New Target Genes for the Peroxisome Proliferator-Activated Receptor-γ (PPARγ) Antitumour Activity: Perspectives from the Insulin Receptor

The insulin receptor (IR) plays a crucial role in mediating the metabolic and proliferative functions triggered by the peptide hormone insulin. There is considerable evidence that abnormalities in both IR expression and function may account for malignant transformation and tumour progression in some human neoplasias, including breast cancer. PPARγ is a ligand-activated, nuclear hormone receptor implicated in many pleiotropic biological functions related to cell survival and proliferation. In the last decade, PPARγ agonists—besides their known action and clinical use as insulin sensitizers—have proved to display a wide range of antineoplastic effects in cells and tissues expressing PPARγ, leading to intensive preclinical research in oncology. PPARγ and activators affect tumours by different mechanisms, involving cell proliferation and differentiation, apoptosis, antiinflammatory, and antiangiogenic effects. We recently provided evidence that PPARγ and agonists inhibit IR by non canonical, DNA-independent mechanisms affecting IR gene transcription. We conclude that IR may be considered a new PPARγ “target” gene, supporting a potential use of PPARγ agonists as antiproliferative agents in selected neoplastic tissues that overexpress the IR

HCV antiviral resistance: The impact of in vitro studies on the development of antiviral agents targeting the viral NS5B polymerase

The high prevalence of the disease caused by hepatitis C virus (HCV) and the limited efficacy of interferon-based therapies have stimulated the search for safer and more effective drugs. The development of inhibitors of the HCV NS5B RNA polymerase represents a promising strategy for identifying novel anti-HCV therapeutics. However, the high genetic diversity, mutation rate and turnover of HCV are expected to favour the emergence of drug resistance, limiting the clinical usefulness of polymerase inhibitors. Thus, the characterization of the drug-resistance profile of these antiviral agents is considered crucial for identifying the inhibitors with a higher probability of clinical success. In the absence of an efficient in vitro infection system, HCV sub-genomic replicons have been used to study viral resistance to both nucleoside and non-nucleoside NS5B inhibitors. While these studies suggest that drug-resistant viruses are likely to evolve in vivo, they provide a wealth of information that should help in the identification of inhibitors with improved and distinct resistance profiles that might be used for combination therapy

The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis

<p>Abstract</p> <p>Background</p> <p>We previously showed that mice lacking the high mobility group A1 gene (<it>Hmga1</it>-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the <it>Hmga1</it>-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in <it>Hmga1</it>-deficient mice could be related to the deficit of an insulin resistance factor is discussed.</p> <p>Results</p> <p>We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (<it>RBP4</it>) gene and protein expression in living cells of both human and mouse origin. Then, by employing the <it>Hmga1</it>-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis <it>in vivo</it>, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in <it>Hmga1</it>-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased <it>Glut4 </it>mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.</p> <p>Conclusion</p> <p>These results indicate that HMGA1 is an important modulator of <it>RBP4 </it>gene expression <it>in vivo</it>. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.</p

Synchronisation of apical constriction and cell cycle progression is a conserved behaviour of pseudostratified neuroepithelia informed by their tissue geometry

Neuroepithelial cells balance tissue growth requirement with the morphogenetic imperative of closing the neural tube. They apically constrict to generate mechanical forces which elevate the neural folds, but are thought to apically dilate during mitosis. However, we previously reported that mitotic neuroepithelial cells in the mouse posterior neuropore have smaller apical surfaces than non-mitotic cells. Here, we document progressive apical enrichment of non-muscle myosin-II in mitotic, but not non-mitotic, neuroepithelial cells with smaller apical areas. Live-imaging of the chick posterior neuropore confirms apical constriction synchronised with mitosis, reaching maximal constriction by anaphase, before division and re-dilation. Mitotic apical constriction amplitude is significantly greater than interphase constrictions. To investigate conservation in humans, we characterised early stages of iPSC differentiation through dual SMAD-inhibition to robustly produce pseudostratified neuroepithelia with apically enriched actomyosin. These cultured neuroepithelial cells achieve an equivalent apical area to those in mouse embryos. iPSC-derived neuroepithelial cells have large apical areas in G2 which constrict in M phase and retain this constriction in G1/S. Given that this differentiation method produces anterior neural identities, we studied the anterior neuroepithelium of the elevating mouse mid-brain neural tube. Instead of constricting, mid-brain mitotic neuroepithelial cells have larger apical areas than interphase cells. Tissue geometry differs between the apically convex early midbrain and flat posterior neuropore. Culturing human neuroepithelia on equivalently convex surfaces prevents mitotic apical constriction. Thus, neuroepithelial cells undergo high-amplitude apical constriction synchronised with cell cycle progression but the timing of their constriction if influenced by tissue geometry

Sardinia Array Demonstrator: Instrument Overview and Status

In the framework of the Square Kilometer Array (SKA) project, the Italian Institute for Astrophysics (INAF) has addressed several efforts in the design and prototyping of aperture arrays for low-frequency radio astronomical research. The Sardinia Array Demonstrator (SAD) is a national project aimed to develop know-how in this area and to test different architectural technologies and calibration algorithms. SAD consists of 128 prototypical dual-polarized Vivaldi antennas designed to operate at radio frequencies below 650 MHz. The antennas will be deployed at the Sardinia Radio Telescope’s site with a versatile approach able to provide two different array configurations: (i) all antennas grouped in one large station or (ii) spread among a core plus few satellite stations. This paper provides an overview of the SAD project from an instrumental point of view, and illustrates its status after 2 years from its start

Treatment of Community-Acquired Pneumonia in Immunocompromised Adults:A Consensus Statement Regarding Initial Strategies

Background Community-acquired pneumonia (CAP) guidelines have improved the treatment and outcomes of patients with CAP, primarily by standardization of initial empirical therapy. But current society-published guidelines exclude immunocompromised patients. Research Question There is no consensus regarding the initial treatment of immunocompromised patients with suspected CAP. Study Design and Methods This consensus document was created by a multidisciplinary panel of 45 physicians with experience in the treatment of CAP in immunocompromised patients. The Delphi survey methodology was used to reach consensus. Results The panel focused on 21 questions addressing initial management strategies. The panel achieved consensus in defining the population, site of care, likely pathogens, microbiologic workup, general principles of empirical therapy, and empirical therapy for specific pathogens. Interpretation This document offers general suggestions for the initial treatment of the immunocompromised patient who arrives at the hospital with pneumonia

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 \ub1 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys

High-resolution and color doppler sonography in the evaluation of skin metastases.

Objective. To evaluate high-resolution sonography in differentiating cutaneous metastases from other benign dermatologic diseases with the final objective of proposing high-resolution sonography in the diagnostic protocol for asymptomatic patients and those with neoplasms who have 1 or more rapidly growing skin nodules. Methods. We selected 57 patients (24 women and 33 men; mean age ± SD, 53 ± 25 years) who underwent high-resolution and color Doppler sonography because they recently noticed 1 or more superficial nodules. Patients were mostly asymptomatic, but 15 had previously diagnosed malignancies. Each nodule was classified by measurement of fundamental sonographic parameters (major diameter, shape, borders, echo texture, and homogeneity) and by assessment of vascularity (presence or absence of flow and vascular pattern) with color Doppler sonography. All nodules were ablated and histologically examined. Results. Of 68 nodules, 23 were malignant (21 metastases and 2 B-cell lymphomas), and 45 were benign (22 sebaceous cysts, 18 granulomas of different origins, 3 fibromas, and 2 neurofibromas). The nodules were all localized in the subcutaneous space, had clearly demarcated borders, and were hypoechoic; a circular or oval shape was predominant, but 7 metastases had an irregular, polycyclic shape. On color Doppler sonography, none of the benign nodules or B-cell lymphomas showed signs of vascularity, whereas the metastatic nodules were all vascularized, with 1 or more peripheral poles (21 of 21 nodules) and internal vessels (11 of 21 nodules). Conclusions. A polycyclic shape and hypervascularity, with multiple peripheral poles and, eventually, internal vessels, should be considered the most indicative signs of metastasis

Acoustic Measurements In A Small Trasmission Loss Facility

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