julilili42/papers huggingface dataset:
Progression-Free Survival and Overall Survival in Patients with Advanced HER2-Positive Breast Cancer Treated with Trastuzumab Emtansine (T-DM1) after Previous Treatment with Pertuzumab
2020-10-17

The approval of trastuzumab emtansine (T-DM1) was conducted without pertuzumab as previous therapy. Efficacy data on T-DM1 following pertuzumab treatment are therefore limited. This study explores this issue in a real-world setting. Within the prospective PRAEGNANT (Prospective Academic Translational Research Network for the Optimization of the Oncological Health Care Quality in the Advanced Setting) metastatic breast cancer registry (NCT02338167), patients in all therapy lines receiving any kind of treatment were eligible for inclusion. This report describes patient characteristics and progression-free survival (PFS) in human epidermal growth factor receptor 2 (HER2)-positive patients receiving T-DM1 after pertuzumab treatment. Seventy-six patients were identified, 39 of whom received T-DM1 as second-line therapy, 25 as third-line, and 12 as fourth-line therapy or higher. Pertuzumab was mostly administered as a first-line treatment (n = 61; 80.3%). The median PFS in all patients was 3.5 months (95% CI: 2.8–7.8); in second-line treatment, 7.7 months (95% CI: 2.8–11.0); in third-line, 3.4 months (95% CI: 2.3–not reached (NR)); and in fourth-line therapy or higher, 2.7 months (95% CI: 1.2–NR). T-DM1 was mainly administered second-line after pertuzumab, but also in more heavily pretreated patients. The PFS in higher therapy lines appears to be shorter than in second-line.
Contested Science: Individual-level insight into interpretation of evidence explains group- level polarization
2020-10-17

Societal polarization over contested science has increased in the recent years. To explain thisworrisome trend, political, sociological, and psychological research has identified societal macro-phenomena as well as cognitive micro-level factors that explain how citizens reason about thescience. Here we take a radically different perspective, and highlight the effects of metacognition:How citizens reason about their own reasoning. Leveraging methods from Signal DetectionTheory, we investigated the importance of individual-level metacognitive insight for group-levelpolarization for the heavily contested topic of climate change, and the less heavily contested topicof nanotechnology. We found that, for climate change (but not for nanotechnology), increasedinsight into the accuracy of own interpretations of the available scientific evidence related tolower group-level polarization over the science. This finding held irrespective of the direction ofthe scientific evidence (endorsing or rejecting anthropogenicity of climate change). Furthermore,the polarizing effect of scientific evidence could be traced back to higher metacognitive insightfostering belief-updating in the direction of the evidence at the expense of own, prior beliefs. Bydemonstrating how individual-level metacognition links to group-level polarization, the presentresearch adds to our understanding of the drivers of societal polarization over science.
Arabidopsis AZG2 transports cytokinins in vivo and regulates lateral root emergence
2020-10-18

Summary Cytokinin and auxin are key regulators of plant growth and development. During the last decade transport mechanisms have turned out to be the key for the control of local and long‐distance hormone distributions. In contrast with auxin, cytokinin transport is poorly understood. Here, we show that Arabidopsis thaliana AZG2, a member of the AZG purine transporter family, acts as cytokinin transporter involved in root system architecture determination. Even though purines are substrates for both AZG1 and AZG2, we found distinct transport mechanisms. The expression of AZG2 is restricted to a small group of cells surrounding the lateral root (LR) primordia and induced by auxins. Compared to the wild‐type (WT), mutants carrying loss‐of‐function alleles of AZG2 have higher LR density, suggesting that AZG2 is part of a regulatory pathway in LR emergence. Moreover, azg2 is partially insensitive to exogenous cytokinin, which is consistent with the observation that the cytokinin reporter TCSn pro :GFP showed lower fluorescence signal in the roots of azg2 compared to the WT. These results indicate a defective cytokinin signalling pathway in the region of LR primordia. The integration of AZG2 subcellular localization and cytokinin transport capacity data allowed us to propose a local cytokinin : auxin signalling model for the regulation of LR emergence.
Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns
2020-10-18

Abstract Recent studies in animal models demonstrate that certain misfolded proteins associated with neurodegenerative diseases can support templated misfolding of cognate native proteins, to propagate across neural systems, and to therefore have some of the properties of classical prion diseases like Creutzfeldt-Jakob disease. The National Institute of Aging convened a meeting to discuss the implications of these observations for research priorities. A summary of the discussion is presented here, with a focus on limitations of current knowledge, highlighting areas that appear to require further investigation in order to guide scientific practice while minimizing potential exposure or risk in the laboratory setting. The committee concluded that, based on all currently available data, although neurodegenerative disease-associated aggregates of several different non-prion proteins can be propagated from humans to experimental animals, there is currently insufficient evidence to suggest more than a negligible risk, if any, of a direct infectious etiology for the human neurodegenerative disorders defined in part by these proteins. Given the importance of this question, the potential for noninvasive human transmission of proteopathic disorders is deserving of further investigation.
Management of patients with chronic rhinosinusitis during the COVID‐19 pandemic—An EAACI position paper
2020-10-19

Abstract Background Chronic rhinosinusitis is regarded as a chronic airway disease. According to WHO recommendations, it may be a risk factor for COVID‐19 patients. In most CRSwNP cases, the inflammatory changes affecting the nasal and paranasal mucous membranes are type‐2 (T2) inflammation endotypes. Methods The current knowledge on COVID‐19 and on treatment options for CRS was analyzed by a literature search in Medline, Pubmed, international guidelines, the Cochrane Library and the Internet. Results Based on international literature, on current recommendations by WHO and other international organizations as well as on previous experience, a panel of experts from EAACI and ARIA provided recommendations for the treatment of CRS during the COVID‐19 pandemic. Conclusion Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS‐CoV‐2 infection. Surgical treatments should be reduced to a minimum and surgery preserved for patients with local complications and for those with no other treatment options. Systemic corticosteroids should be avoided. Treatment with biologics can be continued with careful monitoring in noninfected patients and should be temporarily interrupted during the course of the COVID‐19 infection.
Influence of PVA Molecular Weight and Concentration on Electrospinnability of Birch Bark Extract-Loaded Nanofibrous Scaffolds Intended for Enhanced Wound Healing
2020-10-19

Triterpenes from the outer bark of birch (TE) are known for various pharmacological effects including enhanced wound healing. Apart from an already authorized oleogel, electrospun nanofiber mats containing these triterpenes in a polyvinyl alcohol (PVA) matrix appear to be an advantageous application form. The effects of PVA molecular weight and concentration on the fiber morphology have been investigated. Three different molecular weights of PVA ranging from 67 to 186 kDa were used. The concentration of PVA was varied from 5 to 20 wt%. Polymer solutions were blended with colloidal dispersions of birch bark extract at a weight ratio of 60:40 (wt.%). The estimated viscosity of polymer solutions was directly linked to their concentration and molecular weight. In addition, both pure and blended solutions showed viscoelastic properties with a dominant viscous response in the bulk. Fiber morphology was confirmed using scanning electron microscopy (SEM). Both polymer concentration and molecular weight were found to be significant factors affecting the diameter of the fibers. Fiber diameter increased with a higher molecular weight and polymer concentration as more uniform fibers were obtained using PVA of higher molecular weight (146–186 kDa). In vitro drug release and ex vivo permeation studies indicated a faster drug release of betulin from electrospun scaffolds with lower PVA molecular weight. Our research suggests that the fabricated TE-loaded PVA electrospun dressings represent potential delivery systems of TE for wound care applications.
Evaluation of the first immunosuppressive drug assay available on a fully automated LC-MS/MS-based clinical analyzer suggests a new era in laboratory medicine
2020-10-19

Abstract Objectives Due to its high specificity, liquid chromatography-tandem mass spectrometry (LC-MS/MS) is considered the gold standard in diagnostic areas such as therapeutic monitoring of immunosuppressive drugs (ISDs). However, many laboratories still rely on immunoassays for ISD quantification in a tradeoff between analytical performance and the advantages of fully automated analyzers – shorter turnaround times, greater ease of use, and 24/7 availability. Methods The LC-MS/MS-based Thermo ScientificTM CascadionTM SM Immunosuppressant Panel was evaluated for &gt;6 months in the routine laboratory of a university hospital. We assessed the analytical performance of the panel and compared it to conventional LC-MS/MS as well as to immunoassays (cyclosporine A, sirolimus, tacrolimus (Siemens) and everolimus (Thermo Fisher)). In addition, both ISD panel and Cascadion analyzer were scrutinized with regards to, e.g., turnaround time, usability, and robustness. Results All ISDs showed high linearity and precision (CV≤6%) and a good correlation with conventional LC-MS/MS. The mean deviation to the immunoassays was 17–19% and negative for all ISDs except everolimus with a positive 19% bias. No weak points were revealed when challenging assay and system with, e.g., high haematocrit, sedimented whole blood or priority samples. The Cascadion integrated well into our 24/7 routine and could easily be operated simultaneously with several other analyzers by technical staff without LC-MS experience. Conclusions The ISD panel showed excellent analytical performance and demonstrated that a fully automated LC-MS-based analysis starting from primary samples is feasible, suggesting that LC-MS could become an integral part of 24/7 diagnostics in the near future.
Comprehensive Analysis of Tumour Sub-Volumes for Radiomic Risk Modelling in Locally Advanced HNSCC
2020-10-19

Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTVentire). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTVentire was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTVentire achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend (p = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models.
CD276 as a novel CAR NK‐92 therapeutic target for neuroblastoma
2020-10-19

Despite advanced understanding of its biology and improvements in standard of care treatment, the outcome for children with neuroblastoma (NB), the most common solid extracranial tumor in pediatrics, remains poor. Particularly, frequent relapse and high mortality rates of high-risk NB patients necessitate new therapeutic approaches such as chimeric antigen receptor (CAR)-modified immune cells. CAR T cells recently showed incredible clinical response targeting CD19 and CD22 in hematological malignancies. However, targeting solid cancers remains a difficult challenge and production of autologous CAR T-cell products still requires an extensive manufacturing process. The well-established natural killer (NK)-92 cell line provides a promising alternative to produce “off-the-shelf” CAR-modified effector cells. In the present study, we demonstrate that the immune checkpoint molecule B7-H3 (CD276) is aberrantly expressed on NB cells. Second generation CD276-CAR-engineered but not parental NK-92 cells were capable of specific and long-term elimination of NB cells in vitro while sparing CD276-negative cancer cells. Furthermore, CD276-CAR NK-92 cells showed increased cytotoxicity in a three-dimensional NB spheroid model which can recapitulate in vivo morphology as well as cell connectivity, polarity, gene expression, and tissue architecture, thereby, bridging the gap between in vitro and in vivo models. CD276-CAR NK-92 cells produced a multitude of NK effector molecules as well as pro-inflammatory cytokines that can stimulate the immune system. CD276-CAR surface expression and cytotoxic effector function remained stable for more than 6 months. Data show that CD276-CAR NK-92 may be a promising treatment option for patients with high-risk NB.
Adolescent Nonalcoholic Fatty Liver Disease and Type 2 Diabetes in Young Adulthood
2020-10-19

Abstract Context The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. Objective To assess type 2 diabetes risk among adolescents with NAFLD. Design and Setting A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997–2011 and were followed until December 31, 2016. Participants A total of 1 025 796 normoglycemic adolescents were included. Interventions Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. Main Outcome Measures Type 2 diabetes incidence. Results During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47–4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). Conclusions Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.
One-loop corrections to the two-body decays of the neutral Higgs bosons in the complex NMSSM
2020-10-19

Abstract Since no direct signs of new physics have been observed so far indirect searches in the Higgs sector have become increasingly important. With the discovered Higgs boson behaving very standard model (SM)-like, however, indirect new physics manifestations are in general expected to be small. On the theory side, this makes precision predictions for the Higgs parameters and observables indispensable. In this paper, we provide in the framework of the CP-violating next-to-minimal supersymmetric extension of the SM (NMSSM) the complete next-to-leading order (SUSY-)electroweak corrections to the neutral Higgs boson decays that are on-shell and non-loop induced. We also investigate possible gauge-dependence issues in the decays of light Higgs bosons into fermion pairs. Together with the also provided SUSY-QCD corrections to colored final states, the newly calculated SUSY-electroweak corrections are implemented in the Fortran code which already includes the state-of-the art QCD corrections. The new code is called . This way we provide the NMSSM Higgs boson decays and branching ratios at presently highest possible precision and thereby contribute to the endeavor of searching for New Physics at present and future colliders.
Germaborenes: Borylene Transfer Agents for the Synthesis of Iminoboranes
2020-10-19

Abstract Halide and phenyl substituted germaborenes were shown to react with azides at room temperature and transfer a borylene moiety to give iminoboranes. This iminoborane synthesis based on a borylene transfer route was investigated computationally in the case of the phenyl substituted germaborene.
Social citizenship in federations: free movement and social assistance rights in the EU and beyond
2020-10-19

When and how have free movement and social citizenship been reconciled in federal settings characterised by devolved welfare responsibilities and extensive internal diversity? The EU fails to guarantee minimum social protection rights for EU citizens migrating within the Union, as access to social assistance in countries of destination is highly conditional. This situation is very similar to historical experiences in other federations, where fears of welfare migration and tensions between federal and sub-federal competencies made it difficult to guarantee social assistance rights for all citizens. A comparison of the North German Confederation, Switzerland and the USA, demonstrates that such rights nonetheless have been extended to all citizens in federations and that this occurred along two pathways: (a) a judicial pathway through the intervention of a constitutional court; or (b) a political pathway through incremental change. The conclusion considers possible implications of these findings for the EU.
Emotional policies: Introducing branding as a tool for science diplomacy
2020-10-19

Abstract This article seeks to expand the science diplomacy (SD) discourse by introducing the concept of branding, focusing on its use as a tool for nation state decision makers. Although the current literature on SD has explored the relation between science and diplomacy, the question of how individual science projects can effectively aid SD has been left largely unanswered. Drawing on the SD as well as on the place and policy branding literature, a framework for the analysis and conceptualization of branding as a tool for SD and for Public Diplomacy in general is developed. This framework introduces three distinct branding styles: nation branding, policy branding and policy tool branding. The applicability of the framework is demonstrated by the comparison of two cases of branding by nation state policy makers: branding in the field of German transnational education and in the science and knowledge-based Dutch Water Diplomacy. The German case study shows that branding activities relating to ‘German’ SD are fragmented and focus mostly on individual projects, while the use of transnational education as an instrument to advance policy branding or nation branding remains largely underdeveloped. Such a lopsided branding process undermines the effectiveness of branding as an effective SD tool. In contrast, the potential of coordinated branding strategies as a foreign policy tool becomes apparent in the ‘Dutch Delta Approach’. In this centralised and coordinated branding process, activities on all three proposed branding layers were implemented, effectively employing branding to increase the visibility of the Dutch nation state, increase the attraction of its high-tech water management sector as well as to rejuvenate the Netherland’s bi-lateral relations with selected partner countries. Branding, as we argue, should be added to the analysis of contemporary science diplomacy as well as of broader foreign policies, adding to the understanding of SD as an instrument of cross-border communication and global opinion shaping. The paper ends with a discussion of potential limitations of branding, in order to illustrate that branding can be an effective instrument but should not be seen as an international relations panacea.
Downregulation of 15-hydroxyprostaglandin dehydrogenase during acquired tamoxifen resistance and association with poor prognosis in ERα-positive breast cancer
2020-10-19

Aim: Tamoxifen (TAM) resistance remains a clinical issue in breast cancer. The authors previously reported that 15-hydroxyprostaglandin dehydrogenase (HPGD) was significantly downregulated in tamoxifen-resistant (TAMr) breast cancer cell lines. Here, the authors investigated the relationship between HPGD expression, TAM resistance and prediction of outcome in breast cancer. Methods: HPGD overexpression and silencing studies were performed in isogenic TAMr and parental human breast cancer cell lines to establish the impact of HPGD expression on TAM resistance. HPGD expression and clinical outcome relationships were explored using immunohistochemistry and in silico analysis. Results: Restoration of HPGD expression and activity sensitised TAMr MCF-7 cells to TAM and 17β-oestradiol, whilst HPGD silencing in parental MCF-7 cells reduced TAM sensitivity. TAMr cells released more prostaglandin E2 (PGE2) than controls, which was reduced in TAMr cells stably transfected with HPGD. Exogenous PGE2 signalled through the EP4 receptor to reduce breast cancer cell sensitivity to TAM. Decreased HPGD expression was associated with decreased overall survival in ERα-positive breast cancer patients. Conclusions: HPGD downregulation in breast cancer is associated with reduced response to TAM therapy via PGE2-EP4 signalling and decreases patient survival. The data offer a potential target to develop combination therapies that may overcome acquired tamoxifen resistance.
First-order evolution equations with dynamic boundary conditions
2020-10-19

In this paper, we introduce a general framework to study linear first-order evolution equations on a Banach space X with dynamic boundary conditions, that is with boundary conditions containing time derivatives. Our method is based on the existence of an abstract Dirichlet operator and yields finally to equivalent systems of two simpler independent equations. In particular, we are led to an abstract Cauchy problem governed by an abstract Dirichlet-to-Neumann operator on the boundary space ∂ X . Our approach is illustrated by several examples and various generalizations are indicated. This article is part of the theme issue ‘Semigroup applications everywhere’.