant tumors.Methods: Characteristics and survival of patients treated with afatinib after resistance to erlotinib or gefitinib in two large Dutch centers were collected. Whole exome sequencing (WES) and pathway analysis was performed on available pre-and post-afatinib tumor biopsies and normal tissue.Results: A total of 38 patients were treated with afatinib. T790M mutations were identified in 22/29 (76%) pre-afatinib treatment tumor samples. No difference in median progression-free-survival (2.8 months (95% CI 2.3-3.3) and 2.7 months (95% CI 0.9-4.6), p = 0.55) and median overall-survival (8.8 months (95% CI 4.2-13.4) and 3.6 months (95% CI 2.3-5.0), p = 0.14) were observed in T790M+ patients compared to T790M-mutations. Somatic mutations in TP53, ADAMTS2, CNN2 and multiple genes in the Wnt and PI3K-AKT pathway were observed in post-afatinib tumors of six afatinib-responding and in one non-responding patient. No new EGFR mutations were found in the post-afatinib samples of the six responding patients. Further analyses of post-afatinib progressive tumors revealed 28 resistant specific mutations in six genes (HLA-DRB1, AQP7, FAM198A, SEC31A, CNTLN, and ESX1) in three afatinib responding patients. No known EGFR-TKI resistant-associated copy number gains were acquired in the post-afatinib samples.Conclusion: No differences in survival were observed in patients with EGFR-T790M treated with afatinib compared to those without T790M. Tumors from patients who had progressive disease during afatinib treatment were enriched for mutations in genes involved in Wnt and PI3K-AKT pathways.

Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation have a median progression-free survival of 12 months on treatment with tyrosine kinase inhibitors (TKIs). Clearly, the introduction of these agents had major implications for the treatment of NSCLC, but new questions and challenges arise as well. Traditionally, response assessments of anti-cancer treatment are conducted according to the RECIST criteria. Progressive disease is usually indicative of a change of therapy. In the current era of targeted therapies, it has become clear that different patterns of progressive disease are observed with TKI treatment in EGFR-mutated NSCLC patients, with potential consequences for therapeutic decision-making. In this review, we will discuss whether the RECIST criteria are still optimal for response evaluation. Rebiopsy studies have provided more insight into different resistance mechanisms at the time of acquired resistance to TKIs. These mechanisms, as well as the role of rebiopsy in daily clinical practice, will subsequently be covered. Finally, treatment strategies for different types of progressive disease will be discussed.

Pulsars emit low-frequency radio waves through to high-energy gamma-rays that are generated anywhere from the surface out to the edges of the magnetosphere. Detecting correlated mode changes in the multi-wavelength emission is therefore key to understanding the physical relationship between these emission sites. Through simultaneous observations, we have detected synchronous switching in the radio and X-ray emission properties of PSR B0943+10. When the pulsar is in a sustained radio 'bright' mode, the X-rays show only an un-pulsed, non-thermal component. Conversely, when the pulsar is in a radio 'quiet' mode, the X-ray luminosity more than doubles and a 100%-pulsed thermal component is observed along with the non-thermal component. This indicates rapid, global changes to the conditions in the magnetosphere, which challenge all proposed pulsar emission theories., Paper published in Science including supplementary material

BACKGROUND: The serum proteomic test VeriStrat has been shown to be able to classify advanced non-small cell lung cancer (NSCLC) patients for overall survival (OS) after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In this study, VeriStrat was evaluated as a pre-treatment stratification tool in patients with advanced stage NSCLC for treatment with the combination of erlotinib and sorafenib, considering both OS and progression-free survival (PFS) as end points.METHODS: Serum samples from 50 patients treated within the context of a phase II trial of first-line erlotinib and sorafenib were analysed with VeriStrat, a fully locked mass spectrometry-based test that identifies patients likely to have good or poor outcome on EGFR therapy based on eight distinct features in mass spectra. Analysis was performed fully blinded to all clinical data, and then the outcome data were analysed with respect to the obtained serum classifications.RESULTS: VeriStrat classified pre-treatment samples into two groups, VeriStrat Good and VeriStrat Poor, which were significantly different in OS (hazard ratio (HR) 0.30, log-rank P = 0.009) and in PFS (HR 0.40, log-rank P = 0.035).CONCLUSION: VeriStrat has shown its potential for stratification of unselected, advanced stage NSCLC patients treated in first line with a combination of erlotinib and sorafenib. British Journal of Cancer (2012) 107, 1820-1825. doi:10.1038/bjc.2012.470 www.bjcancer.com Published online 18 October 2012 (C) 2012 Cancer Research UK

We report on simultaneous X-ray and radio observations of the mode-switching pulsar PSR B0943+10 obtained with the XMM-Newton satellite and the LOFAR, LWA and Arecibo radio telescopes in November 2014. We confirm the synchronous X-ray/radio switching between a radio-bright (B) and a radio-quiet (Q) mode, in which the X-ray flux is a factor ~2.4 higher than in the B-mode. We discovered X-ray pulsations, with pulsed fraction of 38+/-5% (0.5-2 keV), during the B-mode, and confirm their presence in Q-mode, where the pulsed fraction increases with energy from ~20% up to ~65% at 2 keV. We found marginal evidence for an increase in the X-ray pulsed fraction during B-mode on a timescale of hours. The Q-mode X-ray spectrum requires a fit with a two-component model (either a power-law plus blackbody or the sum of two blackbodies), while the B-mode spectrum is well fit by a single blackbody (a single power-law is rejected). With a maximum likelihood analysis, we found that in Q-mode the pulsed emission has a thermal blackbody spectrum with temperature ~3.4x10^6 K and the unpulsed emission is a power-law with photon index ~2.5, while during B-mode both the pulsed and unpulsed emission can be fit by either a blackbody or a power law with similar values of temperature and photon index. A Chandra image shows no evidence for diffuse X-ray emission. These results support a scenario in which both unpulsed non-thermal emission, likely of magnetospheric origin, and pulsed thermal emission from a small polar cap (~1500 m^2) with a strong non-dipolar magnetic field (~10^{14} G), are present during both radio modes and vary in intensity in a correlated way. This is broadly consistent with the predictions of the partially screened gap model and does not necessarily imply global magnetospheric rearrangements to explain the mode switching., Comment: To be published on The Astrophysical Journal

Aim: To determine causative respiratory pathogens and describe epidemiological and clinical characteristics in a paediatric population with influenza-like illness during the 2009 H1N1-pandemic. Methods: Observational study of 412 children visiting an outpatient clinic of a Dutch teaching hospital. Results: From August to December 2009, 412 children were tested at the clinic; 32% proved H1N1-positive, confirmed by reverse-transcriptase-polymerase-chain-reaction (RT-PCR). Pathogens were detected in 65% of samples. Influenza A(H1N1) (n = 132), human rhinovirus (n = 55), respiratory syncytial virus (n = 45) and adenovirus (n = 34) were mostly identified. Co-infections were seen in 34 children (8.3%). Mean age was 6.8 and 4.2 years in H1N1-positive and H1N1-negative cases, respectively (p

We investigate a sample of 11 Galactic X-ray sources recently discovered with INTEGRAL or RXTE with the goal of identifying their optical and/or near-infrared (NIR) counterpart. For this purpose, new Chandra positions of nine objects are presented together with follow-up observations of all the targets in the optical and NIR. For the four sources IGR J16194-2810, IGR J 16479-4514, IGR J 16500-3307 and IGR J 19308+0530, the Chandra position confirms an existing association with an optical/NIR object, while for two sources, XTE J1716-389 and IGR J18490-0000, it rules out previously proposed counterparts indicating new ones. In the case of IGR J17597-220, a counterpart is selected out of the several possibilities proposed in the literature, and we present the first association with an optical/NIR source for IGR J16293-4603 and XTE J1743-363. Moreover, optical/NIR observations are reported for XTE J1710-281 and IGR J17254-3257; we investigate the counterpart to the X-ray sources based on their XMM-Newton positions. We discuss the nature of each system considering its optical/NIR and X-ray properties.

The mode-switching pulsar PSR B0943+10 has been extensively studied in the radio band for many years and, more recently, it has been found to vary also in X-rays, with a flux anticorrelated with the radio emission. Here we review the results of long observations of PSR B0943+10 carried out with XMM-Newton and the LOFAR, LWA and Arecibo radio telescopes in 2014. These results support a scenario in which both unpulsed non-thermal emission, likely of magnetospheric origin, and pulsed thermal emission from a small polar cap (~1500 m2) with a strong non-dipolar magnetic field (~ 1014 G), are present during both radio modes and vary in intensity in a correlated way.

Aims. PSR J1846-0258 is a young rotation-powered pulsar with one of the highest surface magnetic field strengths, located in the centre of SN-remnant Kes-75. In June 2006 a magnetar-like outburst took place. Using multi-year RXTE and INTEGRAL observations covering the epoch of the outburst, we aim to study the temporal and spectral characteristics of PSR J1846-0258 over a broad similar to 3-300 keV energy range to derive constraints on theoretical scenarios aiming to explain this schizophrenic behaviour.Methods. We explored all publically available RXTE observations of PSR J1846-0258 to generate accurate ephemerides over the period January 30, 2000-November 7, 2007. Phase-folding procedures yielded pulse profiles for RXTE PCA (similar to 3-30 keV), RXTE HEXTE (similar to 15-250 keV) and INTEGRAL ISGRI (similar to 20-300 keV). The pulsed spectrum over the full similar to 3-300 keV energy range was derived, as well as the total spectrum (including the pulsar wind nebula) over the 20-300 keV band with the ISGRI. The timing, spatial, and spectral analyses were applied for epochs before, during, and after the magnetar-like outburst to study the evolution of the high-energy characteristics.Results. ISGRI detected PSRJ1846-0258/Kes-75 before outburst during 2003-2006 with a power-law-shape spectrum over the 20300 keV energy range with photon index Gamma = 1.80 +/- 0.06 and energy flux (20-300 keV) of (6.62 +/- 0.35) x 10(-11) erg/cm(2) s. More than 90 days after the onset of the outburst, still during the decay phase, the same spectral shape was measured (Gamma = 1.75(-0.31)(+ 0.27) - 0.31) with an indication for a 52% (2.3 sigma) enhanced total emission, while one year after the outburst the hard X-ray non-thermal emission of PSR J1846-0258/Kes-75 was found to be back to its pre-outburst values. PCA monitoring of PSR J1846-0258 before the outburst yielded phase-coherent ephemerides confirming the earlier derived breaking index of the spindown. During the outburst, incoherent solutions have been derived. We show that the radiative outburst was triggered by a major spin-up glitch near MJD 53 883 +/- 3 with a glitch size Delta nu/nu in the range (2.0-4.4) x 10(-6). Using all pre-outburst observations of ISGRI and HEXTE for the first time pulse profiles have been obtained up to 150 keV with a broad single asymmetric pulse. The pulse shape did not vary with energy over the 2.9-150 keV energy range, nor did it change during the magnetar-like outburst. The time-averaged pre-outburst similar to 3-300 keV pulsed spectrum measured with the PCA, HEXTE, and ISGRI was fitted with a power-law model with Gamma = 1.20 +/- 0.01. A fit with a curved power-law model gives an improved fit. Around 150 keV the pulsed fraction approaches 100%. For the first 32 days of the magnetar-like outburst, the 3-30 keV pulsed spectrum can be represented with two power laws, a soft component with index Gamma(s) = 2.96 +/- 0.06 and a hard component with the pre-outburst value Gamma(h) similar to 1.2. Above similar to 9 keV, all spectra during outburst are consistent with the latter single power-law shape with index similar to 1.2. The 2-10 keV flux increased by a factor similar to 5 and the 10-30 keV flux increased with only 35%. After similar to 120 days the soft outburst and the enhancement of the hard non-thermal component both vanish.Conclusions. The varying temporal and spectral characteristics of PSR J1846-0258 can be explained in a scenario of a young high-B-field pulsar in which a major glitch triggered a sudden release of energy. Resonant cyclotron upscattering could subsequently generate the decaying/cooling soft pulsed component measured during outburst between 3 and 10 keV. The (variation in the) non-thermal hard X-ray component can be explained with synchrotron emission in a slot-gap or outer-gap pulsar model.

The reaction between the new hydroxy compound [PPh 4 ][Ru(N)(OH) 2 Me 2 ] and Pd(OSiMe 3 ) 2 ((−)-sparteine) produces (Me 3 Si) 2 O, H 2 O and a new heterobimetallic compound [PPh 4 ][Ru(N)Me 2 (μ 2 -O) 2 Pd((−)-sparteine)] in good yield. The Ru/Pd bimetallic compound catalyzes the oxidation of aryl and allyl alcohols to the corresponding carbonyl compound in air and the rearrangement of allylic alcohols unsaturated aldehydes. It also oxidizes PPh 3 to O–PPh 3 under O 2 .

Serendipitous and dedicated observations with the Rossi X-ray Timing Explorer (RXTE) and the International Gamma-Ray Astrophysics Laboratory (INTEGRAL) were analyzed to study the transient high-mass X-ray binary IGR J00370+6122, in particular to search for an accretion-powered pulsar as companion to the optically identified (Reig et al. 2005, A&A, 440, 637) B0.5 II-III donor star. Highly variable fluxes were measured in the RXTE data during outbursts of up to 2.2 × 10-10 erg cm-2 s-1 (3-20 keV; averaged over 1 h). During a 1-h time span with RXTE flaring activity was detected with an oscillating signal repeating 7 times. Epoch folding reveals a 346 ± 6 s period. We propose that this is the period of the putative pulsar. This measurement puts the source in the wind-fed accretion region of the P_orb (=15.7 d) versus P_pulse ``Corbet'' diagram. The 3 to 60 keV flare spectrum was modeled with an absorbed power law and the absorption column was found to be 15-20 times larger than the interstellar value and the value obtained for the optical counterpart, suggesting an accretor embedded in the wind of the donor star.

// R. Jonas A. Nilsson 1,2,3,* , Niki Karachaliou 4,* , Jordi Berenguer 1 , Ana Gimenez-Capitan 5 , Pepijn Schellen 1,3 , Cristina Teixido 5 , Jihane Tannous 6 , Justine L. Kuiper 7 , Esther Drees 1 , Magda Grabowska 1 , Marte van Keulen 6 , Danielle A. M. Heideman 8 , Erik Thunnissen 8 , Anne-Marie C. Dingemans 9 , Santiago Viteri 4 , Bakhos A. Tannous 6 , Ana Drozdowskyj 10 , Rafael Rosell 4,5,11,12,** , Egbert F. Smit 7,** and Thomas Wurdinger 1,3,6,** 1 Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden 3 ThromboDx B.V., Amsterdam, The Netherlands 4 Translational Research Unit, Dr, Rosell Oncology Institute, Quiron Dexeus University Hospital, Barcelona, Spain 5 Pangaea Biotech SL, Barcelona, Spain 6 Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA 7 Cancer Center Amsterdam, Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands 8 Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands 9 Department of Pulmonary Diseases, Maastricht University Medical Center, Maastricht, The Netherlands 10 Pivotal, Madrid, Spain 11 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain 12 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain * These two authors are co-first authors of the manuscript ** These three authors are co-senior authors of the manuscript Correspondence to: Thomas Wurdinger, email: // Keywords : diagnostics, NSCLC, liquid biopsies, platelets, EML4-ALK Received : August 23, 2015 Accepted : October 06, 2015 Published : November 02, 2015 Abstract Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers. Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival. Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK− platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression. Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.

Tumor heterogeneity plays an important role in the development of treatment-resistance, especially in the current era of targeted therapies. Although tumor heterogeneity is a widely recognized phenomenon, it is at present unclear how this knowledge should be incorporated into daily clinical practice. In this report, we describe an innovative nuclear imaging method that may play a role in detecting tumor heterogeneity in the future.

This chapter presents differences between dispersions, amorphous materials, and crystalline forms, and discusses the impact of excipient selection, especially polymers. It provides guidance for solubility and dissolution testing of amorphous dispersions. Crystalline solids are mostly used in pharmaceutical drug formulations because of their physical and chemical stabilities. Amorphous solids are commonly described as condensed phases that lack the long-range translational order typical of a crystalline solid, although the molecules may have short-range order. The success of amorphous solids as a supersaturating dosage form depends on the choice of processing conditions to yield a pure amorphous solid with no or minimal crystallization of the amorphous drug during storage and upon dosing. The use of amorphous solid dispersions has become a well-known strategy for inhibiting crystallization, as the amorphous solid dispersions can have increased physical stability over neat amorphous material. Keywords: amorphous solid dispersions; crystalline solid; dissolution; polymers; solubility; supersaturation

At high-energy gamma-rays (>100 MeV) the Large Area Telescope (LAT) on the Fermi satellite already detected more than 145 rotation-powered pulsars (RPPs), while the number of pulsars seen at soft gamma-rays (20 keV - 30 MeV) remained small. We present a catalogue of 18 non-recycled RPPs from which presently non-thermal pulsed emission has been securely detected at soft gamma-rays above 20 keV, and characterize their pulse profiles and energy spectra. For 14 of them we report new results, (re)analysing mainly data from RXTE, INTEGRAL, XMM-Newton and Chandra. The soft gamma-pulsars are all fast rotators and on average ~9.3x younger and ~ 43x more energetic than the Fermi LAT sample. The majority (11 members) exhibits broad, structured single pulse profiles, and only 6 have double (or even multiple, Vela) pulses. Fifteen soft gamma-ray pulsar show hard power-law spectra in the hard X-ray band and reach maximum luminosities typically in the MeV range. For only 7 of the 18 soft gamma-ray pulsars pulsed emission has also been detected by the LAT, but 12 have a pulsar wind nebula (PWN) detected at TeV energies. For six pulsars with PWNe, we present also the spectra of the total emissions at hard X-rays, and for IGR J18490-0000, associated with HESS J1849-000 and PSR J1849-0001, we used our Chandra data to resolve and characterize the contributions from the point-source and PWN. Finally, we also discuss a sample of 15 pulsars which are candidates for future detection of pulsed soft gamma-rays, given their characteristics at other wavelengths., Accepted for MNRAS; 39 pages, 33 Figures of which 11 in color, 2 tables

The reaction between Ni(dppe)(SSiMe3)2 and 2 equiv of [N(n-Bu)4][Ru(N)Cl2Me2] produces ClSiMe3 and the heterometallic complex (dppe)Ni(μ3-S)2{Ru(N)Me2}2. The molecular structure of this complex shows the three metals and the two nitrido ligands in a plane with the bridging sulfur atoms above and below that plane. There is an interaction between one of the ruthenium centers and the nickel. The structure differs from that of the closely related complex (dppe)Pt(μ3-S)2{Ru(N)Me2}2, which has equivalent Pt−Ru distances and no strong metal−metal interactions. The complexes (dppe)M(μ3-S)2{Ru(N)Me2}2 (M = Pt, Pd, Ni) catalyze the oxidation of benzyl alcohol to benzaldehyde in toluene and in supercritical carbon dioxide.

We present the results of a BeppoSAX observation of the fastest rotating pulsar known: PSR B1937+21. The ~200 ks observation (78.5 ks MECS/34 ks LECS on-source time) allowed us to investigate with high statistical significance both the spectral properties and the pulse profile shape. The pulse profile is clearly double peaked at energies > ~4 keV. Peak widths are compatible with the instrumental time resolution and the second pulse lags the main pulse 0.52 in phase, like is the case in the radio. In the 1.3-4 keV band we detect a ~45% DC component; conversely the 4-10 keV pulsed fraction is consistent with 100%. The on-pulse spectrum is fitted with an absorbed power-law of spectral index ~1.2, harder than that of the total flux which is ~1.9. The total unabsorbed (2-10 keV) flux is F_{2-10} = 4.1 10^-13 cgs, implying a luminosity of L_X = 5.0 10^31 \Theta (d/3.6 kpc)^2 erg s^-1 and a X-ray efficiency of \eta = 4.5 10^-5 \Theta, where \Theta is the solid angle spanned by the emission beam. These results are in agreement with those obtained by ASCA and a more recent Rossi-XTE observation. The hydrogen column density N_H ~2 10^22 cm^-2 is ~10 times higher than expected from the radio dispersion measure and average Galactic density of e-. Though it is compatible (within 2\sigma) with the Galactic (HI derived) value of ~1 10^22 cm^-2, inspection of dust extinction maps reveal that the pulsar falls in a highly absorbed region. In addition, 1.4 GHz radio map shows that the nearby (likely unrelated) HII source 4C21.53W is part of a circular emission region ~4' across., Comment: 8 pages, 5 figures; accepted for publication in A&A

We have verified the absolute timing capabilities of the high-energy instruments aboard INTEGRAL, i.e. the imager IBIS, the spectrometer SPI and the X-ray monitor JEM-X. Calibration observations of the Crab, contemporaneous with the Rossi X-ray Timing Explorer (RXTE), have been used to measure the absolute phase of the main pulse of the Crab pulse profile using the same Jodrell Bank radio ephemeris. The three INTEGRAL instruments and RXTE give within the statistical and systematic uncertainties consistent results: The X-ray main pulse is leading the radio pulse by 280 ′ 40 μs. Also the shapes of the X-ray pulse profiles as measured by the different instruments are fully consistent with each other. In addition, we present the first measurement of the absolute phase of the main pulse at γ-ray energies above 30 MeV using data from the EGRET instrument aboard the Compton Gamma-Ray Observatory: The γ-ray main pulse is leading the radio one by 241 ′ 29 μs, consistent with the value for the X-ray main pulse. Comparing absolute arrival times at multiple frequencies gives important constraints to models explaining the production of non-thermal emission in magnetospheres of rotation powered neutron stars.

We report on high-resolution spatial and timing results for binary millisecond pulsar PSR J0218+4232 obtained with the Chandra HRC-I and HRC-S in imaging mode. We found no indications for extended emission at 1 arcsec scales. With the HRC-S observation we obtained a 0.08-10 keV pulse profile with high statistics which could be compared in absolute time with the pulse profiles at radio-frequencies and at high-energy gamma-rays. The two X-ray pulses at aligned with 2 of the 3 radio-pulses, and with the 2 gamma-ray pulses., 8 pages, 4 figures, 1 table, Accepted for publication in ApJ Part-1

9042 Background: HER2 expression as well as amplification has been well recognized in tumor biopsies of pts with an EGFR mutation who developed EGFR TKI resistance. It is unknown whether HER2 targeting in this setting can result in tumor responses. Methods: Single arm open label phase II study to study the safety and efficacy of paclitaxel-trastuzumab treatment in pts with a sensitizing EGFR mutation who show tumor membrane HER2 expression in a tumor biopsy (immunohistochemistry (IHC) ≥1) after progression on EGFR TKI treatment. Paclitaxel (60 mg/m2) and trastuzumab (first dose 4 mg/kg, thereafter 2 mg/kg) were dosed weekly until disease progression or unacceptable toxicity. Primary end-point was tumor response according to RECIST. Sample size of 20 pts was calculated to evaluate the primary objective of ≥30% objective response rate. The study was deemed positive when ≥7 pts would show a partial or complete response. Results: 21 pts were enrolled from 08-2012 to 02-2017. 7 pts were exon 21 L858R positive and 14 exon 19 del. Last TKI was erlotinib (n = 6), gefitinib (n = 4), rociletinib (n = 3) or osimertinib (n = 8). Median HER2 IHC was 2+ (range 1-3). 17 pts were evaluable for response assessment, while 4 pts are awaiting their first response scan. The primary end-point was met with 7/17 pts (41%) showing a partial response. 2 pts showed stable disease, 7 progressive disease and 1 pt had clinical progression before CT response evaluation. Median duration of response was 9 (range 6-18) months with one ongoing responder. 3 pts experienced grade ≥3 toxicity, including fatigue, neuropathy and neutropenia. Upon progression on study treatment, all responding pts were rebiopsied. 4/6 samples were negative for HER2 (IHC), suggesting that the combination effectively targeted HER2 positive tumor cells. Conclusions: The study met its primary end-point. Paclitaxel-trastuzumab induces durable objective tumor responses in EGFR TKI pretreated pts with an activating EGFR mutation and HER2 bypass track activation. The treatment was well tolerated. Post-progression tumor biopsies showed absence of HER2 staining in the majority of pts, suggesting effective HER2 targeting. Clinical trial information: NCT02226757.

The conproportionation reaction between the dimeric diimidouranium(V) species [U(N(t)Bu)(2)(I)((t)Bu(2)bpy)](2) ((t)Bu(2)bpy = 4,4'-di-tert-butyl-2,2'-bipyridyl) and UI(3)(THF)(4) in the presence of additional (t)Bu(2)bpy yields U(N(t)Bu)(I)(2)((t)Bu(2)bpy)(THF)(2) (2), an unprecedented example of a monoimidouranium(IV) dihalide complex. The general synthesis of this family of uranium(IV) derivatives can be achieved more readily by adding 2 equiv of MN(H)R (M = Li, K; R = (t)Bu, 2,6-(i)PrC(6)H(3), 2-(t)BuC(6)H(4)) to UX(4) in the presence of coordinating Lewis bases to give complexes with the general formula U(NR)(X)(2)(L)(n) (X = Cl, I; L = (t)Bu(2)bpy, n = 1; L = THF, n = 2). The complexes were characterized by (1)H NMR spectroscopy and single-crystal X-ray diffraction analysis of compounds 2 and {U[N(2,6-(i)PrC(6)H(3))](Cl)(2)(THF)(2)}(2) (4). (The X-ray structures of 5 and 6 are reported in the Supporting Information.)

The Large Observatory For x-ray Timing (LOFT) was studied within ESA M3 Cosmic Vision framework and participated in the final down-selection for a launch slot in 2022-2024. Thanks to the unprecedented combination of effective area and spectral resolution of its main instrument, LOFT will study the behaviour of matter under extreme conditions, such as the strong gravitational field in the innermost regions of accretion flows close to black holes and neutron stars, and the supra-nuclear densities in the interior of neutron stars. The science payload is based on a Large Area Detector (LAD, 10 m 2 effective area, 2-30 keV, 240 eV spectral resolution, 1 deg collimated field of view) and a WideField Monitor (WFM, 2-50 keV, 4 steradian field of view, 1 arcmin source location accuracy, 300 eV spectral resolution). The WFM is equipped with an on-board system for bright events (e.g. GRB) localization. The trigger time and position of these events are broadcast to the ground within 30 s from discovery. In this paper we present the status of the mission at the end of its Phase A study., Proc. SPIE 9144, Space Telescopes and Instrumentation 2014: Ultraviolet to Gamma Ray, 91442T

We present the time-averaged characteristics of the Crab pulsar in the 0.75-30 MeV energy window using data from the imaging Compton Telescope COMPTEL aboard the Compton Gamma-Ray Observatory (CGRO) collected over its 9 year mission. Exploiting the exceptionally long COMPTEL exposure on the Crab allowed us to derive significantly improved COMPTEL spectra for the Crab nebula and pulsar emissions, and for the first time to accurately determine at low-energy gamma-rays the pulse profile as a function of energy. These timing data, showing the well-known main pulse and second pulse at a phase separation of 0.4 with strong bridge emission, are studied together with data obtained at soft/hard X-ray energies from the ROSAT HRI, BeppoSAX LECS, MECS and PDS, at soft gamma-rays from CGRO BATSE and at high-energy gamma-rays from CGRO EGRET in order to obtain a coherent high-energy picture of the Crab pulsar from 0.1 keV up to 10 GeV.

GRB 991014 is one of the shortest gamma-ray bursts detected so far with the Wide Field Cameras aboard BeppoSAX, both in gamma-rays and X-rays. The duration is 9.6 sec in 2-28 keV and 3.2 sec in 40 to 700 keV (as measured between the times when 5 and 95% of the burst photons have been accumulated). We refine the InterPlanetary Network annulus of the burst, present the detection of the X-ray afterglow of GRB 991014 within this refined annulus, and discuss X-ray and gamma-ray observations of the prompt and afterglow emission. Except for the briefness of the prompt event, no other unusual aspects were found in the prompt and afterglow observations as compared to such measurements in previous gamma-ray bursts., accepted for publication in Astrophysical Journal

The imaging Compton telescope COMPTEL aboard NASA's Compton Gamma-Ray Observatory has opened the MeV gamma-ray band as a new window to astronomy. COMPTEL provided the first complete all-sky survey in the energy range 0.75 to 30 MeV. The catalogue, presented here, is largely restricted to published results. It contains firm as well as marginal detections of continuum and line emitting sources and presents upper limits for various types of objects. The numbers of the most significant detections are 32 for steady sources and 31 for gamma-ray bursters. Among the continuum sources, detected so far, are spin-down pulsars, stellar black-hole candidates, supernova remnants, interstellar clouds, nuclei of active galaxies, gamma-ray bursters, and the Sun during solar flares. Line detections have been made in the light of the 1.809 MeV 26Al line, the 1.157 MeV 44Ti line, the 847 and 1238 keV 56Co lines, and the neutron capture line at 2.223 MeV. For the identification of galactic sources, a modelling of the diffuse galactic emission is essential. Such a modelling at this time does not yet exist at the required degree of accuracy. Therefore, a second COMPTEL source catalogue will be produced after a detailed and accurate modelling of the diffuse interstellar emission has become possible., Comment: 50 pages including 4 figures; accepted for publication in A&A Supplements

We report on the likely detection of pulsed high-energyγ-rays from the binary millisecond pulsar PSR J0218+4232 in 100–1000 MeV data from CGRO EGRET. Imaging analysis demonstrates that the highly significantγ-ray source 2EG J0220+4228 (∼ 10σ) is for energies > 100 MeV positionally consistent with both PSR J0218+4232 and the BL Lac 3C66A. However, above 1 GeV 3C66A is the evident counterpart, whereas between 100 and 300 MeV PSR J0218+4232 is the most likely one. Timing analysis using one ephemeris valid for all EGRET observations yields in the 100-1000 MeV range a double-pulse profile at a ∼ 3.5σsignificance level. The phase separation is similar to the component separation of ∼ 0.47 observed at X-rays. A comparison of theγ-ray profile with the 610 MHz radio profile in absolute phase shows that the twoγ- ray pulses coincide with two of the three emission features in the complex radio profile.

Activating mutations in the epidermal growth factor receptor ( EGFR ) are detected in approximately 10% of Caucasian and up to 50% of Asian patients with non-small cell lung cancer (NSCLC).1 EGFR-tyrosine kinase inhibitors (TKIs) constitute the preferred first-line treatment for these patients. Unfortunately, all patients eventually develop resistance to EGFR-TKI after a median of 13 months.2 Several different resistance mechanisms have been demonstrated in biopsies of recurrent tumours after EGFR-TKI treatment. Among these are the T790M secondary resistance mutation on EGFR exon 20 and amplification of alternative pathways such as hepatocyte growth factor receptor (MET) and human epidermal growth factor receptor 2 (HER2), but also morphological changes with epithelial-to-mesenchymal transition and transformation to a small cell lung cancer (SCLC) phenotype.2 Here we report a case with transformation to a squamous cell carcinoma (SqCC) phenotype. To the best of our knowledge, …

We present results from the spectral analysis of 29 gamma-ray bursts measured by the COMPTEL Telescope instrument (0.75–30 MeV) during the period from April 1991 through May 1995. The time-averaged spectra of these events are consistent with a simple power law model with spectral index in the range 1.5–3.5, whereas simple thermal models are statistically inconsistent with the burst sample. We find good agreement between burst spectra measured simultaneously by BATSE, COMPTEL and EGRET, which typically show a spectral transition or “break” in the BATSE energy range around a few hundred keV followed by simple power law emission extending to hundreds of MeV. Observations of rapid intensity variations up to a few MeV in the stronger bursts are used to investigate the importance of photon-photon opacity and to place limits on the source distance and bulk Lorentz factor.

Responses to drug information questions posted on the Internet Usenet pharmacy newsgroup sci.med. pharmacy were compared for accuracy with responses from drug information centers (DICs). Twenty-five questions were randomly selected from the past five years' continuing-education sections of the Annals of Pharmacotherapy, and possible answers were determined on the basis of corresponding articles. The questions were randomly submitted to sci.med.pharmacy from various e-mail accounts over a 10-week period. The same questions were submitted by telephone to randomly selected DICs. The correctness of responses was judged by a panel of four pharmacists. The questions received 31 responses from sci.med. pharmacy and 38 from the DICs. The responses from sci.med.pharmacy received 38 (31%) judgments of correct and the responses from the DICs, 85 (56%). A significantly smaller proportion of drug information responses from the Usenet newsgroup sci.med.pharmacy were judged as being accurate compared with responses from DICs.

A considerable number of patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) develop leptomeningeal metastases. Leptomeningeal metastases are associated with deterioration of clinical symptoms and poor survival. Traditionally, treatment of metastases in the central nervous system consists of radiotherapy and less frequently, surgery. The role of systemic therapy is limited due to the blood–brain barrier inhibiting pharmacological doses to be reached in the central nervous system. Several case reports have described high-dose, pulsatile tyrosine kinase inhibitors as an effective treatment of leptomeningeal metastases, based on the hypothesis that higher concentrations in the cerebrospinal fluid can be reached by higher systemic concentrations. Here, we describe two patients with EGFR-mutated non-small cell lung cancer, with both clinical and radiological response to this high-dose, pulsatile regimen. Interestingly, one patient showed a remarkable response of intrathoracic response as well.