"Rescue surgery" nel colangiocarcinoma in stadio avanzato : razionale e risultati di un atteggiamento terapeutico aggressivo

Le neoplasie delle vie biliari costituiscono circa il 2% di tutte le neoplasie maligne. La confluenza biliare (colangiocarcinoma ilare) è la sede più frequente di insorgenza, comprendendo il 60% dei casi. Nel periodo gennaio 1997-novembre 2008 presso l’Istituto di Clinica Chirugica e Trapianti d’Organo dell’Università di Parma sono stati sottoposti a resezione epatica o epato-biliare (HB) 80 pazienti affetti da colangiocarcinoma (CC) su un totale di 575 (80/575: 14%) interventi di chirurgia HB per patologia neoplastica. 47, pari all’8.2% (47/575) erano affetti da colangiocarcinoma intraepatico (IHCC), mentre 33, il 5.8% (33/575) da tumore di Klatskin (TK). I TK e gli IHCC, non sono stati differenziati in quanto tali, ma sulla base dell’infiltrazione delle strutturre vasculo-biliari viciniori, unico discrimine per l’assegnazione di ogni singolo paziente all’uno o all’altro dei due gruppi in esame (pz. affetti da neoplasia epatobiliare localmente avanzata/ pz. affetti da neoplasia epatobiliare confinata). L’obiettivo del nostro studio è stato quello di confrontare i due gruppi di pazienti (16 con malattia localmente avanzata e 64 con neoplasia epato-biliare confinata) in termini di morbilità/mortalità perioperatoria, intervallo libero da malattia (FDI), sopravvivenza a distanza dopo resezione, con intento curativo (R0). Dal nostro studio, emergono i seguenti elementi a sostegno di una chirurgia aggressiva (rescue surgery), appunto “di salvataggio”, nei confronti dei colangiocarcinomi in fase localmente avanzata: l’incidenza globale di complicanze non aumenta (p = 0.0725), estendendo la resezione, ben oltre le strutture epatobiliari, agli organi circostanti; il tasso di recidiva è significativamente maggiore nelle resezioni epatobiliari isolate (p = 0.0001); l’intervallo libero da malattia non appare influenzato negativamente dall’estensione extraepatica della neoplasia, se trattata adeguatamente con chirurgia radicale (p = 0,2758); unico elemento prognosticamente rilevante sulla sopravvivenza a distanza risulta essere la metastatizzazione dei linfonodi di I e II livello (p = 0.0012), ma l’infiltrazione di visceri e strutture vascolo-biliari viciniori non è associata ad un coinvolgimento linfodale significativamente superiore (p = 0.237); nei colangiocarcinomi localmente avanzati trattati con “rescue surgery”, la sopravvivenza, rispettivamente a 1, 3 e 5 anni, risulta essere: 84.6%, 37.5% e 25%. L’estensione dell’intervento resettivo agli organi viciniori non condiziona quindi una riduzione della sopravvivenza globale statisticamente significativa (p = 0.8777). Una chirurgia “di salvataggio” in cui si associno resezioni epatobiliari maggiori estese ad organi e strutture circostanti, con linfoadenectomie radicali portate anche oltre il II livello costituisce oggigiorno una reale possibilità di cura e si avvia a costituire il futuro gold standard nel trattamento dei colangiocarcinomi localmente avanzati

The true story of Yeti, the "abominable" heterochromatic gene of drosophila melanogaster

The Drosophila Yeti gene (CG40218) was originally identified by recessive lethal mutation and subsequently mapped to the deep pericentromeric heterochromatin of chromosome 2. Functional studies have shown that Yeti encodes a 241 amino acid protein called YETI belonging to the evolutionarily conserved family of Bucentaur (BCNT) proteins and exhibiting a widespread distribution in animals and plants. Later studies have demonstrated that YETI protein: (i) is able to bind both subunits of the microtubule-based motor kinesin-I; (ii) is required for proper chromosome organization in both mitosis and meiosis divisions; and more recently (iii) is a new subunit of dTip60 chromatin remodeling complex. To date, other functions of YETI counterparts in chicken (CENtromere Protein 29, CENP-29), mouse (Cranio Protein 27, CP27), zebrafish and human (CranioFacial Development Protein 1, CFDP1) have been reported in literature, but the fully understanding of the multifaceted molecular function of this protein family remains still unclear. In this review we comprehensively highlight recent work and provide a more extensive hypothesis suggesting a broader range of YETI protein functions in different cellular processes

Flow hydraulic characteristics determining the occurrence of either smooth or abrupt sewer pressurization

Laboratory experiments showed that pipe pressurization consequent on a drastic reduction in the downstream discharge can occur either by a gradual rising of the free-surface (“smooth” pressurization) or by propagation of a front filling the whole cross-section (“abrupt” pressurization). This study examines the free-surface flow characteristics that determine smooth or abrupt pressurization pattern through a theoretical approach using dimensionless variables. A critical flow rate value, which separates the pressurization patterns, exists for any given pipe diameter. For flow rates higher than this specific value, only abrupt pressurization occurs. For lower flow rates, either smooth or abrupt pressurization can take place; smooth pressurization occurs when the free-surface flow depth falls within a specified range, depending on the flow rate itself and the pipe diameter, whereas abrupt pressurization occurs when the depth falls outside this range. The comparison with actual uniform-flow conditions allows one to predict the pressurization pattern and the related pipe surcharge (in the case of abrupt pressurization). The analysis also shows that, in practice, severe surcharges can be expected even in the case of only partial reduction of the downstream discharge

Analysis of tide measurements in a Sicilian harbour

Designing of ports and coastal protection works as well as planning of coastal human activities require knowledge of tidal oscillations. The latter vary noticeably from site to site and present an “astronomic” component, which is roughly periodic, and a “meteorological” component which is usually considered as random. In this paper, the tidal oscillations observed in a Sicilian harbour in the period 1999-2009 are analysed statistically, in order to recognize a probability distribution which allows one to predict the highest tidal levels. First, the measurements are used to obtain, for each year, the astronomic tide by the harmonic analysis by the software package T_TIDE. The difference between the observed tide and the astronomic tide, indicated as “noise”, is imputed to meteorological factors and treated by a statistical approach. The noise imputable to sea storms moving onshore is divided from that imputable to storms moving offshore. Several probability distributions are then considered for each noise and it is established that each noise closely follows the Weibull extreme value distribution better than other distributions

Storm sewer pressurization transient – an experimental investigation

Pipe pressurization is examined experimentally by 144 laboratory experiments in a circular tilting pipe between two tanks, in which the transient was triggered by sudden closing of the downstream tank outlet. The experiments cover ranges of values of slope, velocity and filling ratio of the open-channel flow not explored in previous studies. Situations involving considerable air quantity and consequent intense pressure oscillations were also reproduced. Two different pressurization patterns, defined as “smooth” and “abrupt”, were observed, but only the abrupt pattern produced intense pressure oscillations. The comparison among all the abrupt pressurization surges showed how the oscillations changed in starting time, intensity and duration as the pipe slope, the flow rate and the free-surface flow filling ratio varied. The experimental results also stressed the major role of entrapped air in determining the oscillation characteristics, showing that oscillations were actually produced by the pulsating of large air pockets during their migration along the pipe and their release through the upstream manhole

Experimental investigation on a geocontainer Submerged reef

Geotextile sand containers (GSC) have been used as permanent construction elements in coastal works for more than 20 years,becoming more and more popular as an alternative to the most typical coastal structures. Aim of this work is to analyze the hydrodynamic, stability and morphodynamic response of a GSC submerged reef by means of an experimental campaign. The first investigated aspect concerned the hydrodynamics. The reflection and transmission coefficients for regular and random waves were determined: the reflection coefficient decreases with increasing of kh; the transmission coefficient decreases with the increase of the incident wave. As regards the stability of the structure, it was observed that the strongest waves were able to lift the row of GSC more exposed to the wave action. An instability curve for the GSC as a function of the hydrodynamic characteristics was then found. Flow visualization close to the reef was performed by means of ink, showing that the flow becomes asymmetric in the proximity of the structure. Concerning the morphodynamics, long-term tests were performed to calculate the scour. This reached its maximum value at the end of each test and it is present in all three cases. The scour causes serious problems of instability to the structure

Particle tracking in a gap of aquatic vegetation meadow

Aquatic vegetation considerably affects the flow field in water bodies, with influence increasing as the depth decreases. As a consequence, vegetation also affects suspended particle transport. In inshore sandy beds less than 40 m deep of the Mediterranean Sea, meadows of Posidonia oceanica are widespread. This plant is constituted by a tuft of very thin and flexible ribbon-like leaves about 1 cm wide and up to 1.5 m long; the meadow areal density can reach 1000-1200 plant/m2. Frequently, such meadows are not continuous but vegetated areas alternate with sand strips (“gaps”). The presence of such discontinuities noticeably affects the flow field and gaps can actually act as particle traps. Some laboratory experiments were performed aiming at studying the flow field in a gap of artificial Posidonia oceanica canopy. In this paper, the measured flow field is used to track single particles within the gap. A simple particle tracking model which assumes no-slip condition and random velocity fluctuations is adopted. A large number of single-particle tracking were performed considering several release elevations of particles as well as several falling velocities of the latters. The examination of the whole tracks allows one to recognize the particle fate as the simulation parameters vary. In spite of the model assumptions, the study gives useful indications on the behavior of a gap towards the suspended particle transport

Random wave run-up with a physically-based Lagrangian shoreline model

n the present paper the run-up of random waves was calculated by means of a numerical method. In situ measurements based on a video imaging technique have been used for the validation of the present numerical model. The on-site run-up measurements have been carried out at Lido Signorino beach, near Marsala, Italy,along a transect, normal to the shore. A video camera and a linear array of rods have been used to obtain field data. Numerical simulations with a 1DH Boussinesq-type of model for breaking waves which takes into account the wave run-up by means of a Lagrangian shoreline model have been carried out. In such simulations random waves of given spectrum have been propagated in a numerical flume having the same beach slope of the measured transect. The comparison between registered and estimated run-up underlined an acceptable agreement. Indeed, the numerical model tends to underestimate the actual R2%, with the maximum underestimate being less than 24%, which is a reasonable error in many cases of engineering interest

Knockdown of DOM/Tip60 complex subunits impairs male meiosis of Drosophila melanogaster

ATP-dependent chromatin remodeling complexes are involved in nucleosome sliding and eviction and/or the incorporation of histone variants into chromatin to facilitate several cellular and biological processes, including DNA transcription, replication and repair. The DOM/TIP60 chromatin remodeling complex of Drosophila melanogaster contains 18 subunits, including the DOMINO (DOM), an ATPase that catalyzes the exchange of the canonical H2A with its variant (H2A.V), and TIP60, a lysine-acetyltransferase that acetylates H4, H2A and H2A.V histones. In recent decades, experimental evidence has shown that ATP-dependent chromatin remodeling factors, in addition to their role in chromatin organization, have a functional relevance in cell division. In particular, emerging studies suggested the direct roles of ATP-dependent chromatin remodeling complex subunits in controlling mitosis and cytokinesis in both humans and D. melanogaster. However, little is known about their possible involvement during meiosis. The results of this work show that the knockdown of 12 of DOM/TIP60 complex subunits generates cell division defects that, in turn, cause total/partial sterility in Drosophila males, providing new insights into the functions of chromatin remodelers in cell division control during gametogenesis

Targeted protein degradation tools: overview and future perspectives

Targeted protein inactivation (TPI) is an elegant approach to investigate protein function and its role in the cellular landscape, overcoming limitations of genetic perturbation strategies. These systems act in a reversible manner and reduce off-target effects exceeding the limitations of CRISPR/Cas9 and RNA interference, respectively. Several TPI have been developed and wisely improved, including compartment delocalization tools and protein degradation systems. However, unlike chemical tools such as PROTACs (PROteolysis TArgeting Chimeras), which work in a wild-type genomic background, TPI technologies require adding an aminoacidic signal sequence (tag) to the protein of interest (POI). On the other hand, the design and optimization of PROTACs are very laborious and time-consuming. In this review, we focus on anchor-away, deGradFP, auxin-inducible degron (AID) and dTAG technologies and discuss their recent applications and advances. Finally, we propose nano-grad, a novel nanobody-based protein degradation tool, which specifically proteolyzes endogenous tag-free target protein