512 research outputs found
The Adenosinergic Pathway in Non-Small Cell Lung Cancer
No full textSimple Summary Lung cancer remains the most important cause of cancer-related mortality worldwide. Immune checkpoint inhibitors revolutionized lung cancer care. These molecules restore the host's immune response against tumor cells and led to impressive results in non-small cell lung cancer patients. However, these benefits are only observed in a minority of patients. Extracellular adenosine is an immune checkpoint that contributes to immune evasion in tumor cells. Current research focuses on targeting this pathway with the aim of inducing durable treatment effects in a greater proportion of lung cancer patients.Abstract Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 and CTLA-4 have revolutionized the systemic treatment of non-small cell lung cancer (NSCLC), achieving impressive results. However, long-term clinical benefits are only seen in a minority of patients. Extensive research is being conducted on novel potential immune checkpoints and the mechanisms underlying ICI resistance. The tumor microenvironment (TME) plays a critical role in modulating the immune response and influencing the efficacy of ICIs. The adenosinergic pathway and extracellular adenosine (eADO) are potential targets to improve the response to ICIs in NSCLC patients. First, this review delves into the adenosinergic pathway and the impact of adenosine within the TME. Second, we provide an overview of relevant preclinical and clinical data on molecules targeting this pathway, particularly focusing on NSCLC
Diagnostic Validation of a Comprehensive Targeted Panel for Broad Mutational and Biomarker Analysis in Solid Tumors
No full textSIMPLE SUMMARY: The analysis of tumor-associated genetic variants and biomarkers is critical for therapy choice, as specific mutations allow for a personalized treatment. Because more and more mutation-treatment combinations become available, screening should be performed on many genes simultaneously. The use of large and comprehensive gene panel screenings in molecular diagnostics, however, requires an extensive and thorough validation to demonstrate the correctness of all clinically relevant data. Here, we describe such validation using a large number of samples and confirmed effective detection of several types of mutations for different validation parameters. Samples of tumor patients thus can be reliably tested with a comprehensive assay to maximize their personalized treatment regimen. ABSTRACT: The use of targeted Next Generation Sequencing (NGS) for the diagnostic screening of somatic variants in solid tumor samples has proven its high clinical value. Because of the large number of ongoing clinical trials for a multitude of variants in a growing number of genes, as well as the detection of proven and emerging pan-cancer biomarkers including microsatellite instability (MSI) and tumor mutation burden (TMB), the currently employed diagnostic gene panels will become vastly insufficient in the near future. Here, we describe the validation and implementation of the hybrid capture-based comprehensive TruSight Oncology (TSO500) assay that is able to detect single-nucleotide variants (SNVs) and subtle deletions and insertions (indels) in 523 tumor-associated genes, copy-number variants (CNVs) of 69 genes, fusions with 55 cancer driver genes, and MSI and TMB. Extensive validation of the TSO500 assay was performed on DNA or RNA from 170 clinical samples with neoplastic content down to 10%, using multiple tissue and specimen types. Starting with 80 ng DNA and 40 ng RNA extracted from formalin-fixed and paraffine-embedded (FFPE) samples revealed a precision and accuracy >99% for all variant types. The analytical sensitivity and specificity were at least 99% for SNVs, indels, CNVs, MSI, and gene rearrangements. For TMB, only values around the threshold could yield a deviating outcome. The limit-of-detection for SNVs and indels was well below the set threshold of 5% variant allele frequency (VAF). This validated comprehensive genomic profiling assay was then used to screen 624 diagnostic samples, and its success rate for adoption in a clinical diagnostic setting of broad solid tumor screening was assessed on this cohort
MAES: A Multi-Agent Systems Framework for Embedded Systems
No full textMiniaturization and cost reduction of hardware components have created a trend in the space industry where the traditional centralized computer is being replaced by distributed computer architecture. However, this trend comes with a cost: the on-board software complexity of the space missions has increased. The complexity has origins in the requirements of the missions where in general, these are coordination and control-related processes. As the coordination and the control of the satellite's activities are not trivial tasks, the Multi-Agent Systems(MAS)-approach has been proposed as a new architectural style due to its distributed nature. There are several existing frameworks for implementing MAS-based applications, however, most of them are neither designed to satisfy real-time requirements nor designed to be implemented in highly-constrained embedded systems. Therefore, the purpose of this thesis is to develop a new tool for MAS-based applications: A Multi-Agent Framework for Embedded Systems (MAES).The framework was implemented on top of a Real-Time Operating System: TI-RTOS, therefore, applications implemented with MAES have realtime characteristics. Experiments have shown that the execution time of an Attitude Determination algorithm is consistent on each call with a variance value of the order of 10^5 [s^2], demonstrating the predictability of the framework. Furthermore, the user coding effort is reduced as several routines are standardized and encapsulated into MAES' API. However, the predictability and ease-of-use come with a slight cost: experiments have shown that MAES-based applications lead to an increase of 6.7 KB in average in Flash memory and 4.5 KB in average in SRAM memory with respect to its non-agent implementation. Also, the CPU utilization increases as inter-agent communication requires additional processing time, also increasing the power consumption. However, the increase is low as the results have shown that is less than 1% in average
Regulation of Trading in Ginnie Maes
No full textWhile Ginnie Maes have undergone spectacular growth, the trading markets for these government-sponsored securities have spawned a number of financial scandals, thus becoming a cynosure of regulatory scrutiny. The author explores these markets and their problems and analyzes the responses to the problems by regulators and participants
Liquid Biopsy in Early-Stage Lung Cancer: Current and Future Clinical Applications
No full textLung cancer remains the leading cause of cancer death worldwide, with the majority of cases diagnosed in an advanced stage. Early-stage disease non-small cell lung cancer (NSCLC) has a better outcome, nevertheless the 5-year survival rates drop from 60% for stage IIA to 36% for stage IIIA disease. Early detection and optimized perioperative systemic treatment are frontrunner strategies to reduce this burden. The rapid advancements in molecular diagnostics as well as the growing availability of targeted therapies call for the most efficient detection of actionable biomarkers. Liquid biopsies have already proven their added value in the management of advanced NSCLC but can also optimize patient care in early-stage NSCLC. In addition to having known diagnostic benefits of speed, accessibility, and enhanced biomarker detection compared to tissue biopsy, liquid biopsy could be implemented for screening, diagnostic, and prognostic purposes. Furthermore, liquid biopsy can optimize therapeutic management by overcoming the issue of tumor heterogeneity, monitoring tumor burden, and detecting minimal residual disease (MRD), i.e., the presence of tumor-specific ctDNA, post-operatively. The latter is strongly prognostic and is likely to become a guidance in the postsurgical management. In this review, we present the current evidence on the clinical utility of liquid biopsy in early-stage lung cancer, discuss a selection of key trials, and suggest future applications.This research received no external funding
Corrole basicity in the excited states: Insights on structure-property relationships
No full textSteady-state fluorescence measurements and quantum-chemical DFT geometry optimizations are applied to extend the structure-property relationships between the free-base corrole macrocycle conformation and its basicity to the lowest excited S-1 and T-1 states. Direct basicity estimation in the lowest excited S-1 state is demonstrated by means of fluorescence quantum yield measurements. The long wavelength T1 tautomer is found to retain its basicity in the S(1 )state, whereas the short wavelength T2 tautomer shows a noticeable decrease in basicity in the S-1 state, which is related to the in-plane tilting of the pyrrole ring to be protonated. The conformational changes upon going from the ground to the lowest excited T-1 state and the influence of the meso-aryl substitution pattern on the overall degree of distortions and tilting of the pyrrole ring to be protonated are also discussed from the point of view of macrocycle basicity.Prof. W. Maes acknowledges the Research Foundation-Flanders (FWO) and Hasselt University for financial support. Prof. M. Kruk, Prof. L. Gladkov and Ass. Prof. D. Klenitsky acknowledge the State Program of Scientific Researches of the Republic of Belarus "Photonics, opto-and microelectronics", grant no.1.3.01, for financial support.Maes, W (corresponding author), Hasselt Univ, Inst Mat Res IMO IMOMEC, Agoralaan 1, B-3590 Diepenbeek, Belgium.
Kruk, MM (corresponding author), Belarusian State Technol Univ, Phys Dept, Sverdlov Str 13a, Minsk 220006, BELARUS.
[email protected]; [email protected]
Verdi als politiek theater: Peter Konwitschny regisseert Aida en Don Carlos
No full textPeter Konwitschny is a German stage director who belongs to the modern tradition of "Regie-Theater". His opera productions are notoriously provocative. In this paper, the author examines two of his Verdi productions, Aida and Don Carlos, in order to demonstrate that his radical stagings go to the core of the works with unprecedented vividness and richness of meaning. Konwitschny's work is governed by a profound challenge of the patriarchal political relationships that are thematized in an exemplary way in Verdi's operas
Wat verstaan we onder operakritiek?
No full textThis chapter aims to define opera criticism in the context of the modern operatic practice, characterized by innovative stagings that appear to contradict the original operatic text at different levels. The author argues that such radical productions should nevertheless be considered in the light of an opera's history and reception, confronting the meaning of the opera as a historical text with its functioning in a contemporary vision. The aim of opera criticism is precisely to bridge these two levels in the construction of the meaning of an operatic text
Data for "Association between adolescents’ family socioeconomic status and working memory updating functioning: role of parental educational involvement"
No full textThe research (doi: 10.1111/jora.12848) related to these data concerned a study on the association between the socioeconomic status (SES) of the family of young adolescents and working memory updating ability of the adolescents, and whether this association is (partly) mediated by different aspects of parental educational involvement. A total of 260 Chinese young adolescents completed questionnaires about their family’s SES, the intellectual, behavioral, and emotional involvement of the mother and father in the education of the adolescent, two versions of a computerized running memory task, Raven’s Standard Progressive Matrices (RSPM) test, and questions about additional demographic characteristics. The results revealed a positive association between family SES and working memory updating task performance, and between working memory updating and RSPM performance. This SES-updating association was partly mediated by behavioral educational involvement of the mother (indirect effect with a positive coefficient) and the mother’s intellectual involvement (indirect effect with a negative coefficient). The three aspects of the father’s educational involvement did not play a significant mediating role.These results might inform interventions aimed at enhancing cognitive skills of children with a poor SES background.The data file concerns an SPSS data file. The data consist of each participant’s score on the outcome measure for each of the demographic and socioeconomic variables, the mother’s and father’s intellectual, behavioral, and emotional educational involvement (questionnaires), the different items of the RSPM, and the working memory updating tasks (two versions of a running memory task with different stimulus-presentation times). These scores were used in analyses of variance, correlational analyses, and regression (mediation) analyses, to assess the relations between SES, working memory updating ability, and aspects of parental educational involvement, as described in the target article. The meaning of each column in the data file is described under the tap Variable View --> Label. The raw data of the running memory tasks (in eprime format) on which the corresponding pre-processed data are based are available from the corresponding author upon request
Immune checkpoint inhibition in early-stage non-small cell lung cancer
No full textThe introduction of immune checkpoint inhibitors significantly advanced outcomes in both metastatic and locally advanced non-small cell lung cancer. Despite these advancements, the 5-year survival rate remains suboptimal. Even in early-stage disease a significant portion of patients relapse and die from metastatic progression. The integration of immunotherapy in the management of early-stage NSCLC demonstrated promising results, supported by a plethora of positive clinical trials conducted in recent years. Nonetheless, numerous questions persist. In this manuscript we comprehensively review the currently available data on adjuvant, neoadjuvant, and perioperative treatment strategies. We also address the challenges inherent to these approaches from different stakeholders' perspective
- …
