Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype

Background Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types. Methods We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects. Results A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers. Conclusions The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.Peer reviewe

Vitamin C boosts DNA demethylation in TET2 mutation carriers

Background Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation.Methods In a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members.Results We show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals.Conclusions These results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations.Peer reviewe

A mental health and wellbeing chatbot: user event log analysis

Background: Conversational user interfaces, or chatbots, are becoming more popular in the realm of digital health and well-being. While many studies focus on measuring the cause or effect of a digital intervention on people’s health and well-being (outcomes), there is a need to understand how users really engage and use a digital intervention in the real world. Objective: In this study, we examine the user logs of a mental well-being chatbot called ChatPal, which is based on the concept of positive psychology. The aim of this research is to analyze the log data from the chatbot to provide insight into usage patterns, the different types of users using clustering, and associations between the usage of the app’s features. Methods: Log data from ChatPal was analyzed to explore usage. A number of user characteristics including user tenure, unique days, mood logs recorded, conversations accessed, and total number of interactions were used with k-means clustering to identify user archetypes. Association rule mining was used to explore links between conversations. Results: ChatPal log data revealed 579 individuals older than 18 years used the app with most users being female (n=387, 67%). User interactions peaked around breakfast, lunchtime, and early evening. Clustering revealed 3 groups including “abandoning users” (n=473), “sporadic users” (n=93), and “frequent transient users” (n=13). Each cluster had distinct usage characteristics, and the features were significantly different (P&lt;.001) across each group. While all conversations within the chatbot were accessed at least once by users, the “treat yourself like a friend” conversation was the most popular, which was accessed by 29% (n=168) of users. However, only 11.7% (n=68) of users repeated this exercise more than once. Analysis of transitions between conversations revealed strong links between “treat yourself like a friend,” “soothing touch,” and “thoughts diary” among others. Association rule mining confirmed these 3 conversations as having the strongest linkages and suggested other associations between the co-use of chatbot features. Conclusions: This study has provided insight into the types of people using the ChatPal chatbot, patterns of use, and associations between the usage of the app’s features, which can be used to further develop the app by considering the features most accessed by users.Validerad;2023;Nivå 2;2023-08-14 (joosat);Funder: Interreg Northern Periphery and Arctic Programme (grant number 345)Licens fulltext: CC BY License</p

Developing a decomposable measure of profit efficiency using DEA

In for-profit organizations efficiency measurement with reference to the potential for profit augmentation is particularly important as is its decomposition into technical, and allocative components. Different profit efficiency approaches can be found in the literature to measure and decompose overall profit efficiency. In this paper, we highlight some problems within existing approaches and propose a new measure of profit efficiency based on a geometric mean of input/output adjustments needed for maximizing profits. Overall profit efficiency is calculated through this efficiency measure and is decomposed into its technical and allocative components. Technical efficiency is calculated based on a non-oriented geometric distance function (GDF) that is able to incorporate all the sources of inefficiency, while allocative efficiency is retrieved residually. We also define a measure of profitability efficiency which complements profit efficiency in that it makes it possible to retrieve the scale efficiency of a unit as a component of its profitability efficiency. In addition, the measure of profitability efficiency allows for a dual profitability interpretation of the GDF measure of technical efficiency. The concepts introduced in the paper are illustrated using a numerical example

Next-generation sequencing in a large pedigree segregating visceral artery aneurysms suggests potential role of COL4A1/COL4A2 in disease etiology

Background Visceral artery aneurysms (VAAs) can be fatal if ruptured. Although a relatively rare incident, it holds a contemporary mortality rate of approximately 12%. VAAs have multiple possible causes, one of which is genetic predisposition. Here, we present a striking family with seven individuals affected by VAAs, and one individual affected by a visceral artery pseudoaneurysm. Methods We exome sequenced the affected family members and the parents of the proband to find a possible underlying genetic defect. As exome sequencing did not reveal any feasible protein-coding variants, we combined whole-genome sequencing of two individuals with linkage analysis to find a plausible non-coding culprit variant. Variants were ranked by the deep learning framework DeepSEA. Results Two of seven top-ranking variants, NC_000013.11:g.108154659C>T and NC_000013.11:g.110409638C>T, were found in all VAA-affected individuals, but not in the individual affected by the pseudoaneurysm. The second variant is in a candidate cis-regulatory element in the fourth intron of COL4A2, proximal to COL4A1. Conclusions As type IV collagens are essential for the stability and integrity of the vascular basement membrane and involved in vascular disease, we conclude that COL4A1 and COL4A2 are strong candidates for VAA susceptibility genes.Peer reviewe

Algorithms and Bounds for Drawing Directed Graphs

In this paper we present a new approach to visualize directed graphs and their hierarchies that completely departs from the classical four-phase framework of Sugiyama and computes readable hierarchical visualizations that contain the complete reachability information of a graph. Additionally, our approach has the advantage that only the necessary edges are drawn in the drawing, thus reducing the visual complexity of the resulting drawing. Furthermore, most problems involved in our framework require only polynomial time. Our framework offers a suite of solutions depending upon the requirements, and it consists of only two steps: (a) the cycle removal step (if the graph contains cycles) and (b) the channel decomposition and hierarchical drawing step. Our framework does not introduce any dummy vertices and it keeps the vertices of a channel vertically aligned. The time complexity of the main drawing algorithms of our framework is $O(kn)$, where $k$ is the number of channels, typically much smaller than $n$ (the number of vertices).Comment: Appears in the Proceedings of the 26th International Symposium on Graph Drawing and Network Visualization (GD 2018

Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype

Background Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types.Methods We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects.Results A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers.Conclusions The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.</p