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

Design and experimental testing of an optimization-based flow control algorithm for Energy Harvesting Wireless Sensor Networks

In this paper a distributed flow control law is proposed to maximize throughput and to minimize energy consumption in Energy Harvesting Wireless Sensor Networks (EH-WSNs). We preliminary recast the control problem in terms of primal–dual optimization one taking into account the bandwidth and energy autonomy node constraint. Then, we devise a distributed flow rate control implemented at each node that allows the overall network to converge to the optimal solution of the original problem. The closed loop EH-WSN stability and convergence to the optimal equilibrium are proven. The effectiveness of the proposed control law in terms of throughput and network lifetime performance is experimentally validated by a small representative EH-WSN. The experimental results are in a good agreement with the theoretical ones

Adaptive FOCV-based Control Scheme to improve the MPP Tracking Performance: an experimental validation

Nowadays the photovoltaic (PV) is one of the most renewable source device used in the harvesting system to support the life time of stand alone devices like sensor node. One of the most diffused method to increase the PV efficiency is the Fractional Open-Circuit Voltage (FOCV) that allows the PV to work around its estimated Maximum Power Point (MPP). To increase the solar harvesting system efficiency both static (in terms of efficiency) and dynamic (in terms of MPP tracking responsiveness) performances are of crucial interest. Most of works in the literature focus on improving the static system performance by giving a more accurate MPP estimation. In this paper, it is proposed a FOCV-based algorithm to improve system dynamic performance in terms of MPP tracking performance and energy conveyed to the load under varying solar irradiance conditions. The MPP system dynamically adapts the MPP estimation to the solar irradiance condition by mean of a ”smart timer” circuitry that continuously adjusts the operative frequency of the sample and hold component. A detailed hardware implementation description of a smart timer as well as a related analytical analysis used for component design are presented. An experimental validation and a comparison of the proposed approach than the standard FOCV based method are carried out. The results show the effectiveness of the proposed scheme in improving dynamic system performance in terms of tracking performance and timeless to convey solar energy to the load storage component (i.e. ultracapacitor)

Stopshock Project

Il Progetto si propone di indentificare e validare principi attivi salvavita di pronto impiego per uso civile (medicina delle catastrofi) e militare (missioni peace keeping) - Il Progetto \ue8 promosso dal Ministero della Difesa e prevede la partecipazione di esperti di altri paesi

Genomic profiling of KRAS/NRAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patients reveals novel mutations in genes potentially associated with resistance to anti-EGFR agents

Previous findings suggest that metastatic colorectal carcinoma (mCRC) patients with KRAS/NRAS/BRAF/PIK3CA wild-type (quadruple-wt) tumors are highly sensitive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). However, additional molecular alterations might be involved in the de novo resistance to these drugs. We performed a comprehensive molecular profiling of 21 quadruple-wt tumors from mCRC patients enrolled in the "Cetuximab After Progression in KRAS wild-type colorectal cancer patients" (CAPRI-GOIM) trial of first line FOLFIRI plus cetuximab. Tumor samples were analyzed with a targeted sequencing panel covering single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and gene fusions in 143 cancer-related genes. The analysis revealed in all 21 patients the presence of at least one SNV/Indel and in 10/21 cases (48%) the presence of at least one CNV. Furthermore, 17/21 (81%) patients had co-existing SNVs/Indels in different genes. Quadruple-wt mCRC from patients with the shorter progression free survival (PFS) were enriched with peculiar genetic alterations in KRAS, FBXW7, MAP2K1, and NF1 genes as compared with patients with longer PFS. These data suggest that a wide genetic profiling of quadruple-wt mCRC patients might help to identify novel markers of de novo resistance to anti-EGFR MoAbs

Selective dicer suppression in the kidney alters gsk3β/β-Catenin Pathways Promoting a Glomerulocystic Disease

Dicer is a crucial enzyme for the maturation of miRNAs. Mutations in the Dicer gene are highly associated with Pleuro Pulmonary Blastoma-Family Dysplasia Syndrome (PPB-FDS, OMIM 601200), recently proposed to be renamed Dicer syndrome. Aside from the pulmonary phenotype (blastoma), renal nephroma and thyroid goiter are frequently part of Dicer syndrome. To investigate the renal phenotype, conditional knockout (cKO) mice for Dicer in Pax8 expressing cells were generated. Dicer cKO mice progressively develop a glomerulocystic phenotype coupled with urinary concentration impairment, proteinuria and severe renal failure. Higher cellular turnover of the parietal cells of Bowman's capsule precedes the development of the cysts and the primary cilium progressively disappears with cyst-enlargement. Upregulation of GSK3β precedes the development of the glomerulocystic phenotype. Downregulation of β-catenin in the renal cortex and its cytosolic removal in the cells lining the cysts may be associated with observed accumulation of GSK3β. Alterations of β-catenin regulating pathways could promote cystic degeneration as in other models. Thus, miRNAs are fundamental in preserving renal morphology and function. Alteration of the GSK3β/β-catenin pathway could be a crucial mechanism linking miRNA dysregulation and the development of a glomerulocystic disease

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non-small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR-21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation