Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

Single-cell RNA-seq reveals as a prognostic biomarker in low-grade endometrial stromal sarcoma.

Background: Low-grade endometrial stromal sarcoma (LG-ESS) is a rare uterine malignancy characterized by its complex tumor microenvironment (TME) and high recurrence rates, posing challenges to accurate prognosis and effective treatment. Identifying prognostic biomarkers is essential for improving patient stratification and guiding therapeutic strategies.

Methods: Using single-cell transcriptome analysis combined with H&E and multiplex immunofluorescence staining, we identified a subpopulation of tumor cells in LG-ESS and further validated the association of this subpopulation and its characteristic genes with LG-ESS prognosis by molecular characterization and bulk transcriptome data.

Chemogenomic Screening in a Patient-Derived 3D Fatty Liver Disease Model Reveals the CHRM1-TRPM8 Axis as a Novel Module for Targeted Intervention.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver model from primary human hepatocytes and non-parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease-relevant endpoints, such as steatosis, inflammation and fibrosis, and multi-omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls.

PharmFreq: a comprehensive atlas of ethnogeographic allelic variation in clinically important pharmacogenes.

Genetic polymorphisms in drug metabolizing enzymes, drug transporters as well as in genes encoding the human major histocompatibility complex contribute to inter-individual differences in drug efficacy and safety. The extent, pattern and complexity of such pharmacogenetic variation differ drastically across human populations. Here, we present PharmFreq, a global repository of pharmacogenetic frequency information that aggregates frequency data of 658 allelic variants from over 10 million individuals collected from >1200 studies across 144 countries.

Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of neoplasms, with many cases remaining unclassifiable and categorized as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated 2 prognostic subtypes within PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including T follicular helper [T] biomarkers), and GEP analyses, separating them into PTCL-NOS (n = 63) and PTCL-TFH (also known as nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n = 38).

Corrigendum to Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment.

This corrects the article DOI: 10.14573/altex.2212081.

The 75-Year Anniversary of the Department of Physiology and Pharmacology at Karolinska Institutet-Examples of Recent Accomplishments and Future Perspectives.

Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking.

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Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g.

Histomorphologic spectrum of nodal marginal zone lymphoma as defined by its methylome.

Objectives: Primary nodal marginal B-cell lymphoma (NMZL) is rare and histologically very variable. Its large-cell presentation is difficult to distinguish from nodal diffuse large B-cell lymphoma (nDLBCL) due to the absence of specific markers for nodal marginal zone lymphomas in general.

Methods: Using a comprehensive cohort of NMZLs and a control cohort of nDLBCLs, we conducted a methylome analysis on subgroups of both.

Hepatic Amyloid Beta-42-Metabolizing Proteins in Liver Steatosis and Metabolic Dysfunction-Associated Steatohepatitis.

Amyloid beta (Aβ) plays a major role in the pathogenesis of Alzheimer's disease and, more recently, has been shown to protect against liver fibrosis. Therefore, we studied Aβ-42 levels and the expression of genes involved in the generation, degradation, and transport of Aβ proteins in liver samples from patients at different stages of metabolic dysfunction-associated liver disease (MASLD) and under steatotic conditions in vitro/in vivo. Amyloid precursor protein (APP), key Aβ-metabolizing proteins, and Aβ-42 were analyzed using RT-PCR, Western blotting, Luminex analysis in steatotic in vitro and fatty liver mouse models, and TaqMan qRT-PCR analysis in hepatic samples from patients with MASLD.

Metabolic activation of WHO-congeners PCB28, 52, and 101 by human CYP2A6: evidence from in vitro and in vivo experiments.

Despite extensive research on the metabolism of polychlorinated biphenyls (PCBs), knowledge gaps persist regarding their isoform-specific biotransformation pathways. This study aimed to elucidate the role of different cytochrome P450 enzymes in PCB metabolism, focusing on WHO-congeners 2,4,4'-trichlorobiphenyl (PCB28), 2,2',5,5'-tetrachlorobiphenyl (PCB52), and 2,2',4,5,5'-pentachlorobiphenyl (PCB101). Utilizing engineered HEK293 cell lines, we investigated the in vitro metabolism of these PCBs by CYP1A2, CYP2C8, CYP2C9, CYP3A4, CYP2A6, and CYP2E1, revealing robust production of hydroxylated metabolites.

Comparison of drug-induced liver injury risk between propylthiouracil and methimazole: A quantitative systems toxicology approach.

Propylthiouracil (PTU) and methimazole (MMI), two classical antithyroid agents possess risk of drug-induced liver injury (DILI) with unknown mechanism of action. This study aimed to examine and compare their hepatic toxicity using a quantitative system toxicology approach. The impact of PTU and MMI on hepatocyte survival, oxidative stress, mitochondrial function and bile acid transporters were assessed in vitro.

In silico and biological analyses of missense variants of the human biliary efflux transporter ABCC2: effects of novel rare missense variants.

Background And Purpose: The ATP-dependent biliary efflux transporter ABCC2, also known as multidrug resistance protein 2 (MRP2), is essential for the cellular disposition and detoxification of various xenobiotics including drugs as well as endogenous metabolites. Common functionally relevant ABCC2 genetic variants significantly alter drug responses and contribute to side effects. The aim of this study was to determine functional consequences of rare variants identified in subjects with European ancestry using in silico tools and in vitro analyses.

OCT1 (SLC22A1) transporter kinetics and regulation in primary human hepatocyte 3D spheroids.

3D spheroids of primary human hepatocytes (3D PHH) retain a differentiated phenotype with largely conserved metabolic function and proteomic fingerprint over weeks in culture. As a result, 3D PHH are gaining importance as a model for mechanistic liver homeostasis studies and in vitro to in vivo extrapolation (IVIVE) in drug discovery. However, the kinetics and regulation of drug transporters have not yet been assessed in 3D PHH.

Population-scale variability of the human UDP-glycosyltransferase gene family.

Human UDP-glycosyltransferases (UGTs) are responsible for the glycosylation of a wide variety of endogenous substrates and commonly prescribed drugs. Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk. However, the genetic complexity beyond these variants has not been comprehensively assessed.

Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge.

Background And Purpose: The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose-stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR-targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C-terminus.

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta-Blocker Therapy.

Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g.

Loss of Toll-like receptor 9 protects from hepatocellular carcinoma in murine models of chronic liver disease.

Background & Aims: Toll-like receptor 9 (Tlr9) is a pathogen recognition receptor detecting unmethylated DNA derivatives of pathogens and damaged host cells. It is therefore an important modulator of innate immunity. Here we investigated the role of Tlr9 in fibrogenesis and progression of hepatocellular carcinoma in chronic liver disease.

Conformation- and activation-based BRET sensors differentially report on GPCR-G protein coupling.

G protein-coupled receptors (GPCRs) regulate cellular signaling processes by coupling to diverse combinations of heterotrimeric G proteins composed of Gα, Gβ, and Gγ subunits. Biosensors based on bioluminescence resonance energy transfer (BRET) have advanced our understanding of GPCR functional selectivity. Some BRET biosensors monitor ligand-induced conformational changes in the receptor or G proteins, whereas others monitor the recruitment of downstream effectors to sites of G protein activation.