Probing the Protein Kinases' Cysteinome by Covalent Fragments.

Protein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non-covalent counterparts, covalent inhibitors offer the advantage of selectively targeting structurally similar kinases by modifying specific protein side chains, particularly non-conserved cysteines.

European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2024.

A unique collaboration of multi-disciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with one to two-centimeter safety margins. For a correct stage classification and treatment decision, a sentinel lymph node biopsy shall be offered in patients with tumor thickness ≥ 1.

European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics - Update 2024.

This guideline was developed in close collaboration with multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF) and the European Organization for Research and Treatment of Cancer (EORTC). Recommendations for the diagnosis and treatment of melanoma were developed on the basis of systematic literature research and consensus conferences. Cutaneous melanoma (CM) is the most dangerous form of skin tumor and accounts for 90 % of skin cancer mortality.

Soft tissue tumor imaging in adults: European Society of Musculoskeletal Radiology-Guidelines 2024: imaging immediately after neoadjuvant therapy in soft tissue sarcoma, soft tissue tumor surveillance, and the role of interventional radiology.

Objectives: An update of the first European Society of Musculoskeletal Radiology (ESSR) consensus on soft tissue tumor imaging in 2015 became necessary due to technical advancements, further insights into specific entities, and the revised WHO classification (2020) and AJCC staging system (2017). The third part of the revised guidelines covers algorithms and techniques beyond initial imaging: (1) Imaging after neoadjuvant therapy in soft tissue sarcoma, (2) sarcoma surveillance, and (3) special aspects, including surveillance of non-malignant entities and the role of interventional radiology.

Materials And Methods: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries.

Ancient genomes reveal a deep history of treponemal disease in the Americas.

Human treponemal infections are caused by a family of closely related Treponema pallidum that give rise to the diseases yaws, bejel, pinta and, most famously, syphilis. Debates on both a common origin for these pathogens and the history of syphilis itself has weighed evidence for the "Columbian hypothesis", which argues for an American origin, against that for the "pre-Columbian hypothesis", which argues for presence of the disease in Eurasia in the Medieval period and possibly earlier. While molecular data has provided a genetic basis for distinction of the typed subspecies, deep evolution of the complex has remained unresolved due to limitations in the conclusions that can be drawn from the sparse paleogenomic data currently available.

Broad ligament ectopic pregnancy with full-term live birth: a rare case report from Syria.

Ectopic pregnancy, the implantation of a fertilized zygote outside the uterine cavity, presents with abdominal pain and vaginal bleeding. Diagnosis relies on clinical signs, and treatment involves surgery or methotrexate in selected cases. A 24-year-old woman at 37 weeks of gestation underwent elective cesarean delivery under general anesthesia, revealing an unexpected broad ligament ectopic pregnancy.

Symmetric dimethylguanidino valeric acid, a novel single biomarker of hepatic steatosis.

There is an unmet need for a biomarker of liver fat. We identified dimethylguanidino valeric acid (DMGV) as a circulating biomarker of liver fat. Here, we assess its two isoforms-symmetric (SDGV) and asymmetric (ADGV)-as biomarkers of steatosis.

Plasmodium knowlesi Infection Is Associated With Elevated Circulating Biomarkers of Brain Injury and Endothelial Activation.

Background: Malaria remains a major public health concern with substantial morbidity and mortality worldwide. In Malaysia, the emergence of Plasmodium knowlesi has led to a surge in zoonotic malaria cases and deaths in recent years. Signs of cerebral involvement have been observed in a noncomatose, fatal case of knowlesi infection, but the potential impact of this malaria species on the brain remains unexplored.

Transferable situation recognition system for scenario-independent context-aware surgical assistance systems: a proof of concept.

Purpose: Surgical interventions and the intraoperative environment can vary greatly. A system that reliably recognizes the situation in the operating room should therefore be flexibly applicable to different surgical settings. To achieve this, transferability should be focused during system design and development.

International Consensus Statement on Platelet Function and Genetic Testing in Percutaneous Coronary Intervention: 2024 Update.

Current evidence indicates that dual antiplatelet therapy with aspirin plus a P2Y inhibitor is essential for the prevention of thrombotic events after percutaneous coronary interventions. However, dual antiplatelet therapy is associated with increased bleeding which may outweigh the benefits. This has set the foundations for customizing antiplatelet treatments to the individual patient.

Carmaphycin B-Based Proteasome Inhibitors to Treat Human African Trypanosomiasis: Structure-Activity Relationship and Efficacy.

The proteasome is essential for eukaryotic cell proteostasis, and inhibitors of the 20S proteasome are progressing preclinically and clinically as antiparasitics. We screened, the causative agent of human and animal African trypanosomiasis, with a set of 27 carmaphycin B analogs, irreversible epoxyketone inhibitors that were originally developed to inhibit the20S (Pf20S). The structure-activity relationship was distinct from that of the human c20S antitarget by the acceptance of d-amino acids at the P3 position of the peptidyl backbone to yield compounds with greatly decreased toxicity to human cells.

Slowing myopia progression with cylindrical annular refractive elements (CARE) spectacle lenses-Year 1 results from a 2-year prospective, multi-centre trial.

Purpose: To evaluate the effectiveness of 12 months of spectacle lens wear incorporating cylindrical annular refractive elements (CARE) in slowing myopia progression compared to single vision (SV) spectacle wear.

Methods: In an ongoing 2-year prospective, double-masked, multi-centre clinical trial, 240 Chinese children aged 6-13 years, spherical equivalent refractive error (SE) -0.75 D to -5.

Longitudinal Follow-up Reveals Peripheral Immunological Changes Upon Tick Bite in a-Gal-Sensitized Individuals.

Background And Objectives: α-Gal syndrome is characterized by specific IgE (sIgE) antibodies to the carbohydrate galactose-α-1,3-galactose (α-Gal) and delayed onset of allergic symptoms after ingestion of mammalian meat. While tick bites are assumed to mediate sensitization, the immune response to tick bites has not yet been investigated. To investigate the peripheral immune response to tick bites in humans over time.

ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model.

Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis.

2-[18F]F-p-aminobenzoic acid specifically detects infective endocarditis in positron emission tomography.

Background: To the present day infective endocarditis (IE) represents a life-threatening disease with high mortality rate especially when caused by Staphylococcus aureus (S. aureus), the most common causative pathogen in this disease. Diagnosis of IE is based on clinical manifestations, pathogen detection by blood cultures and echocardiographic or other imaging findings.

Continuous Blood Pressure Indices During the First 72 Hours and Functional Outcome in Patients with Spontaneous Intracerebral Hemorrhage.

Background: Management of intracerebral hemorrhage (ICH) is challenged by limited therapeutic options and a complex relationship between blood pressure (BP) dynamics, especially BP variability (BPV) and ICH outcome.

Methods: In an exploratory analysis of prospectively collected data on consecutive patients with nontraumatic ICH between 2015 and 2020, continuous BP accessed via an arterial line extracted from the Intellispace Critical Care and Anesthesia information system (Philips Healthcare) was analyzed over the first 72 h post admission. Arterial lines were used as part of standard clinical practice in the intensive care, ensuring high fidelity and real-time data essential for acute care settings.

Heterogeneity of Endothelial Cells Impacts the Functionality of Human Pancreatic Models.

Endothelial cells (ECs) play a crucial role in maintaining tissue homeostasis and functionality. Depending on their tissue of origin, ECs can be highly heterogeneous regarding their morphology, gene and protein expression, functionality, and signaling pathways. Understanding the interaction between organ-specific ECs and their surrounding tissue is therefore critical when investigating tissue homeostasis, disease development, and progression.

Cangrelor versus crushed ticagrelor in patients with acute myocardial infarction and cardiogenic shock: rationale and design of the randomised, double-blind DAPT-SHOCK-AMI trial.

Cardiogenic shock (CS) is a devastating and fatal complication of acute myocardial infarction (AMI). CS can affect the pharmacokinetics and pharmacodynamics of medications. The unique properties of cangrelor make it the optimal P2Y12 inhibitor for CS-AMI, in terms of both efficacy and safety.