The wide spectrum of POT1 gene mutations correlates with multiple cancer types.

The POT1 protein forms part of the shelterin complex, which binds and protects telomeres. Germline mutations in the POT1 gene have recently been shown to be involved in tumors in different tissues such as familial colorectal, glioma and melanoma tumors, which demonstrate the importance of this gene. Recently, we uncovered a mutation in the POT1 gene (p.R117C) as causative of cardiac angiosarcomas in families with multiple tumors. Our in silico studies predicted that the POT1 p.R117C protein had lost the ability to interact with TPP1 and ssDNA. In vitro studies corroborated this prediction, and showed that this lack of function leads to abnormally long telomeres with increased fragility. In order to better understand the spectrum of mutations in the POT1 gene and its relation with tumorigenesis, we extended the study to families with multiple tumors (with and without angiosarcomas) and sporadic angiosarcomas and cardiac sarcomas. We found four new mutations that were not described previously and another patient carrying the previously described p.R117C mutation. In silico studies predicted that these new mutations were damaging in the same manner as previously described for the POT1 p.R117C mutation. These mutations were present in both, families and sporadic cases with angiosarcomas and sarcomas, although the major part was involved in families with AS and in cardiac tumors. The wide spectrum of mutations in the POT1 gene leading to different tumorigenesis processes demonstrates the general importance of this gene.pre-print252 K

The Family Name as Socio-Cultural Feature and Genetic Metaphor: From Concepts to Methods

A recent workshop entitled The Family Name as Socio-Cultural Feature and Genetic Metaphor: From Concepts to Methods was held in Paris in December 2010, sponsored by the French National Centre for Scientific Research (CNRS) and by the journal Human Biology. This workshop was intended to foster a debate on questions related to the family names and to compare different multidisciplinary approaches involving geneticists, historians, geographers, sociologists and social anthropologists. This collective paper presents a collection of selected communications

A gene signature derived from the loss of cdkn1a (P21) is associated with CMS4 colorectal cancer

The epithelial–mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.R.S.-S. was supported by the Emerging Fields Initiative ‘Cell Cycle in Disease and Regeneration’ (CYDER) of the Friedrich Alexander University (Erlangen-Nürnberg, Germany). This article is partly based upon work from COST Action CA17118 TRANSCOLONCAN, supported by COST (European Cooperation in Science and Technology, www.cost.eu, last accessed 20 December 2021). The JDLR research group is supported by the Spanish Government, Instituto de Salud Carlos III (ISCiii, AES project PI18/00591) co-funded by FEDER/ERDF (European Regional Development Fund)

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Supplemental Material, sj-pdf-1-ojs-10.1177_23259671221146815 - Propensity for Clinically Meaningful Improvement and Surgical Failure After Anterior Cruciate Ligament Repair

Supplemental Material, sj-pdf-1-ojs-10.1177_23259671221146815 for Propensity for Clinically Meaningful Improvement and Surgical Failure After Anterior Cruciate Ligament Repair by Jorge Pablo Batista, Rodrigo Maestu, Jose Barbier, Jorge Chahla and Kyle N. Kunze in Orthopaedic Journal of Sports Medicine</p

Highly efficient image navigator based 3D whole-heart cardiac MRA at 0.55T

PurposeTo develop and evaluate a highly efficient free-breathing and contrast-agent-free three-dimensional (3D) whole-heart Cardiac Magnetic Resonance Angiography (CMRA) sequence at 0.55T.MethodsFree-breathing whole-heart CMRA has been previously proposed at 1.5 and 3T. Direct application of this sequence to 0.55T is not possible due to changes in the magnetic properties of the tissues. To enable free-breathing CMRA at 0.55T, pulse sequence design and acquisition parameters of a previously proposed whole-heart CMRA framework are optimized via Bloch simulations. Image navigators (iNAVs) are used to enable nonrigid respiratory motion-correction and 100% respiratory scan efficiency. Patch-based low-rank denoising is employed to accelerate the scan and account for the reduced signal-to-noise ratio at 0.55T. The proposed approach was evaluated on 11 healthy subjects. Image quality was assessed by a clinical expert (1: poor to 5: excellent) for all intrapericardiac structures. Quantitative evaluation was performed by assessing the vessel sharpness of the proximal right coronary artery (RCA).ResultsOptimization resulted in an imaging flip angle of 110 degrees$$11{0}{\circ }$$, fat saturation flip angle of 180 degrees$$18{0}{\circ }$$, and six k-space lines for iNAV encoding. The relevant cardiac structures and main coronary arteries were visible in all subjects, with excellent image quality (mean 4.9/5.0$$4.9/5.0$$) and minimal artifacts (mean 4.9/5.0$$4.9/5.0$$), with RCA vessel sharpness (50.3%+/- 9.8%$$50.3\%\pm 9.8\%$$) comparable to previous studies at 1.5T.ConclusionThe proposed approach enables 3D whole-heart CMRA at 0.55T in a 6-min scan (5.9 +/- 0.7 min$$5.9\pm 0.7\;\min$$), providing excellent image quality, minimal artifacts, and comparable vessel sharpness to previous 1.5T studies. Future work will include the evaluation of the proposed approach in patients with cardiovascular disease