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Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.

Pyrite (FeS 2 ) is one of the most abundant sulfides on Earth and has already been studied in numerous ways for decades because of its rapid oxidation and the associated environmental impacts. This study proposes a new experimental physico-chemical approach (air, tridistilled water and water drip exposure) to determine the oxidation rate of pyrite using surface and depth data via XPS (X-ray Photoelectron Spectroscopy) analyses. Our experimental study of almost pure pyrite reveals a maximum oxidation rate of 11.7 ± 1.8 nm day −1 for drip exposure with precipitation of sulfates or Fe-oxides depending on the experimental condition. The oxidation rates obtained under various experimental conditions may be extrapolated to weathering rates of different zones of supergene profiles/ores (leached zone, saprolite and cementation zone). The extrapolation suggests a maximum rate of 4.3 ± 0.6 m Ma −1 , which is consistent with data obtained by isotope dating of weathering profiles. Under geological conditions however, the oxidation rate of pyrite may be influenced by additional parameters, such as the nature of the host rock, its porosity/permeability, the climate, the influence of an oxidizing environment, and the mineralization of secondary minerals.

A 58-year-old woman had congenital absence of vitamin D–binding protein, normocalcemia, mild disruption of bone metabolism, and severe autoimmune disease. A homozygous deletion of the group-specific component ( GC ) gene that encodes the protein was found, which provided new data about vitamin D metabolism.

Background: Psychiatric symptoms are a common feature of Huntington’s disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period. Objectives: To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non-carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset. Methods: Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non-carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow-up of gene carriers (n = 51) enabled analysis of the role of temporal proximity to clinical onset. Results: Gene carriers and non-carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset. Conclusions: Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.

Multiple tumors in patients are frequently diagnosed, either synchronous or metachronous. The distinction between a second primary and a metastasis is important for treatment. Chromosomal DNA copy number aberrations (CNA) patterns are highly unique to specific tumors. The aim of this study was to assess genome-wide CNA-patterns as method to identify clonally related tumors in a prospective cohort of patients with synchronous or metachronous tumors, with at least one intrapulmonary tumor. In total, 139 tumor pairs from 90 patients were examined: 35 synchronous and 104 metachronous pairs. Results of CNA were compared to histological type, clinicopathological methods (Martini-Melamed-classification (MM) and ACCP-2013-criteria), and, if available, EGFR- and KRAS-mutation analysis. CNA-results were clonal in 74 pairs (53%), non-clonal in 33 pairs (24%), and inconclusive in 32 pairs (23%). Histological similarity was found in 130 pairs (94%). Concordance between histology and conclusive CNA-results was 69% (74 of 107 pairs: 72 clonal and two non-clonal). In 31 of 103 pairs with similar histology, genetics revealed non-clonality. In two out of four pairs with non-matching histology, genetics revealed clonality. The subgroups of synchronous and metachronous pairs showed similar outcome for the comparison of histological versus CNA-results. MM-classification and ACCP-2013-criteria, applicable on 34 pairs, and CNA-results were concordant in 50% and 62% respectively. Concordance between mutation matching and conclusive CNA-results was 89% (8 of 9 pairs: six clonal and two non-clonal). Interestingly, in one patient both tumors had the same KRAS mutation, but the CNA result was non-clonal. In conclusion, although some concordance between histological comparison and CNA profiling is present, arguments exist to prefer extensive molecular testing to determine whether a second tumor is a metastasis or a second primary.

Background Mutations in LMNA , encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly. Results Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA -related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development. Conclusions Our results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages.

[This corrects the article DOI: 10.1371/journal.pone.0223827.].

In clinical practice, dose delivery in proton therapy treatment is affected by uncertainties related to the range of the beam in the patient, which requires medical physicists to introduce safety margins on the penetration depth of the beam. Although this ensures an irradiation of the entire clinical target volume with the prescribed dose, these safety margins also lead to the exposure of nearby healthy tissues and a subsequent risk of side effects. Therefore, non-invasive techniques that allow for margin reduction through online monitoring of prompt gammas emitted along the proton tracks in the patient are currently under development. This study provides the proof-of-concept of metal-based nanoparticles, injected into the tumor, as a prompt gamma enhancer, helping in the beam range verification. It identifies the limitations of this application, suggesting a low feasibility in a realistic clinical scenario but opens some avenues for improvement.

The Payne Effect (also known as the Fletcher–Gent Effect) has a fundamental impact on the behavior of filled rubber composites and therefore must be considered during their design. This study investigates the influence of carbon black (CB) surface area and structure on the observed Payne Effect and builds on the existing models of Kraus and Ulmer to explain this phenomenon. Dynamic strain sweeps were carried out on natural rubber (NR) compounds containing eight different grades of CB at equivalent volume fractions. The loss and storage moduli were modeled according to the Kraus and Ulmer equations, using a curve optimization tool in SciPy. Subsequent regression analysis provided strong correlations between the fitting parameters and the CB structure and surface area. Using this regression analysis, this work provides further insight into the physical meaning behind the Kraus and Ulmer models, which are phenomenological in nature.