The role of DNA methylation in chondrogenesis of human iPSCs as a stable marker of cartilage quality.

Background: Lack of insight into factors that determine purity and quality of human iPSC (hiPSC)-derived neo-cartilage precludes applications of this powerful technology toward regenerative solutions in the clinical setting. Here, we set out to generate methylome-wide landscapes of hiPSC-derived neo-cartilages from different tissues-of-origin and integrated transcriptome-wide data to identify dissimilarities in set points of methylation with associated transcription and the respective pathways in which these genes act.

Methods: We applied in vitro chondrogenesis using hiPSCs generated from two different tissue sources: skin fibroblasts and articular cartilage.

Circulating small non-coding RNAs are associated with the insulin-resistant and obesity-related type 2 diabetes clusters.

Aim: To uncover differences in small non-coding RNAs (sncRNAs) in individuals with type 2 diabetes (T2D) categorized into five clusters based on individual characteristics, which may aid in the identification of those prone to rapid progression.

Materials And Methods: In the Hoorn Diabetes Care System (DCS) cohort, participants were clustered by age, body mass index (BMI), and glycated haemoglobin, C-peptide and high-density lipoprotein (HDL) cholesterol levels, yielding severe insulin-deficient diabetes, severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), mild diabetes, and mild diabetes with high HDL cholesterol clusters (n = 412). Utilizing plasma sncRNA-sequencing, we identified distinct cluster-specific sncRNAs.

Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease.

Introduction: Micro- and macrovascular complications are common among persons with type 2 diabetes. Recently there has been growing interest to investigate the potential of circulating small non-coding RNAs (sncRNAs) as contributors to the development of diabetic complications. In this study we investigate to what extent circulating sncRNAs levels associate with prevalent diabetic kidney disease (DKD) in persons with type 2 diabetes.

Apolipoprotein-CIII O-Glycosylation Is Associated with Micro- and Macrovascular Complications of Type 2 Diabetes.

Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII.

Trajectories of clinical characteristics, complications and treatment choices in data-driven subgroups of type 2 diabetes.

Aims/hypothesis: This study aimed to explore the added value of subgroups that categorise individuals with type 2 diabetes by k-means clustering for two primary care registries (the Netherlands and Scotland), inspired by Ahlqvist's novel diabetes subgroups and previously analysed by Slieker et al. METHODS: We used two Dutch and Scottish diabetes cohorts (N=3054 and 6145; median follow-up=11.2 and 12.

Multi-omics subgroups associated with glycaemic deterioration in type 2 diabetes: an IMI-RHAPSODY Study.

Introduction: Type 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised "bottom-up" approach, we attempt to group T2D patients based solely on -omics data generated from plasma.

An omics-based machine learning approach to predict diabetes progression: a RHAPSODY study.

Aims/hypothesis: People with type 2 diabetes are heterogeneous in their disease trajectory, with some progressing more quickly to insulin initiation than others. Although classical biomarkers such as age, HbA and diabetes duration are associated with glycaemic progression, it is unclear how well such variables predict insulin initiation or requirement and whether newly identified markers have added predictive value.

Methods: In two prospective cohort studies as part of IMI-RHAPSODY, we investigated whether clinical variables and three types of molecular markers (metabolites, lipids, proteins) can predict time to insulin requirement using different machine learning approaches (lasso, ridge, GRridge, random forest).

Branched-chain amino acid levels are inversely associated with incident and prevalent chronic kidney disease in people with type 2 diabetes.

Aim: To investigate the association of plasma metabolites with incident and prevalent chronic kidney disease (CKD) in people with type 2 diabetes and establish whether this association is causal.

Materials And Methods: The Hoorn Diabetes Care System cohort is a large prospective cohort consisting of individuals with type 2 diabetes from the northwest part of the Netherlands. In this cohort we assessed the association of baseline plasma levels of 172 metabolites with incident (N = 462/N = 81) and prevalent (N = 1247/N = 120) CKD using logistic regression.

Genome-wide association study of serum magnesium in type 2 diabetes.

People with type 2 diabetes have a tenfold higher prevalence of hypomagnesemia, which is suggested to be caused by low dietary magnesium intake, medication use, and genetics. This study aims to identify the genetic loci that influence serum magnesium concentration in 3466 people with type 2 diabetes. The GWAS models were adjusted for age, sex, eGFR, and HbA1c.

Perinatal exposure to the immune-suppressant di-n-octyltin dichloride affects brain development in rats.

Disruption of the immune system during embryonic brain development by environmental chemicals was proposed as a possible cause of neurodevelopmental disorders. We previously found adverse effects of di-n-octyltin dichloride (DOTC) on maternal and developing immune systems of rats in an extended one-generation reproductive toxicity study according to the OECD 443 test guideline. We hypothesize that the DOTC-induced changes in the immune system can affect neurodevelopment.

Apolipoprotein-CIII -Glycosylation, a Link between and Plasma Lipids.

Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII, apo-CIII and apo-CIII). Our objective is to determine how apo-CIII glycosylation affects lipid traits and type 2 diabetes prevalence, and to investigate the genetic basis of these relations with a genome-wide association study (GWAS) on apo-CIII glycosylation.

The inactive X chromosome accumulates widespread epigenetic variability with age.

Background: Loss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the aging process in women.

IgG N-glycans are associated with prevalent and incident complications of type 2 diabetes.

Aims/hypothesis: Inflammation is important in the development of type 2 diabetes complications. The N-glycosylation of IgG influences its role in inflammation. To date, the association of plasma IgG N-glycosylation with type 2 diabetes complications has not been extensively investigated.

Potential Value of Identifying Type 2 Diabetes Subgroups for Guiding Intensive Treatment: A Comparison of Novel Data-Driven Clustering With Risk-Driven Subgroups.

Objective: To estimate the impact on lifetime health and economic outcomes of different methods of stratifying individuals with type 2 diabetes, followed by guideline-based treatment intensification targeting BMI and LDL in addition to HbA1c.

Research Design And Methods: We divided 2,935 newly diagnosed individuals from the Hoorn Diabetes Care System (DCS) cohort into five Risk Assessment and Progression of Diabetes (RHAPSODY) data-driven clustering subgroups (based on age, BMI, HbA1c, C-peptide, and HDL) and four risk-driven subgroups by using fixed cutoffs for HbA1c and risk of cardiovascular disease based on guidelines. The UK Prospective Diabetes Study Outcomes Model 2 estimated discounted expected lifetime complication costs and quality-adjusted life-years (QALYs) for each subgroup and across all individuals.

Identification of biomarkers for glycaemic deterioration in type 2 diabetes.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates.

Altered blood gene expression in the obesity-related type 2 diabetes cluster may be causally involved in lipid metabolism: a Mendelian randomisation study.

Aims/hypothesis: The aim of this study was to identify differentially expressed long non-coding RNAs (lncRNAs) and mRNAs in whole blood of people with type 2 diabetes across five different clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), mild diabetes (MD) and mild diabetes with high HDL-cholesterol (MDH). This was to increase our understanding of different molecular mechanisms underlying the five putative clusters of type 2 diabetes.

Methods: Participants in the Hoorn Diabetes Care System (DCS) cohort were clustered based on age, BMI, HbA, C-peptide and HDL-cholesterol.

Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response.

Immune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain further insight in the molecular changes involved, we here perform a transcriptome-wide association analysis of blood triglycerides, HDL cholesterol, and LDL cholesterol in 3229 individuals, followed by a systematic bidirectional Mendelian randomization analysis to assess the direction of effects and control for pleiotropy. Triglycerides are found to induce transcriptional changes in 55 genes and HDL cholesterol in 5 genes.

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches.

Therapeutic Strategies for Targeting CDKN2A Loss in Melanoma.

Loss of the tumor suppressor gene CDKN2A, encoding p16 and p14, is a frequent event driving melanoma progression. Therefore, therapeutic strategies aimed at CDKN2A loss hold great potential to improve melanoma treatment. Pharmacological inhibition of the p16 targets CDK4/6 is a prime example of such a strategy.

Low Transforming Growth Factor-β Pathway Activity in Cervical Adenocarcinomas.

Cervical cancer is the fourth most common cancer in women worldwide. Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the most common histological types, with AC patients having worse prognosis. Over the last two decades, incidence rates of AC have increased, highlighting the importance of further understanding AC tumorigenesis, and the need to investigate new treatment options.