A data-driven approach for simplifying the estimation of time for contaminant plumes to reach their maximum extent.

Globally there exist a very large number of contaminated or possibly contaminated sites where a basic preliminary assessment has not been completed. This is largely, among others, due to limited simple methods/models available for estimating key site quantities such as the maximum plume length, further denoted as Lmax and the corresponding time T=TLmax, at which the plume reaches its maximum extent L=Lmax. An approach to easily obtain an estimate of TLmax in particular is presented in this work. Limited availability of high-quality field data, particularly of TLmax, necessitates the use of synthetic data, which constrains the overall model development works. Taking BIOSCREEN-AT (transient 3D model) as a base model, this work proposes second-order polynomial models, with only two parameters, for estimating Lmax and TLmax. This reformulation of the well established solution significantly reduces data requirement and workload for initial site assessment purposes. A global sensitivity analysis (Morris, 1991), using a large number of random synthetic data, identifies the first-order decay rate constants in the plume λEFF and at the source γ as dominantly most influential for TLmax. For Lmax, the first-order decay rate constant λEFF and groundwater velocity v are the two important parameters. The sensitivity analysis also identifies that these parameters non-linearly impact TLmax or Lmax. With this information, the proposed polynomial models (each for Lmax and TLmax) were trained to obtain model coefficients, using a large amount of synthetic data. For verification, the developed models were tested using four datasets comprising over 100 sample sets against the results obtained from BIOSCREEN-AT and the developed BIOSCREEN-AT-based steady-state model. Additionally, the developed models were evaluated against two well documented field sites. The proposed models largely simplify estimation, particularly, of TLmax, for which only very limited field or literature information is available.

The Plant Vacuole as Heterologous System to Characterize the Functional Properties of TPC Channels.

Human TPC channels are an emerging family of intracellular proteins fundamental for cell physiology and involved in various severe pathologies. Their localization in the membranes of endo-lysosomes, intracellular compartments of submicrometric dimensions, makes their study difficult with usual electrophysiological techniques. In this work, we show how the plant vacuole, a versatile organelle that can occupy up to 90% of the volume in mature plant cells, can be used as a heterologous system of expression for functional characterization. For this purpose, the use of vacuoles isolated from mesophyll cells of the Arabidopsis thaliana mutant lacking the endogenous TPC avoids unwanted interferences. The patch-clamp technique can be successfully applied to plant vacuoles in all different configuration modes; of note, the whole-vacuole configuration allows to study channel modulation by cytosolic factors. The combination of patch-clamp with fluorescence techniques, for example, by using fluorescent probes sensitive to specific ions of interest, represents a useful extension to investigate the selectivity properties of the channels. Therefore, the plant vacuole, similar to Xenopus oocytes for ion channels and transporters localized in the plasma membrane, has the capability to become a model system for functional studies on intracellular ion channels and transporters.

[Cerebral dural arteriovenous fistulas]. / Zerebrale durale arteriovenöse Fisteln.

CLINICAL ISSUE: The cerebral dural arteriovenous (AV) fistula is a rare cerebral vascular malformation. Clinical presentation varies from asymptomatic to acute intracranial bleeding. Classification is based on the venous drainage with a risk assessment of bleeding. The carotid-cavernous fistula is a subtype with its own classification and treatment approaches. PRACTICAL RECOMMENDATIONS: Nowadays, dural fistulas can be diagnosed using high-resolution and time-resolved tomographic methods. Catheter angiography with subsequent interdisciplinary discussion should be performed for precise classification and therapy planning. Both endovascular and surgical treatment methods are available.

Magnetic particle imaging for artifact-free imaging of intracranial flow diverter stents: A phantom study.

PURPOSE: Magnetic Particle Imaging (MPI) is a new, background- and radiation-free tomographic imaging method that enables near real-time imaging of superparamagnetic iron-oxide nanoparticles (SPIONs) with high temporal and spatial resolution. This phantom study aims to investigate the potential of MPI for visualization of the stent lumen in intracranial flow diverters (FD). METHODS: Nitinol FD of different dimensions (outer diameter: 3.5 mm, 4.0 mm, 5.5 mm; total length: 22-40 mm) were scanned in vascular phantoms in a custom-built MPI scanner (in-plane resolution: ~ 2 mm, field of view: 65 mm length, 29 mm diameter). Phantoms were filled with diluted (1:50) SPION tracer agent Ferucarbotran (10 µmol (Fe)/ml; NaCL). Each phantom was measured in 32 different projections (overall acquisition time per image: 3200 ms, 5averages). After image reconstruction from raw data, two radiologists assessed image quality using a 5-point Likert scale. The signal intensity profile was measured using a semi-automatic evaluation tool. RESULTS: MPI visualized the lumen of all FD without relevant differences between the stented vessel phantom and the reference phantom. At 3.5 mm image quality was slightly inferior to the larger diameters. The FD themselves neither generated an MPI signal nor did they lead to relevant imaging artifacts. Ratings of both radiologists showed no significant difference, interrater reliability was good (ICC 0.84). A quantitative evaluation of the signal intensity profile did not reveal any significant differences (p > 0.05) either. CONCLUSION: MPI visualizes the lumen of nitinol FD stents in vessel phantoms without relevant stent-induced artifacts.

[Influence of genetics in intracranial aneurysms]. / Genetischer Einfluss bei intrakraniellen Aneurysmen.

BACKGROUND: The prevalence of unruptured intracranial aneurysms is approximately 3-5%. Subarachnoid hemorrhage caused by rupture of an aneurysm often affects middle-aged people and harbors high morbidity and mortality. The increasing availability of noninvasive imaging techniques over time is accompanied by an increase in the incidental detection of aneurysms. METHODS: The etiology in aneurysm development is heterogeneous. Besides polygenic multifactorial diseases, often triggered by well-established vascular risk factors, monogenic diseases should also be considered. Advances in genetics has helped to identify genes that contribute to the risk of intracranial aneurysm development. CONCLUSION: The genetic basis of intracranial aneurysms shows a broad heterogeneity and complexity. Currently, besides imaging there is no reliable diagnostic test to identify patients who are at higher risk for asymptomatic intracranial aneurysms.

Beyond the border: the use of lenvatinib in advanced hepatocellular carcinoma after different treatment lines: a retrospective analysis.

The systemic treatment of unresectable hepatocellular carcinoma (HCC) has been improved throughout the past years. Different tyrosine kinase inhibitors (TKI) and checkpoint inhibitors have approval for first- and second-line treatment. Still, data are missing about the choice for the right agent and senseful therapy sequences. Between 2017 and 2019 we treated 149 HCC patients. From those, we identified the patients, who received lenvatinib either as a first-line treatment or in a later treatment line. We investigated seven patients retrospectively, who received lenvatinib in second, third, or fourth treatment line regarding efficacy and safety. Besides that, we compared those patients with 13 patients, who received lenvatinib as a first-line treatment regarding duration of therapy, overall survivial (OS), side effects and best response to treatment. We discovered remission (PR) showed 4/7, stable disease (SD) 2/7 and 1/7 mixed response with an overall tolerable safety profile in patients with a later line lenvatinib treatment. The duration and overall survival for therapy is similar in first- and later treatment lines with comparable results. Most side effects are moderate in each treatment line. Remarkably, on patient diagnoses with HCC (the Barcelona Clinic Liver Cancer C algorithm), who received lenvatinib in fourth line reached 67 months OD since diagnosis. We conclude, that lenvatinib could be considered as a treatment option of HCC for later treatment lines.

Application of open-path Fourier transform infrared spectroscopy for atmospheric monitoring of a CO2 back-production experiment at the Ketzin pilot site (Germany).

During a controlled "back-production experiment" in October 2014 at the Ketzin pilot site, formerly injected CO2 was retrieved from the storage formation and directly released to the atmosphere via a vent-off stack. Open-path Fourier transform infrared (OP FTIR) spectrometers, on-site meteorological parameter acquisition systems, and distributed CO2 point sensors monitored gas dispersion processes in the near-surface part of the atmospheric boundary layer. The test site provides a complex and challenging mosaic-like surface setting for atmospheric monitoring which can also be found at other storage sites. The main aims of the atmospheric monitoring of this experiment were (1) to quantify temporal and spatial variations in atmospheric CO2 concentrations around the emitting vent-off stack and (2) to test if and how atmospheric monitoring can cope with typical environmental and operational challenges. A low environmental risk was encountered during the whole CO2 back-production experiment. The study confirms that turbulent wind conditions favor atmospheric mixing processes and are responsible for rapid dilution of the released CO2 leading to decreased detectability at all sensors. In contrast, calm and extremely stable wind conditions (especially occurring during the night) caused an accumulation of gases in the near-ground atmospheric layer with the highest amplitudes in measured gas concentration. As an important benefit of OP FTIR spectroscopic measurements and their ability to detect multiple gas species simultaneously, emission sources could be identified to a much higher certainty. Moreover, even simulation models using simplified assumptions help to find suitable monitoring network designs and support data analysis for certain wind conditions in such a complex environment.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

This corrects the article DOI: 10.1038/bjc.2014.209.

Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum.

We evaluated the impact of early embryonic deletion of huntingtin (htt) from pyramidal neurons on cortical development, cortical neuron survival and motor behavior, using a cre-loxP strategy to inactivate the mouse htt gene (Hdh) in emx1-expressing cell lineages. Western blot confirmed substantial htt reduction in cerebral cortex of these Emx-httKO mice, with residual cortical htt in all likelihood restricted to cortical interneurons of the subpallial lineage and/or vascular endothelial cells. Despite the loss of htt early in development, cortical lamination was normal, as revealed by layer-specific markers. Cortical volume and neuron abundance were, however, significantly less than normal, and cortical neurons showed reduced brain-derived neurotrophic factor (BDNF) expression and reduced activation of BDNF signaling pathways. Nonetheless, cortical volume and neuron abundance did not show progressive age-related decline in Emx-httKO mice out to 24months. Although striatal neurochemistry was normal, reductions in striatal volume and neuron abundance were seen in Emx-httKO mice, which were again not progressive. Weight maintenance was normal in Emx-httKO mice, but a slight rotarod deficit and persistent hyperactivity were observed throughout the lifespan. Our results show that embryonic deletion of htt from developing pallium does not substantially alter migration of cortical neurons to their correct laminar destinations, but does yield reduced cortical and striatal size and neuron numbers. The Emx-httKO mice were persistently hyperactive, possibly due to defects in corticostriatal development. Importantly, deletion of htt from cortical pyramidal neurons did not yield age-related progressive cortical or striatal pathology.

Wild-type KRAS is a novel therapeutic target for melanoma contributing to primary and acquired resistance to BRAF inhibition.

Malignant melanoma reveals rapidly increasing incidence and mortality rates worldwide. By now, BRAF inhibition is the standard therapy for advanced melanoma in patients carrying BRAF mutations. However, only approximately 50% of melanoma patients harbor therapeutically attackable BRAF mutations, and overall survival after treatment with BRAF inhibitors is modest. KRAS (Kirsten Rat sarcoma) proteins are acting upstream of BRAF and have a major role in human cancer. Recent approaches awaken the hope to use KRAS inhibition (KRASi) as a clinical tool. In this study, we identified wild-type KRAS as a novel therapeutic target in melanoma. KRASi functions synergistically with BRAF inhibition to reduce melanoma proliferation and to induce apoptosis independently of BRAF mutational status. Moreover, acquired resistance to BRAF inhibitors in melanoma is dependent on dynamic regulation of KRAS expression with subsequent AKT and extracellular-signal regulated kinase activation and can be overcome by KRASi. This suggests KRASi as novel approach in melanoma-alone or in combination with other therapeutic regimes.

A sealable ultrathin window sample cell for the study of liquids by means of soft X-ray spectroscopy.

A new sample cell concept for the analysis of liquids or solid-liquid interfaces using soft X-ray spectroscopy is presented, which enables the complete sealing of the cell as well as the transport into vacuum via, for example, a load-lock system. The cell uses pressure monitoring and active as well as passive pressure regulation systems, thereby facilitating the full control over the pressure during filling, sealing, evacuation, and measurement. The cell design and sample preparation as well as the crucial sealing procedure are explained in detail. As a first proof-of-principle experiment, successful nitrogen K-edge fluorescence yield near-edge X-ray absorption fine structure experiments of a biomolecular solution are presented. For this purpose, it is shown that the careful evaluation of all involved parameters, such as window type or photon flux, is desirable for optimizing the experimental result.

Spectroscopic evidence for origins of size and support effects on selectivity of Cu nanoparticle dehydrogenation catalysts.

Selective dehydrogenation catalysts that produce acetaldehyde from bio-derived ethanol can increase the efficiency of subsequent processes such as C-C coupling over metal oxides to produce 1-butanol or 1,3-butadiene or oxidation to acetic acid. Here, we use in situ X-ray absorption spectroscopy and steady state kinetics experiments to identify Cuδ+ at the perimeter of supported Cu clusters as the active site for esterification and Cu0 surface sites as sites for dehydrogenation. Correlation of dehydrogenation and esterification selectivities to in situ measures of Cu oxidation states show that this relationship holds for Cu clusters over a wide-range of diameters (2-35 nm) and catalyst supports and reveals that dehydrogenation selectivities may be controlled by manipulating either.

[Degenerative cerebellar diseases and differential diagnoses]. / Degenerative Kleinhirnerkrankungen und Differenzialdiagnosen.

CLINICAL/METHODICAL ISSUE: Cerebellar syndromes result in distinct clinical symptoms, such as ataxia, dysarthria, dysmetria, intention tremor and eye movement disorders. STANDARD RADIOLOGICAL METHODS: In addition to the medical history and clinical examination, imaging is particularly important to differentiate other diseases, such as hydrocephalus and multi-infarct dementia from degenerative cerebellar diseases. Degenerative diseases with cerebellar involvement include Parkinson's disease, multiple system atrophy as well as other diseases including spinocerebellar ataxia. ACHIEVEMENTS: In addition to magnetic resonance imaging (MRI), nuclear medicine imaging investigations are also helpful for the differentiation. PRACTICAL RECOMMENDATIONS: Axial fluid-attenuated inversion recovery (FLAIR) and T2-weighted sequences can sometimes show a signal increase in the pons as a sign of degeneration of pontine neurons and transverse fibers in the basilar part of the pons. The imaging is particularly necessary to exclude other diseases, such as normal pressure hydrocephalus (NPH), multi-infarct dementia and cerebellar lesions.

Human tissue engineering allows the identification of active miRNA regulators of glioblastoma aggressiveness.

Glioblastoma multiforme (GBM) is among the most aggressive cancers associated with massive infiltration of peritumoral parenchyma by migrating tumor cells. The infiltrative nature of GBM cells, the intratumoral heterogeneity concomitant with redundant signaling pathways likely underlie the inability of conventional and targeted therapies to achieve long-term remissions. In this respect, microRNAs (miRNAs), which are endogenous small non-coding RNAs that play a role in cancer aggressiveness, emerge as possible relevant prognostic biomarkers or therapeutic targets for treatment of malignant gliomas. We previously described a tissue model of GBM developing into a stem cell-derived human Engineered Neural Tissue (ENT) that allows the study of tumor/host tissue interaction. Combined with high throughput sequencing analysis, we took advantage of this human and integrated tissue model to understand miRNAs regulation. Three miRNAs (miR-340, -494 and -1293) active on cell proliferation, adhesion to extracellular matrix and tumor cell invasion were identified in GBM cells developing within ENT, and also confirmed in GBM biopsies. The components of miRNAs regulatory network at the transcriptional and the protein level have been also revealed by whole transcriptome analysis and Tandem Mass Tag in transfected GBM cells. Notably, miR-340 has a clinical relevance and modulates the expression of miR-494 and -1293, emphasizing its biological significance. Altogether, these findings demonstrate that human tissue engineering modeling GBM development in neural host tissue is a suitable tool to identify active miRNAs. Collectively, our study identified miR-340 as a strong modulator of GBM aggressiveness which may constitute a therapeutic target for treatment of malignant gliomas.

Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes.

Despite moderate improvements in outcome of glioblastoma after first-line treatment with chemoradiation recent clinical trials failed to improve the prognosis of recurrent glioblastoma. In the absence of a standard of care we aimed to investigate institutional treatment strategies to identify similarities and differences in the pattern of care for recurrent glioblastoma. We investigated re-treatment criteria and therapeutic pathways for recurrent glioblastoma of eight neuro-oncology centres in Switzerland having an established multidisciplinary tumour-board conference. Decision algorithms, differences and consensus were analysed using the objective consensus methodology. A total of 16 different treatment recommendations were identified based on combinations of eight different decision criteria. The set of criteria implemented as well as the set of treatments offered was different in each centre. For specific situations, up to 6 different treatment recommendations were provided by the eight centres. The only wide-range consensus identified was to offer best supportive care to unfit patients. A majority recommendation was identified for non-operable large early recurrence with unmethylated MGMT promoter status in the fit patients: here bevacizumab was offered. In fit patients with late recurrent non-operable MGMT promoter methylated glioblastoma temozolomide was recommended by most. No other majority recommendations were present. In the absence of strong evidence we identified few consensus recommendations in the treatment of recurrent glioblastoma. This contrasts the limited availability of single drugs and treatment modalities. Clinical situations of greatest heterogeneity may be suitable to be addressed in clinical trials and second opinion referrals are likely to yield diverging recommendations.

Diagnosis and Treatment of Intracranial Stenoses.

Stroke is one of the most frequent and most significant vascular diseases. According to estimates, 16.9 million people suffered a stroke in 2010, and over one-third of the incidents were lethal. The risk of suffering a stroke due to intracranial stenosis is between 7 and 24%. As opposed to extracranial stenoses of the internal carotid artery, there is no standardized treatment concept for intracranial stenoses. At present, treatment with a low daily dose of 100 mg aspirin is recommended by the guidelines for intracranial stenoses to additionally prevent dose-dependent gastrointestinal side effects and bleeding complications. The WINGSPAN study showed stroke rates and mortality rates amounting to 4.5% after 30 days and 7.0% after 6 months. The Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis study is a randomized, multicenter study that compared endovascular stent treatment in patients with symptomatic arteriosclerotic intracranial stenoses with intensified drug therapy. After the inclusion of 451 of 764 study patients planned initially, study recruitment was terminated prematurely because the stroke rate or mortality rate within 30 days was 14.7% in the endovascular treatment group compared with 5.8% in the drug therapy group and 20% within 12 months compared with 12.2%. Quite recently the results of a second randomized study of intracranial stents were published in the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy study. In an analysis published by Liebeskind et al. concerning the impact of collateral vessels on the stroke risk based on data from the Warfarin-Aspirin Symptomatic Intracranial Disease study, it was demonstrated that a sufficiently formed collateral network in patients with high-degree vascular constrictions (≥ 70%) plays a crucial role in the avoidance of strokes. If there is no system of collateral vessels or if it is insufficient, the stroke risk in the dependent vascular territory is six times higher. So far it has not yet been possible to conclusively answer the question of optimal treatment for intracranial stenoses. There is particularly need for action regarding the treatment of high-degree recurrent symptomatic stenoses, not only in light of the unfavorable prognosis but also within the scope of demographic change.

Quantification of silane molecules on oxidized silicon: are there options for a traceable and absolute determination?

Organosilanes are used routinely to functionalize various support materials for further modifications. Nevertheless, reliable quantitative information about surface functional group densities after layer formation is rarely available. Here, we present the analysis of thin organic nanolayers made from nitrogen containing silane molecules on naturally oxidized silicon wafers with reference-free total reflection X-ray fluorescence (TXRF) and X-ray photoelectron spectroscopy (XPS). An areic density of 2-4 silane molecules per nm(2) was calculated from the layer's nitrogen mass deposition per area unit obtained by reference-free TXRF. Complementary energy and angle-resolved XPS (ER/AR-XPS) in the Si 2p core-level region was used to analyze the outermost surface region of the organic (silane layer)-inorganic (silicon wafer) interface. Different coexisting silicon species as silicon, native silicon oxide, and silane were identified and quantified. As a result of the presented proof-of-concept, absolute and traceable values for the areic density of silanes containing nitrogen as intrinsic marker are obtained by calibration of the XPS methods with reference-free TXRF. Furthermore, ER/AR-XPS is shown to facilitate the determination of areic densities in (mono)layers made from silanes having no heteroatomic marker other than silicon. After calibration with reference-free TXRF, these areic densities of silane molecules can be determined when using the XPS component intensity of the silane's silicon atom.

[Maintenance chemotherapy: futility or utility?]. / Chimiothérapie de maintenance: futile ou utile?

In incurable diseases, maintenance therapy aims to prolong the response achieved through induction. The goal is to delay disease progression, thus prolonging survival. Two maintenance modalities are used. The first, called continuation maintenance, consists of continuing the same agent used in the initial treatment. The second, called switch-maintenance, introduces an early second line drug immediately after induction. Proving the superiority of a maintenance strategy implies a better outcome with the maintenance compared to the same therapeutic agent used upon disease progression. This benefit may be observed in terms of overall survival and/or quality of life.