EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours

Missense mutations in TP53 gene promote metastasis in human tumours. However, little is known about the complete loss of function of p53 in tumour metastasis. Here we show that squamous cell carcinomas generated by the specific ablation of Trp53 gene in mouse epidermis are highly metastatic. Biochemical and genome-wide mRNA and miRNA analyses demonstrated that metastases are associated with the early induction of epithelial-mesenchymal transition (EMT) and deregulated miRNA expression in primary tumours. Increased expression of miR-21 was observed in undifferentiated, prometastatic mouse tumours and in human tumours characterized by p53 mutations and distant metastasis. The augmented expression of miR-21, mediated by active mTOR and Stat3 signalling, conferred increased invasive properties to mouse keratinocytes in vitro and in vivo, whereas blockade of miR-21 in a metastatic spindle cell line inhibits metastasis development. Collectively these data identify novel molecular mechanisms leading to metastasis in vivo originated by p53 loss in epithelia

PRIMAGE project : predictive in silico multiscale analytics to support childhood cancer personalised evaluation empowered by imaging biomarkers

PRIMAGE is one of the largest and more ambitious research projects dealing with medical imaging, artificial intelligence and cancer treatment in children. It is a 4-year European Commission-financed project that has 16 European partners in the consortium, including the European Society for Paediatric Oncology, two imaging biobanks, and three prominent European paediatric oncology units. The project is constructed as an observational in silico study involving high-quality anonymised datasets (imaging, clinical, molecular, and genetics) for the training and validation of machine learning and multiscale algorithms. The open cloud-based platform will offer precise clinical assistance for phenotyping (diagnosis), treatment allocation (prediction), and patient endpoints (prognosis), based on the use of imaging biomarkers, tumour growth simulation, advanced visualisation of confidence scores, and machine-learning approaches. The decision support prototype will be constructed and validated on two paediatric cancers: neuroblastoma and diffuse intrinsic pontine glioma. External validation will be performed on data recruited from independent collaborative centres. Final results will be available for the scientific community at the end of the project, and ready for translation to other malignant solid tumours

The Thyroid Hormone Receptors Modulate the Skin Response to Retinoids

[Background]: Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice. [Methodology/Principal Findings]: We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA) induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced. [Conclusions/significance]: Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to these compounds could have not only physiological but also therapeutic implications.This work was supported by grants BFU2007-62402 and SAF2008-00121 from Ministerio de Ciencia e Innovación, RD06/0020/0036 and RD06/0020/0029 from the Fondo de Investigaciones Sanitarias and by the European Grant CRESCENDO (FP-018652).Peer reviewe

A Functional Role of RB-Dependent Pathway in the Control of Quiescence in Adult Epidermal Stem Cells Revealed by Genomic Profiling

Continuous cell renewal in mouse epidermis is at the expense of a pool of pluripotent cells that lie in a well defined niche in the hair follicle known as the bulge. To identify mechanisms controlling hair follicle stem cell homeostasis, we developed a strategy to isolate adult bulge stem cells in mice and to define their transcriptional profile. We observed that a large number of transcripts are underexpressed in hair follicle stem cells when compared to non-stem cells. Importantly, the majority of these downregulated genes are involved in cell cycle. Using bioinformatics tools, we identified the E2F transcription factor family as a potential element involved in the regulation of these transcripts. To determine their functional role, we used engineered mice lacking Rb gene in epidermis, which showed increased expression of most E2F family members and increased E2F transcriptional activity. Experiments designed to analyze epidermal stem cell functionality (i.e.: hair regrowth and wound healing) imply a role of the Rb-E2F axis in the control of stem cell quiescence in epidermis

Sensing and Integration of Erk and PI3K Signals by Myc

The transcription factor Myc plays a central role in regulating cell-fate decisions, including proliferation, growth, and apoptosis. To maintain a normal cell physiology, it is critical that the control of Myc dynamics is precisely orchestrated. Recent studies suggest that such control of Myc can be achieved at the post-translational level via protein stability modulation. Myc is regulated by two Ras effector pathways: the extracellular signal-regulated kinase (Erk) and phosphatidylinositol 3-kinase (PI3K) pathways. To gain quantitative insight into Myc dynamics, we have developed a mathematical model to analyze post-translational regulation of Myc via sequential phosphorylation by Erk and PI3K. Our results suggest that Myc integrates Erk and PI3K signals to result in various cellular responses by differential stability control of Myc protein isoforms. Such signal integration confers a flexible dynamic range for the system output, governed by stability change. In addition, signal integration may require saturation of the input signals, leading to sensitive signal integration to the temporal features of the input signals, insensitive response to their amplitudes, and resistance to input fluctuations. We further propose that these characteristics of the protein stability control module in Myc may be commonly utilized in various cell types and classes of proteins

Autolytic processing of a phosphorothioate diester bond.

A small satellite RNA of tobacco ringspot virus replicates in tissues infected with tobacco ringspot virus and accumulates in virus capsids, forming virus-like particles. Previous research showed that multimeric forms of this satellite RNA have tandem repeats of the "monomeric" satellite RNA sequence of 359 or 360 nucleotide residues. The multimeric RNAs undergo autolytic processing at a specific CpA phosphodiester bond, the junction, to generate the monomeric RNA. We substituted phosphorothioate diester bonds for various sets of phosphodiester bonds, in dimeric and truncated forms of the satellite RNA. The degree of reduction in autolytic cleavage varied both with the sites of substitution and the size of the RNA molecules. Analyses of a product of the autolysis reaction suggest that one phosphorothioate diester bond most strongly interferes with processing, the one introduced at the CpA junction during its synthesis from adenosine-5'-0-(1-thiotriphosphate). However, extensive introduction of phosphorothioate diester bonds elsewhere in the molecule also decreased processing, possibly by altering conformation

Ubiquitous healthcare systems and medical rules in COPD Domain

Chronic Obstructive Pulmonary Disease (COPD) is a severe lung illness that causes a progressive deterioration in the function and structure of the respiratory system. Recently, COPD became the fifth cause of mortality and the seventh cause of morbidity in Canada. The advancement of context-aware technology creates a new and important opportunity to transform the standard shape of healthcare services into a more dynamic and interactive form. This research project design and validates a rule-based ontology-reasoning framework that provides a context-aware system for COPD patients. The originality of the proposed approach consists in its methodology to prove the efficiency of this model in simulated examples of real-life scenarios based on collaborative data analysis, recognized by specialized medical experts

Noninvasive ventilation for severely acidotic patients in respiratory intermediate care units : Precision medicine in intermediate care units

Severe acidosis can cause noninvasive ventilation (NIV) failure in chronic obstructive pulmonary disease (COPD) patients with acute hypercapnic respiratory failure (AHRF). NIV is therefore contraindicated outside of intensive care units (ICUs) in these patients. Less is known about NIV failure in patients with acute cardiogenic pulmonary edema (ACPE) and obesity hypoventilation syndrome (OHS). Therefore, the objective of the present study was to compare NIV failure rates between patients with severe and non-severe acidosis admitted to a respiratory intermediate care unit (RICU) with AHRF resulting from ACPE, COPD or OHS. We prospectively included acidotic patients admitted to seven RICUs, where they were provided NIV as an initial ventilatory support measure. The clinical characteristics, pH evolutions, hospitalization or RICU stay durations and NIV failure rates were compared between patients with a pH ≥ 7.25 and a pH < 7.25. Logistic regression analysis was performed to determine the independent risk factors contributing to NIV failure. We included 969 patients (240 with ACPE, 540 with COPD and 189 with OHS). The baseline rates of severe acidosis were similar among the groups (45 % in the ACPE group, 41 % in the COPD group, and 38 % in the OHS group). Most of the patients with severe acidosis had increased disease severity compared with those with non-severe acidosis: the APACHE II scores were 21 ± 7.2 and 19 ± 5.8 for the ACPE patients (p < 0.05), 20 ± 5.7 and 19 ± 5.1 for the COPD patients (p < 0.01) and 18 ± 5.9 and 17 ± 4.7 for the OHS patients, respectively (NS). The patients with severe acidosis also exhibited worse arterial blood gas parameters: the PaCO levels were 87 ± 22 and 70 ± 15 in the ACPE patients (p < 0.001), 87 ± 21 and 76 ± 14 in the COPD patients, and 83 ± 17 and 74 ± 14 in the OHS patients (NS)., respectively Further, the patients with severe acidosis required a longer duration to achieve pH normalization than those with non-severe acidosis (patients with a normalized pH after the first hour: ACPE, 8 % vs. 43 %, p < 0.001; COPD, 11 % vs. 43 %, p < 0.001; and OHS, 13 % vs. 51 %, p < 0.001), and they had longer RICU stays, particularly those in the COPD group (ACPE, 4 ± 3.1 vs. 3.6 ± 2.5, NS; COPD, 5.1 ± 3 vs. 3.6 ± 2.1, p < 0.001; and OHS, 4.3 ± 2.6 vs. 3.7 ± 3.2, NS). The NIV failure rates were similar between the patients with severe and non-severe acidosis in the three disease groups (ACPE, 16 % vs. 12 %; COPD, 7 % vs. 7 %; and OHS, 11 % vs. 4 %). No common predictive factor for NIV failure was identified among the groups. ACPE, COPD and OHS patients with AHRF and severe acidosis (pH ≤ 7.25) who are admitted to an RICU can be successfully treated with NIV in these units. These results may be used to determine precise RICU admission criteria