Efficacy and Safety of Inclisiran in Asian Patients: Results From ORION-18.

Background: Management of low-density lipoprotein cholesterol (LDL-C) in Asia remains suboptimal, with ∼50% of patients who are treated with lipid-lowering therapies (LLTs) unable to achieve their guideline-recommended LDL-C goals. Asian-representative studies of the use of inclisiran are needed.

Objectives: The authors sought to evaluate the efficacy and safety of inclisiran in Asian patients with atherosclerotic cardiovascular disease (ASCVD) or high risk of ASCVD, as an adjunct to diet and maximally tolerated statin dose, with or without additional LLTs.

Emergence of a multilocus mutator genotype in mutator Escherichia coli experimental populations under repeated lethal selection.

Mutator alleles, which confer increased mutation rates, are known to spontaneously emerge and "hitchhike" to fixation in evolving asexual populations. Theory predicts that in an evolving asexual mutator population, a second mutator allele may spontaneously arise and hitchhike to fixation. Here, we describe an empirical test of the hypothesis of repeated hitchhiking.

Clonal Hematopoiesis of Indeterminate Potential With Loss of Enhances Risk for Atrial Fibrillation Through Inflammasome Activation.

Background: Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored.

Methods: CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models.

Anchor-based minimal important difference values are often sensitive to the distribution of the change score.

Purpose: Anchor-based studies are today the most popular approach to determine a minimal important difference value for an outcome variable. However, a variety of construction methods for such values do exist. This constitutes a challenge to the field.

New strategies for confirmatory testing of secondary hypotheses on combined data from multiple trials.

Background: Pivotal evidence of efficacy of a new drug is typically generated by (at least) two clinical trials which independently provide statistically significant and mutually corroborating evidence of efficacy based on a primary endpoint. In this situation, showing drug effects on clinically important secondary objectives can be demanding in terms of sample size requirements. Statistically efficient methods to power for such endpoints while controlling the Type I error are needed.

Electromyogram Power Spectrum and Cardiac Function Changes After Combined Aerobic Interval Training and Inspiratory Muscle Training in Chronic Heart Failure Patients.

Exercise intolerance and dyspnea are the major symptoms of patients with chronic heart failure (CHF) and are associated with a poor quality of life. In addition to impaired central hemodynamics, symptoms may be attributed to changes in peripheral skeletal muscles. This study aimed to evaluate the effects of aerobic interval training (AIT) combined with inspiratory muscle training (IMT) on cardiac and skeletal muscle function and on functional capacity and dyspnea in patients with CHF and inspiratory muscle weakness.

Antibacterial, Resistance Modulation, Anti-Biofilm Formation, and Efflux Pump Inhibition Properties of (Willd.) N. Halle (Celastraceae) Stem Extract and Its Constituents.

This study investigated the antibacterial, resistance modulation, biofilm inhibition, and efflux pump inhibition potentials of stem extract and its constituents. The antimicrobial activity was investigated by the high-throughput spot culture growth inhibition (HT-SPOTi) and broth microdilution assays. The resistance modulation activity was investigated using the anti-biofilm formation and efflux pump inhibition assays.

Tight-Binding Small-Molecule Carboxylesterase 2 Inhibitors Reduce Intracellular Irinotecan Activation.

As the primary enzyme responsible for the activatable conversion of Irinotecan (CPT-11) to SN-38, carboxylesterase 2 (CES2) is a significant predictive biomarker toward CPT-11-based treatments for pancreatic ductal adenocarcinoma (PDAC). High SN-38 levels from high CES2 activity lead to harmful effects, including life-threatening diarrhea. While alternate strategies have been explored, CES2 inhibition presents an effective strategy to directly alter the pharmacokinetics of CPT-11 conversion, ultimately controlling the amount of SN-38 produced.

Intrinsically Disordered Regions in the Transcription Factor MYC:MAX Modulate DNA Binding via Intramolecular Interactions.

The basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor (TF) MYC is in large part an intrinsically disordered oncoprotein. In complex with its obligate heterodimerization partner MAX, MYC preferentially binds E-Box DNA sequences (CANNTG). At promoters containing these sequence motifs, MYC controls fundamental cellular processes such as cell cycle progression, metabolism, and apoptosis.

Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.

The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n = 5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years).

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer.

Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600 mg once daily (QD) during cycles of 21 days on/7 days off, with optional dose reduction to 400 mg and 200 mg.

Proteomic associations with forced expiratory volume: a Mendelian randomisation study.

Background: A decline in forced expiratory volume (FEV1) is a hallmark of respiratory diseases that are an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1.

Methods: Data from the population-based AGES-Reykjavik study were used.

The adhesion GPCR GPR116/ADGRF5 has a dual function in pancreatic islets regulating somatostatin release and islet development.

Glucose homeostasis is maintained by hormones secreted from different cell types of the pancreatic islets and controlled by manifold input including signals mediated through G protein-coupled receptors (GPCRs). RNA-seq analyses revealed expression of numerous GPCRs in mouse and human pancreatic islets, among them Gpr116/Adgrf5. GPR116 is an adhesion GPCR mainly found in lung and required for surfactant secretion.

Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial.

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed.

HDAC6/aggresome processing pathway importance for inflammasome formation is context-dependent.

The inflammasome is a large multiprotein complex that assembles in the cell cytoplasm in response to stress or pathogenic infection. Its primary function is to defend the cell and promote the secretion of pro-inflammatory cytokines, including IL-1β and IL-18. Previous research has shown that in immortalized bone marrow-derived macrophages (iBMDMs) inflammasome assembly is dependent on the deacetylase HDAC6 and the aggresome processing pathway (APP), a cellular pathway involved in the disposal of misfolded proteins.

Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11.

Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1.

Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional proteolysis targeting chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4 adaptor protein DDB1 to degrade neosubstrate proteins.

DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD.

A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies.

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated).

Induced pluripotent stem cell-derived human macrophages as an infection model for Leishmania donovani.

The parasite Leishmania donovani is one of the species causing visceral leishmaniasis in humans, a deadly infection claiming up to 40,000 lives each year. The current drugs for leishmaniasis treatment have severe drawbacks and there is an urgent need to find new anti-leishmanial compounds. However, the search for drug candidates is complicated by the intracellular lifestyle of Leishmania.

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic lipid and carbohydrate metabolism.

Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1.

Discovery of Ligands for TRIM58, a Novel Tissue-Selective E3 Ligase.

Redirecting E3 ligases to neo-substrates, leading to their proteasomal disassembly, known as targeted protein degradation (TPD), has emerged as a promising alternative to traditional, occupancy-driven pharmacology. Although the field has expanded tremendously over the past years, the choice of E3 ligases remains limited, with an almost exclusive focus on CRBN and VHL. Here, we report the discovery of novel ligands to the PRY-SPRY domain of TRIM58, a RING ligase that is specifically expressed in erythroid precursor cells.