Some minimization problems for planar networks of elastic curve

In this note we announce some results that will appear in [6] (joint work with also Matteo Novaga) on the minimization of the functional $F(\Gamma)=\int_\Gamma k^2+1\,\mathrm{d}s$, where $\Gamma$ is a network of three curves with fixed equal angles at the two junctions. The informal description of the results is accompanied by a partial review of the theory of elasticae and a diffuse discussion about the onset of interesting variants of the original problem passing from curves to networks. The considered energy functional $F$ is given by the elastic energy and a term that penalize the total length of the network. We will show that penalizing the length is tantamount to fix it. The paper is concluded with the explicit computation of the penalized elastic energy of the 'Figure Eight', namely the unique closed elastica with self--intersections.Comment: 24 pages, 7 figure

3D human foreskin model for testing topical formulations of sildenafil citrate

: Sildenafil citrate is an approved drug used for the treatment of erectile dysfunction and premature ejaculation. Despite a widespread application, sildenafil citrate shows numerous adverse cardiovascular effects in high-risk patients. Local transdermal drug delivery of this drug is therefore being explored as an interesting and noninvasive alternative administration method that avoids adverse effects arised from peak plasma drug concentrations. Although human and animal skin represents the most reliable models to perform penetration studies, they involve a series of ethical issues and restrictions. For these reasons new in vitro approaches based on artificially reconstructed human skin or "human skin equivalents" are being developed as possible alternatives for transdermal testing. There is little information, however, on the efficiency of such new in vitro methods on cutaneous penetration of active ingredients. The objective of the current study was to investigate the sildenafil citrate loaded in three commercial transdermal vehicles using 3D full-thickness skin equivalent and compare the results with the permeability experiments using porcine skin. Our results demonstrated that, while the formulation plays an imperative role in an appropriate dermal uptake of sildenafil citrate, the D coefficient results obtained by using the 3D skin equivalent are comparable to those obtained by using the porcine skin when a simple drug suspension is applied (1.17 × 10-10 ± 0.92 × 10-10 cm2/s vs 3.5 × 102 ± 3.3 × 102 cm2/s), suggesting that in such case, this 3D skin model can be a valid alternative for ex-vivo skin absorption experiments

SRSF2 mutations in epithelial ovarian cancer

Resistance to platinum chemotherapy regimens represents a major obstacle in the successful treatment of epithelial ovarian cancer (EOC) patients. Among the molecular mechanism responsible for resistance to platinum, alternative splicing, which is induced upon platinum treatment, can control apoptosis by regulating the expression of apoptotic protein variants with opposite functions. Alterations in alternative splicing are found in tumors and can hinder apoptotic response. In the present study we sequenced SRSF2, a splicing factor that regulates Caspase-8 and Caspase-9 variants, in search of mutations that could possibly explain alternative mechanisms of platinum resistant in EOC

Loss of CDKN1B induces an age‐related clonal hematopoietic disorder via Notch2 activity dysregulation

No abstract availabl

CDK6 controls platinum sensitivity via the regulation of FOXO3/ATR: a new actionable pathway for ovarian cancer patients

High Grade Epithelial Ovarian Cancers (HGEOCs) consist in a heterogeneous group of tumors. Late diagnosis and drug-resistant recurrences make HGEOCs the most aggressive among the gynecological malignancies. The central role played by CDKs (Cyclin-Dependent Kinase) in several cellular mechanisms, such as control of cell cycle progression, DNA repair, transcription and apoptosis, make them attractive targets to overcome drug-resistance in HGEOCs. Using the RNA interference technology (targeting 23 members of the CDKs family) we performed a functional genomic screening by which we have identified CDK6 as the CDK most significantly involved in platinum sensitivity. The effect of CDK6 silencing on the sensitivity to both carboplatinum (CBDCA) and cisplatin (CDDP) was confirmed in a panel of EOC cell lines using multiple shRNAs. Next, the use of CDK6 dominant negative CDK6D163N and constitutively active CDK6R31C mutants demonstrated that CDK6 kinase activity is necessary to protect from platinum-induced death. Accordingly, an orally active CDK4/CDK6 inhibitor, PD 0332991, was able to sensitize EOC cells to CBDCA or CDDP treatment both in vitro and in vivo, in a CDK6-dependent and CDK4-independent manner. To understand the molecular mechanism whereby CDK6 regulates platinum-induced cell death in HGEOC we focused on CDK6 specific phosphorylation targets demonstrating that the transcription factor FOXO3 is a relevant downstream target of CDK6. FOXO3a downregulation sensitizes HGEOC cells to platinum while FOXO3a overexpression in CDK6 silenced cells was able to rescue the effect of CDK6 silencing on platinum-induced cell death. Functional and biochemical analyses showed that upon platinum exposure, Cyclin D3-CDK6 complex binds and phosphorylates FOXO3 on Serine 325, preventing FOXO3 degradation and promoting FOXO3 nuclear translocation. We showed that CDK6/FOXO3 axis is necessary to control the DNA damage response in HGEOC cells through the regulation of ATR/CHK1 pathway, and using a chromatin immunoprecipitation approach we demonstrated that FOXO3 binds the ATR promoter confirming the role of FOXO3 and CDK6 as upstream mediators of ATR transcription upon DNA damage. Accordingly, the silencing of both CDK6 or FOXO3 induced ATR downregulation, decreased CHK1 phosphorylation and increased platinum dependent-cell death via the induction of the so-called Premature Chromosome Condensation (PCC) mechanism by which cells undergo to death when the ATR/CHK1 pathway is inhibited. In accord with these findings, high CDK6 and FOXO3 expression levels predict poor survival of EOC patients further increasing the translational relevance of this work. Therefore, CDK6 represents an actionable target that could be exploited to improve platinum efficacy in HGEOC patients

Long-term performance of enviromentally-friendly blown polyurethane foams

We studied the long-term performance of new environmentally-friendly blowing agents for polyurethane foams. Several blowing agents, hydrofluorocarbons, hydrocarbons, and a possible hydrochlorofluorocarbon substitute (dimethoxymethane), as well as hydrochlorofluorocarbons, were analyzed. The determination of effective diffusion coefficients (knowledge of which is required to study long-term performance) was per formed by means of a classical gas chromatographic technique and by a new method based on infrared spectroscopy. The reliability of the experimental procedure used is showed by comparing experimental and predicted aging, as the slope of the aging curve (i.e., thermal conductivity vs. time) depends only on effective diffusion coefficients. Our study of long-term performance of foams blown with alternative blowing agents shows that hydrofluorocarbons represent a proper alternative to hydrochlorofluorocarbons, as the foams show similar initial thermal conductivity and a slower aging rate (i.e., better long-term performance)