Multiplexed imaging technologies enable the study of biological tissues at single-cell resolution while preserving spatial information. Currently, high-dimension imaging data analysis is ...technology-specific and requires multiple tools, restricting analytical scalability and result reproducibility. Here we present SIMPLI (Single-cell Identification from MultiPLexed Images), a flexible and technology-agnostic software that unifies all steps of multiplexed imaging data analysis. After raw image processing, SIMPLI performs a spatially resolved, single-cell analysis of the tissue slide as well as cell-independent quantifications of marker expression to investigate features undetectable at the cell level. SIMPLI is highly customisable and can run on desktop computers as well as high-performance computing environments, enabling workflow parallelisation for large datasets. SIMPLI produces multiple tabular and graphical outputs at each step of the analysis. Its containerised implementation and minimum configuration requirements make SIMPLI a portable and reproducible solution for multiplexed imaging data analysis. Software is available at "SIMPLI https://github.com/ciccalab/SIMPLI ".
Structure-based virtual screening simulations, which are often used in drug discovery, can be very computationally demanding. This is why user-friendly domain-specific web or desktop applications ...that enable running simulations on powerful computing infrastructures have been created. This article investigates how domain-specific desktop applications can be extended to use cloud computing and how they can be part of scenarios that require sharing and analysing previous molecular docking results. A generic approach based on interviews with scientists and analysis of existing systems is proposed. A proof of concept is implemented using the Raccoon2 desktop application for virtual screening, WS-PGRADE workflows, gUSE services with the CloudBroker Platform, the structural alignment tool DeepAlign, and the ligand similarity tool LIGSIFT. The presented analysis illustrates that this approach of extending a domain-specific desktop application can use different types of clouds, thus facilitating the execution of virtual screening simulations by life scientists without requiring them to abandon their favourite desktop environment and providing them resources without major capital investment. It also shows that storing and sharing molecular docking results can produce additional conclusions such as viewing similar docking input files for verification or learning.
•Cloud computing capabilities can be added to domain-specific desktop applications.•Virtual screening can be conducted with less funds using a familiar GUI.•Sharing previous docking results make them useful to other scientists.
Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). We conducted an integrated study of the ...cancer tissue and associated tumor microenvironment (TME) from patients treated with pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab to dissect the cellular and molecular determinants of response to anti- programmed cell death 1 (PD1) immunotherapy.
We selected multiple regions per tumor showing variable T-cell infiltration for a total of 738 regions from 29 patients, divided into discovery and validation cohorts. We performed multiregional whole-exome and RNA sequencing of the tumor cells and integrated these with T-cell receptor sequencing, high-dimensional imaging mass cytometry, detection of programmed death-ligand 1 (PDL1) interaction in situ, multiplexed immunofluorescence, and computational spatial analysis of the TME.
In hypermutated CRCs, response to anti-PD1 immunotherapy was not associated with TMB but with high clonality of immunogenic mutations, clonally expanded T cells, low activation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1+CD8 T cells interacting with PDL1+ antigen-presenting macrophages.
Our study clarified the limits of TMB as a predictor of response of CRC to anti-PD1 immunotherapy. It identified a population of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity.
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Colorectal cancers responsive to anti-programmed cell death 1 immunotherapy show clonal immunogenic mutations, low Wnt activation, beta-2-microglobulin deregulation, and high infiltration of antigen presenting macrophages interacting with programmed cell death 1-positive cluster of differentiation 8 T cells.
Molecular docking and virtual screening experiments require large computational and data resources and high-level user interfaces in the form of science gateways. While science gateways supporting ...such experiments are relatively common, there is a clearly identified need to design and implement more complex environments for further analysis of docking results. This paper describes a generic framework and a related methodology that supports the efficient development of such environments. The framework is modular enabling the reuse of already existing components. The methodology, which proposes three techniques that the development team can use, is agile and encourages active participation of end-users. Based on the framework and methodology, two prototype implementations of science-gateway-based docking environments are presented and evaluated. The first system recommends a receptor-ligand pair for the next docking experiment, and the second filters docking results based on ligand properties.
The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a ...machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.
The knowledge of the protein functions is very important in the development of new drugs. Many experimental methods for determining protein function exist, but due to their complexity the number of ...protein structures with unknown functions is rapidly growing. So, there is an obvious necessity for development of computer methods for annotating protein structures. In this paper we present a fuzzy decision tree based method for protein active sites detection, which could be used for annotating protein structures. We extract several features of the amino acids, and then using different membership functions we build fuzzy decision trees in order to detect the possible active sites. We provide some experimental results of the evaluation of our method. Additionally, our method is compared with several existing methods for protein active sites detection.
Complex Real-Time Embedded Systems (RTESs) can be developed using model-based engineering. The problem is choosing a modeling language that has capabilities to model the most important characteristic ...of RTESs: timing. This paper shows an analysis of the most popular modeling languages and their capabilities to model timing constraints in RTESs. It includes UML, SysML, AADL, MARTE and EAST-ADL. A brief comparison between MARTE and EAST-ADL, based on the case study from the automotive industry, is also included.
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