Search

Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters.

AbstractFast quench detection is a key requirement for the successful implementation of superconducting magnet technology. In high temperature superconductor (HTS) magnets, this issue is especially challenging due to the low quench propagation velocity, and presently represents one of the main factors limiting their application. A new detection technique based on stray-capacitance monitoring is proposed. The capacitance between electrically-insulated magnet elements, such as magnet structure and end parts, is utilized as an indication of local heat deposition in the conductor. In fact, the relative permittivity of helium drops when it changes from the liquid to the gaseous phase. Thus, when heating occurs, part of the helium impregnating the insulation layers boils off, and the monitored stray-capacitance decreases. The proposed technique is successfully demonstrated on three small-scale Bi-2212 magnets manufactured at the Lawrence Berkeley National Laboratory. Results from the detection of thermal runaways and spot-heater induced quenches are reported and discussed. Advantages and limitations of the stray-capacitance method with respect to conventional quench detection methods are assessed.Export citation and abstract BibTeX RISCC BYAs the Version of Record of this article is going to be/has been published on a gold open access basis under a CC BY 3.0 licence, this Accepted Manuscript is available for reuse under a CC BY 3.0 licence immediately.Although reasonable endeavours have been taken to obtain all necessary permissions from third parties to include their copyrighted content within this article, their full citation and copyright line may not be present in this Accepted Manuscript version. Before using any content from this article, please refer to the Version of Record on IOPscience once published for full citation and copyright details, as permission may be required. All third party content is fully copyright protected, and is not published on a gold open access basis under a CC BY licence, unless that is specifically stated in the figure caption in the Version of Record.

This article, within the field of mountain geographies, proposes a critical analysis of collective property, as a virtuous example of territorial governance, connecting property studies with the concepts of common and convivial conservation. Structuring a series of social relations based on mutual obligations and shared values between community members, within an active participation to the territorial management fostered by the collective status of land property, collective land structures represent peculiar commons that local communities use and take care of. In particular, collective land property and collective territorial management foster convivial conservation processes at the socioecological level, while the implementation of individual private property relations tends to promote uncontrolled phenomena of exploitation of resources and individualistic attitudes. The analysis of the case studies, that are the Umbrian Comunanze Agrarie of Massa Martana and Colpetrazzo, confirms the positive relationality of collective property, counterposed to the socialisation of people and spaces linked to the territorialisation of individual private property, as it allows the maintenance of common goods and spaces which guarantee a direct and democratic territorial governance able to contrast the present socio-environmental challenges.

This article, within the field of mountain geographies, proposes a critical analysis of collective property, as a virtuous example of territorial governance, connecting property studies with the concepts of common and convivial conservation. Structuring a series of social relations based on mutual obligations and shared values between community members, within an active participation to the territorial management fostered by the collective status of land property, collective land structures represent peculiar commons that local communities use and take care of. In particular, collective land property and collective territorial management foster convivial conservation processes at the socioecological level, while the implementation of individual private property relations tends to promote uncontrolled phenomena of exploitation of resources and individualistic attitudes. The analysis of the case studies, that are the Umbrian Comunanze Agrarie of Massa Martana and Colpetrazzo, confirms the positive relationality of collective property, counterposed to the socialisation of people and spaces linked to the territorialisation of individual private property, as it allows the maintenance of common goods and spaces which guarantee a direct and democratic territorial governance able to contrast the present socio-environmental challenges.

BackgroundMR fingerprinting (MRF) is a novel method for quantitative assessment of in vivo MR relaxometry that has shown high precision and accuracy. However, the method requires data acquisition using customized, complex acquisition strategies and dedicated post processing methods thereby limiting its widespread application.ObjectiveTo develop a deep learning (DL) network for synthesizing MRF signals from conventional magnitude-only MR imaging data and to compare the results to the actual MRF signal acquired.MethodsA U-Net DL network was developed to synthesize MRF signals from magnitude-only 3D T1-weighted brain MRI data acquired from 37 volunteers aged between 21 and 62 years of age. Network performance was evaluated by comparison of the relaxometry data (T1, T2) generated from dictionary matching of the deep learning synthesized and actual MRF data from 47 segmented anatomic regions. Clustered bootstrapping involving 10,000 bootstraps followed by calculation of the concordance correlation coefficient were performed for both T1 and T2 MRF data pairs. 95% confidence limits and the mean difference between true and DL relaxometry values were also calculated.ResultsThe concordance correlation coefficient (and 95% confidence limits) for T1 and T2 MRF data pairs over the 47 anatomic segments were 0.8793 (0.8136–0.9383) and 0.9078 (0.8981–0.9145) respectively. The mean difference (and 95% confidence limits) were 48.23 (23.0–77.3) s and 2.02 (−1.4 to 4.8) s.ConclusionIt is possible to synthesize MRF signals from MRI data using a DL network, thereby creating the potential for performing quantitative relaxometry assessment without the need for a dedicated MRF pulse sequence.

Background & Aims: Sarcopenia is associated with increased morbidity and mortality in patients with cirrhosis, but its definition in current literature is very heterogeneous. We performed a systematic review and meta-analysis to assess the association between mortality and sarcopenia evaluated by computed tomography (CT) in patients with cirrhosis, both overall and stratified for the criteria used to define sarcopenia. Methods: Medline, Embase, Scopus, and Cochrane Library were searched up to January 2023. We included studies assessing sarcopenia presence with CT scans and providing data on the risk of mortality. Adjusted hazard ratios (HRs) and 95% CIs were pooled using a random-effects model. Results: Thirty-nine studies comprising 12,827 patients were included in the meta-analysis. The summary prevalence of sarcopenia was 44% (95% CI 38-50%). The presence of sarcopenia (any definition) was an independent predictor of mortality with an adjusted HR of 2.07 (95% CI 1.81-2.36), and the result was consistent in all subgroup analyses. The prognostic role of the EASL/AASLD criteria was confirmed for the first time with an HR of 1.86 (95% CI 1.53-2.26) (n = 14 studies). The cut-offs used to define sarcopenia based on psoas muscle parameters varied among studies, thus, a subgroup analysis was not feasible. There was no substantial heterogeneity for the main estimates and no significant risk of publication bias. Conclusions: Sarcopenia on CT is associated with a 2-fold higher risk of mortality in patients with cirrhosis. The cut-offs proposed by EASL/AASLD are prognostically relevant and should be the recommended criteria used to define sarcopenia in clinical practice. Impact and implications:: Sarcopenia assessed by the reference standard (computed tomography scan) is an independent predictor of mortality in patients with cirrhosis, with a 2-fold increase in the risk of death in all sensitivity analyses. This finding is particularly valid in patients from Europe and North America, and in transplant candidates. Stratifying for the parameters and cut-offs used, we confirmed for the first time the prognostic impact of the definition proposed by EASL/AASLD, supporting their use in clinical practice. Psoas muscle assessment is promising, but data are still limited and too heterogeneous to recommend its routine use at present.

Background: Neuronal loss is a major pathological feature of neurodegenerative diseases. The analysis of plasma cell-free DNA (cfDNA) is an emerging approach to track cell death events in a minimally invasive way and from inaccessible areas of the body, such as the brain. Previous studies showed that DNA methylation (DNAm) profiles can be used to map the tissue of origin of cfDNA and to identify molecules released from the brain upon cell death. The aim of the present study is to contribute to this research field, presenting the development and validation of an assay for the detection of brain-derived cfDNA (bcfDNA). Methods: To identify CpG sites with brain-specific DNAm, we compared brain and non-brain tissues for their chromatin state profiles and genome-wide DNAm data, available in public datasets. The selected target genomic regions were experimentally validated by bisulfite sequencing on DNA extracted from 44 different autoptic tissues, including multiple brain regions. Sequencing data were analysed to identify brain-specific epihaplotypes. The developed assay was tested in plasma cfDNA from patients with immune effector cell-associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor T (CAR-T) therapy. Results: We validated five genomic regions with brain-specific DNAm (four hypomethylated and one hypermethylated in the brain). DNAm analysis of the selected genomic regions in plasma samples from CAR-T patients revealed higher levels of bcfDNA in participants with ongoing neurotoxicity syndrome. Conclusions: We developed an assay for the analysis of bcfDNA in plasma. The assay is a promising tool for the early detection of neuronal loss in neurodegenerative diseases.

Down syndrome (DS) is a segmental progeroid genetic disorder associated with multi-systemic precocious aging phenotypes, which are particularly evident in the immune and nervous systems. Accordingly, people with DS show an increased biological age as measured by epigenetic clocks. The Ts65Dn trisomic mouse, which harbors extra-numerary copies of chromosome 21 (Hsa21)-syntenic regions, was shown to recapitulate several progeroid features of DS, but no biomarkers of age have been applied to it so far. In this pilot study, we used a mouse-specific epigenetic clock to measure the epigenetic age of hippocampi from Ts65Dn and euploid mice at 20 weeks. Ts65Dn mice showed an increased epigenetic age in comparison with controls, and the observed changes in DNA methylation partially recapitulated those observed in hippocampi from people with DS. Collectively, our results support the use of the Ts65Dn model to decipher the molecular mechanisms underlying the progeroid DS phenotypes.

In recent decades, the risk of developing opportunistic infections has increased in parallel with the ever-increasing number of people suffering from chronic immunosuppressive diseases or undergoing prosthetic surgery. Staphylococcus warneri is a Gram-positive and coagulase-negative bacterium. Usually found as a component of the healthy human and animal microbiota of the skin and mucosae, it can take on the role of an opportunistic pathogen capable of causing a variety of infections, ranging from mild to life-threatening, not only in immunocompromised patients but even, although rarely, in healthy people. Here, in addition to a concise discussion of the identification and distinguishing features of S. warneri compared to other staphylococcal species, a systematic overview of the findings from case reports and clinical studies is provided. The paper highlights the virulence and antibiotic resistance profiles of S. warneri, the different clinical contexts in which it has proven to be a serious pathogen, emphasizing its ability to colonize artificial prosthetic materials and its tropism for musculoskeletal and cardiovascular tissues. Some original data on orthopedic implant infections by S. warneri complement the discussion. Finally, from a different perspective, the paper addresses the possibilities of industrial exploitation of this bacterium.

AbstractFast quench detection is a key requirement for the successful implementation of superconducting magnet technology. In high temperature superconductor (HTS) magnets, this issue is especially challenging due to the low quench propagation velocity, and presently represents one of the main factors limiting their application. A new detection technique based on stray-capacitance monitoring is proposed. The capacitance between electrically-insulated magnet elements, such as magnet structure and end parts, is utilized as an indication of local heat deposition in the conductor. In fact, the relative permittivity of helium drops when it changes from the liquid to the gaseous phase. Thus, when heating occurs, part of the helium impregnating the insulation layers boils off, and the monitored stray-capacitance decreases. The proposed technique is successfully demonstrated on three small-scale Bi-2212 magnets manufactured at the Lawrence Berkeley National Laboratory. Results from the detection of thermal runaways and spot-heater induced quenches are reported and discussed. Advantages and limitations of the stray-capacitance method with respect to conventional quench detection methods are assessed.Export citation and abstract BibTeX RISCC BYAs the Version of Record of this article is going to be/has been published on a gold open access basis under a CC BY 3.0 licence, this Accepted Manuscript is available for reuse under a CC BY 3.0 licence immediately.Although reasonable endeavours have been taken to obtain all necessary permissions from third parties to include their copyrighted content within this article, their full citation and copyright line may not be present in this Accepted Manuscript version. Before using any content from this article, please refer to the Version of Record on IOPscience once published for full citation and copyright details, as permission may be required. All third party content is fully copyright protected, and is not published on a gold open access basis under a CC BY licence, unless that is specifically stated in the figure caption in the Version of Record.