AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: two randomized phase I trials.

Background & Aims: A common genetic variant (rs738409) encoding isoleucine to methionine at position 148 in the PNPLA3 protein is a determinant of hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver-related mortality. AZD2693 is a liver-targeted antisense oligonucleotide against PNPLA3 mRNA. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics in single ascending dose (SAD) and multiple ascending dose (MAD) studies.

MARC1 downregulation reduces hepatocyte lipid content by increasing beta-oxidation.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic. MASLD has a strong genetic component, and a common missense variant (rs2642438) in the mitochondrial amidoxime-reducing component 1 (MARC1) gene confers protection against its onset and severity. However, there are contrasting results regarding the mechanisms entangling this protection.

Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an excess of lipids, mainly triglycerides, in the liver and components of the metabolic syndrome, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence that MASLD clusters with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity identifying 27 previously unknown genetic loci associated with MASLD (n = 36,394), six replicated in four independent cohorts (n = 3,903).

Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits considerable variability in clinical outcomes. Identifying specific phenotypic profiles within MASLD is essential for developing targeted therapeutic strategies. Here we investigated the heterogeneity of MASLD using partitioning around medoids clustering based on six simple clinical variables in a cohort of 1,389 individuals living with obesity.

Survival Risk Score for Invasive Nonmetastatic Breast Cancer: A Real-World Analysis.

Purpose: This study aimed to develop a multivariable, weighted overall survival (OS) risk score (SRS) for nonmetastatic (M0) invasive breast cancer (M0-BC, SRS).

Materials And Methods: This study included a training (1,890 patients) and a validation cohort (850 patients) from the Reggio Emilia Cancer Registry (RE-CR). Ten traditional prognostic variables were evaluated.

Genotoxicity of radiofrequency electromagnetic fields on mammalian cells in vitro: A systematic review with narrative synthesis.

Background: Over the last decades, great concern has been raised about possible adverse effects to human health due to exposures to radiofrequency electromagnetic fields (RF-EMF, 100 kHz - 300 GHz) emitted by wireless communication technologies. In 2011 the International Agency for Research on Cancer classified RF-EMF as possibly carcinogenic to humans, highlighting that the evidence was weak and far from conclusive. Updated systematic reviews of the scientific literature on this topic are lacking, especially for mechanistic studies.

Protective effect of radiofrequency exposure against menadione-induced oxidative DNA damage in human neuroblastoma cells: The role of exposure duration and investigation on key molecular targets.

In our previous studies, we demonstrated that 20 h pre-exposure of SH-SY5Y human neuroblastoma cells to 1950 MHz, UMTS signal, at specific absorption rate of 0.3 and 1.25 W/kg, was able to reduce the oxidative DNA damage induced by a subsequent treatment with menadione in the alkaline comet assay while not inducing genotoxicity per se.

Protein Phosphatase 1 Regulatory Subunit 3 Beta rs4240624 Genotype Is Associated With Gallstones and With Significant Changes in Bile Lipidome.

Background And Aims: Gallstone disease (GSD) associates with significant morbidity and mortality. Decreased secretion of bile acids has been suggested as a driving factor for GSD. Recently, we linked the protein phosphatase 1 regulatory subunit 3 beta ( rs4240624 genotype to decreased bile acid levels in bile.

Experimental Observation of Space-Charge Field Screening of a Relativistic Particle Bunch in Plasma.

The space-charge field of a relativistic charged bunch propagating in plasma is screened due to the presence of mobile charge carriers. We experimentally investigate such screening by measuring the effect of dielectric wakefields driven by the bunch in a uncoated dielectric capillary where the plasma is confined. We show that the plasma screens the space-charge field and therefore suppresses the dielectric wakefields when the distance between the bunch and the dielectric surface is much larger than the plasma skin depth.

The Efficacy of for Improving Oral Language in Third-Grade Spanish-English Bilingual Students With Developmental Language Disorder.

Purpose: We investigated the efficacy of for improving oral language in third-grade Spanish-English bilingual children with developmental language disorder (DLD).

Method: We implemented a concurrent multiple-baseline across-participants single-case design with four bilingual Spanish-English third-grade students with DLD. Treatment was carried out over 12 sessions with approximately two sessions per week.

A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

Background: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11.

Methods: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members.

Guiding of Charged Particle Beams in Curved Plasma-Discharge Capillaries.

We present a new approach that demonstrates the deflection and guiding of relativistic electron beams over curved paths by means of the magnetic field generated in a plasma-discharge capillary. We experimentally prove that the guiding is much less affected by the beam chromatic dispersion with respect to a conventional bending magnet and, with the support of numerical simulations, we show that it can even be made dispersionless by employing larger discharge currents. This proof-of-principle experiment extends the use of plasma-based devices, that revolutionized the field of particle accelerators enabling the generation of GeV beams in few centimeters.

Machine Learning Reveals the Contribution of Lipoproteins to Liver Triglyceride Content and Inflammation.

Context: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide and is strongly associated with metabolic comorbidities, including dyslipidemia.

Objective: Herein, we aim to estimate the prevalence of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in Europeans with isolated hypercholesterolemia and isolated hypertriglyceridemia in the UK Biobank and to estimate the independent contribution of lipoproteins to liver triglyceride content.

Methods: We selected 218 732 Europeans from the UK Biobank without chronic viral hepatitis and other causes of liver disease, of whom 14 937 with liver magnetic resonance imaging data available.

3D culture models to study pathophysiology of steatotic liver disease.

Steatotic liver disease (SLD) refers to a spectrum of diseases caused by hepatic lipid accumulation. SLD has emerged as the leading cause of chronic liver disease worldwide. Despite this burden and many years, understanding the pathophysiology of this disease is challenging due to the inaccessibility to human liver specimens.

The contribution of genetics and epigenetics to MAFLD susceptibility.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD.

Effect of Tofacitinib on One-Year Colectomy Risk in Anti-TNF Refractory Ulcerative Colitis: A Prospective Multicenter Italian Study.

Background: Tofacitinib is an oral Janus kinase inhibitor recently approved to induce and maintain remission in ulcerative colitis (UC).

Aims: Considering the number of anti-TNF non-responders, this study aims to assess the effectiveness and safety of tofacitinib in a cohort of multi-failure patients with moderate-to-severe UC at 52 weeks.

Methods: From January 2021 to March 2023, we performed a prospective multicenter study observing adult patients with moderate-to-severe UC starting tofacitinib after an anti-TNF failure for a 52-week-long period.

Poor accuracy and sustainability of the first-step FIB4 EASL pathway for stratifying steatotic liver disease risk in the general population.

Background And Aims: The European Association for the Study of the Liver introduced a clinical pathway (EASL CP) for screening significant/advanced fibrosis in people at risk of steatotic liver disease (SLD). We assessed the performance of the first-step FIB4 EASL CP in the general population across different SLD risk groups (MASLD, Met-ALD and ALD) and various age classes.

Methods: We analysed a total of 3372 individuals at risk of SLD from the 2017-2018 National Health and Nutrition Examination Survey (NHANES17-18), projected to 152.

Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic associated with MASLD.