Three STEPs forward: A trio of unexpected structures of PTPN5.

Protein tyrosine phosphatases (PTPs) play pivotal roles in myriad cellular processes by counteracting protein tyrosine kinases. Striatal-enriched protein tyrosine phosphatase (STEP, PTPN5) regulates synaptic function and neuronal plasticity in the brain and is a therapeutic target for several neurological disorders. Here, we present three new crystal structures of STEP, each with unexpected features.

MV-GNN: Generation of continuous geometric representations of mitral valve motion from 3D+t echocardiography.

We present a geometric deep-learning method for reconstructing a temporally continuous mitral valve surface mesh from 3D transesophageal echocardiography sequences. Our approach features a supervised end-to-end deep learning architecture that combines a convolutional neural network-based voxel encoder and decoder with a graph neural network-based multi-resolution mesh decoder, all trained on sparse landmark annotations. Key elements of our methodology include a tube-shaped prototype mesh with labeled vertices, a specialized loss function to preserve the known inlet and outlet, and a rigid alignment system for anatomical landmarks.

Blood-Based DNA Methylation Analysis by Multiplexed OBBPA-ddPCR to Verify Indications for Prostate Biopsies in Suspected Prostate Cancer Patients.

Current prostate carcinoma (PCa) biomarkers, including total prostate-specific antigen (tPSA), have unsatisfactory diagnostic sensitivity and specificity resulting in overdiagnosis and overtreatment. Previously, we described an optimised bias-based preamplification-digital droplet PCR (OBBPA-ddPCR) technique, which detects tumour DNA in blood-derived cell-free DNA (cfDNA) of cancer patients. The current study investigated the performance of newly developed OBBPA-ddPCR-based biomarkers.

Enzyme mechanistic studies of NMA1982, a protein tyrosine phosphatase and potential virulence factor in Neisseria meningitidis.

Protein phosphorylation is an integral part of many cellular processes, not only in eukaryotes but also in bacteria. The discovery of both prokaryotic protein kinases and phosphatases has created interest in generating antibacterial therapeutics that target these enzymes. NMA1982 is a putative phosphatase from Neisseria meningitidis, the causative agent of meningitis and meningococcal septicemia.

Enzyme Mechanistic Studies of NMA1982, a Protein Tyrosine Phosphatase and Potential Virulence Factor in Neisseria meningitidis.

Protein phosphorylation is an integral part of many cellular processes, not only in eukaryotes but also in bacteria. The discovery of both prokaryotic protein kinases and phosphatases has created interest in generating antibacterial therapeutics that target these enzymes. NMA1982 is a putative phosphatase from , the causative agent of meningitis and meningococcal septicemia.

A simulation-based phantom model for generating synthetic mitral valve image data-application to MRI acquisition planning.

Purpose: Numerical phantom methods are widely used in the development of medical imaging methods. They enable quantitative evaluation and direct comparison with controlled and known ground truth information. Cardiac magnetic resonance has the potential for a comprehensive evaluation of the mitral valve (MV).

Detection of Cellular Target Engagement for Small-Molecule Modulators of Striatal-Enriched Protein Tyrosine Phosphatase (STEP).

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific enzyme that regulates the signaling molecules that control synaptic plasticity and neuronal function. Dysregulation of STEP is linked to the pathophysiology of Alzheimer's disease and other neuropsychiatric disorders. Experimental results from neurological deficit disease models suggest that the modulation of STEP could be beneficial in a number of these disorders.

NMA1982 is a Novel Phosphatase and Potential Virulence Factor in .

Protein phosphorylation is an integral part of many cellular processes, not only in eukaryotes but also in bacteria. The discovery of both prokaryotic protein kinases and phosphatases has created interest in generating antibacterial therapeutics that target these enzymes. NMA1982 is a putative phosphatase from , the causative agent of meningitis and meningococcal septicemia.

Deep Learning Segmentation of the Right Ventricle in Cardiac MRI: The M&Ms Challenge.

In recent years, several deep learning models have been proposed to accurately quantify and diagnose cardiac pathologies. These automated tools heavily rely on the accurate segmentation of cardiac structures in MRI images. However, segmentation of the right ventricle is challenging due to its highly complex shape and ill-defined borders.

Protein Tyrosine Phosphatase Biochemical Inhibition Assays.

Disturbance of the dynamic balance between protein tyrosine phosphorylation and dephosphorylation, modulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is known to be crucial for the development of many human diseases. The discovery of agents that restore this balance has been the subject of many drug research efforts, most of which have focused on tyrosine kinase inhibitors (TKIs), resulting in the development of more than 50 FDA-approved TKIs during the past two decades. More recently, accumulating evidence has suggested that members of the PTP superfamily are also promising drug targets, and efforts to discover tyrosine phosphatase inhibitors (TPIs) have increased dramatically.

CT-Based Analysis of Left Ventricular Hemodynamics Using Statistical Shape Modeling and Computational Fluid Dynamics.

Background: Cardiac computed tomography (CCT) based computational fluid dynamics (CFD) allows to assess intracardiac flow features, which are hypothesized as an early predictor for heart diseases and may support treatment decisions. However, the understanding of intracardiac flow is challenging due to high variability in heart shapes and contractility. Using statistical shape modeling (SSM) in combination with CFD facilitates an intracardiac flow analysis.

CT-Based Simulation of Left Ventricular Hemodynamics: A Pilot Study in Mitral Regurgitation and Left Ventricle Aneurysm Patients.

Background: Cardiac CT (CCT) is well suited for a detailed analysis of heart structures due to its high spatial resolution, but in contrast to MRI and echocardiography, CCT does not allow an assessment of intracardiac flow. Computational fluid dynamics (CFD) can complement this shortcoming. It enables the computation of hemodynamics at a high spatio-temporal resolution based on medical images.

A Collaborative Approach for the Development and Application of Machine Learning Solutions for CMR-Based Cardiac Disease Classification.

The quality and acceptance of machine learning (ML) approaches in cardiovascular data interpretation depends strongly on model design and training and the interaction with the clinical experts. We hypothesize that a software infrastructure for the training and application of ML models can support the improvement of the model training and provide relevant information for understanding the classification-relevant data features. The presented solution supports an iterative training, evaluation, and exploration of machine-learning-based multimodal data interpretation methods considering cardiac MRI data.

Cascaded neural network-based CT image processing for aortic root analysis.

Purpose: Careful assessment of the aortic root is paramount to select an appropriate prosthesis for transcatheter aortic valve implantation (TAVI). Relevant information about the aortic root anatomy, such as the aortic annulus diameter, can be extracted from pre-interventional CT. In this work, we investigate a neural network-based approach for segmenting the aortic root as a basis for obtaining these parameters.

Discovery of novel furanylbenzamide inhibitors that target oncogenic tyrosine phosphatase SHP2 in leukemia cells.

Disturbance of the dynamic balance between tyrosine phosphorylation and dephosphorylation of signaling molecules, controlled by protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is known to lead to the development of cancer. While most approved targeted cancer therapies are tyrosine kinase inhibitors, PTPs have long been stigmatized as undruggable and have only recently gained renewed attention in drug discovery. One PTP target is the Src-homology 2 domain-containing phosphatase 2 (SHP2).

Increased Sensitivity of Detection of and DNA Fragments in Serum of Prostate Cancer Patients: Optimisation of Diagnostics Using OBBPA-ddPCR.

Identification of aberrant DNA methylation is a promising tool in prostate cancer (PCa) diagnosis and treatment. In this study, we evaluated a two-step method named optimised bias-based preamplification followed by digital PCR (OBBPA-dPCR). The method was used to identify promoter hypermethylation of 2 tumour suppressor genes and in the circulating cell-free DNA (cfDNA) from serum samples of PCa patients ( = 75), benign prostatic hyperplasia (BPH, = 58), and healthy individuals (controls, = 155).

Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP).

Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as "undruggable" and only recently have gained increased attention in drug discovery.

Design, Synthesis, and Characterization of an Orally Active Dual-Specific ULK1/2 Autophagy Inhibitor that Synergizes with the PARP Inhibitor Olaparib for the Treatment of Triple-Negative Breast Cancer.

Inhibition of autophagy, the major cellular recycling pathway in mammalian cells, is a promising strategy for the treatment of triple-negative breast cancer (TNBC). We previously reported SBI-0206965, a small molecule inhibitor of unc-51-like autophagy activating kinase 1 (ULK1), which is a key regulator of autophagy initiation. Herein, we describe the design, synthesis, and characterization of new dual inhibitors of ULK1 and ULK2 (ULK1/2).

Interactive editing of virtual chordae tendineae for the simulation of the mitral valve in a decision support system.

Purpose: Decision support systems for mitral valve disease are an important step toward personalized surgery planning. A simulation of the mitral valve apparatus is required for decision support. Building a model of the chordae tendineae is an essential component of a mitral valve simulation.

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors.

The Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2), encoded by the PTPN11 proto-oncogene, is a key mediator of receptor tyrosine kinase (RTK)-driven cell signaling, promoting cell survival and proliferation. In addition, SHP2 is recruited by immune check point receptors to inhibit B and T cell activation. Aberrant SHP2 function has been implicated in the development, progression, and metastasis of many cancers.

Analysis of three-chamber view conventional and tagged cine MRI in patients with suspected hypertrophic cardiomyopathy.

Objectives: To investigate the potential value of adding a tagged three-chamber (3Ch) cine to clinical hypertrophic cardiomyopathy (HCM) magnetic resonance imaging (MRI) protocols, including to help distinguish HCM patients with regionally impaired cardiac function.

Methods: Forty-eight HCM patients, five patients with "septal knuckle" (SK), and 20 healthy volunteers underwent MRI at 1.5T; a tagged 3Ch cine was added to the protocol.

A cellular target engagement assay for the characterization of SHP2 (PTPN11) phosphatase inhibitors.

The nonreceptor protein-tyrosine phosphatase (PTP) SHP2 is encoded by the proto-oncogene and is a ubiquitously expressed key regulator of cell signaling, acting on a number of cellular processes and components, including the Ras/Raf/Erk, PI3K/Akt, and JAK/STAT pathways and immune checkpoint receptors. Aberrant SHP2 activity has been implicated in all phases of tumor initiation, progression, and metastasis. Gain-of-function mutations drive oncogenesis in several leukemias and cause developmental disorders with increased risk of malignancy such as Noonan syndrome.

An extensible software platform for interdisciplinary cardiovascular imaging research.

Background And Objective: Cardiovascular imaging is an exponentially growing field with aspects ranging from image acquisition and analysis to disease characterization, and evaluation of therapy approaches.The transfer of innovative new technological and algorithmic solutions into clinical practice is still slow. In addition to the verification of solutions, their integration in the clinical processing workflow must be enabled for the assessment of clinical impact and risks.

Combining position-based dynamics and gradient vector flow for 4D mitral valve segmentation in TEE sequences.

Purpose: For planning and guidance of minimally invasive mitral valve repair procedures, 3D+t transesophageal echocardiography (TEE) sequences are acquired before and after the intervention. The valve is then visually and quantitatively assessed in selected phases. To enable a quantitative assessment of valve geometry and pathological properties in all heart phases, as well as the changes achieved through surgery, we aim to provide a new 4D segmentation method.

User-dependent variability in mitral valve segmentation and its impact on CFD-computed hemodynamic parameters.

Purpose: While novel tools for segmentation of the mitral valve are often based on automatic image processing, they mostly require manual interaction by a proficient user. Those segmentations are essential for numerical support of mitral valve treatment using computational fluid dynamics, where the reconstructed geometry is incorporated into a simulation domain. To quantify the uncertainty and reliability of hemodynamic simulations, it is crucial to examine the influence of user-dependent variability in valve segmentation.