Unusual case of myocardial injury induced by Escherichia coli sepsis

The typical symptoms and signs of myocardial infarction are well known. Alterations in electrocardiogram (ECG), echocardiography or biochemical markers of myocardial necrosis are usually helpful to confirm the diagnosis. Some of these features, however, also occur in myocarditis, which is a potential differential diagnosis. We describe an unusual case of bacterial sepsis due to Escherichia coli that caused myocardial damage (myocarditis) with ECG changes mimicking acute myocardial infarction. The possible pathophysiological mechanisms of myocardial injury in sepsis are also reviewed

FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes.

The transcription factor SOX2 is important for brain development and for neural stem cells (NSC) maintenance. Sox2-deleted (Sox2-del) NSC from neonatal mouse brain are lost after few passages in culture. Two highly expressed genes, Fos and Socs3, are strongly downregulated in Sox2-del NSC; we previously showed that Fos or Socs3 overexpression by lentiviral transduction fully rescues NSC\u27s long-term maintenance in culture. Sox2-del NSC are severely defective in neuronal production when induced to differentiate. NSC rescued by Sox2 reintroduction correctly differentiate into neurons. Similarly, Fos transduction rescues normal or even increased numbers of immature neurons expressing beta-tubulinIII, but not more differentiated markers (MAP2). Additionally, many cells with both beta-tubulinIII and GFAP expression appear, indicating that FOS stimulates the initial differentiation of a mixed neuronal/glial progenitor. The unexpected rescue by FOS suggested that FOS, a SOX2 transcriptional target, might act on neuronal genes, together with SOX2. CUT&RUN analysis to detect genome-wide binding of SOX2, FOS, and JUN (the AP1 complex) revealed that a high proportion of genes expressed in NSC are bound by both SOX2 and AP1. Downregulated genes in Sox2-del NSC are highly enriched in genes that are also expressed in neurons, and a high proportion of the neuronal genes are bound by both SOX2 and AP1

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Unexpected survival of mice carrying a mutation in Pygo2 that strongly reduces its binding to Bcl9/9l

Pygopus is a transcriptional activator important for the Wnt signaling pathway. It binds to the beta-catenin transcriptional complex via the adaptor proteins Bcl9 and Bcl9l (Bcl9/9l). This complex is considered to be a suitable target for the treatment of tumors that display activated Wnt signaling. In the mouse, there are two Pygopus-encoding genes, Pygo1 and Pygo2 (Pygo1/2), with the latter playing a major role. Here we introduce a single amino acid substitution in Pygo2, which was previously shown to abrogate binding to Bcl9/9l, and cause lethality in Drosophila melanogaster. We confirm that mutant Pygo2 protein fails in interacting with Bcl9 but, unexpectedly, homozygous mice with this mutation are viable and fertile, even when this mutant allele is combined with a null mutation of the potentially redundant Pygo1. Based on this observation, we conjecture that the Pygo-Bcl9/9l interaction requires scant affinity in vivo to fulfill developmental functions and thrust forward the notion that this interaction surface could be targeted in cancer therapy without major consequences on homeostatic functions

Early determination of the periodontal domain by the wnt-antagonist Frzb/Sfrp3

Odontogenesis results from the continuous and reciprocal interaction between cells of the oral epithelium and cranial neural crest-derived mesenchyme. The canonical Wnt signaling pathway plays a fundamental role in mediating these interactions from the earliest stages of tooth development. Here we analyze by in situ hybridization the expression patterns of the extracellular Wnt antagonist Frzb/Sfrp3. Although Frzb is expressed in dental mesenchymal cells from the earliest stages of odontogenesis, its expression is absent from a tiny population of mesenchymal cells immediately adjacent to the invaginating dental epithelium. Cell proliferation studies using BrdU showed that the Frzb expressing and Frzb non-expressing cell populations display different proliferative behavior during the initial stages of odontogenesis. DiI-mediated cell-fate tracing studies demonstrated that the Frzb expressing cells contribute to the formation of the dental follicle, the future periodontium. In contrast, the Frzb non-expressing cells give rise to the dental pulp. The present results indicate that Frzb is discriminating the presumptive periodontal territory from the rest of the dental mesenchyme from the very beginning of odontogenesis, where it might act as a barrier for the diffusion of Wnt molecules, thus regulating the activation of Wnt-dependent transcription within dental tissues

The WNT/beta-catenin dependent transcription: A tissue-specific business

beta-catenin-mediated Wnt signaling is an ancient cell-communication pathway in which beta-catenin drives the expression of certain genes as a consequence of the trigger given by extracellular WNT molecules. The events occurring from signal to transcription are evolutionarily conserved, and their final output orchestrates countless processes during embryonic development and tissue homeostasis. Importantly, a dysfunctional Wnt/beta-catenin pathway causes developmental malformations, and its aberrant activation is the root of several types of cancer. A rich literature describes the multitude of nuclear players that cooperate with beta-catenin to generate a transcriptional program. However, a unified theory of how beta-catenin drives target gene expression is still missing. We will discuss two types of beta-catenin interactors: transcription factors that allow beta-catenin to localize at target regions on the DNA, and transcriptional co-factors that ultimately activate gene expression. In contrast to the presumed universality of beta-catenin s action, the ensemble of available evidence suggests a view in which beta-catenin drives a complex system of responses in different cells and tissues. A malleable armamentarium of players might interact with beta-catenin in order to activate the right "canonical" targets in each tissue, developmental stage, or disease context. Discovering the mechanism by which each tissue-specific beta-catenin response is executed will be crucial to comprehend how a seemingly universal pathway fosters a wide spectrum of processes during development and homeostasis. Perhaps more importantly, this could ultimately inform us about which are the tumor-specific components that need to be targeted to dampen the activity of oncogenic beta-catenin. This article is categorized under: Cancer &amp;gt; Molecular and Cellular Physiology Cancer &amp;gt; Genetics/Genomics/Epigenetics Cancer &amp;gt; Stem Cells and DevelopmentFunding Agencies|CancerfondenSwedish Cancer Society [CAN 2018/542]; Knut och Alice Wallenbergs StiftelseKnut &amp; Alice Wallenberg Foundation</p

Signaling Pathways in Developing and Pathological Tissues and Organs of the Craniofacial Complex

Head formation requires the well-orchestrated and harmonised development of various tissues and organs within the craniofacial complex. A big variety of signaling pathways are involved in this process by controlling cell proliferation, migration, differentiation, tissue morphogenesis, homeostasis and regeneration. Deregulation and malfunction of these signaling molecules may lead to mild or severe craniofacial pathologies. This eBook is a collection of articles dealing with a variety of important signals involved in the control of developmental and pathological events of craniofacial organs and tissues. These recent advances show the importance of signaling pathways in craniofacial physiology and pathology and generate important new knowledge aiming the development of new pharmaceutical products that mimic and/or block the actions of specific molecules

Editorial : Signaling Pathways in Developing and Pathological Tissues and Organs of the Craniofacial Complex

Head formation requires the well-orchestrated and harmonised development of various tissues and organs within the craniofacial complex. A big variety of signaling pathways are involved in this process by controlling cell proliferation, migration, differentiation, tissue morphogenesis, homeostasis and regeneration. Deregulation and malfunction of these signaling molecules may lead to mild or severe craniofacial pathologies. This eBook is a collection of articles dealing with a variety of important signals involved in the control of developmental and pathological events of craniofacial organs and tissues. These recent advances show the importance of signaling pathways in craniofacial physiology and pathology and generate important new knowledge aiming the development of new pharmaceutical products that mimic and/or block the actions of specific molecules