Controversies in the treatment of mild asthma. What novelties and practical implications?

Mild asthma is prevalent in childhood and causes as many as 30%–40% asthma exacerbations requiring emergency visits. The management of "intermittent" and "mild persistent" asthma phenotypes is still a matter of debate, even if the role of inhaled corticosteroids, both continuous and intermittent, is a cornerstone in this field. Recent updates of the guidelines on the strategies to manage these patients are coming, since the role of inflammation in these asthma phenotypes is crucial, as well as the potential side effect and risks of short-acting beta 2 agonists overuse, prescribed as the only "as-needed" treatments. In this paper, we overview the new (r)evolution regarding intermittent and mild persistent asthma management

Depth profiling of melting and metallization in Si(111) and Si(001) surfaces

International audienc

Selective inhibition of genomic and non-genomic effects of thyroid hormone regulates muscle cell differentiation and metabolic behavior

Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are still poorly understood. Skeletal muscle is a classical target tissue for TH, which regulates muscle strength and contraction, as well as energetic metabolism of myofibers. Here we address the different contribution of genomic and non-genomic action of TH in skeletal muscle cells by specifically silencing the deiodinase Dio2 or the β3-Integrin expression via CRISPR/Cas9 technology. We found that myoblast proliferation is inversely regulated by integrin signal and the D2-dependent TH activation. Similarly, inhibition of the nuclear receptor action reduced myoblast proliferation, confirming that genomic action of TH attenuates proliferative rates. Contrarily, genomic and non-genomic signals promote muscle differentiation and the regulation of the redox state. Taken together, our data reveal that integration of genomic and non-genomic signal pathways finely regulates skeletal muscle physiology. These findings not only contribute to the understanding of the mechanisms involved in TH modulation of muscle physiology but also add insight into the interplay between different mechanisms of action of TH in muscle cells

Phase transitions of alluminosilicate refractories by temperature resolved XRD

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The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome.

Epigenetic mechanisms oversee epidermal homeostasis and oncogenesis. The identification of kinases controlling these processes has direct therapeutic implications. We show that ULK3 is a nuclear kinase with elevated expression levels in squamous cell carcinomas (SCCs) arising in multiple body sites, including skin and Head/Neck. ULK3 loss by gene silencing or deletion reduces proliferation and clonogenicity of human keratinocytes and SCC-derived cells and affects transcription impinging on stem cell-related and metabolism programs. Mechanistically, ULK3 directly binds and regulates the activity of two histone arginine methyltransferases, PRMT1 and PRMT5 (PRMT1/5), with ULK3 loss compromising PRMT1/5 chromatin association to specific genes and overall methylation of histone H4, a shared target of these enzymes. These findings are of translational significance, as downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in two orthotopic models of skin cancer

Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi

Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and β [TRα and TRβ]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRα mediate resistance to thyroid hormone alpha (RTHα), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHα cases have been recorded worldwide. Methods: RTHα cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHα patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results: Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRα1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRα1 and TRα2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n = 2 cases) and melanoma (c-kit, MAGE, CDK4, n = 1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRα mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients were markedly increased. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHα, with cutaneous cells from patients being in a hyperproliferative state. Such excess of skin lesions, including nevi expressing oncogenic markers, indicates that dermatologic surveillance of RTHα patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted

Free electron laser-driven ultrafast rearrangement of the electronic structure in Ti

High-energy density extreme ultraviolet radiation delivered by the FERMI seeded free-electron laser has been used to create an exotic nonequilibrium state of matter in a titanium sample characterized by a highly excited electron subsystem at temperatures in excess of 10 eV and a cold solid-density ion lattice. The obtained transient state has been investigated through ultrafast absorption spectroscopy across the Ti M2,3-edge revealing a drastic rearrangement of the sample electronic structure around the Fermi level occurring on a time scale of about 100 fs

The NANOG transcription factor induces type 2 deiodinase expression and regulates the intracellular activation of thyroid hormone in keratinocyte carcinomas

Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissues, is expressed in cutaneous squamous cell carcinomas (SCCs) during late tumorigenesis, and its repression attenuates the invasiveness and metastatic spread of SCC. Although D2 plays multiple roles in cancer progression, nothing is known about the mechanisms regulating D2 in cancer. To address this issue, we investigated putative upstream regulators of D2 in keratinocyte carcinomas. We found that the expression of D2 in SCC cells is positively regulated by the NANOG transcription factor, whose expression, besides being causally linked to embryonic stemness, is associated with many human cancers. We also found that NANOG binds to the D2 promoter and enhances D2 transcription. Notably, blockage of D2 activity reduced NANOG-induced cell migration as well as the expression of key genes involved in epithelial–mesenchymal transition in SCC cells. In conclusion, our study reveals a link among endogenous endocrine regulators of cancer, thyroid hormone and its activating enzyme, and the NANOG regulator of cancer biology. These findings could provide the basis for the development of TH inhibitors as context-dependent anti-tumor agents