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Viral genome sequencing can address key questions about SARS-CoV-2 evolution and viral transmission. Here, we present an integrated system of genomic surveillance in the German city of Düsseldorf, combining a) viral surveillance sequencing, b) genetically based identification of infection clusters in the population, c) analysis of hospital outbreaks, d) integration of public health authority contact tracing data, and e) a user-friendly dashboard application as a central data analysis platform. The generated surveillance sequencing data (n = 320 SARS-CoV-2 genomes) showed that the development of the local viral population structure from August to December 2020 was consistent with European trends, with the notable absence of SARS-CoV-2 variants 20I/501Y.V1/B.1.1.7 and B.1.351 until the end of the local sampling period. Against a background of local surveillance and other publicly available SARS-CoV-2 data, four putative SARS-CoV-2 outbreaks at Düsseldorf University Hospital between October and December 2020 (n = 44 viral genomes) were investigated and confirmed as clonal, contributing to the development of improved infection control and prevention measures. An analysis of the generated surveillance sequencing data with respect to infection clusters in the population based on a greedy clustering algorithm identified five candidate clusters, all of which were subsequently confirmed by the integration of public health authority contact tracing data and shown to be represent transmission settings of particular relevance (schools, care homes). A joint analysis of outbreak and surveillance data identified a potential transmission of an outbreak strain from the local population into the hospital and back; and an in-depth analysis of one population infection cluster combining genetic with contact tracing data enabled the identification of a previously unrecognized population transmission chain involving a martial arts gym. Based on these results and a real-time sequencing experiment in which we demonstrated the feasibility of achieving sample-to-turnaround times of

Prophylactic drainage after major liver resection remains controversial. This systematic review and meta-analysis evaluate the value of prophylactic drainage after major liver resection. PubMed, Web of Science, and Cochrane Central were searched. Postoperative bile leak, bleeding, interventional drainage, wound infection, total complications, and length of hospital stay were the outcomes of interest. Dichotomous outcomes were presented as odds ratios (OR) and for continuous outcomes, weighted mean differences (MDs) were computed by the inverse variance method. Summary effect measures are presented together with their corresponding 95% confidence intervals (CI). The certainty of evidence was evaluated using the Grades of Research, Assessment, Development and Evaluation (GRADE) approach, which was mostly moderate for evaluated outcomes. Three randomized controlled trials and five non-randomized trials including 5,050 patients were included. Bile leakage rate was higher in the drain group (OR: 2.32; 95% CI 1.18–4.55; p = 0.01) and interventional drains were inserted more frequently in this group (OR: 1.53; 95% CI 1.11–2.10; p = 0.009). Total complications were higher (OR: 1.71; 95% CI 1.45–2.03; p

The absorption and emission properties of organic dyes are generally tuned by altering the substitution pattern. However, tuning the fluorescence lifetimes over a range of several 10 ns while barely affecting the spectral features and maintaining a moderate fluorescence quantum yield is challenging. Such properties are required for lifetime multiplexing and barcoding applications. Here, we show how this can be achieved for the class of fluoranthene dyes, which have substitution-dependent lifetimes between 6 and 33 ns for single wavelength excitation and emission. We explore the substitution-dependent emissive properties in the crystalline solid state that would prevent applications. Furthermore, by analyzing dye mixtures and embedding the dyes in carboxy-functionalized 8 μm-sized polystyrene particles, the unprecedented potential of these dyes as labels and encoding fluorophores for time-resolved fluorescence detection techniques is demonstrated.

In this work, we describe a simple solvothermal route for the synthesis of Eu3+-doped gadolinium orthovanadate nanocrystals (Eu:GdVO4–PAA) functionalized with poly(acrylic)acid (PAA), that are applicable as cell labeling probes for multimodal cellular imaging. The Eu3+ doping of the vanadate matrix provides optical functionality, due to red photoluminescence after illumination with UV light. The Gd3+ ions of the nanocrystals reduce the T1 relaxation time of surrounding water protons, allowing these nanocrystals to act as a positive MRI contrast agent with a r1 relaxivity of 1.97 mM–1 s–1. Low background levels of Eu3+, Gd3+, and V5+ in biological systems make them an excellent label for elemental microscopy by Laser Ablation (LA)-ICP-MS. Synthesis resulted in polycrystalline nanocrystals with a hydrodynamic diameter of 55 nm and a crystal size of 36.7 nm, which were further characterized by X-ray diffraction (XRD), photoluminescence spectroscopy (PL) and transmission electron microscopy (TEM). The multifu...

Simple Summary Gallbladder cancer (GBC) is an aggressive malignancy with poor prognosis. Currently, therapeutic options are mostly limited to palliative chemotherapy. Considering the advances of immunotherapy, we assessed the expression of the programmed cell death ligand-1 (PD-L1) as the most widely used predictive marker for immunotherapy response in a large Western-world GBC cohort. Additionally, we quantified the expression of the T-cell immunoreceptor with Ig and ITIM domains TIGIT/CD155 axis as an emerging immune checkpoint. Our results indicate that PD-L1 is heterogeneously expressed in Western-world GBC and associated with distinct histomorphological tumor subtypes and increased immune cell densities. We show that a high tumoral PD-L1 expression is a significant negative prognosticator. In a subset of patients, we identified expression of TIGIT in scattered immune cells, which correlated with tumoral expression of its ligand CD155. Our results suggest a subset of GBC patients to be candidates for immunotherapy via (combined) PD-L1 and TIGIT/CD155 inhibition. Abstract Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 GBC patients as Tumor Proportion Score (TPS), Immune Cell Score (IC) and Combined Positivity Score (CPS). Tumor cells expressed PD-L1 in a subset of 14.7% GBC patients at a TPS cut-off of 1%. Higher PD-L1 levels above 10% and 25% TPS were reached in 4.7% and 3.1% of GBC cases, respectively. At a 10% cut-off, TPS was associated with distinct histomorphological subtypes and correlated with poor tumor differentiation. Survival analysis revealed a TPS above 10% to be a highly significant and independent negative prognosticator in GBC. PD-L1 expression was associated with increased CD4+, CD8+ and PD-1+ immune cell densities. In 14.8% of the cases, scattered immune cells expressed T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which was correlated to tumoral expression of its ligand CD155. We here show that a high PD-L1 expression confers a negative prognostic value in Western-world GBC and highlight the TIGIT/CD155 immune checkpoint as a potential new target for GBC immunotherapy.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide and features various tumor escape mechanisms from treatment-induced stress. HSP70 plays a critical role in cell protection under stress. eIF4G physiologically regulates the formation of the protein-ribosomal complex and maintains cellular protein synthesis. However, the precise cooperation of both in HCC remains poorly understood. In this study, we demonstrate that HSP70 expression is positively correlated with eIF4G in tumor specimens from 25 HCC patients, in contrast to the adjacent non-tumorous tissues, and that both influence the survival of HCC patients. Mechanistically, this study indicates that HSP70 and eIF4G interact with each other in vitro. We further show that the HSP70-eIF4G interaction contributes to promoting cellular protein synthesis, enhancing cell proliferation, and inhibiting cell apoptosis. Collectively, this study reveals the pivotal role of HSP70-eIF4G interaction as an escape mechanism in HCC. Therefore, modulation of the HSP70-eIF4G interaction might be a potential novel therapeutic target of HCC treatment.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide and features various tumor escape mechanisms from treatment-induced stress. HSP70 plays a critical role in cell protection under stress. eIF4G physiologically regulates the formation of the protein-ribosomal complex and maintains cellular protein synthesis. However, the precise cooperation of both in HCC remains poorly understood. In this study, we demonstrate that HSP70 expression is positively correlated with eIF4G in tumor specimens from 25 HCC patients, in contrast to the adjacent non-tumorous tissues, and that both influence the survival of HCC patients. Mechanistically, this study indicates that HSP70 and eIF4G interact with each other in vitro. We further show that the HSP70&ndash, eIF4G interaction contributes to promoting cellular protein synthesis, enhancing cell proliferation, and inhibiting cell apoptosis. Collectively, this study reveals the pivotal role of HSP70&ndash, eIF4G interaction as an escape mechanism in HCC. Therefore, modulation of the HSP70&ndash, eIF4G interaction might be a potential novel therapeutic target of HCC treatment.

Pancreatoduodenectomy is the standard treatment for pathologies of the pancreatic head and is performed routinely worldwide. The aim of the study was to analyze this procedure in terms of extent of surgery, technical difficulty, and clinical outcomes and thereby provide a standardized surgical categorization of pancreatoduodenectomies for future reference.For this cohort study, all patients who underwent pancreatoduodenectomy at a single center within an 18-year period (October 2001 to December 2019) were identified in a prospectively maintained database. Based on technical difficulty and extent of surgery, 4 pancreatoduodenectomy types were proposed: (1) standard pancreatoduodenectomy; (2) pancreatoduodenectomy with portal vein/superior mesenteric vein resection; (3) pancreatoduodenectomy with multivisceral resection; and (4) pancreatoduodenectomy with arterial resection. Patient characteristics, surgical parameters, and perioperative morbidity and mortality were analyzed. The 4 types were compared with regard to their surgical outcomes.A total of 3,953 pancreatoduodenectomies were performed in the study period. Standard pancreatoduodenectomy (type 1) was the most frequent procedure (n = 2,931, 74.1%), followed by pancreatoduodenectomy with portal vein/superior mesenteric vein resection (type 2: n = 568, 14.4%), pancreatoduodenectomy with multivisceral resection (type 3: n = 415, 10.5%), and pancreatoduodenectomy with arterial resection (type 4: n = 39, 1.0%). Demographic baseline characteristics were clinically comparable among pancreatoduodenectomy types. Mortality within 90-days correlated with the type of pancreatoduodenectomy (type 1: 2.9%; type 2: 4.2%; type 3: 6.3%; type 4: 10.3%; P = .0007). Overall surgical morbidity was 41.7% (type 1), 40.8% (type 2), 52.5% (type 3), and 59.0% (type 4) (P.0001), including postoperative pancreatic fistula type B/C (type 1: 11.9%; type 2: 7.7%; type 3: 14.7%; type 4: 15.4; P = .0031) and delayed gastric emptying (type 1: 19.4%; type 2: 22.5%; type 3: 22.0%; type 4: 25.6%; P = .187) as the most frequent complications. Relaparotomies were more frequent in type 4 (20.5%) and type 3 (20.6%) than in type 2 (12.0%) or type 1 (10.4%) pancreatoduodenectomy (P.0001). Intensive care unit stay ≥2 days was more frequent in type 4 (48.7%) compared with type 3 (25.7%) or type 2 (27.1%) and type 1 (18.6%) (P.0001).The results show different clinical outcomes for the 4 types of pancreatoduodenectomy. Morbidity and mortality correlate with pancreatoduodenectomy type. The proposed pancreatoduodenectomy classification is useful for reporting pancreatoduodenectomy procedures, enhances the comparability of future studies, may be used for training purposes, and may guide intra and postoperative decision-making.

Eine professionelle Projektentwicklung ist das Fundament für jeden langfristig erfolgreichen Hotelbetrieb. Viele unterschiedliche Akteure – ob Berater, Architekten, Hotelgesellschaften, Bauherren oder Investoren – sind darin involviert: Mangelnde Kommunikation und fehlendes Wissen vom Tun der jeweils anderen können zum Scheitern des gesamten Hotelprojektes führen. Mit fundierten Expertenbeiträgen im Spannungsfeld des Hotel-, Immobilien- und Projektmanagements macht dieses Buch die Zusammenhänge transparent. Die 3. Auflage des Standardwerks wurde umfassend aktualisiert und z.B. zur Rolle von Rechtsanwälten und (Interieur-)Designern erweitert. Interviews mit Branchenpersönlichkeiten geben exklusive Einblicke in die Perspektiven beteiligter Stakeholder.

UNSTRUCTURED Serious games are digital games that have an additional goal beyond entertainment. Recently, many studies have explored different quality criteria for serious games, including effectiveness and attractiveness. Unfortunately, the double mission of serious games, that is, simultaneous achievement of intended effects (serious part) and entertainment (game part), is not adequately considered in these studies. This paper aims to identify essential quality criteria for serious games. The fundamental goal of our research is to identify important factors of serious games and to adapt the existing principles and requirements from game-related literature to effective and attractive serious games. In addition to the review of the relevant literature, we also include workshop results. Furthermore, we analyzed and summarized 22 state-of-the-art serious games for education and health. The selected best-practice serious games either prove their effectiveness through scientific studies or by winning game awards. For the analysis of these games, we refer to “DIN SPEC 91380 Serious Games Metadata Format.” A summarized text states quality criteria for both the serious and the game part, and especially the balance between them. We provide guidelines for high-quality serious games drawn from literature analysis and in close cooperation with domain experts.

Serious games are digital games that have an additional goal beyond entertainment. Recently, many studies have explored different quality criteria for serious games, including effectiveness and attractiveness. Unfortunately, the double mission of serious games, that is, simultaneous achievement of intended effects (serious part) and entertainment (game part), is not adequately considered in these studies. This paper aims to identify essential quality criteria for serious games. The fundamental goal of our research is to identify important factors of serious games and to adapt the existing principles and requirements from game-related literature to effective and attractive serious games. In addition to the review of the relevant literature, we also include workshop results. Furthermore, we analyzed and summarized 22 state-of-the-art serious games for education and health. The selected best-practice serious games either prove their effectiveness through scientific studies or by winning game awards. For the analysis of these games, we refer to “DIN SPEC 91380 Serious Games Metadata Format.” A summarized text states quality criteria for both the serious and the game part, and especially the balance between them. We provide guidelines for high-quality serious games drawn from literature analysis and in close cooperation with domain experts.

Background: There is little population-based data on hepatocellular carcinoma (HCC) with brain metastases at initial diagnosis published. This study aimed to estimate incidence of brain metastases in initial metastatic HCC and its impact on prognosis.Methods: Newly diagnosed HCC cases from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were screened for the presence of brain metastases. Data were stratified by age and ethnicity. Multivariable logistic and Cox regression were used to identify factors associated with brain metastases and factors associated with overall survival (OS) and cancer-specific survival (CSS), respectively. Kaplan-Meier method and log-rank test were used for survival analysis.Results: 141 cases presenting with brain metastases were identified, accounting for 0.35% of all HCC cases and 2.37% of cases with metastatic HCC disease. The incidence rate was highest among cases with age 50-59 (2.74%), respectively. Ethnicity was not associated with the presence of brain metastases at the time of HCC diagnosis. However, African American patients presented significantly lower disease-specific survival (median time: 1month; interquartile range (IQR):0-3.0 months). Initial lung or bone metastasis was independently associated with an increased risk of the presence of brain metastases (odds ratio (OR) 12.62, 95%CI 8.40-18.97), but not associated with worse OS and CSS among brain metastases cases. Conclusions: The study shows population-based incidence and survival of brain metastases at diagnosis of HCC. Brain metastases are most prevalent in initial metastatic HCC patients with lung or bone metastasis. The results may contribute to consider screening of the brain among HCC with initial lung or bone metastasis.

The aim of this study was to assess and compare the discriminatory performance of well-known risk assessment scores in predicting mortality risk after extended hepatectomy (EH). A series of 250 patients who underwent EH (≥5 segments resection) were evaluated. Aspartate aminotransferase-to-platelet ratio index (APRI), albumin to bilirubin (ALBI) grade, predictive score developed by Breitenstein et al., liver fibrosis (FIB-4) index, and Heidelberg reference lines charting were used to compute cut-off values, and the sensitivity and specificity of each risk assessment score for predicting mortality were also calculated. Major morbidity and 90-day mortality after EH increased with increasing risk scores. APRI (86%), ALBI (86%), Heidelberg score (81%), and FIB-4 index (79%) had the highest sensitivity for 90-day mortality. However, only the FIB-4 index and Heidelberg score had an acceptable specificity (70% and 65%, respectively). A two-stage risk assessment strategy (Heidelberg–FIB-4 model) with a sensitivity of 70% and a specificity 86% for 90-day mortality was proposed. There is no single specific risk assessment score for patients who undergo EH. A two-stage screening strategy using Heidelberg score and FIB-4 index was proposed to predict mortality after major liver resection.

Background Non-alcoholic steatohepatitis (NASH) associated hepatocellular carcinomas (NASH-HCC) are increasing. NASH-HCC often develops in the fibrotic liver. Several analyses report conflicting results regarding the outcome of non-cirrhotic NASH-HCC. Furthermore, type 2 diabetes (T2D) is considered a risk factor for poor survival. The aim of this study was to investigate oncological outcomes of non-cirrhotic NASH-HCC and the impact of T2D. Methods Patients with non-cirrhotic NASH-HCC with T2D as determined by an expert pathologist conducting histological slide review were matched for risks factors for poor outcome (age, gender, body mass index) with patients with NASH-HCC without T2D. These patients were then matched 1:1 with HCCs of other underlying liver diseases with and without T2D. Oncological outcomes were assessed using Kaplan-Meier curves. Results Out of 365 HCCs resected between 2001 and 2017, 34 patients with non-cirrhotic NASH-HCC were selected (17 with T2D, 17 without T2D) and matched with 26 patients with hepatitis-HCC and 28 patients with alcohol-related HCC. Oncological risk factors such as tumor size, resection margin, and vessel invasion were comparable. There was no difference in overall survival (5-year survival 71.3% for NASH-HCC, 60.4% for hepatitis-HCC, 79.9% for alcohol-HCC). NASH-HCC was associated with longer disease-specific survival than hepatitis-HCC (5-year 87.5% vs. 63.7%, p = 0.048), while recurrence-free survival was identical. T2D had no impact on oncological outcomes in either liver disease. Conclusion Non-cirrhotic NASH-HCC has outcomes comparable with other underling etiologies. Despite a lack of cirrhosis, patients with non-cirrhotic NASH-HCC have the same risks of HCC recurrence as patients with cirrhotic liver disease of other etiologies.

Redox switches are applied in various fields of research, including molecular lifts, electronic devices and sensors. Switching the absorbance between UV and Vis/NIR by redox processes is of interest for applications in light harvesting or biomedicine. Here, we present a series of push-pull benzothiadiazole derivatives with high fluorescence quantum yields in solution and in the crystalline solid state. Spectroelectrochemical analysis reveals the switching of UV-absorption in the neutral state to Vis/NIR absorption in the reduced state. We identify the partial irreversibility of the switching process, which appears to be reversible on the cyclic voltammetry timescale.

Reversibly switching the light absorption of organic molecules by redox processes is of interest for applications in sensors, light harvesting, smart materials, and medical diagnostics. This work presents a symmetrical benzothiadiazole (BTD) derivative with a high fluorescence quantum yield in solution and in the crystalline state and shows by spectroelectrochemical analysis that reversible switching of UV absorption in the neutral state, to broadband Vis/NIR absorption in the 1st oxidized state, to sharp band Vis absorption in the 2nd oxidized state, is possible. For the one‐electron oxidized species, formation of a delocalized radical is confirmed by electron paramagnetic resonance spectroelectrochemistry. Furthermore, our results reveal an increasing quinoidal distortion upon the 1st and 2nd oxidation, which can be used as the leitmotif for the development of BTD based redox switches., The quinoidial distortion induced in benzothidiazoles upon oxidation was used in this work to design an absorption redox switch. Using spectroelectrochemical analysis, the absorption, fluorescence and localization of the radical were investigated during the redox processes. The symmetrical benzothiadiazole derivative can thus be used as a UV to Vis/NIR absorption switch or as a fluorescence ON/OFF switch. With deeper understanding of the quinodial distortion, it can furthermore be used as the basis for development of other small organic redox switches.

SARS-CoV-2 utilizes the ACE2 transmembrane peptidase as essential cellular entry receptor. Several studies have suggested abundant ACE2 expression in the human lung, inferring strong permissiveness to SARS-CoV-2 infection with resultant alveolar damage and lung injury. Against this expectation, we provide evidence that ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation in the human alveolus. Instead, spectral imaging of ex vivo infected human lungs and COVID-19 autopsy samples depicted that alveolar macrophages were frequently positive for SARS-CoV-2, indicating viral phagocytosis. Single-cell transcriptomics of SARS-CoV-2 infected human lung tissue further revealed strong inflammatory and anti-viral activation responses in macrophages and monocytes, comparable to those induced by MERS-CoV, but with virus-specific gene expression profiles. Collectively, our findings indicate that severe lung injury in COVID-19 likely results from an overwhelming immune activation rather than direct viral damage of the alveolar compartment. Funding: ACH, LES, SH were supported by Berlin University Alliance GC2 Global Health (Corona Virus Pre-Exploration Project). ACH, SH, TW and CD were supported by BMBF (RAPID) and ACH, SH by BMBF (alvBarriereCOVID-19). KH, LB, SL, SH, CD, TW, ACH were funded by BMBF (NFN-COVID 19, Organo-Strat). KH, NS, LES, MW, SH, ADG, CD, TW and ACH were supported by DFG (SFB-TR 84). ACH was supported by BIH, Charite 3R, and Charite-Zeiss MultiDim. KH was supported by BMBF (Camo-COVID-19). MW, NS and SH was supported by BMBF (PROVID). MW and NS was supported by BIH and BMBF (SYMPATH, CAPSyS, NAPKON). BO and DB were funded through the BIH Clinical Single Cell Bioinformatics Pipeline. LB was supported by the BMBF (CoIMMUNE), the DFG (KFO 342) and the IZKF of the Medical Faculty of the WWU. Conflict of Interest: The authors declare no competing interests. Ethical Approval: The study was approved by the ethics committee at the Charite clinic (projects EA2/079/13) and Arztekammer Westfalen-Lippe and of the Westfalischen Wilhelms-Universitat (AZ: 2016-265-f-S). Written informed consent was obtained from all patients.

The fluorescence lifetime is a key property of fluorophores that can be utilized for microenvironment probing, analyte sensing, and multiplexing as well as barcoding applications. For the rational design of lifetime probes and barcodes, theoretical methods have been developed to enable the ab initio prediction of this parameter, which depends strongly on interactions with solvent molecules and other chemical species in the emitters' immediate environment. In this work, we investigate how a conductor-like screening model (COSMO) can account for variations in fluorescence lifetimes that are caused by such fluorophore−solvent interactions. Therefore, we calculate vibrationally broadened fluorescence spectra using the nuclear ensemble method to obtain distorted molecular geometries to sample the electronic transitions with time-dependent density functional theory (TDDFT). The influence of the solvent on fluorescence lifetimes is accounted for with COSMO. For example, for 4-hydroxythiazole fluorophore containing different heteroatoms and acidic and basic moieties in aprotic and protic solvents of varying polarity, this approach was compared to experimentally determined lifetimes in the same solvents. Our results demonstrate a good correlation between theoretically predicted and experimentally measured fluorescence lifetimes except for the polar solvents Ethanol and acetonitrile that can specifically interact with the heteroatoms and the carboxylic acid of the thiazole derivative.

In recent years, the profile for patients undergoing complex liver resections has changed, with mortality rates remaining generally stable. With these factors in mind, the objective of this study was to evaluate the variables associated with surgical outcomes after hepatectomy and identify groups at high risk for postoperative mortality.The records of 1,796 patients who underwent liver resection of more than one liver segment at the Department of General and Transplantation Surgery, University Hospital Heidelberg, Germany, were analyzed. The primary end point was a 90-day in-hospital mortality. Logistic regression analyses were performed to identify risk factors associated with mortality. A risk score was created in accordance with weighted points based on the odds ratios obtained from multivariate logistic regression analyses. External validation of the score was performed, using data derived from 281 patients at the board-certified center for liver surgery in Karlsruhe, Germany.The overall patient morbidity rate (Clavien-Dindo Grade II or greater) was 32%. The 30- and 90-day mortality rates were 3.0% and 4.5%, respectively. In multivariate analysis, factors independently associated with risk for 90-day in-hospital mortality were age ≥60 years (OR 3.71), ASA classification III (OR 2.94), ASA IV (15.66), perihilar cholangiocarcinoma (OR 5.65), intrahepatic cholangiocarcinoma (OR 3.08), INR ≥ 1.1 (OR 2.43), g-GT ≥ 60 U/L (OR 2.86), platelet count ≤ 120/nL (OR 5.52), creatinine ≥ 2 mg/dL (OR 9.85), and right trisectionectomy (OR 2.88). The 90-day mortality-risk score that was created based on these factors effectively stratified patients into very low risk (0-1 points, 0.2% mortality rate in 662 patients), low risk (2-3 points, 2.9% mortality rate in 769 patients), medium risk (4-5 points, 14.7% mortality rate in 232 patients), and high risk (≥6 points, 33% mortality rate in 57 patients) groups (P.0001). As a performance metric, the C-index for the proposed risk score for 90-day mortality was 0.86; whereas external validation revealed that this C-index was 0.89 (P = .0002).Based on patient-related factors and procedure-specific variables, the proposed preoperative-risk score can be used to identify high-risk patients to determine 90-day mortality after liver resection.

Dye-stained micrometer-sized polymer beads are important tools in the life sciences with applications in biomedical, biochemical, and clinical research. Here, bead-based assays are increasingly used, for example, in DNA sequencing and the detection of autoimmune diseases or pathogenic microorganisms. Moreover, stained beads are employed as calibration tools for fluorescence microscopy and flow cytometry methods with increasing complexity. To address the requirements concerning the relevant fluorescence features, the spectroscopic properties of representative polymer beads with diameters ranging from about 1 to 10 μm stained with varying concentrations of rhodamine 6G were systematically assessed. The observed dependence of the spectral properties, fluorescence decay kinetics, and fluorescence quantum yields on bead size and dye loading concentration is attributed to different fluorescence characteristics of fluorophores located in the particle core and near-surface dye molecules. Supported by the fluorescence anisotropy measurements, the origin of the observed alteration of fluorescence features is ascribed to a combination of excitation energy transfer and polarity-related effects that are especially pronounced at the interface of the bead and the surrounding medium. The results of our studies underline the need to carefully control and optimize all Parameters that can affect the fluorescence properties of the dye-stained beads.

Aggregation-induced emission (AIE) has been meanwhile observed for many dye classes and particularly for fluorophores containing propeller-like groups. Herein, we report on the AIE characteristics of a series of four hydrophobic pyrrolidinylvinylquinoxaline (PVQ) derivatives with phenyl, pyrrolyl, indolyl, and methoxythienyl substituents used to systematically vary the torsion angle between this substituent at the quinoxaline C2 position and the planar PVQ moiety. These molecules, which are accessible via four- or five-component one-pot syntheses, were spectroscopically studied in organic solvents and solvent–water mixtures, as dye aggregates, solids, and entrapped in polystyrene particles (PSP). Steady-state and time-resolved fluorescence measurements revealed a strong fluorescence enhancement for all dyes in ethanol–water mixtures of high water content, accompanying the formation of dye aggregates with sizes of a few hundred nm, overcoming polarity and H-bonding-induced fluorescence quenching of the cha...

Objectives To determine the inpatient management for patients with acute idiopathic facial palsy (IFP) in Thuringia, Germany. Design Population-based study. Setting All inpatients with IFP in all hospitals with departments of otolaryngology and neurology in 2012 in the German federal state Thuringia. Main outcome measures Patients’ characteristics and treatment were compared between departments, and the probability of recovery was tested. Results 291 patients were mainly treated in departments of otolaryngology (55%) and neurology (36%). Corticosteroid treatment was the predominant therapy (84.5%). The probability to receive a facial nerve grading (Odds ratio [OR] =12.939; 95% confidence interval [CI] = 3.599 to 46.516), gustatory testing (OR = 6.878; CI =1.064 to 44.474), and audiometry (OR = 32.505; CI = 1.485 to 711.257) was significantly higher in otolaryngology departments, but lower for cranial CT (OR = 0.192; CI = 0.061 to 0.602), CSF examination (OR = 0.024; CI = 0.006 to 0.102). 131 patients (45%) showed a recovery to House-Brackmann grade ≤II. A pathological stapedial reflex test (Hazard ratio [HR] = 0.416; CI = 0.180 to 0.959) was the only independent diagnostic predictor of worse outcome. Prednisolone dose >500 mg (HR = 0.579; CI 0.400 to 0.838), and no adjuvant physiotherapy (HR = 0.568; CI = 0.407 to 0.794) were treatment-related predictors of worse outcome. Conclusions Inpatient treatment of IFP seems to be highly variable in daily practice, partly depending on the treating discipline, and despite the availability of evidence-based guidelines. The population-based recovery rate was worse than reported in clinical trials. This article is protected by copyright. All rights reserved.

The nuclear morphology of neutrophils depends on different endogenous and exogenous factors, which can lead to hypo- or hypersegmentation of the normally 2-4 segmented nucleus. Hyposegmentation can be due to mutations in the LBR-gene (Pelger-Huet-Anomaly) or can be induced, for example, by colchicine treatment. The range of this phenotypic variation is known as "norm of reaction," which can be of major relevance for clinical diagnosis and therapeutic intervention. In this project, we studied the norm of reaction in 26 subjects with 0-3 wild type LBR alleles. In addition, the phenotypic variation was analyzed in 3 patients with Familial Mediterranean Fever (FMF), before and after colchicine treatment. We measured the phenotype nuclear segmentation of neutrophils based on two conventional qualitative methods, the "rule of threads" and the "rule of thirds." In addition, we tested a morphometric quantitative approach, the "circularity index." The circularity index was superior in cases with hyposegmentation; the rule of thirds with respect to hypersegmentation. Approximately 65% of the observed phenotypic variance was explainable by the number of LBR wild type alleles. The gene-dosage effect followed a non-additive, hysteresis-like characteristic with lower and upper plateaus. Colchicine treatment had a clear, although minor phenotypic effect compared to the number of LBR wild type genes or the mutation type. Thus, the nuclear morphology of granulocytes and its norm of reaction can be regarded as an excellent model both for detailing the interplay between endogenous and exogenous factors and for clinical diagnostic purposes. © 2016 International Clinical Cytometry Society.

A series of twelve 3-piperazinyl propenylidene indolone merocyanines was synthesized in a one-pot fashion using a consecutive three-component insertion-coupling-Michael addition sequence. Physical-organic treatment of the absorption data of a consanguineous series of this library allows semiquantitative Linear Free Energy Relationships (LFERs) to be established and confirmation of the positive absorption solvatochromicity. All Boc-substituted piperazinyl merocyanines display aggregation induced emission (AIE), which was corroborated for two solvent systems. In particular, crystallization-induced emission enhancement (CIEE) induced by ultrasonication could be shown for a model chromophore by confocal laser scanning microscopy (CLSM).

Background: Hepatocellular carcinoma (HCC) has a poor prognosis. Selective internal radiation therapy (SIRT) with microspheres is a treatment option for HCC. This study aimed to assess safety and survival (OS) in patients with HCC treated with SIRT, to stratify patients with tumor vascularization and analyze the impact of sequential sorafenib treatment. Methods: Thirty-nine patients who received SIRT for HCC between 2010 and 2013 at our center were included in this retrospective analysis. Tumor vascularization was assessed using a combination of MRI, MAA-scintigraphy and angiography. Tumor vascularization was correlated with survival. Subgroups are treated with two commercially available 90Y-labeled products SIR-Spheres (n = 16) and TheraSpheres (n = 23) and sequential therapy with sorafenib compared to SIRT only was analyzed. Results: Adverse events occurred in 49% of patients with only four grade 3 and no grade 4 event. Median survival for all patients was 12.5 months (95% CI: 8.7 - 16.3). No significant differences were detectable between Thera Spheres or SIR Spheres. Survival was shorter in patients with low tumor vascularization score (OS: 3.8 months (95% CI 0 - 15.0), p = 0.043). Survival was longer with sorafenib upon progression after SIRT (n=16) with an OS of 17.4 months (95% CI: 12.1 – 22.7) compared to no sorafenib (n = 13; 9.1 months; 95% CI: 3.0 - 15.1) or progression upon sorafenib before SIRT (n = 10; 8.6 months; 95% CI: 5.5 - 11.7). Conclusions: SIRT is safe in HCC patients. Tumor vascularization by radiography and scintigraphy may predict survival benefit. Sorafenib is active after SIRT and significantly prolongs survival.

Background Clinicopathological features and surgical outcomes of patients with fibrolamellar hepatocellular carcinoma (FL-HCC) are underreported. The aim of this study is to describe clinical characteristics and surgical outcomes for patients with this rare tumor to raise awareness among clinicians and surgeons. Methods Retrospective review of records of a tertiary referral center and specialized liver unit was performed. Out of 3623 patients who underwent liver resection, 366 patients received surgical treatment for HCC; of them, eight (2.2%) had FL-HCC and were resected between October 2001 and December 2018. Results Eight patients (3 males and 5 females) with FL-HCC (median age 26 years) underwent primary surgical treatment. All patients presented with unspecific symptoms or were diagnosed as incidental finding. No patient had cirrhosis or other underlying liver diseases. Coincidentally, three patients (37.5%) had a thromboembolic event prior to admission. The majority of patients had BCLC stage C and UICC stage IIIB/IVA; four patients (50%) presented with lymph node metastases. The median follow-up period was 33.5 months. The 1-year survival was 71.4%, and 3-year survival was 57.1%. Median survival was at 36.4 months. Five patients (62.5%) developed recurrent disease after a median disease-free survival of 9 months. Two patients (25.0%) received re-resection. Conclusion FL-HCC is a rare differential diagnosis of liver masses in young patients. Since the prognosis is limited, patients with incidental liver tumors or lesions with suspicious features in an otherwise healthy liver should be presented at a specialized hepatobiliary unit. Thromboembolism might be an early paraneoplastic symptom and needs to be elucidated further in the context of FL-HCC.

We present here the design and characterization of a set of spectral calibration beads. These calibration beads are intended for the determination and regular control of the spectral characteristics of fluorescence microscopes and other fluorescence measuring devices for the readout of bead-based assays. This set consists of micrometer-sized polymer beads loaded with dyes from the liquid Calibration Kit Spectral Fluorescence Standards developed and certified by BAM for the wavelength-dependent determination of the spectral responsivity of fluorescence measuring devices like spectrofluorometers. To cover the wavelength region from 400 to 800 nm, two new near-infrared emissive dyes were included, which were spectroscopically characterized in solution and encapsulated in the beads. The resulting set of beads presents the first step towards a new platform of spectral calibration beads for the determination of the spectral characteristics of fluorescence instruments like fluorescence microscopes, FCM setups, and microtiter plate readers, thereby meeting the increasing demand for reliable and comparable fluorescence data especially in strongly regulated areas, e.g., medical diagnostics. This will eventually provide the basis for standardized calibration procedures for imaging systems as an alternative to microchannel slides containing dye solutions previously reported by us. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00216-020-02664-y) contains supplementary material, which is available to authorized users.

Distal cholangiocarcinoma (dCCA) is a biliary tract cancer with a dismal prognosis and is often preceded by biliary intraepithelial neoplasia (BilIN), representing the most common biliary non-invasive precursor lesion. BilIN are histologically well defined but have not so far been characterised systematically at the molecular level. The aim of this study was to determine miRNA-regulated genes in cholangiocarcinogenesis via BilIN. We used a clinicopathologically well-characterised cohort of 12 dCCA patients. Matched samples of non-neoplastic biliary epithelia, BilIN and invasive tumour epithelia of each patient were isolated from formalin-fixed paraffin-embedded tissue sections by laser microdissection. The resulting 36 samples were subjected to total RNA extraction and the expression of 798 miRNAs was assessed using the Nanostring® technology. Candidate miRNAs were validated by RT-qPCR and functionally investigated following lentiviral overexpression in dCCA-derived cell lines. Potential direct miRNA target genes were identified by microarray and prediction algorithms and were confirmed by luciferase assay. We identified 49 deregulated miRNAs comparing non-neoplastic and tumour tissue. Clustering of these miRNAs corresponded to the three stages of cholangiocarcinogenesis, supporting the concept of BilIN as a tumour precursor. Two downregulated miRNAs, i.e. miR-451a (-10.9-fold down) and miR-144-3p (-6.3-fold down), stood out by relative decrease. Functional analyses of these candidates revealed a migration inhibitory effect in dCCA cell lines. Activating transcription factor 2 (ATF2) and A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) were identified as direct miR-451a target genes. Specific ATF2 inhibition by pooled siRNAs reproduced the inhibitory impact of miR-451a on cancer cell migration. Thus, our data support the concept of BilIN as a direct precursor of invasive dCCA at the molecular level. In addition, we identified miR-451a and miR-144-3p as putative tumour suppressors attenuating cell migration by inhibiting ATF2 in the process of dCCA tumorigenesis. © The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes ( The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years. LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed. Das Lynch-Syndrom (LS) ist die häufigste Form des erblichen Darmkrebses und verursacht ca. 3 % aller kolorektalen Karzinome (KRK). Ursächlich ist eine pathogene Sequenzvariante in einem Mismatch-Reparaturgen ( Das Deutsche Konsortium Familiärer Darmkrebs besteht aus 14 universitären Zentren in Deutschland. Das Ziel des Konsortiums ist es, geeignete Vorsorgeprogramme zu entwickeln und zu evaluieren, damit diese später in die allgemeine Patientenversorgung übernommen werden können. Wir haben aktuell die Empfehlung zur klinischen Betreuung von LS-Patienten überarbeitet. Eine Koloskopie sollte ab dem 25. Lebensjahr alle 12–24 Monate erfolgen. Bei Diagnose eines KRK ist eine onkologische Resektion notwendig, eine Kolektomie mit ileorektaler Anastomose sollte individuell mit dem Patienten besprochen werden. Das Lebenszeitrisiko für ein Magenkarzinom liegt bei 0,2–13 %. Im Rahmen der endoskopischen Überwachung können signifikant mehr Magenkarzinome in früheren Tumorstadien entdeckt werden im Vergleich zur symptomgetriggerten Endoskopie. Das Lebenszeitrisiko für ein Dünndarmkarzinom liegt bei 4–8 %. Dünndarmkarzinome treten zur Hälfte im Duodenum auf, in 10 % der Fälle vor dem 35. Lebensjahr. Eine ÖGD sollte deshalb ab dem 25. Lebensjahr alle 12–36 Monate erfolgen. Die Früherkennung, Vorsorge und Behandlung von kolonischen und extrakolonischen Karzinomen bei Patienten mit LS reduziert die Mortalität und Morbidität, ist aber komplex und in verschiedenen Aspekten noch nicht umfassend evaluiert. Weitere gen- und geschlechtsspezifische Vorsorgeempfehlungen sind wünschenswert und sollen in prospektiven Studien evaluiert werden.

Modeling and predicting load courses and HR responses enables individually optimal training control. In HR controlled endurance training, load is expected to gradually decrease to keep HR levels constant due to cardiac drift. This paper analyzes if gender, time under load or progress of training influences characteristics of load controlled by HR in continuous exercise during a long-term training intervention. Nine healthy adults performed a twelve-week training intervention on a bike ergometer. During the Intensive Continuous Method, load was automatically adjusted (ALC) to keep individual HR in the range of 75% HRmax ± 5 bpm.

IntroductionLiver resection is the only curative treatment for primary and secondary hepatic tumours. Improvements in perioperative preparation of patients and new surgical developments have made complex liver resections possible. However, small for size and flow syndrome (SFSF) is still a challenging issue, rendering patients inoperable and causing postoperative morbidity and mortality. Although the role of transhepatic flow in the postoperative outcome has been shown in small partial liver transplantation and experimental studies of SFSF, this has never been studied in the clinical setting following liver resection. The aim of this study is to systematically evaluate transhepatic flow changes following major liver resection and its correlation with postoperative outcomes.Methods and analysisThe TransHEpatic FLOW (THEFLOW) study is a single-centre, non-interventional cohort study, and aims to enrol 50 patients undergoing major hepatectomy (defined as hemihepatectomy or extended hepatectomy based on the Brisbane classification) with or without prior chemotherapy. The portal venous flow, hepatic artery flow and portal venous pressure are measured before and after each resection. All patients are followed-up for 3 months after the operation. During each evaluation, standard clinical data, posthepatectomy liver failure and overall morbidity and mortality will be recorded. THEFLOW study was initiated on 25 March 2018 and is expected to progress for 2 years.Ethics and disseminationThis protocol study received approval from the Ethics Committee of the University of Heidelberg (registration number: S576/2017). The results of this study will be published in a peer-reviewed journal, and will also be presented at medical meetings.Trial registration numberNCT03762876.

The major extended donor criteria (maEDC, steatosis &gt, 40%, age &gt, 65 years, and cold ischemia time &gt, 14 h) influence graft and patient outcomes after liver transplantation. Despite organ shortages, maEDC organs are often considered unsuitable for transplantation. We investigated the outcomes of maEDC organ liver transplantation in patients with hepatocellular carcinoma (HCC). Two hundred and sixty-four HCC liver transplant patients were eligible for analysis. Risk factor analysis was performed for early allograft dysfunction, primary nonfunction, 30-day and 90-day graft failure, and 30-day, 90-day, and 1-year patient mortality. One-year graft survival was higher in recipients of no-maEDC grafts. One-year patient survival did not differ between the recipients of no-maEDC and maEDC organs. The univariate and multivariate analyses revealed no association between maEDC grafts and one-year patient mortality. Graft survival differed between the recipients of no-maEDC and maEDC organs after correcting for a laboratory model of end-stage liver disease (labMELD) score with a cut-off value of 20, but patient survival did not. Patient survival did not differ between recipients who did and did not meet the Milan criteria and who received grafts with and without maEDC. Instead of being discarded, maEDC grafts may expand the organ pool for patients with HCC without impairing patient survival or recurrence-free survival.

A new fluorescent pentaphene derivative is presented that differs from hexabenzocoronene (HBC) by one carbon atom in the basal plane skeleton. A 500% increased fluorescence quantum yield is measured compared to the HBC derivative. The pentaphene compound, obtained by a modified Scholl oxidation, is also emissive in the solid-state, due to the packing motif in the crystal.

Context Studies on the surgical outcome in living kidney donors mainly report perioperative complications with short follow-up. Objective The objectives of this study are to evaluate the long-term surgical outcome in living kidney donors and to identify donors with an increased risk for a complicated postoperative course. Basic Procedures A prospectively collected database of 496 living kidney donors at the Department of General, Visceral, and Transplantation Surgery of the Ruprecht Karls University Heidelberg was retrospectively analyzed in a retrospective, observational single-center study. Results The median follow-up time was 37 months. The perioperative severe complication (Clavien-Dindo IIIb) rate was 2.8%, the early postoperative (PO) severe complication rate (1-3 months post operation) was 0.7%, and the late PO severe complication rate (> 3 months post operation) was 8.4%. In multivariate analyses, male sex was associated with higher overall perioperative complication rate (odds ratio [OR], 1.930; P = .005) as well as higher rate of late PO complications (OR, 2.243; P = .014). An increased body mass index was associated with a higher late and severe (Clavien-Dindo ≥ IIIb) PO complication rate (OR, 1.107; P = .009 and OR, 1.105; P = .008, respectively). Conclusions and Relevance Long-term surgery-associated severe complications occur in 8.4% of kidney donors. Older age is associated with an increased operative time, greater intraoperative blood loss, and longer PO hospital stay. Male donors and donors with an increased body mass index have a higher risk for a complicated PO course after kidney donation. Within a shared decision-making process before living kidney donation, special awareness should be brought to these facts.

Livedoid vasculopathy (LV) has been shown to be associated with hypercoagulability. However, relevant genetic and exogenous thrombophilic factors are not fully determined.To evaluate the frequency of hyperhomocysteinaemia (HHCE) and genotypes of hypercoagulative factors in LV patients.Plasma homocysteine level was measured in 42 LV patients. Polymorphism of MTHFR (677C T and 1298A C), PAI1 (-675 5G/4G and -844A G), and F2 (20210G A), and the F5 Leiden mutation, as well as biochemical parameters for hypercoagulability, were analysed.Of the LV patients, 62% revealed mild HHCE. Polymorphisms of MTHFR were observed in 75% and 56% and the PAI1 -675 5G/4G polymorphism in 100% and 83% of patients with and without HHCE, respectively. All LV patients with renal failure had mild HHCE. A high level of comorbidity of hypertension (99%) and diabetes type 2 (44%) were noted.HHCE seems to play a major pathogenetic role in LV. A high prevalence of further procoagulative factors might support the view that LV is a "complex disease".

BACKGROUND The pre-procurement pancreas suitability score (P-PASS) and the pancreas donor risk index (pDRI) are established predictive scores for graft survival and patient outcome following pancreatic transplantation. This retrospective study aimed to evaluate the predictive value of P-PASS and pDRI following simultaneous pancreas and kidney (SPK) transplantation, or pancreas after kidney (PAK) transplantation, and the clinical impact of donor-specific factors on the postoperative graft and recipient outcome at a single transplant center. MATERIAL AND METHODS The study included 105 patients who underwent SPK (n=104) or PAK (n=4) between 2000 and 2017. Donor-specific and recipient-specific parameters were recorded. Kaplan-Meier analysis and Cox regression analysis were used to assess the outcome after transplantation. RESULTS Overall, the mean 1-year and 5-year pancreas graft survival and patient survival rates were 78.7% and 93.2%, and 76.9% and 90.0%, respectively. The postoperative outcome in patients with a P-PASS score of

The large number of nanomaterial-based applications emerging in the materials and life sciences and the foreseeable increasing use of these materials require methods that evaluate and characterize the toxic potential of these nanomaterials to keep safety risks to people and environment as low as possible. As nanomaterial toxicity is influenced by a variety of parameters like size, shape, chemical composition, and surface chemistry, high throughput screening (HTS) platforms are recommended for assessing cytotoxicity. Such platforms are not yet available for genotoxicity testing. Here, we present first results obtained for application-relevant nanomaterials using an automatable genotoxicity platform that relies on the quantification of the phosphorylated histone H2AX (γ-H2AX) for detecting DNA double strand breaks (DSBs) and the automated microscope system AKLIDES® for measuring integral fluorescence intensities at different excitation wavelengths. This platform is used to test the genotoxic potential of 30 nm-sized citrate-stabilized gold nanoparticles (Au-NPs) as well as micellar encapsulated iron oxide nanoparticles (FeOx-NPs) and different cadmium (Cd)-based semiconductor quantum dots (QDs), thereby also searching for positive and negative controls as reference materials. In addition, the influence of the QD shell composition on the genotoxic potential of these Cd-based QDs was studied, using CdSe cores as well as CdSe/CdS core/shell and CdSe/CdS/ZnS core/shell/shell QDs. Our results clearly revealed the genotoxicity of the Au-NPs and its absence in the FeOx-NPs. The genotoxicity of the Cd-QDs correlates with the shielding of their Cd-containing core, with the core/shell/shell architecture preventing genotoxicity risks. The fact that none of these nanomaterials showed cytotoxicity at the chosen particle concentrations in a conventional cell viability assay underlines the importance of genotoxicity studies to assess the hazardous potential of nanomaterials.

Background Two surgical options are available for cystic echinococcosis (CE). The two principal approaches are radical (resection of the cyst) and conservative (evacuation of the cyst content and partial removal of the cyst capsule). Here, we describe a standardized endocystectomy technique for hepatic echinococcosis. Subjects and methods Twenty-one patients (male/female: 4/3; median age: 28 years) with uncomplicated, isolated hepatic CE (cyst stages WHO CE1, 2, 3a, and 3b) that were treated with the standardized endocystectomy described in this paper. Before the operation and during the follow-up period (mean: 33.8 months, median: 24 months), patients underwent clinical and sonographical and/or magnetic resonance imaging assessment during regular visits managed by an interdisciplinary team. Results Forty-seven cysts were treated with the standardized endocystectomy technique. The median number of cysts per patient was two (range: 1–8). Nine patients (43%) had a single cystic lesion. The median operation time was 165 minutes and the median intraoperative bleeding volume was 200 mL. The median hospital stay was nine days (range: 6–28 days). Morbidity (Clavien-Dindo III) occurred in four patients (19%). No mortality and no recurrence were found during the median follow-up time of 24 months. Conclusions The standardized endocystectomy technique presented is a safe procedure with acceptable morbidity, no mortality, and without recurrences in our patient series. Important components of our CE management are interdisciplinary patient care, adequate diagnostic work-ups, and regular pre- and postoperative visits, including long-term follow-up for early and reliable capture of recurrences., Author summary Cystic echinococcosis (CE) is a parasitic disease caused by ingestion of the larval stage of Echinococcus granulosus. The liver is the most commonly infected organ. There are currently four treatments for CE: surgery, percutaneous treatment, medical treatment (benzimidazoles), and watch-and-wait strategy. Treatment is decided based on the WHO cyst staging. The surgical techniques employed depend on the cyst location and related complications (e.g. cyst-biliary fistulas, rupture, and secondary bacterial infection). The two principal surgical approaches are radical (resection of the cyst) and conservative (evacuation of the cyst content and partial removal of the cyst capsule) surgeries. In this study, we presented a conservative surgical approach, a standardized endocystectomy technique, that is suitable for surgical residents. This standardized endocystectomy technique is a safe procedure with acceptable morbidity, no mortality, and without recurrences in our patient series. Important components of CE management are interdisciplinary patient care, adequate diagnostic work-ups, and regular pre- and postoperative visits, including long-term follow-up for early and reliable capture of recurrences.

Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNα signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model‐based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNα dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNα leads to a dose‐dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient‐specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient‐specific pathway desensitization, while the abundance of STAT2 predicts the patient‐specific IFNα signal response., Mathematical modeling based on quantitative data reveals the molecular mechanisms that cause hypersensitization of interferon alpha (IFNα) signaling by pre‐exposure with a low dose of IFNα and desensitization with a high dose of IFNα.

Clinical treatment options for human cholangiocarcinoma (CC) are limited. c-MET, a high-affinity receptor for hepatocyte growth factor (HGF), is deregulated in many cancers. Its role in cholangiocarcinogenesis remains unclear. In current study, 23 corresponding tumor- and non-tumor tissues, taken from patients with intrahepatic (iCC) and perihilar cholangiocarcinoma (pCC), who underwent liver resection, were analyzed. The relationship of clinicopathological features and c-MET, as well as c-jun N-terminal kinase (JNK) was evaluated. The anti-tumor effects of Tivantinib, a small-molecule inhibitor with potent activity against the c-MET kinase, was investigated in three human CC cell lines, namely HUCC-T1, TFK-1, and EGI-1. In comparison with the results obtained in non-tumor tissue samples, c-MET was overexpressed in 91.3 % of tumor tissues (p p p

Acquired tamoxifen resistance is a persistent problem for the treatment of estrogen receptor positive, premenopausal breast cancer patients and predictive biomarkers are still elusive. We here analyzed gene expression changes in a cellular model to identify early and late changes upon tamoxifen exposure and thereby novel prognostic biomarkers. Estrogen receptor positive MCF-7 cells were incubated with 4OH-tamoxifen (10 nM) and gene expression analyzed by array hybridization during 12 weeks. Array results were confirmed by nCounter- and qRT-PCR technique. Pathway enrichment analysis revealed that early responses concerned mainly amine synthesis and NRF2-related signaling and evolved into a stable gene expression pattern within 4 weeks characterized by changes in glucuronidation-, estrogen metabolism-, nuclear receptor- and interferon signaling pathways. As a large number of long non coding RNAs was subject to regulation, we investigated 5 of these (linc01213, linc00632 linc0992, LOC101929547 and XR_133213) in more detail. From these, only linc01213 was upregulated but all were less abundant in estrogen-receptor negative cell lines (MDA-MB 231, SKBR-3 and UACC3199). In a web-based survival analysis linc01213 and linc00632 turned out to have prognostic impact. Linc01213 was investigated further by plasmid-mediated over-expression as well as siRNA down-regulation in MCF-7 cells. Nevertheless, this had no effect on proliferation or expression of tamoxifen regulated genes, but migration was increased. In conclusion, the cellular model identified a set of lincRNAs with prognostic relevance for breast cancer. One of these, linc01213 although regulated by 4OH-tamoxifen, is not a central regulator of tamoxifen adaption, but interferes with the regulation of migration.

Correlating the photoluminescence (PL) properties of nanomaterials like semiconductor nanocrystals (QDs) and lanthanide-based upconversion nanocrystals (UCNPs) at the ensemble and single particle level is increasingly relevant for applications of these nanomaterials in the life sciences like bioimaging studies or their use as reporters in microfluidic assays. Aiming to derive particle architectures well suited for spectroscopic and microscopic applications, we compared the spectroscopic properties of different QDs like II/VI QDs and cadmium-free AIS/ZnS QDs as well as UCNPs of different chemical composition for particle ensembles and single particles. This included the PL spectra, fluorescence quantum yields (ΦF), brightness values, blinking behavior, and PL decay kinetics of these nanomaterials. Special emphasis was focused on measurements of the fluorescence quantum yield (ΦF) and brightness, that determine the signal size and provide a measure for the quality of nanocrystals like QDs and UCNPs which are prone to surface quenching and stabilized with coordinatively bound surface ligands. [1-3] In this respect, the potential of fluorescence correlation spectroscopy (FCS) for relative ΦF measurements of nanoparticles at ultralow concentration was explored exemplarily for ligand-stabilized CdTe nanocrystals in water. [4] References. (1) Grabolle, M.; Spieles, M.; Lesnyak, V.; Gaponik, N.; Eychmuller, A.; Resch-Genger, U., Anal. Chem 2009, 81, 6285-6294. (2) Wurth, C.; Grabolle, M.; Pauli, J.; Spieles, M.; Resch-Genger, U., Nat. Prot. 2013, 8, 1535-1550. (3) Kaiser, M.; Wurth, C.; Kraft, M.; Hyppanen, I.;Soukka, T.; Resch-Genger, U., Nanoscale 2017, 9, 10051 - 10058. (4) Abbandonato, G.; Hoffmann, K.; Resch-Genger, U., Nanoscale 2018, 10, 7147-7154.

A 37-year-old male patient with Crohn's disease and multiple liver hemangiomas was referred to our hospital for an atypical hypervascular hepatic lesion detected on an external magnetic resonance imaging (MRI) scan. The patient was otherwise well and had no history of any liver disease. Liver values and tumor markers were normal. Contrast-enhanced ultrasound confirmed multiple hemangiomas in different liver segments and a hypervascular tumor with a hypovascular rim in segment II/IV. Repeat MRI showed a strongly enhancing neoplasm of 2.6 cm with a texture distinctly different from the otherwise relatively uniform hemangiomas, without evidence of interim growth. Ultrasound-guided biopsy revealed a hepatic small vessel neoplasm. Due to the unknown malignant potential, atypical segmental surgical resection was performed. Final histopathological analysis confirmed the complete resection of the lesion. The postoperative course was uneventful.Ein 37-jähriger M.-Crohn-Patient mit bekannten Leberhämangiomen wurde uns zur weiteren Abklärung einer unklaren, unscharf begrenzten Leberläsion zugewiesen. Vorerkrankungen der Leber bestanden nicht. Die Leberwerte und Tumormarker waren unauffällig. Ein Kontrastmittelultraschall bestätigte mehrere Hämangiome in der Leber und charakterisierte die Läsion in Segment II/IV als hypervaskularisiert mit einem hypovaskulären Randsaum. Das wiederholte MRT zeigte einen stark Kontrastmittel aufnehmenden 2,6 cm großen Tumor, der sich in der Textur deutlich von den ansonsten uniform aussehenden Hämangiomen unterschied und kein zwischenzeitliches Wachstum aufwies. Die sonografisch gesteuerte Biopsie ergab eine Gefäßneoplasie (“hepatic small vessel neoplasm”). Aufgrund der unbekannten Entartungstendenz dieser Entität wurde eine atypische Segmentresektion durchgeführt. Die endgültige Histopathologie bestätigte die Diagnose der vorherigen Biopsie und die vollständige Entfernung der Läsion. Der postoperative Verlauf war komplikationslos.