DSTYK inhibition increases the sensitivity of lung cancer cells to T cell–mediated cytotoxicity

Lung cancer cells; CytotoxicityCèl·lules canceroses de pulmó; CitotoxicitatCélulas cancerosas de pulmón; CitotoxicidadLung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant lung tumors to anti-PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.This work was supported by Fundación para la investigación médica aplicada (FIMA), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC; CB16/12/00443), Spanish Association Against Cancer Scientific Foundation (AECC; GCB14-2170), Fundación Ramón Areces, Instituto de Salud Carlos III, and co-funded by the European Union (European Regional Development Fund, “A way to make Europe”; PI19/00098; PI19/00230; PI20/00419), Fundación Roberto Arnal Planelles, and International Association for the Study of Lung Cancer (IASLC) Fellowship funding (K. Valencia). M. Echepare was supported by Contratos Predoctorales de Formación en Investigación en Salud (PFIS), Instituto de Salud Carlos III, and co-funded by the European Union (European Social Fund, "Investing in your future"; FI20/00295)

Extending a Fuzzy Polarity Propagation Method for Multi-Domain Sentiment Analysis with Word Embedding and POS Tagging

International audienceWithin multi-domain sentiment analysis, we study how different domain-dependent polarities can be learned for the same concepts. To this aim, we extend an existing approach based on the propagation of fuzzy polarities over a semantic graph capturing background linguistic knowledge to learn concept polarities with respect to various domains and their uncertainty from labeled datasets. In particular, we use POS tagging to refine the association between terms and concepts and word embedding to enhance the construction of the semantic graph. The proposed approach is then evaluated on a standard benchmark, showing that the combined use of POS tagging and word embedding improves its performance. One particularly strong point of the proposed approach is its recall, which is always very close to 100%. In addition, we observe that it exhibits good cross-domain generalization capabilities

Thermal Transport in Chiral Conformal Theories and Hierarchical Quantum Hall States

Chiral conformal field theories are characterized by a ground-state current at finite temperature, that could be observed, e.g. in the edge excitations of the quantum Hall effect. We show that the corresponding thermal conductance is directly proportional to the gravitational anomaly of the conformal theory, upon extending the well-known relation between specific heat and conformal anomaly. The thermal current could signal the elusive neutral edge modes that are expected in the hierarchical Hall states. We then compute the thermal conductance for the Abelian multi-component theory and the W-infinity minimal model, two conformal theories that are good candidates for describing the hierarchical states. Their conductances agree to leading order but differ in the first, universal finite-size correction, that could be used as a selective experimental signature.Comment: Latex, 17 pages, 2 figure

In Utero Exposure to Persistent Organic Pollutants and Childhood Lipid Levels

Animal studies have shown that developmental exposures to polybrominated diphenyl ethers (PBDE) permanently affect blood/liver balance of lipids. No human study has evaluated associations between in utero exposures to persistent organic pollutants (POPs) and later life lipid metabolism. In this pilot, maternal plasma levels of PBDEs (BDE-47, BDE-99, BDE-100, and BDE-153) and polychlorinated biphenyls (PCB-138, PCB-153, and PCB-180) were determined at delivery in participants of GESTation and Environment (GESTE) cohort. Total cholesterol (TCh), triglycerides (TG), low- and high-density lipoproteins (LDL-C and HDL-C), total lipids (TL), and PBDEs were determined in serum of 147 children at ages 6–7. General linear regression was used to estimate the relationship between maternal POPs and child lipid levels with adjustment for potential confounders, and adjustment for childhood POPs. In utero BDE-99 was associated with lower childhood levels of TG (p = 0.003), and non-significantly with HDL-C (p = 0.06) and TL (p = 0.07). Maternal PCB-138 was associated with lower childhood levels of TG (p = 0.04), LDL-C (p = 0.04), and TL (p = 0.02). Our data indicate that in utero exposures to POPs may be associated with long lasting decrease in circulating lipids in children, suggesting increased lipid accumulation in the liver, a mechanism involved in NAFLD development, consistent with previously reported animal data

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity

Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α–mediated CD8+-killing and immune-resistant lung tumors to anti–PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.This work was supported by Fundación para la investigación medica aplicada (FIMA), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC; CB16/12/00443), Spanish Association Against Cancer Scientific Foundation (AECC; GCB14-2170), Fundación Ramón Areces, Instituto de Salud Carlos III, and cofunded by the European Union (European Regional Development Fund, “A way to make Europe”; PI19/00098; PI19/00230; PI20/ 00419), Fundación Roberto Arnal Planelles, and International Association for the Study of Lung Cancer (IASLC) Fellowship funding (K. Valencia). M. Echepare was supported by Contratos Predoctorales de Formación en Investigación en Salud (PFIS), Instituto de Salud Carlos III, and co-funded by the European Union (European Social Fund, "Investing in your future"; FI20/00295)

Scientific Evaluation of Nanomaterials of TiO{sub 2} and Related Derivatives in a Variety of Applications

Altair Nanotechnolgies, Inc. (Altair) has performed and hereby reports on research and development of novel nanomaterials for applications in 1) advanced power storage devices, 2) sensors for chemical, biological and radiological agents and on an 3) investigation into mechanisms of living cell-nanoparticle interactions that will allow predictions of health and safety issues and potentially result in novel agents for remediation of chemical and biological hazards. The project was organized around four distinct objectives. Two of the objectives are focused on developments designed to dramatically improve the performance of rechargeable Li-Ion batteries. These efforts are based on extensions of Altair's proprietary TiO{sub 2} nanoparticles and nanoparticle aggregates in the form of lithium titanate spinel, lithium manganates and lithium cobaltates. A third objective leverages the core Altair nanomaterials technology to develop a unique (nanosensor) platform for the error-free, "lab on a chip" detection of chemical, biological and radiological agents for hazardous materials remediation and threat detection. The innovative approach taken by the Altair/Western Michigan team develops individual nanosensor elements built upon a construct that includes a target-specific receptor molecule coupled through a signal transducing nanomolecule to a gold, TiO{sub 2} or SiO{sub 2} nanoparticle coated with a high density of strongfluorescing molecules for signal amplification The final objective focuses on interaction mechanisms between cells and nanoparticles with the goal of understanding how specific chemical and physical properties of these nanoparticles influence that interaction. The effort will examine a range of microbes that have environmental or societal importance

Galaxy Formation and Symbiotic Evolution with the Inter-Galactic Medium in the Age of ELT-ANDES

High-resolution absorption spectroscopy toward bright background sources has had a paramount role in understanding early galaxy formation, the evolution of the intergalactic medium and the reionisation of the Universe. However, these studies are now approaching the boundaries of what can be achieved at ground-based 8-10m class telescopes. The identification of primeval systems at the highest redshifts, within the reionisation epoch and even into the dark ages, and of the products of the first generation of stars and the chemical enrichment of the early Universe, requires observing very faint targets with a signal-to-noise ratio high enough to detect very faint spectral signatures. In this paper, we describe the giant leap forward that will be enabled by ANDES, the high-resolution spectrograph for the ELT, in these key science fields, together with a brief, non-exhaustive overview of other extragalactic research topics that will be pursued by this instrument, and its synergistic use with other facilities that will become available in the early 2030s.Comment: 40 pages, 7 figures; submitted to Experimental Astronomy on behalf of the ANDES Science Tea

MP2RAGE provides new clinically-compatible correlates of mild cognitive deficits in relapsing-remitting multiple sclerosis

Despite that cognitive impairment is a known early feature present in multiple sclerosis (MS) patients, the biological substrate of cognitive deficits in MS remains elusive. In this study, we assessed whether T1 relaxometry, as obtained in clinically acceptable scan times by the recent Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) sequence, may help identifying the structural correlate of cognitive deficits in relapsing-remitting MS patients (RRMS). Twenty-nine healthy controls (HC) and forty-nine RRMS patients underwent high-resolution 3T magnetic resonance imaging to obtain optimal cortical lesion (CL) and white matter lesion (WML) count/volume and T1 relaxation times. T1 z scores were then obtained between T1 relaxation times in lesion and the corresponding HC tissue. Patient cognitive performance was tested using the Brief Repeatable Battery of Neuro-psychological Tests. Multivariate analysis was applied to assess the contribution of MRI variables (T1 z scores, lesion count/volume) to cognition in patients and Bonferroni correction was applied for multiple comparison. T1 z scores were higher in WML (p<0.001) and CL-I (p<0.01) than in the corresponding normal-appearing tissue in patients, indicating relative microstructural loss. (1) T1 z scores in CL-I (p=0.01) and the number of CL-II (p=0.04) were predictors of long-term memory; (2) T1 z scores in CL-I (β=0.3; p=0.03) were independent determinants of long-term memory storage, and (3) lesion volume did not significantly influenced cognitive performances in patients. Our study supports evidence that T1 relaxometry from MP2RAGE provides information about microstructural properties in CL and WML and improves correlation with cognition in RRMS patients, compared to conventional measures of disease burden

Recommendations for radiation therapy in oligometastatic prostate cancer:An ESTRO-ACROP Delphi consensus

Background and purpose: Oligometastatic prostate cancer is a new and emerging treatment field with only few prospective randomized studies published so far. Despite the lack of strong level I evidence, metastasis-directed therapies (MDT) are widely used in clinical practice, mainly based on retrospective and small phase 2 studies and with a large difference across centers. Pending results of ongoing prospec-tive randomized trials, there is a clear need for more consistent treatment indications and radiotherapy practices.Material and methods: A European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee consisting of radiation oncologists' experts in prostate cancer was asked to answer a dedicated question-naire, including 41 questions on the main controversial issues with regard to oligometastatic prostate cancer.Results: The panel achieved consensus on patient selection and routine use of prostate-specific mem-brane antigen positron emission tomography (PSMA PET) imaging as preferred staging and restaging imaging. MDT strategies are recommended in the de novo oligometastatic, oligorecurrent and oligopro-gressive disease setting for nodal, bone and visceral metastases. Radiation therapy doses, volumes and techniques were discussed and commented.Conclusion: These recommendations have the purpose of providing standardization and consensus to optimize the radiotherapy treatment of oligometastatic prostate cancer until mature results of random-ized trials are available.AT would like to acknowledge the support of Cancer Research UK (C33589/A28284 and C7224/A28724) . This project represents independent research supported by the National Institute for Health research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care