MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686.

Taking the structural information into account, we were able to tune the TEAD selectivity for a specific chemotype. However, different TEAD selectivity profiles did not affect the compound potency or efficacy in the NCI-H226 viability assay. Amides based on or analogues showed improved viability efficacy compared with the corresponding acids.

Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold.

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit 1, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition.

Tuning polymer-blood and polymer-cytoplasm membrane interactions by manipulating the architecture of poly(2-oxazoline) triblock copolymers.

Bioactive moieties designed to bind to cell membrane receptors benefit from coupling with polymeric carriers that have enhanced affinity to the cell membrane. When bound to the cell surface, such carriers create a "2D solution" of a ligand with a significantly increased concentration near a membrane-bound receptor compared to a freely water-soluble ligand. Bifunctional polymeric carriers based on amphiphilic triblock copolymers were synthesized from 2-pent-4-ynyl oxazoline, 2-nonyl oxazoline and 2-ethyl oxazoline.

Discovery of Cycloalkyl[]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors.

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy-aryl scaffold.

Selective Wee1 Inhibitors Led to Antitumor Activity and Correlated with Myelosuppression.

Wee1 is a tyrosine kinase that is highly expressed in several cancer types. Wee1 inhibition can lead to suppression of tumor cell proliferation and sensitization of cells to the effects of DNA-damaging agents. AZD1775 is a nonselective Wee1 inhibitor for which myelosuppression has been observed as a dose-limiting toxicity.

[Benefit of Arthroscopy in Differential Diagnostics and Therapy of Lateral Epicondylitis].

PURPOSE OF THE STUDY The aim of this study is to confirm that the involvement of arthroscopy in the surgical treatment of painful elbow syndrome, when proper and long enough conservative treatment failed, has better results than open radial epicondylitis surgery alone. MATERIAL AND METHODS A total of 144 patients included 65 men and 79 women, with the mean age of 45.3 years, namely 44.

[Management Strategy and Evaluation of Surgical Outcomes in Patients with Recurrent Patellar Instability between 2010-2020].

PURPOSE OF THE STUDY The study retrospectively reviews the outcomes of patella stabilisation surgeries performed at our department in the period 2010-2020. It aimed to provide a more thorough evaluation, to compare the respective types of MPFL reconstruction and to confirm the beneficial effect of tibial tubercle ventromedialization on patella height. MATERIAL AND METHODS In the period 2010-2020, a total of 72 stabilisation surgeries of patellofemoral joint in 60 patients with objective patellar instability (OPI) were performed at our department.

[Development of recommendations for the use of venoactive drugs in the treatment of chronic venous disease - where they are effective and where they are not].

The article provides an overview of the development of recommendations for indications of venoactive drugs for treating symptoms and signs associated with chronic venous disease (CVD). Venoactive drugs may be beneficial in patients with subjective problems and/or swelling of the lower limbs, after surgery for varicose veins, in chronic venous insufficiency or in microcirculatory disorders. They are not indicated in asymptomatic patients with CVD, in the prevention of varicose veins or to prevent their progression.

[Anticoagulation in cancer patients; new recommendations based on randomized clinical trials].

Venous thromboembolic disease (VTD) is currently the second leading cause of death in cancer patients with a prevalence of approximately 20% compared with that of 5% in the entire adult population. Cancer patients are a heterogeneous group with significant differences in the risk of VTD which is, in particular, determined by the type of tumour, its extent, location, and the presence of metastases. Some tumours represent a mean 3- to 5-fold increase in risk, while in others the risk of developing VTD is even several times higher.

R399E, A Mutated Form of Growth and Differentiation Factor 5, for Disease Modification of Osteoarthritis.

Objective: To preclinically characterize a mutant form of growth and differentiation factor 5, R399E, with reduced osteogenic properties as a potential disease-modifying osteoarthritis (OA) drug.

Methods: Cartilage, synovium, and meniscus samples from patients with OA were used to evaluate anabolic and antiinflammatory properties of R399E. In the rabbit joint instability model, 65 rabbits underwent transection of the anterior cruciate ligament plus partial meniscectomy.

Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead .

The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable.

[Native Joint Septic Arthritis in Adults: Incidence in Our Group of Patients and Antibiotic Therapy Guidelines].

PURPOSE OF THE STUDY The purpose of the study is to analyse the number of adult patients treated in our department for native joint septic arthritis and to outline guidelines for antibiotic therapy. MATERIAL AND METHODS From the beginning of 2003 to the end of 2020, a total of 36,342 surgeries were performed at our department. We retrospectively reviewed and analysed all surgeries for native joint septic arthritis (a total of 538 surgical interventions).

[Accuracy of Alignment of Femoral and Tibial Component of the Oxford Medial Unicompartmental Knee Arthroplasty Using Zimmer Microplasty® Instrumentation].

PURPOSE OF THE STUDY The purpose of the study is to verify the correct alignment of components of the Oxford medial unicompartmental knee arthroplasty using the Zimmer Microplasty® instrumentation at the beginning of the learning curve. The implantation of prosthetic components of partial knee arthroplasty in proper alignment has an effect on long-term survival of the prosthesis and should eliminate the occurrence of frequent complications. MATERIAL AND METHODS The study group includes 20 patients, 9 men with the mean age of 68 years (range 62-78 years) and 11 women with the mean age of 69 years (range 52-81 years).

Delay between clinical presentation and treatment of deep venous thrombosis in the lower limbs and regression of thrombosis.

Introduction: The objective was to investigate the delay between the onset of DVT symptoms and start of anticoagulation in common practice, assess whether this has any impact on the recanalization of venous thrombosis over one year follow up.

Methods: A prospective observational study on 76 consecutive patients (39 men, 51.3%) with DVT diagnosed using compression ultrasound (CUS).

Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models.

Constitutive activation of the canonical Wnt signaling pathway, in most cases driven by inactivation of the tumor suppressor APC, is a hallmark of colorectal cancer. Tankyrases are druggable key regulators in these malignancies and are considered as attractive targets for therapeutic interventions, although no inhibitor has been progressed to clinical development yet. We continued our efforts to develop tankyrase inhibitors targeting the nicotinamide pocket with suitable drug-like properties for investigating effects of Wnt pathway inhibition on tumor growth.

Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i).

Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (β1, β2, and β5). LMP7 (β5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs.

[What's new in the 2020 update of the CEAP classification system of chronic venous disease?].

The aim of the 2020 update of the CEAP (Clinical-Etiology-Anatomy-Pathophysiology) classification is provide the reproducibility of clinical findings between physicians, enable comparison of old and new versions of the CEAP classification, incorporate new evidence- based knowledge into the classification, and provide a balance between simple practical use and highly specific and detailed description of patient with chronic venous disease (CVD) in clinical and other studies. Clinical (C) classification remained unchanged and clinical definitions of all seven classes C0-C6 have been preserved. Class C4 is newly divided into three subclasses: C4a - pigmentation or eczema, C4b - lipodermatosclerosis or atrophie blanche and corona phlebectatica as the C4c clinical subclass has been added.

M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models.

Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the preclinical profile of M3258; an orally bioavailable, potent, reversible and highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy in multiple myeloma xenograft models, including a novel model of the human bone niche of multiple myeloma.

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2.

There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2.

[Outcomes of Revisions of the Acetabular Component of THA with Paprosky Type 3a and 3b Defects Using Tantalum Trabecular Metal Implants 2-10 Years Postoperatively].

PURPOSE OF THE STUDY Tantallum trabecular metal implants (Trabecular Metal Technology - TMT) considerably changed the acetabular reconstruction options in revision surgeries with extensive bone defects and distorted pelvic ring integrity. The purpose of this study is to ascertain the short-term to medium-term outcomes of acetabular reconstruction through TMT implants in patients with Paprosky type 3a and 3b acetabular defects and in case of pelvic discontinuity. MATERIAL AND METHODS The prospective monocentric study included patients in whom the revision of acetabular components in total hip arthroplasty was performed, the acetabular defect was classified as Paprosky 3a and higher, a TMT implant was used for reconstruction, and the follow-up period was at least 2 years after surgery.

[Uncommon thrombotic complications after SARS-CoV-2 vaccination].

Shortly after the worldwide initiation of vaccination against SARS-CoV-2, concerns emerged about a possible link between vaccination, severe thrombocytopenia, and the development of atypical venous thrombosis. Concerns were primarily about AstraZeneca (ChAdOx1 nCov-19), later Johnson & Johnson (Ad26.COV2.

Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity.

Toll-like receptor (TLR) 7 and TLR8 are transmembrane receptors that recognize single-stranded RNA. Activation of these receptors results in immune cell stimulation and inflammatory cytokine production, which is normally a protective host response. However, aberrant activation of TLR7/8 is potentially pathogenic and linked to progression of certain autoimmune diseases such as lupus.