Modeling tumor size dynamics based on real-world electronic health records and image data in advanced melanoma patients receiving immunotherapy.

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy but only a fraction of patients benefits from this therapy. Model-informed drug development can be used to assess prognostic and predictive clinical factors or biomarkers associated with treatment response. Most pharmacometric models have thus far been developed using data from randomized clinical trials, and further studies are needed to translate their findings into the real-world setting.

Semiautomated Pipeline to Quantify Tumor Evolution From Real-World Positron Emission Tomography/Computed Tomography Imaging.

Purpose: A semiautomated pipeline for the collection and curation of free-text and imaging real-world data (RWD) was developed to quantify cancer treatment outcomes in large-scale retrospective real-world studies. The objectives of this article are to illustrate the challenges of RWD extraction, to demonstrate approaches for quality assurance, and to showcase the potential of RWD for precision oncology.

Methods: We collected data from patients with advanced melanoma receiving immune checkpoint inhibitors at the Lausanne University Hospital.

Interactive process mining of cancer treatment sequences with melanoma real-world data.

The growing availability of clinical real-world data (RWD) represents a formidable opportunity to complement evidence from randomized clinical trials and observe how oncological treatments perform in real-life conditions. In particular, RWD can provide insights on questions for which no clinical trials exist, such as comparing outcomes from different sequences of treatments. To this end, process mining is a particularly suitable methodology for analyzing different treatment paths and their associated outcomes.

A differential process mining analysis of COVID-19 management for cancer patients.

During the acute phase of the COVID-19 pandemic, hospitals faced a challenge to manage patients, especially those with other comorbidities and medical needs, such as cancer patients. Here, we use Process Mining to analyze real-world therapeutic pathways in a cohort of 1182 cancer patients of the Lausanne University Hospital following COVID-19 infection. The algorithm builds trees representing sequences of coarse-grained events such as Home, Hospitalization, Intensive Care and Death.

Structural Prediction of Peptide-MHC Binding Modes.

The immune system is constantly protecting its host from the invasion of pathogens and the development of cancer cells. The specific CD8 T-cell immune response against virus-infected cells and tumor cells is based on the T-cell receptor recognition of antigenic peptides bound to class I major histocompatibility complexes (MHC) at the surface of antigen presenting cells. Consequently, the peptide binding specificities of the highly polymorphic MHC have important implications for the design of vaccines, for the treatment of autoimmune diseases, and for personalized cancer immunotherapy.

Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma.

How targeted therapies and immunotherapies shape tumors, and thereby influence subsequent therapeutic responses, is poorly understood. In the present study, we show, in melanoma patients and mouse models, that when tumors relapse after targeted therapy with MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite the different modes of action of these therapies. We find that cross-resistance is mediated by a cancer cell-instructed, immunosuppressive tumor microenvironment that lacks functional CD103 dendritic cells, precluding an effective T cell response.

Turning tumors from cold to inflamed to improve immunotherapy response.

Immune checkpoint inhibitors have revolutionized the treatment landscape for a number of cancers over the last few decades. Nevertheless, a majority of patients still do not benefit from these treatments. Such patient-specific lack of response can be predicted, in part, from the immune phenotypes present in the tumor microenvironment.

Truly privacy-preserving federated analytics for precision medicine with multiparty homomorphic encryption.

Using real-world evidence in biomedical research, an indispensable complement to clinical trials, requires access to large quantities of patient data that are typically held separately by multiple healthcare institutions. We propose FAMHE, a novel federated analytics system that, based on multiparty homomorphic encryption (MHE), enables privacy-preserving analyses of distributed datasets by yielding highly accurate results without revealing any intermediate data. We demonstrate the applicability of FAMHE to essential biomedical analysis tasks, including Kaplan-Meier survival analysis in oncology and genome-wide association studies in medical genetics.

Unusual mode of dimerization of retinitis pigmentosa-associated F220C rhodopsin.

Mutations in the G protein-coupled receptor (GPCR) rhodopsin are a common cause of autosomal dominant retinitis pigmentosa, a blinding disease. Rhodopsin self-associates in the membrane, and the purified monomeric apo-protein opsin dimerizes in vitro as it transitions from detergent micelles to reconstitute into a lipid bilayer. We previously reported that the retinitis pigmentosa-linked F220C opsin mutant fails to dimerize in vitro, reconstituting as a monomer.

Probing the Conformational Dynamics of Affinity-Enhanced T Cell Receptor Variants upon Binding the Peptide-Bound Major Histocompatibility Complex by Hydrogen/Deuterium Exchange Mass Spectrometry.

Binding of the T cell receptor (TCR) to its cognate, peptide antigen-loaded major histocompatibility complex (pMHC) is a key interaction for triggering T cell activation and ultimately elimination of the target cell. Despite the importance of this interaction for cellular immunity, a comprehensive molecular understanding of TCR specificity and affinity is lacking. We conducted hydrogen/deuterium exchange mass spectrometry (HDX-MS) analyses of individual affinity-enhanced TCR variants and clinically relevant pMHC class I molecules (HLA-A*0201/NY-ESO-1) to investigate the causality between increased binding affinity and conformational dynamics in TCR-pMHC complexes.

What Role Can Process Mining Play in Recurrent Clinical Guidelines Issues? A Position Paper.

In the age of Evidence-Based Medicine, Clinical Guidelines (CGs) are recognized to be an indispensable tool to support physicians in their daily clinical practice. Medical Informatics is expected to play a relevant role in facilitating diffusion and adoption of CGs. However, the past pioneering approaches, often fragmented in many disciplines, did not lead to solutions that are actually exploited in hospitals.

SPHN/PHRT - MedCo in Action: Empowering the Swiss Molecular Tumor Board with Privacy-Preserving and Real-Time Patient Discovery.

MedCo is the first operational system that makes sensitive medical-data available for research in a simple, privacy-conscious and secure way. It enables a consortium of clinical sites to collectively protect their data and to securely share them with investigators, without single points of failure. In this short paper, we report on our ongoing effort for the operational deployment of MedCo within the context of the Swiss Personalized Health Network (SPHN) for the Swiss Molecular Tumor Board.

The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.

Background: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS.

CD8 Binding of MHC-Peptide Complexes in cis or trans Regulates CD8 T-cell Responses.

The coreceptor CD8αβ can greatly promote activation of T cells by strengthening T-cell receptor (TCR) binding to cognate peptide-MHC complexes (pMHC) on antigen presenting cells and by bringing p56 to TCR/CD3. Here, we demonstrate that CD8 can also bind to pMHC on the T cell (in cis) and that this inhibits their activation. Using molecular modeling, fluorescence resonance energy transfer experiments on living cells, biochemical and mutational analysis, we show that CD8 binding to pMHC in cis involves a different docking mode and is regulated by posttranslational modifications including a membrane-distal interchain disulfide bond and negatively charged O-linked glycans near positively charged sequences on the CD8β stalk.

A Graphic Encoding Method for Quantitative Classification of Protein Structure and Representation of Conformational Changes.

In order to successfully predict a proteins function throughout its trajectory, in addition to uncovering changes in its conformational state, it is necessary to employ techniques that maintain its 3D information while performing at scale. We extend a protein representation that encodes secondary and tertiary structure into fix-sized, color images, and a neural network architecture (called GEM-net) that leverages our encoded representation. We show the applicability of our method in two ways: (1) performing protein function prediction, hitting accuracy between 78 and 83 percent, and (2) visualizing and detecting conformational changes in protein trajectories during molecular dynamics simulations.

Endpoint-restricted adiabatic free energy dynamics approach for the exploration of biomolecular conformational equilibria.

A method for calculating the free energy difference between two structurally defined conformational states of a chemical system is developed. A path is defined using a previously reported collective variable that interpolates between two or more conformations, and a restraint is introduced in order to keep the system close to the path. The evolution of the system along the path, which typically presents a high free energy barrier, is generated using enhanced sampling schemes.

Substrate-modulated unwinding of transmembrane helices in the NSS transporter LeuT.

LeuT, a prokaryotic member of the neurotransmitter:sodium symporter (NSS) family, is an established structural model for mammalian NSS counterparts. We investigate the substrate translocation mechanism of LeuT by measuring the solution-phase structural dynamics of the transporter in distinct functional states by hydrogen/deuterium exchange mass spectrometry (HDX-MS). Our HDX-MS data pinpoint LeuT segments involved in substrate transport and reveal for the first time a comprehensive and detailed view of the dynamics associated with transition of the transporter between outward- and inward-facing configurations in a Na- and K-dependent manner.

Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter.

Allostery plays a crucial role in the mechanism of neurotransmitter-sodium symporters, such as the human dopamine transporter. To investigate the molecular mechanism that couples the transport-associated inward release of the Na ion from the Na2 site to intracellular gating, we applied a combination of the thermodynamic coupling function (TCF) formalism and Markov state model analysis to a 50-μs data set of molecular dynamics trajectories of the human dopamine transporter, in which multiple spontaneous Na release events were observed. Our TCF approach reveals a complex landscape of thermodynamic coupling between Na release and inward-opening, and identifies diverse, yet well-defined roles for different Na-coordinating residues.

Cholesterol Promotes Protein Binding by Affecting Membrane Electrostatics and Solvation Properties.

Binding of the retroviral structural protein Gag to the cellular plasma membrane is mediated by the protein's matrix (MA) domain. Prominent among MA-PM interactions is electrostatic attraction between the positively charged MA domain and the negatively charged plasma membrane inner leaflet. Previously, we reported that membrane association of HIV-1 Gag, as well as purified Rous sarcoma virus (RSV) MA and Gag, depends strongly on the presence of acidic lipids and is enhanced by cholesterol (Chol).

The T-Cell Receptor Can Bind to the Peptide-Bound Major Histocompatibility Complex and Uncomplexed β-Microglobulin through Distinct Binding Sites.

T-Cell receptor (TCR)-mediated recognition of the peptide-bound major histocompatibility complex (pMHC) initiates an adaptive immune response against antigen-presenting target cells. The recognition events take place at the TCR-pMHC interface, and their effects on TCR conformation and dynamics are controversial. Here, we have measured the time-resolved hydrogen/deuterium exchange (HDX) of a soluble TCR in the presence and absence of its cognate pMHC by mass spectrometry to delineate the impact of pMHC binding on solution-phase structural dynamics in the TCR.

The Allostery Landscape: Quantifying Thermodynamic Couplings in Biomolecular Systems.

Allostery plays a fundamental role in most biological processes. However, little theory is available to describe it outside of two-state models. Here we use a statistical mechanical approach to show that the allosteric coupling between two collective variables is not a single number, but instead a two-dimensional thermodynamic coupling function that is directly related to the mutual information from information theory and the copula density function from probability theory.