ANKRd44 gene silencing: A putative role in trastuzumab resistance in HER2-like breast cancer

Trastuzumab is an effective therapeutic treatment for Her2-like breast cancer; despite this most of these tumors develop resistance to therapy due to specific gene mutations or alterations in gene expression. Understanding the mechanisms of resistance to Trastuzumab could be a useful tool in order to identify combinations of drugs that elude resistance and allow a better response for the treated patients. Twelve primary biopsies of Her2+/hormone receptor negative (ER-/PgR-) breast cancer patients were selected based on the specific response to neoadjuvant therapy with Trastuzumab and their whole exome was sequenced leading to the identification of 18 informative gene mutations that discriminate patients selectively based on response to treatment. Among these genes, we focused on the study of the ANKRD44 gene to understand its role in the mechanism of resistance to Trastuzumab. The ANKRD44 gene was silenced in Her2-like breast cancer cell line (BT474), obtaining a partially Trastuzumab-resistant breast cancer cell line that constitutively activates the NF-kb protein via the TAK1/AKT pathway. Following this activation an increase in the level of glycolysis in resistant cells is promoted, also confirmed by the up-regulation of the LDHB protein and by an increased TROP2 protein expression, found generally associated with aggressive tumors. These results allow us to consider the ANKRD44 gene as a potential gene involved in Trastuzumab resistance

Prevalence of metabolic syndrome: a comparative analysis in an unselected sample of mediterranean subjects.

Abstract AIM: The metabolic syndrome (MS) is associated with increased cardiovascular and cerebrovascular risk. This study aimed to compare the difference of the three established diagnostic criteria of MS, developed by Adult Treatment Panel III (ATP III), American Heart Association (AHA) and National Heart Lung and Blood Institute (NHLBI), and International Diabetes Federation (IDF), with regard to the prevalence of the syndrome and the ability to correctly identify individuals with cardiovascular or cerebrovascular disease or subclinical atherosclerosis. METHODS: We studied 947 consecutive patients underwent clinical evaluation between the 1997-2002. The project design included a medical assessment, biochemical analyses and the ecocolordoppler examination of carotid arteries. RESULTS: The MS prevalence was 37% in ATPIII subjects, 36% in AHA/NHLBI subjects and 43% in IDF subjects. Excluding patients with diabetes (N.=259), the MS prevalence ranged from 32% (ATPIII and AHA/NHLBI subjects) and 40% (IDF subjects). By most criteria, MS-positive subjects had significant incidence of carotid atherosclerosis (P<0.05) and cardiovascular events (P<0.05) than MS-negative subjects, but not cerebrovascular events. Finally, patients with MS had higher serum levels of fibrinogen (P<0.04). CONCLUSION: Subclinical atherosclerosis and cardiovascular events were increased in presence of the MS, irrespective of the several definitions

Super-heavy fermion material as metallic refrigerant for adiabatic demagnetization cooling

Low-temperature refrigeration is of crucial importance in fundamental research of condensed matter physics, as the investigations of fascinating quantum phenomena, such as superconductivity, superfluidity and quantum criticality, often require refrigeration down to very low temperatures. Currently, cryogenic refrigerators with $^3$He gas are widely used for cooling below 1 Kelvin. However, usage of the gas is being increasingly difficult due to the current world-wide shortage. Therefore, it is important to consider alternative methods of refrigeration. Here, we show that a new type of refrigerant, super-heavy electron metal, YbCo$_2$Zn$_{20}$, can be used for adiabatic demagnetization refrigeration, which does not require 3He gas. A number of advantages includes much better metallic thermal conductivity compared to the conventional insulating refrigerants. We also demonstrate that the cooling performance is optimized in Yb$_{1-x}$Sc$_x$Co$_2$Zn$_{20}$ by partial Sc substitution with $x\sim$0.19. The substitution induces chemical pressure which drives the materials close to a zero-field quantum critical point. This leads to an additional enhancement of the magnetocaloric effect in low fields and low temperatures enabling final temperatures well below 100 mK. Such performance has up to now been restricted to insulators. Since nearly a century the same principle of using local magnetic moments has been applied for adiabatic demagnetization cooling. This study opens new possibilities of using itinerant magnetic moments for the cryogen-free refrigeration

Uncoupled activation and cyclization in catmint reductive terpenoid biosynthesis

Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyzes the activation of its substrate 8-oxogeranial into a reactive enol intermediate, but does not catalyze the subsequent cyclization into nepetalactol. This discovery led us to identify a class of nepetalactol-related short-chain dehydrogenase enzymes (NEPS) from catmint (Nepeta mussinii) that capture this reactive intermediate and catalyze the stereoselective cyclisation into distinct nepetalactol stereoisomers. Subsequent oxidation of nepetalactols by NEPS1 provides nepetalactones, metabolites that are well known for both insect-repellent activity and euphoric effect in cats. Structural characterization of the NEPS3 cyclase reveals that it binds to NAD+ yet does not utilize it chemically for a non-oxidoreductive formal [4 + 2] cyclization. These discoveries will complement metabolic reconstructions of iridoid and monoterpene indole alkaloid biosynthesis

Insegne e legittimazione nell’impero romano

Le insegne imperiali costituiscono un tema insidioso: studiarle obbliga a interrogarsi sui fondamenti ideologici del potere che queste sono chiamati a rappresentare, fondamenti che, nella Roma dei Cesari, sono notoriamente difficili da definire in modo lineare. Una difficoltà ulteriore è costituita dalla natura della documentazione: a fronte di un numero limitato di fonti testuali, l’abbondante dossier iconografico – essenzialmente numismatico- può esser usato solo con estrema cautela, poiché offre per lo più rappresentazioni idealizzate o simboliche. Il presente contributo si concentra sul rapporto tra insegne - intese nella loro realtà di oggetti - e la legittimazione del sovrano. Tale rapporto è indagabile soprattutto in particolari momenti della vita pubblica: accessione e funerali dei principi, trasmissione del potere da un principe all’altro. Da un riesame delle testimonianze per il periodo compreso tra II e IV secolo, emerge che le insegne costituivano un elemento sostanzialmente accessorio in tali circostanze. In mancanza di rituali codificati, il significato attribuito a questi oggetti appare in effetti alquanto debole ed elastico; l’uso delle insegne, e persino l’eventuale loro trasmissione da un imperatore all’altro, sembra sempre un fatto scarsamente ideologizzato. Nonostante il processo di sacralizzazione di almeno alcune di queste insegne (soprattutto il mantello di porpora) ), esse non giunsero mai a significare per i Romani ciò che furono in altri regimi monarchici. Ciò appare coerente con il persistere di una concezione secondo la quale cui il principe non è che un mandatario di un potere altrui (quello del popolo romano), e con un sistema che non ha mai veramente accettato le idee di legittimazione divina, o di diritti di sangue

Panegirici e altri 'elogi' nelle città tardoantiche

Tra le pratiche celebrative che caratterizzano la tarda antichità, ben documentata è una particolare forma di celebrazione di imperatori e funzionari: quella costituita dalle iscrizioni che corredano i monumenti onorari eretti per omaggiarli. In che misura e attraverso quali canali il linguaggio dell’epigrafia onoraria interagisce con quello di altre forme di celebrazione, in particolare con i panegirici? E soprattutto, in che modo lo studio di queste testimonianze ‘minori’ può esser utile a chiarire la genesi e il ruolo del discorso di elogio ? Per cercare di rispondere a queste domande sono prese in esame due epigrafi dell’epoca di Giuliano (una fase che appare caratterizzata, soprattutto per l’entusiasmo suscitato in taluni ambienti dall’avvento del nuovo principe, da un’epigrafia particolarmente originale). La prima, da Ancyra, è conosciuta da tempo ma scarsamente studiata (CIL III 247=ILS 754), la seconda, da Samo, è stata invece pubblicata di recente (IG XII 6, 1, 427). In entrambi i testi si possono rilevare delle rielaborazioni originali di temi, riguardanti la figura del principe e la glorificazione del suo operato, che erano stati senza dubbio sviluppati o trattati in un contesto più ‘alto’. Ciò induce a interrogarsi sui canali attraverso i quali tali temi circolavano, su quale eco potesse avere, a sua volta, la loro trasposizione epigrafica, sull’applicabilità del concetto di propaganda alle forme della celebrazione nel mondo tardoantico

Memmius Vitrasius Orfitus: signo Honorius?

A supposed signum Honorius is traditionally attributed to some late roman aristocrats. In this paper the auhor argues that this assumption is not correct. The genitive Honori which can be read at the beginning of a certain number of inscriptions is not an onomastic element but a formula used to celebrate the honoran