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Marine cold-air outbreaks (MCAOs) strongly affect the Arctic water cycle and, thus, climate through large-scale air mass transformations. The description of air mass transformations is still challenging, partly because previous observations do not resolve fine scales, particularly for the initial development of an MCAO, and due to a lack of information about the thermodynamical evolution starting over sea ice and continuing over open ocean and associated cloud microphysical properties. Therefore, we focus on the crucial initial development within the first 200 km over open water for two case studies in April 2022 during the HALO-(AC)3 campaign (named after the High Altitude and Long Range Research Aircraft and Transregional Collaborative Research Centre ArctiC Amplification: Climate Relevant Atmospheric and SurfaCe Processes and Feedback Mechanisms (AC)3). The two events, just 3 d apart, belong to a particularly long-lasting MCAO and occurred under relatively similar thermodynamic conditions. Even though both events were stronger than the climatological 75th percentile of that period, the first event was characterized by colder air masses from the central Arctic which led to an MCAO index twice as high compared to that of the second event. The evolution and structure were assessed by flight legs crossing the Fram Strait multiple times at the same location, sampling perpendicularly to the cloud streets. Airborne remote sensing and in situ measurements were used to build statistical descriptions of the boundary layer, dynamics, clouds, and precipitation. For this purpose, we established a novel approach based solely on radar reflectivity measurements to detect roll circulation that forms cloud streets. The two cases exhibit different properties of clouds, riming, and roll circulations, though the width of the roll circulation is similar. For the stronger event, cloud tops are higher; more liquid-topped clouds exist; the liquid water path, mean radar reflectivity, precipitation rate, and precipitation occurrence have increased; and riming is active. The variability in rime mass has the same horizontal scale as the roll circulation, implying the importance of roll circulation on cloud microphysics and precipitation. Boundary layer and cloud properties evolve with distance over open water, as seen by, e.g., cloud top height rising. In general, cloud streets form after traveling 15 km over open water. After 20 km, this formation enhances cloud cover to just below 100 %. After around 30 km, precipitation forms, though for the weaker event, the development of precipitation is shifted to larger distances. Within our analysis, we developed statistical descriptions of various parameters (i) within the roll circulation and (ii) as a function of distance over open water. These detailed cloud metrics are particularly well suited for the evaluation of cloud-resolving models close to the sea ice edge to evaluate their representation of dynamics and microphysics.

Abstract Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the significantly most upregulated proteins in GBC. CEACAM6 overexpression has been observed in other cancer entities but the molecular function remains unclear. Our functional analyses in vitro and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer progression and metastasis by decreasing cell adhesion and promoting migration and invasion of GBC cells. Conversely, CEACAM6 knockdown abolished GBC aggressiveness by increasing cell adhesion while reducing cell migration, cell proliferation, and colony formation. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 supporting GBC cell migration. ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.

Global warming is amplified in the Arctic. However, numerical models struggle to represent key processes that determine Arctic weather and climate. To collect data that help to constrain the models, the HALO–(𝒜𝒞)3 aircraft campaign was conducted over the Norwegian and Greenland seas, the Fram Strait, and the central Arctic Ocean in March and April 2022. The campaign focused on one specific challenge posed by the models, namely the reasonable representation of transformations of air masses during their meridional transport into and out of the Arctic via northward moist- and warm-air intrusions (WAIs) and southward marine cold-air outbreaks (CAOs). Observations were made over areas of open ocean, the marginal sea ice zone, and the central Arctic sea ice. Two low-flying and one long-range, high-altitude research aircraft were flown in colocated formation whenever possible. To follow the air mass transformations, a quasi-Lagrangian flight strategy using trajectory calculations was realized, enabling us to sample the same moving-air parcels twice along their trajectories. Seven distinct WAI and 12 CAO cases were probed. From the quasi-Lagrangian measurements, we have quantified the diabatic heating/cooling and moistening/drying of the transported air masses. During CAOs, maximum values of 3 K h−1 warming and 0.3 g kg−1 h−1 moistening were obtained below 1 km altitude. From the observations of WAIs, diabatic cooling rates of up to 0.4 K h−1 and a moisture loss of up to 0.1 g kg−1 h−1 from the ground to about 5.5 km altitude were derived. Furthermore, the development of cloud macrophysical (cloud-top height and horizontal cloud cover) and microphysical (liquid water path, precipitation, and ice index) properties along the southward pathways of the air masses were documented during CAOs, and the moisture budget during a specific WAI event was estimated. In addition, we discuss the statistical frequency of occurrence of the different thermodynamic phases of Arctic low-level clouds, the interaction of Arctic cirrus clouds with sea ice and water vapor, and the characteristics of microphysical and chemical properties of Arctic aerosol particles. Finally, we provide a proof of concept to measure mesoscale divergence and subsidence in the Arctic using data from dropsondes released during the flights.

How air masses transform during meridional transport into and out of the Arctic is not well represented by numerical models. The airborne field campaign HALO-(𝒜𝒞)3 applied the High Altitude and Long-range Research Aircraft (HALO) within the framework of the collaborative research project on Arctic amplification (𝒜𝒞)3 to address this question by providing a comprehensive observational basis. The campaign took place from 7 March to 12 April 2022 in the North Atlantic sector of the Arctic, a main gateway of atmospheric transport into and out of the Arctic. Here, we investigate to which degree the meteorological and sea ice conditions during the campaign align with the long-term climatology (1979–2022). For this purpose, we use the European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis v5 (ERA5), satellite data, and measurements at Ny-Ålesund, including atmospheric soundings. The observations and reanalysis data revealed two distinct periods with different weather conditions during HALO-(𝒜𝒞)3: the campaign started with a warm period (11–20 March 2022) where strong southerly winds prevailed that caused poleward transport of warm and moist air masses, so-called moist and warm air intrusions (WAIs). Two WAI events were identified as atmospheric rivers (ARs), which are narrow bands of strong moisture transport. These warm and moist air masses caused the highest measured 2 m temperatures (5.5 °C) and daily precipitation rates (42 mm d−1) at Ny-Ålesund for March since the beginning of the record (1993). Over the sea ice northwest of Svalbard, ERA5 indicated record-breaking rainfall. After the passage of a strong cyclone on 21 March 2022, a cold period followed. Northerly winds advected cold air into the Fram Strait, causing marine cold air outbreaks (MCAOs) until the end of the campaign. This second phase included one of the longest MCAO events found in the ERA5 record (19 d). On average, the entire campaign period was warmer than the climatological mean due to the strong influence of the ARs. In the Fram Strait, the sea ice concentration was well within the climatological variability over the entire campaign duration. However, during the warm period, a large polynya opened northeast of Svalbard, untypical for this season. Compared to previous airborne field campaigns focusing on the evolution of (mixed-phase) clouds, a larger variety of MCAO conditions was observed during HALO-(𝒜𝒞)3. In summary, air mass transport into and out of the Arctic was more pronounced than usual, providing exciting prospects for studying air mass transformation using HALO-(𝒜𝒞)3.

Institutes for pathology act as operators, users and in-house manufacturers of in vitro diagnostic medical devices and are subject to national and European regulations depending on their function. The entry into force of the EU regulation on medical devices (Regulation (EU) 2017/745, MDR) and the EU regulation on in vitro diast medical devices (Regulation (EU) 2017/746, IVDR) resulted in a need for regulatory adjustments to German medical device law. This has created a new legal framework in which institutes for pathology operate, depending on their function as users, operators or in-house manufacturers of in vitro diagnostic medical devices. This overview of the current legal situation represents a snapshot and provides an up-to-date overview of the landscape of European and German medical device law.

Abstract The frequency scaling exponent of low-frequency excitations in microscopically small glasses, which do not allow for the existence of waves (phonons), has been in the focus of the recent literature. The density of states g(ω) of these modes obeys an ω s scaling, where the exponent s, ranging between 2 and 5, depends on the quenching protocol. The orgin of these findings remains controversal. Here we show, using heterogeneous-elasticity theory, that in a marginally-stable glass sample g(ω) follows a Debye-like scaling (s = 2), and the associated excitations (type-I) are of random-matrix type. Further, using a generalisation of the theory, we demonstrate that in more stable samples, other, (type-II) excitations prevail, which are non-irrotational oscillations, associated with local frozen-in stresses. The corresponding frequency scaling exponent s is governed by the statistics of small values of the stresses and, therefore, depends on the details of the interaction potential.

Arctic air masses undergo intense transformations when moving southward from closed sea ice to warmer open waters in marine cold-air outbreaks (CAOs). Due to the lack of measurements of diabatic heating and moisture uptake rates along CAO flows, studies often depend on atmospheric reanalysis output. However, the uncertainties connected to those datasets remain unclear. Here, we present height-resolved airborne observations of diabatic heating, moisture uptake, and cloud evolution measured in a quasi-Lagrangian manner. The investigated CAO was observed on 1 April 2022 during the HALO-(AC)3 campaign. Shortly after passing the sea-ice edge, maximum diabatic heating rates over 6 K h−1 and moisture uptake over 0.3 gkg-1h-1 were measured near the surface. Clouds started forming and vertical mixing within the deepening boundary layer intensified. The quasi-Lagrangian observations are compared with the fifth-generation global reanalysis (ERA5) and the Copernicus Arctic Regional Reanalysis (CARRA). Compared to these observations, the mean absolute errors of ERA5 versus CARRA data are 14 % higher for air temperature over sea ice (1.14 K versus 1.00 K) and 62 % higher for specific humidity over ice-free ocean (0.112 g kg−1 versus 0.069 g kg−1). We relate these differences to issues with the representation of the marginal ice zone and corresponding surface fluxes in ERA5, as well as the cloud scheme producing excess liquid-bearing, precipitating clouds, which causes a too-dry marine boundary layer. CARRA's high spatial resolution and demonstrated higher fidelity towards observations make it a promising candidate for further studies on Arctic air mass transformations.

Purpose: Superior sulcus tumors are frequently treated with neoadjuvant chemoradiation therapy (nCRT) followed by surgery via a trimodal approach. The INKA study evaluated the replacement of photon irradiation by carbon ion radiation therapy (C12-RT) in this regimen. Methods and Materials: The prospective INKA study included patients with locally advanced non-small cell superior sulcus tumors (

Introduction: Pathogenic variants in the XK gene are associated with dysfunction or loss of XK protein leading to McLeod syndrome (MLS), a rare X-linked neuroacanthocytosis syndrome with multisystemic manifestation. Here we present clinical, genetic and immunological data on a patient originally admitted to our clinic for presumed post-COVID-19 syndrome, where thorough clinical work-up revealed a novel frameshift deletion in XK causal for the underlying phenotype. We additionally review the clinicogenetic spectrum of reported McLeod cases in the literature.Methods: We performed in-depth clinical characterization and flow cytometry of cerebrospinal fluid (CSF) in a patient where multi-gene panel sequencing identified a novel hemizygous frameshift deletion in XK. Additionally, Kell (K) and Cellano (k) antigen expression was analysed by Fluorescence-activated Cell Sorting (FACS). KEL gene expression was examined by RNA sequencing.Results: A novel hemizygous frameshift deletion in the XK gene resulting in premature termination of the amino acid chain was identified in a 46-year old male presenting with decrease in physical performance and persisting fatigue after COVID-19 infection. Examinations showed raised creatine kinase (CK) levels, neuropathy and clinical features of myopathy. FACS revealed the K-k+ blood type and reduced Cellano density. CSF flow cytometry showed elevation of activated T Cells.Conclusion: In-depth clinical, genetic, immunological and ribonucleic acid (RNA) expression data revealed axonal neuropathy, myopathy and raised levels of activated CSF-T-lymphocytes in a patient with a previously unpublished frameshift deletion in the XK gene.

Summary: Background: The accuracy of blood-based early tumour recognition is compromised by signal production at non-tumoral sites, low amount of signal produced by small tumours, and variable tumour production. Here we examined whether tumour-specific enhancement of vascular permeability by the particular tumour homing peptide, iRGD, which carries dual function of binding to integrin receptors overexpressed in the tumour vasculature and is known to promote extravasation via neuropilin-1 receptor upon site-specific cleavage, might be useful to improve blood-based tumour detection by inducing a yet unrecognised vice versa tumour-to-blood transport. Methods: To detect an iRGD-induced tumour-to-blood transport, we examined the effect of intravenously injected iRGD on blood levels of α-fetoprotein (AFP) and autotaxin in several mouse models of hepatocellular carcinoma (HCC) or in mice with chronic liver injury without HCC, and on prostate-specific antigen (PSA) levels in mice with prostate cancer. Findings: Intravenously injected iRGD rapidly and robustly elevated the blood levels of AFP in several mouse models of HCC, but not in mice with chronic liver injury. The effect was primarily seen in mice with small tumours and normal basal blood AFP levels, was attenuated by an anti-neuropilin-1 antibody, and depended on the concentration gradient between tumour and blood. iRGD treatment was also able to increase blood levels of autotaxin in HCC mice, and of PSA in mice with prostate cancer. Interpretation: We conclude that iRGD induces a tumour-to-blood transport in a tumour-specific fashion that has potential of improving diagnosis of early stage cancer. Funding: Deutsche Krebshilfe, DKTK, LOEWE-Frankfurt Cancer Institute.

Riming is a key precipitation formation process in mixed-phase clouds which efficiently converts cloud liquid to ice water. Here, we present two methods to quantify riming of ice particles from airborne observations with the normalized rime mass, which is the ratio of rime mass to the mass of a size-equivalent spherical graupel particle. We use data obtained during the HALO-(AC)3 aircraft campaign, where two aircraft collected radar and in situ measurements that were closely spatially and temporally collocated over the Fram Strait west of Svalbard in spring 2022. The first method is based on an inverse optimal estimation algorithm for the retrieval of the normalized rime mass from a closure between cloud radar and in situ measurements during these collocated flight segments (combined method). The second method relies on in situ observations only, relating the normalized rime mass to optical particle shape measurements (in situ method). We find good agreement between both methods during collocated flight segments with median normalized rime masses of 0.024 and 0.021 (mean values of 0.035 and 0.033) for the combined and in situ method, respectively. Assuming that particles with a normalized rime mass smaller than 0.01 are unrimed, we obtain average rimed fractions of 88 % and 87 % over all collocated flight segments. Although in situ measurement volumes are in the range of a few cubic centimeters and are therefore much smaller than the radar volume (about 45 m footprint diameter at an altitude of 500 m above ground, with a vertical resolution of 5 m), we assume they are representative of the radar volume. When this assumption is not met due to less homogeneous conditions, discrepancies between the two methods result. We show the performance of the methods in a case study of a collocated segment of cold-air outbreak conditions and compare normalized rime mass results with meteorological and cloud parameters. We find that higher normalized rime masses correlate with streaks of higher radar reflectivity. The methods presented improve our ability to quantify riming from aircraft observations.

Background & Aims: Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I. Methods: CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1–10.5 Gy (total doses 32.4–42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks. Results: Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression. Conclusions: CIRT of HCC yields excellent local control without dose-limiting toxicity. Impact and implications: To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials. Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT01167374).

Background & Aims: In clinical practice, the diagnosis of alcohol-associated hepatitis (AH) is mostly based on non-invasive criteria, which were defined at a consensus conference by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). These criteria were recently modified by adding C-reactive protein (CRP) and termed NIAAAm-CRP criteria, which showed superior diagnostic accuracy for presence of alcohol-associated steatohepatitis (ASH) on liver histology. The aim of our study was to validate the diagnostic accuracy of both original NIAAA criteria and NIAAAm-CRP criteria for presence of ASH on liver histology in an independent cohort. Methods: Data from a large multinational cohort of 445 patients with alcohol-associated liver disease (ALD) that served to establish a novel grading and staging system of alcohol-associated liver disease were analyzed retrospectively. Diagnosis of ASH was based on presence of hepatocyte ballooning plus lobular neutrophil infiltration and established in virtual consensus meetings of multiple expert liver pathologists. Results: Complete data including CRP values were available in 346 patients. Overall diagnostic accuracy for prediction of ASH was 73% for NIAAA criteria and 77% for NIAAAm-CRP criteria. In a subgroup with suspected severe AH (MELD >20, n = 123), overall diagnostic accuracy for prediction of ASH was 69% for NIAAA criteria and 74% for NIAAAm-CRP criteria. Conclusion: Our findings confirm recent data on suboptimal diagnostic accuracy of original NIAAA criteria and validate slightly better but still suboptimal performance of NIAAAm-CRP criteria for presence of ASH. Impact and Implications: Alcohol-associated steatohepatitis (ASH) is diagnosed on liver histology but liver biopsy is not always feasible. Non-invasive diagnosis based on clinical findings has been proposed using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria and recently improved using NIAAAm-CRP criteria. Our findings validate slightly better but still suboptimal performance of NIAAAm-CRP criteria for the presence of histological ASH. Clinical trials of novel drugs should focus on histologically proven ASH.

Due to their potential to either warm or cool the surface, liquid-phase clouds and their interaction with the ice-free and sea-ice-covered ocean largely determine the energy budget and surface temperature in the Arctic. Here, we use airborne measurements of solar spectral cloud reflectivity obtained during the Arctic CLoud Observations Using airborne measurements during polar Day (ACLOUD) campaign in summer 2017 and the Arctic Amplification: FLUXes in the Cloudy Atmospheric Boundary Layer (AFLUX) campaign in spring 2019 in the vicinity of Svalbard to retrieve microphysical properties of liquid-phase clouds. The retrieval was tailored to provide consistent results over sea-ice and open-ocean surfaces. Clouds including ice crystals that significantly bias the retrieval results were filtered from the analysis. A comparison with in situ measurements shows good agreement with the retrieved effective radii and an overestimation of the liquid water path and reduced agreement for boundary-layer clouds with varying fractions of ice water content. Considering these limitations, retrieved microphysical properties of clouds observed over the ice-free ocean and sea ice in spring and early summer in the Arctic are compared. In early summer, the liquid-phase clouds have a larger median effective radius (9.5 µm), optical thickness (11.8) and effective liquid water path (72.3 g m−2) compared to spring conditions (8.7 µm, 8.3 and 51.8 g m−2, respectively). The results show larger cloud droplets over the ice-free Arctic Ocean compared to sea ice in spring and early summer caused mainly by the temperature differences in the surfaces and related convection processes. Due to their larger droplet sizes, the liquid clouds over the ice-free ocean have slightly reduced optical thicknesses and lower liquid water contents compared to the sea-ice surface conditions. The comprehensive dataset on microphysical properties of Arctic liquid-phase clouds is publicly available and could, e.g., help to constrain models or be used to investigate effects of liquid-phase clouds on the radiation budget.

Abstract Since decades, the concept of vibrational density of states in glasses has been mirrored in liquids by the instantaneous-normal-mode spectrum. In glasses instantaneous configurations are believed to be situated close to minima of the potential-energy hypersurface and all eigenvalues of the associated Hessian matrix are positive. In liquids this is no longer true, and modes corresponding to both positive and negative eigenvalues exist. The instantaneous-normal-mode spectrum has been numerically investigated in the past, and it has been demonstrated to bring important information on the liquid dynamics and transport properties. A systematic deeper theoretical understanding is now needed. Heterogeneous-elasticity theory has proven to be particularly successful in explaining many details of the low-frequency excitations in glasses, ranging from the thoroughly studied boson peak, to other anomalies related to the crossover between wave-like and random-matrix-like excitations. Here we present an extension of heterogeneous-elasticity theory to the liquid state, and show that the outcome of the theory agrees well to the results of extensive molecular-dynamics simulations of a model liquid at different temperatures. We find that the spectrum of eigenvalues $$\rho (\lambda )$$ ρ ( λ ) has a sharp maximum close to (but not at) $$\lambda =0$$ λ = 0 , and decreases monotonically with $$|\lambda |$$ | λ | on both its stable and unstable side. We show that the spectral shape strongly depends on temperature, being symmetric at high temperatures and becoming rather asymmetric at low temperatures, close to the dynamical critical temperature. Most importantly, we demonstrate that the theory naturally reproduces a surprising phenomenon, a zero-energy spectral singularity with a cusp-like character developing in the vibrational spectra upon cooling. This feature, known from a few previous numerical studies, has been generally overlooked in the past due to a misleading representation of the data. We provide a thorough analysis of this issue, based on both very accurate predictions of our theory, and computational studies of model liquid systems with extended size.

Abstract A growing number of druggable targets and national initiatives for precision oncology necessitate broad genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and accurate determination of complex biomarkers including tumor mutational burden (TMB), homologous recombination repair deficiency (HRD), and microsatellite instability (MSI). To assess the inter-institution variability of clinical WES, we performed a comparative pilot study between German Centers of Personalized Medicine (ZPMs) from five participating institutions. Tumor and matched normal DNA from 30 patients were analyzed using custom sequencing protocols and bioinformatic pipelines. Calling of somatic variants was highly concordant with a positive percentage agreement (PPA) between 91 and 95% and a positive predictive value (PPV) between 82 and 95% compared with a three-institution consensus and full agreement for 16 of 17 druggable targets. Explanations for deviations included low VAF or coverage, differing annotations, and different filter protocols. CNAs showed overall agreement in 76% for the genomic sequence with high wet-lab variability. Complex biomarkers correlated strongly between institutions (HRD: 0.79–1, TMB: 0.97–0.99) and all institutions agreed on microsatellite instability. This study will contribute to the development of quality control frameworks for comprehensive genomic profiling and sheds light onto parameters that require stringent standardization.

Most Arctic clouds occur below 2 km altitude, as revealed by CloudSat satellite observations. However, recent studies suggest that the relatively coarse spatial resolution, low sensitivity, and blind zone of the radar installed on CloudSat may not enable it to comprehensively document low-level clouds. We investigate the impact of these limitations on the Arctic low-level cloud fraction, which is the number of cloudy points with respect to all points as a function of height, derived from CloudSat radar observations. For this purpose, we leverage highly resolved vertical profiles of low-level cloud fraction derived from down-looking Microwave Radar/radiometer for Arctic Clouds (MiRAC) radar reflectivity measurements. MiRAC was operated during four aircraft campaigns that took place in the vicinity of Svalbard during different times of the year, covering more than 25 000 km. This allows us to study the dependence of CloudSat limitations on different synoptic and surface conditions. A forward simulator converts MiRAC measurements to synthetic CloudSat radar reflectivities. These forward simulations are compared with the original CloudSat observations for four satellite underflights to prove the suitability of our forward-simulation approach. Above CloudSat's blind zone of 1 km and below 2.5 km, the forward simulations reveal that CloudSat would overestimate the MiRAC cloud fraction over all campaigns by about 6 percentage points (pp) due to its horizontal resolution and by 12 pp due to its range resolution and underestimate it by 10 pp due to its sensitivity. Especially during cold-air outbreaks over open water, high-reflectivity clouds appear below 1.5 km, which are stretched by CloudSat's pulse length causing the forward-simulated cloud fraction to be 16 pp higher than that observed by MiRAC. The pulse length merges multilayer clouds, whereas thin low-reflectivity clouds remain undetected. Consequently, 48 % of clouds observed by MiRAC belong to multilayer clouds, which reduces by a factor of 4 for the forward-simulated CloudSat counterpart. Despite the overestimation between 1 and 2.5 km, the overall low-level cloud fraction is strongly reduced due to CloudSat's blind zone that misses a cloud fraction of 32 % and half of the total (mainly light) precipitation amount.

Abstract Background In the present retrospective analysis we analysed the therapeutic outcome of a set of patients, who were treated with chemoradiation (CRT) for recurrent pancreatic cancer (RPC) in a single institution. Patients and Methods Forty-one patients had a history of primary resection for pancreatic cancer. In case of an unresectable recurrency patients were treated with CRT at our institution between 2002 and 2010 with a median dose of 48.4 Gy (range 39.6–54 Gy). Concurrent chemotherapy regimes included Gemcitabine (GEM) in 37/41 patients (90%) and Fluorouracil (FU) or Capecitabine (CAP) in 4/41 patients (10%). Patients were re-evaluated after CRT with computed tomography and/or explorative laparotomy. During re-resection or laparotomy 15 patients received an additional intraoperative radiotherapy (IORT) with a median dose of 15 Gy (range 12–15 Gy). Median age was 65 years (range 39–76 years) and there were 26 male and 15 female patients. Results The median overall survival (mOS), local control (LC) and progression-free survival (PFS) were 16.1, 13.8 and 6.9 months respectively for all patients after the first day of CRT. Re-resection was possible in five patients (12%) and a complete remission (CR) as defined by tumor-free biopsy was seen in 6 patients (15%). When re-resection could be achieved after CRT mOS was improved to 28.3 months (n = 5 patients, 95%-CI 10.2 – 46.3 months). Patients receiving IORT had a significantly improved mOS compared to no IORT (p = 0.034). Fifteen patients (37%) experienced a local tumour progression and main site of distant metastasis was the liver (11 patients, 27%).Overall treatment-related toxicity was mild, grade III hematologic toxicity was observed in 11 patients (27%). Conclusion In summary we observed a good therapeutic response with mild to moderate toxicity levels for CRT in RPC. Overall survival and PFS were clearly improved in case of induction of a complete remission (tumor-free biopsies) or after achieving a re-resection, thus providing a curative intended therapy even in case of disease recurrence.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (

Abstract Introduction To evaluate efficacy and secondary resectability in patients with locally advanced pancreatic cancer (LAPC) treated with neoadjuvant chemoradiotherapy (CRT). Patients and methods A total of 215 patients with locally advanced pancreatic cancer were treated with chemoradiation at a single institution. Radiotherapy was delivered with a median dose of 52.2 Gy in single fractions of 1.8 Gy. Chemotherapy was applied concomitantly as gemcitabine (GEM) at a dose of 300 mg/m2 weekly, followed by adjuvant cycles of full-dose GEM (1000 mg/m2). After neoadjuvant CRT restaging was done to evaluate secondary resectability. Overall and disease-free survival were calculated and prognostic factors were estimated. Results After CRT a total of 26% of all patients with primary unresectable LAPC were chosen to undergo secondary resection. Tumour free resection margins could be achieved in 39.2% (R0-resection), R1-resections were seen in 41.2%, residual macroscopic tumour in 11.8% (R2) and in 7.8% resection were classified as Rx. Patients with complete resection after CRT showed a significantly increased median overall survival (OS) with 22.1 compared to 11.9 months in non-resected patients. Median OS and disease-free survival (DFS) of all patients were 12.3 and 8.1 months respectively. In most cases the first site of disease progression was systemic with hepatic (52%) and peritoneal (36%) metastases. Discussion A high percentage of patients with locally advanced pancreatic cancer can undergo secondary resection after gemcitabine-based chemoradiation and has a relative long-term prognosis after complete resection.

Abstract Background Tissue inhibitors of metalloproteinases (TIMPs) and the corresponding metalloproteinases are integral parts of the protease network and have been shown to be involved in cancer development and metastasis. Paradoxically, for TIMP-1, tumor promoting as well as tumor inhibitory effects have been observed. Methods To address this paradox, we utilized the BALB/c/CT26 mouse model that reliably leads to liver metastasis after splenic tumor cell injection and variegated the type of target cells for therapeutic intervention and the modalities of gene transfer. Since we have observed before that over-expression of TIMP-1 in liver host cells leads to efficient tumor growth inhibition in this model, we now examined whether targeting the tumor cells themselves will have a similar effect. Results In concordance with the earlier results, TIMP-1 over-expression in tumor cells led to a dramatic reduction of tumor growth as well. To evaluate any influence of treatment modality, we further examined whether TIMP-1 knockdown in the same animal model would have the opposite effect on tumor growth than TIMP-1 over-expression. Indeed, TIMP-1 knockdown led to a marked increase in tumor burden. Conclusion These data indicate that in the BALB/c/CT26 model, the modification of TIMP-1 has concordant effects irrespective of the type of target cell or the technique of modulation of TIMP-1 activity, and that TIMP-1 is unequivocally tumor inhibitory in this model.

Abstract Background Aquaporins (AQPs) have been recognized to promote tumor progression, invasion, and metastasis and are therefore recognized as promising targets for novel anti-cancer therapies. Potentially relevant AQPs in distinct cancer entities can be determined by a comprehensive expression analysis of the 13 human AQPs. Methods We analyzed the presence of all AQP transcripts in 576 different normal lung and non-small cell lung cancer (NSCLC) samples using microarray data and validated our findings by qRT-PCR and immunohistochemistry. Results Variable expression of several AQPs (AQP1, -3, -4, and -5) was found in NSCLC and normal lung tissues. Furthermore, we identified remarkable differences between NSCLC subtypes in regard to AQP1, -3 and -4 expression. Higher transcript and protein levels of AQP4 in well-differentiated lung adenocarcinomas suggested an association with a more favourable prognosis. Beyond water transport, data mining of co-expressed genes indicated an involvement of AQP4 in cell-cell signalling, cellular movement and lipid metabolism, and underlined the association of AQP4 to important physiological functions in benign lung tissue. Conclusions Our findings accentuate the need to identify functional differences and redundancies of active AQPs in normal and tumor cells in order to assess their value as promising drug targets.

Abstract Background The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. Here, we studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC). Methods EZH2 protein expression in RCC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing RCC tumor tissue and corresponding normal tissue samples of 520 patients. For immunohistochemical assessment of EZH2 expression, nuclear staining quantity was evaluated using a semiquantitative score. The effect of EZH2 expression on cancer specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. Results During follow-up, 147 patients (28%) had died of their disease, median follow-up of patients still alive was 6.0 years (range 0-16.1 years). EZH2 nuclear staining was present in tumor cores of 411 (79%) patients. A multivariate Cox regression analysis revealed that high nuclear EZH2 expression was an independent predictor of poor CSS (> 25-50% vs. 0%: HR 2.72, p = 0.025) in patients suffering from non-metastatic RCC. Apart from high nuclear EZH2 expression, tumor stage and Fuhrman's grading emerged as significant prognostic markers. In metastatic disease, nuclear EZH2 expression and histopathological subtype were independent predictive parameters of poor CSS (EZH2: 1-5%: HR 2.63, p = 0.043, >5-25%: HR 3.35, p = 0.013, >25%-50%: HR 4.92, p = 0.003, all compared to 0%: HR 0.36, p = 0.025, respectively). Conclusions This study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC.

Abstract Background Adherens junctions (AJs) facilitate cell–cell contact and contribute to cellular communication as well as signaling under physiological and pathological conditions. Aberrant expression of AJ proteins is frequently observed in human cancers; however, how these factors contribute to tumorigenesis is poorly understood. In addition, for some factors such as α‐catenin contradicting data has been described. In this study we aim to decipher how the AJ constituent α‐catenin contributes to liver cancer formation. Methods TCGA data was used to detect transcript changes in 23 human tumor types. For the detection of proteins, liver cancer tissue microarrays were analyzed by immunohistochemistry. Liver cancer cell lines (HLF, Hep3B, HepG2) were used for viability, proliferation, and migration analyses after RNAinterference-mediated gene silencing. To investigate the tumor initiating potential, vectors coding for α‐catenin and myristoylated AKT were injected in mice by hydrodynamic gene delivery. A BioID assay combined with mass spectrometry was performed to identify α‐catenin binding partners. Results were confirmed by proximity ligation and co-immunoprecipitation assays. Binding of transcriptional regulators at gene promoters was investigated using chromatin-immunoprecipitation. Results α‐catenin mRNA was significantly reduced in many human malignancies (e.g., colon adenocarcinoma). In contrast, elevated α‐catenin expression in other cancer entities was associated with poor clinical outcome (e.g., for hepatocellular carcinoma; HCC). In HCC cells, α‐catenin was detectable at the membrane as well as cytoplasm where it supported tumor cell proliferation and migration. In vivo, α‐catenin facilitated moderate oncogenic properties in conjunction with AKT overexpression. Cytokinesis regulator centrosomal protein 55 (CEP55) was identified as a novel α‐catenin-binding protein in the cytoplasm of HCC cells. The physical interaction between α‐catenin and CEP55 was associated with CEP55 stabilization. CEP55 was highly expressed in human HCC tissues and its overexpression correlated with poor overall survival and cancer recurrence. Next to the α‐catenin-dependent protein stabilization, CEP55 was transcriptionally induced by a complex consisting of TEA domain transcription factors (TEADs), forkhead box M1 (FoxM1), and yes-associated protein (YAP). Surprisingly, CEP55 did not affect HCC cell proliferation but significantly supported migration in conjunction with α‐catenin. Conclusion Migration-supporting CEP55 is induced by two independent mechanisms in HCC cells: stabilization through interaction with the AJ protein α‐catenin and transcriptional activation via the FoxM1/TEAD/YAP complex.

Abstract TP53 is the most frequently mutated gene in human cancer. While no TP53-targeting drugs have been approved in the USA or Europe so far, preclinical and clinical studies are underway to investigate targeting of specific or all TP53 mutations, for example, by restoration of the functionality of mutated TP53 (TP53mut) or protecting wildtype TP53 (TP53wt) from negative regulation. We performed a comprehensive mRNA expression analysis in 24 cancer types of TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between tumors harboring different TP53 mutation types such as loss of function, gain of function or dominant-negative mutations, and (iii) cancer-type-specific patterns of gene expression and immune infiltration. Analysis of mutational hotspots revealed both similarities across cancer types and cancer type-specific hotspots. Underlying ubiquitous and cancer type-specific mutational processes with the associated mutational signatures contributed to explaining this observation. Virtually no genes were differentially expressed between tumors harboring different TP53 mutation types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus list included 178 genes that were overexpressed and 32 genes that were underexpressed in the TP53mut tumors of at least 16 of the investigated 24 cancer types. In an association analysis of immune infiltration with TP53 mutations in 32 cancer subtypes, decreased immune infiltration was observed in six subtypes, increased infiltration in two subtypes, a mixed pattern of decreased and increased immune cell populations in four subtypes, while immune infiltration was not associated with TP53 status in 20 subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and supports the view that TP53 mutations should be further evaluated as predictive markers for immunotherapy and targeted therapies.