Single tube liquid biopsy for advanced non-small cell lung cancer

The need for a liquid biopsy in non-small cell lung cancer (NSCLC) patients is rapidly increasing. We studied the relation between overall survival (OS) and the presence of four cancer biomarkers from a single blood draw in advanced NSCLC patients: EpCAM(high) circulating tumor cells (CTC), EpCAM(low) CTC, tumor-derived extracellular vesicles (tdEV) and cell-free circulating tumor DNA (ctDNA). EpCAM(high) CTC were detected with CellSearch, tdEV in the CellSearch images and EpCAM(low) CTC with filtration after CellSearch. ctDNA was isolated from plasma and mutations present in the primary tumor were tracked with deep sequencing methods. In 97 patients, 21% had >= 2 EpCAM(high) CTC, 15% had >= 2 EpCAM(low) CTC, 27% had >= 18 tdEV and 19% had ctDNA with >= 10% mutant allele frequency. Either one of these four biomarkers could be detected in 45% of the patients and all biomarkers were present in 2%. In 11 out of 16 patients (69%) mutations were detected in the ctDNA. Two or more unfavorable biomarkers were associated with poor OS. The presence of EpCAM(high) CTC and elevated levels of tdEV and ctDNA was associated with a poor OS; however, the presence of EpCAM(low) CTC was not. This single tube approach enables simultaneous analysis of multiple biomarkers to explore their potential as a liquid biopsy

High-resolution analysis of HLA class I alterations in colorectal cancer

BACKGROUND: Previous studies indicate that alterations in Human Leukocyte Antigen (HLA) class I expression are frequent in colorectal tumors. This would suggest serious limitations for immunotherapy-based strategies involving T-cell recognition. Distinct patterns of HLA surface expression might conceal different immune escape mechanisms employed by the tumors and are worth further study. METHOD: We applied four-color multiparameter flow cytometry (FCM), using a large panel of alloantigen-specific anti-HLA-A and -B monoclonal antibodies, to study membranous expression of individual HLA alleles in freshly isolated colorectal cancer cell suspensions from 21 patients. RESULTS: Alterations in HLA class I phenotype were observed in 8 (38%) of the 21 tumors and comprised loss of a single A or B alleles in 4 cases, and loss of all four A and B alleles in the other 4 cases. Seven of these 8 tumors were located on the right side of the colon, and those showing loss of both HLA-A and -B membranous expression were all of the MSI-H phenotype. CONCLUSION: FCM allows the discrimination of complex phenotypes related to the expression of HLA class I. The different patterns of HLA class I expression might underlie different tumor behavior and influence the success rate of immunotherapy

Severe Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children from Wild-type to Population Immunity: A Prospective Multicenter Cohort Study with Real-time Reporting

Background: SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data. Methods: This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity. Results: We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curaçao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies. Conclusions: Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections

Quantitative temporal viromics: an approach to investigate host-pathogen interaction

A systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection could provide dynamic insights into virus-host interaction. We developed a proteomic technique called “quantitative temporal viromics” (QTV), which employs multiplexed tandem-mass-tag-based mass spectrometry. Human cytomegalovirus (HCMV) is not only an important pathogen but a paradigm of viral immune evasion. QTV detailed how HCMV orchestrates the expression of >8,000 cellular proteins, including 1,200 cell-surface proteins to manipulate signaling pathways and counterintrinsic, innate, and adaptive immune defenses. QTV predicted natural killer and T cell ligands, as well as 29 viral proteins present at the cell surface, potential therapeutic targets. Temporal profiles of >80% of HCMV canonical genes and 14 noncanonical HCMV open reading frames were defined. QTV is a powerful method that can yield important insights into viral infection and is applicable to any virus with a robust in vitro model

Atlantis : a tool for language definition and interpreter synthesis.

Programming language semantics are usually defined informally in some form of technical natural language, or in a very mathematical manner with techniques such as the Vienna Definition Method (VDM) or denotational semantics. One difficulty which arises from serious attempts to define language semantics is that the resulting definition is generally suitable for a single limited kind of reader. For example, the more formal kind of definition may suit a compiler writer or a language designer, but will be less convenient for other potential classes of reader, such as programmers. The latter frequently make use of some completely separate description (e.g., an introductory text book on the language); not surprisingly, inconsistencies between these separate descriptions and the language definition are commonplace. This thesis develops a technique for the definition of programming language semantics which is suitable for a wide range of potential readers. This technique employs an operational semantic model which is based on the algebraic specifiication of abstract data types; the semantic model manipulates multi-layer descriptions of language semantics and supports multiple passes in these descriptions. The semantic technique described in this thesis lends itself to the semi-automatic generation of an interpreter from the language definition, a fact which acts as an incentive to language designers to produce a formal definition of any new programming language, since the prototype implementation allows experimentation with new language features and their semantics. The system which generates an interpretive implementation from a language definition is called ATLANTIS, A Tool for LANguage definiTion and Interpreter Synthesis, and is also described in this thesis.Thesis (Ph.D.) -- University of Adelaide, Dept. of Computer Science, 199

Persistence, Programming Languages and Supercomputing. Where is it All Going?

: This paper discusses the research into persistence undertaken at the University of Adelaide in the 1990's, what we are currently doing and where we plan to take it. Persistence deals with the longevity of data beyond the execution of the application that created it. Our interest is in the support of persistence through the development of efficient persistent data stores and appropriate support at the programming language level with the intention of making the technology a part of every software engineers toolkit. 1. Introduction Persistence is a general term for mechanisms that save data from a program's execution space so that it can be used in a later execution; i.e., by making the program's data "persist" from one execution to the next. In its broadest sense, the term covers conventional and object-oriented databases, execution checkpointing and data structure pickling as well as more sophisticated mechanisms. There are several possible schemes for supporting persistence for appli..

Generating an Interpretive Language Implementation From a Layered Operational Model

This paper describes a technique for the automatic generation of an interpretive implementation for a programming language from a layered operational semantic description of the language. Layers in the semantic model represent levels of abstraction which correspond to the needs of various classes of user of the semantic description (programmers, language designers, and so on). The layers are built one atop the other, with the innermost layer of the model being based on the algebraic specification of abstract data types. Different kinds of user can thus use the same language definition, examining it to differing levels of detail. The complete layered programming language definition can be submitted to a system which automatically generates an interpretive implementation of the language. The implementation will hence be consistent with the description of the language being used by each kind of user. In particular, this technique presents many advantages for language designers, since aspe..

Visor++: A visualisation tool for concurrent object-oriented programs

The use of program visualisation for understanding and ne-tuning task-parallel object-oriented programs is desirable. One reason is that such programs typically involve complex interactions between the program entities. Combined with other tools, program visualisation tools can make understanding and ne-tuning of such programs easier. For maximum bene t, the visualisation of task-parallel object-oriented programs should not focus only on a small section of program features, but rather on a wide cross section which covers all the important program interactions. The resulting views should be presented in ways that facilitate ease of use, ease of relating one view to another, and should assist users in building a mental model of the program. In other words, a holistic approach to visualisation is required. This paper discusses Visor++, a tool for visualising CC++ programs. This tool embodies the concepts of a holistic approach to present views which are integrated and inter-related. Although the underlying system of CC++ does not support program visualisation, it is indeed possible to devise such visualisation at the language level. The usefulness of Visor++ is demonstrated by some representative cases