Triphilic ionic-liquid mixtures: fluorinated and non-fluorinated aprotic ionic-liquid mixtures

We present here the possibility of forming triphilic mixtures from alkyl- and fluoroalkylimidazolium ionic liquids, thus, macroscopically homogeneous mixtures for which instead of the often observed two domainspolar and nonpolarthree stable microphases are present: polar, lipophilic, and fluorous ones. The fluorinated side chains of the cations indeed self-associate and form domains that are segregated from those of the polar and alkyl domains. To enable miscibility, despite the generally preferred macroscopic separation between fluorous and alkyl moieties, the importance of strong hydrogen bonding is shown. As the long-range structure in the alkyl and fluoroalkyl domains is dependent on the composition of the liquid, we propose that the heterogeneous, triphilic structure can be easily tuned by the molar ratio of the components. We believe that further development may allow the design of switchable, smart liquids that change their properties in a predictable way according to their composition or even their environment

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

While sarcomas account for approximately 1% of malignant tumors of adults, they are particularly more common in children and adolescents affected by cancer. In contrast to malignancies that occur in later stages of life, childhood tumors, including sarcoma, are characterized by a striking paucity of somatic mutations. However, entity-defining fusion oncogenes acting as the main oncogenic driver mutations are frequently found in pediatric bone and soft-tissue sarcomas such as Ewing sarcoma (EWSR1-FLI1), alveolar rhabdomyosarcoma (PAX3/7-FOXO1), and synovial sarcoma (SS18-SSX1/2/4). Since strong oncogene-dependency has been demonstrated in these entities, direct pharmacological targeting of these fusion oncogenes has been excessively attempted, thus far, with limited success. Despite apparent challenges, our increasing understanding of the neomorphic features of these fusion oncogenes in conjunction with rapid technological advances will likely enable the development of new strategies to therapeutically exploit these neomorphic features and to ultimately turn the \textquotedblundruggable\textquotedbl into first-line target structures. In this review, we provide a broad overview of the current literature on targeting neomorphic features of fusion oncogenes found in Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma, and give a perspective for future developments. Graphical abstract Scheme depicting the different targeting strategies of fusion oncogenes in pediatric fusion-driven sarcomas. Fusion oncogenes can be targeted on their DNA level (1), RNA level (2), protein level (3), and by targeting downstream functions and interaction partners (4)

Impact of Breathing Phase, Liver Segment, and Prandial State on Ultrasound Shear Wave Speed, Shear Wave Dispersion, and Attenuation Imaging of the Liver in Healthy Volunteers

OBJECTIVES: Measurement location and patient state can impact noninvasive liver assessment and change clinical staging in ultrasound examinations. Research into differences exists for Shear Wave Speed (SWS) and Attenuation Imaging (ATI), but not for Shear Wave Dispersion (SWD). The aim of this study is to assess the effect of breathing phase, liver lobe, and prandial state on SWS, SWD, and ATI ultrasound measurements. METHODS: Two experienced examiners performed SWS, SWD, and ATI measurements in 20 healthy volunteers using a Canon Aplio i800 system. Measurements were taken in the recommended condition (right lobe, following expiration, fasting state), as well as (a) following inspiration, (b) in the left lobe, and (c) in a nonfasting state. RESULTS: SWS and SWD measurements were strongly correlated (r = 0.805, p < 0.001). Mean SWS was 1.34 ± 0.13 m/s in the recommended measurement position and did not change significantly under any condition. Mean SWD was 10.81 ± 2.05 m/s/kHz in the standard condition and significantly increased to 12.18 ± 1.41 m/s/kHz in the left lobe. Individual SWD measurements in the left lobe also had the highest average coefficient of variation (19.68%). No significant differences were found for ATI. CONCLUSION: Breathing and prandial state did not significantly affect SWS, SWD, and ATI values. SWS and SWD measurements were strongly correlated. SWD measurements in the left lobe showed a higher individual measurement variability. Interobserver agreement was moderate to good

Impact of Breathing Phase, Liver Segment, and Prandial State on Ultrasound Shear Wave Speed, Shear Wave Dispersion, and Attenuation Imaging of the Liver in Healthy Volunteers.

OBJECTIVES Measurement location and patient state can impact noninvasive liver assessment and change clinical staging in ultrasound examinations. Research into differences exists for Shear Wave Speed (SWS) and Attenuation Imaging (ATI), but not for Shear Wave Dispersion (SWD). The aim of this study is to assess the effect of breathing phase, liver lobe, and prandial state on SWS, SWD, and ATI ultrasound measurements. METHODS Two experienced examiners performed SWS, SWD, and ATI measurements in 20 healthy volunteers using a Canon Aplio i800 system. Measurements were taken in the recommended condition (right lobe, following expiration, fasting state), as well as (a) following inspiration, (b) in the left lobe, and (c) in a nonfasting state. RESULTS SWS and SWD measurements were strongly correlated (r = 0.805, p < 0.001). Mean SWS was 1.34 ± 0.13 m/s in the recommended measurement position and did not change significantly under any condition. Mean SWD was 10.81 ± 2.05 m/s/kHz in the standard condition and significantly increased to 12.18 ± 1.41 m/s/kHz in the left lobe. Individual SWD measurements in the left lobe also had the highest average coefficient of variation (19.68%). No significant differences were found for ATI. CONCLUSION Breathing and prandial state did not significantly affect SWS, SWD, and ATI values. SWS and SWD measurements were strongly correlated. SWD measurements in the left lobe showed a higher individual measurement variability. Interobserver agreement was moderate to good

Transport Properties of One-Dimensional Hubbard Models

We present results for the zero and finite temperature Drude weight D(T) and for the Meissner fraction of the attractive and the repulsive Hubbard model, as well as for the model with next nearest neighbor repulsion. They are based on Quantum Monte Carlo studies and on the Bethe ansatz. We show that the Drude weight is well defined as an extrapolation on the imaginary frequency axis, even for finite temperature. The temperature, filling, and system size dependence of D is obtained. We find counterexamples to a conjectured connection of dissipationless transport and integrability of lattice models.Comment: 10 pages, 14 figures. Published versio

Using smartphone survey and GPS data to inform smoking cessation intervention delivery: Case study

Background: Interest in quitting smoking is common among young adults who smoke, but it can prove challenging. Although evidence-based smoking cessation interventions exist and are effective, a lack of access to these interventions specifically designed for young adults remains a major barrier for this population to successfully quit smoking. Therefore, researchers have begun to develop modern, smartphone-based interventions to deliver smoking cessation messages at the appropriate place and time for an individual. A promising approach is the delivery of interventions using geofences—spatial buffers around high-risk locations for smoking that trigger intervention messages when an individual’s phone enters the perimeter. Despite growth in personalized and ubiquitous smoking cessation interventions, few studies have incorporated spatial methods to optimize intervention delivery using place and time information. Objective: This study demonstrates an exploratory method of generating person-specific geofences around high-risk areas for smoking by presenting 4 case studies using a combination of self-reported smartphone-based surveys and passively tracked location data. The study also examines which geofence construction method could inform a subsequent study design that will automate the process of deploying coping messages when young adults enter geofence boundaries. Methods: Data came from an ecological momentary assessment study with young adult smokers conducted from 2016 to 2017 in the San Francisco Bay area. Participants reported smoking and nonsmoking events through a smartphone app for 30 days, and GPS data was recorded by the app. We sampled 4 cases along ecological momentary assessment compliance quartiles and constructed person-specific geofences around locations with self-reported smoking events for each 3-hour time interval using zones with normalized mean kernel density estimates exceeding 0.7. We assessed the percentage of smoking events captured within geofences constructed for 3 types of zones (census blocks, 500 ft2 fishnet grids, and 1000 ft2 fishnet grids). Descriptive comparisons were made across the 4 cases to better understand the strengths and limitations of each geofence construction method. Results: The number of reported past 30-day smoking events ranged from 12 to 177 for the 4 cases. Each 3-hour geofence for 3 of the 4 cases captured over 50% of smoking events. The 1000 ft2 fishnet grid captured the highest percentage of smoking events compared to census blocks across the 4 cases. Across 3-hour periods except for 3:00 AM-5:59 AM for 1 case, geofences contained an average of 36.4%-100% of smoking events. Findings showed that fishnet grid geofences may capture more smoking events compared to census blocks. Conclusions: Our findings suggest that this geofence construction method can identify high-risk smoking situations by time and place and has potential for generating individually tailored geofences for smoking cessation intervention delivery. In a subsequent smartphone-based smoking cessation intervention study, we plan to use fishnet grid geofences to inform the delivery of intervention messages

Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer.

Chromosomal instability (CIN) is a hallmark of cancer1. Yet, many childhood cancers, such as Ewing sarcoma (EwS), feature remarkably 'silent' genomes with minimal CIN2. Here, we show in the EwS model how uncoupling of mitosis and cytokinesis via targeting protein regulator of cytokinesis 1 (PRC1) or its activating polo-like kinase 1 (PLK1) can be employed to induce fatal genomic instability and tumor regression. We find that the EwS-specific oncogenic transcription factor EWSR1-FLI1 hijacks PRC1, which physiologically safeguards controlled cell division, through binding to a proximal enhancer-like GGAA-microsatellite, thereby promoting tumor growth and poor clinical outcome. Via integration of transcriptome-profiling and functional in vitro and in vivo experiments including CRISPR-mediated enhancer editing, we discover that high PRC1 expression creates a therapeutic vulnerability toward PLK1 inhibition that can repress even chemo-resistant EwS cells by triggering mitotic catastrophe.Collectively, our results exemplify how aberrant PRC1 activation by a dominant oncogene can confer malignancy but provide opportunities for targeted therapy, and identify PRC1 expression as an important determinant to predict the efficacy of PLK1 inhibitors being used in clinical trials.This work was mainly supported by a grant from the German Cancer Aid (DKH-70114111). In addition, the laboratory of T.G.P.G. was supported by the LMU Munich’s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Matthias-Lackas Foundation, the Dr. Leopold and Carmen Ellinger Foundation, the Boehringer-Ingelheim Foundation, the Wilhelm Sander-Foundation (2016.167.1), the Barbara and Hubertus Trettner Foundation, the Dr. Rolf M. Schwiete Foundation, the Friedrich-Baur Foundation, the German Cancer Aid (DKH-70112257 and DKH-111886), the Gert und Susanna Mayer Foundation, the Barbara und Wilfried Mohr Foundation, the SMARCB1 association, and the Deutsche Forschungsgemeinschaft (DFG-391665916). J.L. was supported by a scholarship of the Chinese Scholarship Council (CSC), and a grant of the German Cancer Aid (DKH-70114111). M.D. was by a scholarship of the ‘Deutsche Stiftung für junge Erwachsene mit Krebs‘, J.M. by a scholarship of the Kind-Philipp-Foundation, and C.M.F., M.K. and T.L.B.H. by scholarships from the German Cancer Aid. The laboratory of J.A. was supported by grants from the Instituto de Salud Carlos III (PI16CIII/00026; DTS18CIII/00005), Asociación Pablo Ugarte, ASION, Fundación Sonrisa de Alex, Asociación Todos somos Iván y Asociación Candela Riera. Freely available clipart used for design of parts of figures was kindly provided by Servier Medical Art (https://smart.servier.com/).S

54P Efficacy of first-line immunotherapy for non-small cell lung cancer with MET exon 14 skipping according to PD-L1 expression [Abstract]

Background METΔ14ex is the driver alteration for approximately 3% of non-small cell lung cancers (NSCLC) and associated with a higher PD-L1 expression, but unclear benefit from immunotherapy (IO). Methods Seventy-eight consecutive patients with metastatic NSCLC harboring METΔex14 who received first-line IO as monotherapy or chemoimmunotherapy (CHT+IO) in 10 German academic lung cancer centers were analyzed. Results The median age was 72 years (range 49-86), 34 patients (44%) were female, 47 (60%) were active or former smokers, and 23 (29%) presented with brain metastases. The Eastern Cooperative Group (ECOG) performance status was 0, 1, 2 and 3 in 27 (35%), 28 (36%), 18 (23%) and 4 (5%) cases, respectively. The most common histology was adenocarcinoma (n=61, 78%). IO was given to 43 (55%) patients as monotherapy, and to 35 (45%) combined with CHT. For patients with PD-L1 tumor proportion score (TPS) ≥50% (n=52, 67%), 1-49% (n=14, 18%) and <1% (n=12, 15%), disease control rates (DCR) were 56%, 57% and 100% (p=0.015), respectively. Other efficacy parameters including overall response rate (ORR), median progression-free survival (mPFS) and median overall survival (mOS) by PD-L1 tumor proportion score (TPS) and type of treatment are summarized in the table. Primary progressive disease/early death (before radiologic reassessment) under IO monotherapy, but not under CHT+IO, was significantly associated with never-smoker status (p=0.041). No significant correlations were found between smoking status and PD-L1 TPS (p=0.595). Conclusions Our exploratory analysis suggests an association between higher PD-L1 TPS and worse clinical outcomes under IO in patients with NSCLC harboring METΔ14ex. Although these results should be interpreted with caution, they contrast the favorable effect of PD-L1 expression for IO efficacy in other NSCLC and underline the need for alternative biomarkers for IO in this patient population

CRNKL1 is a highly selective regulator of intron-retaining HIV-1 and cellular mRNAs

The HIV-1 Rev protein is a nuclear export factor for unspliced and incompletely spliced HIV-1 RNAs. Without Rev, these intron-retaining RNAs are trapped in the nucleus. A genome-wide screen identified nine proteins of the spliceosome, which all enhanced expression from the HIV-1 unspliced RNA after CRISPR/Cas knockdown. Depletion of DHX38, WDR70, and four proteins of the Prp19-associated complex (ISY1, BUD31, XAB2, and CRNKL1) resulted in a more than 20-fold enhancement of unspliced HIV-1 RNA levels in the cytoplasm. Targeting of CRNKL1, DHX38, and BUD31 affected nuclear export efficiencies of the HIV-1 unspliced RNA to a much larger extent than splicing. Transcriptomic analyses further revealed that CRNKL1 also suppresses cytoplasmic levels of a subset of cellular mRNAs, including some with selectively retained introns. Thus, CRNKL1-dependent nuclear retention is a novel cellular mechanism for the regulation of cytoplasmic levels of intron-retaining HIV-1 mRNAs, which HIV-1 may have harnessed to direct its complex splicing pattern. IMPORTANCE: To regulate its complex splicing pattern, HIV-1 uses the adaptor protein Rev to shuttle unspliced or partially spliced mRNA from the nucleus to the cytoplasm. In the absence of Rev, these RNAs are retained in the nucleus, but it is unclear why. Here we identify cellular proteins whose depletion enhances cytoplasmic levels of the HIV-1 unspliced RNA. Depletion of one of them, CRNKL1, also increases cytoplasmic levels of a subset of intron-retaining cellular mRNA, suggesting that CRNKL1-dependent nuclear retention may be a basic cellular mechanism exploited by HIV-1

Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy. Ewing sarcoma is characterized by the fusion of EWSR1 and FLI1. Here, the authors show that EWSR1-FLI1 increases the activity of the developmental transcription factor SOX6, which promotes tumor growth but also increases sensitivity to oxidative stress