Targeting the phosphatidylinositol 3-kinase/Akt/mechanistic target of rapamycin signaling pathway in B-lineage acute lymphoblastic leukemia: An update

Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15–20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents

Effects of increased space allowance on animal welfare, meat and ham quality of heavy pigs slaughtered at 160Kg

Sixty barrows (Body Weight-BW- range: 23.9-160 kg) were allotted to two experimental groups (6 pens of 5 pigs each): the control group was kept at a space allowance of 1m2/head; the second group was kept at 1.3m2/head. Behaviour, growth parameters, carcass and meat quality were assessed, as well as fat and cured ham quality. Results showed that pigs raised at 1.3m2/head spent more time laying (particularly in lateral recumbency, P<0.01 and P<0.001, respectively) compared to pigs kept at lower space allowance. They also reduced the aimless exploration of the slatted pen floor (P<0.001) and increased overall expression of other, mainly active, behaviors (e.g., drinking, walking and standing, P<0.01). Pigs raised at 1.3m2/head showed higher final BW (P = 0.02), more favourable Average Daily Gain (ADG) and gain-to-Feed ratio (G:F) both during the last period of the trial (P<0.05 for both parameters) and over the entire trial (P = 0.01 for both parameters). No significant difference was observed between groups for carcass traits and the main meat quality attributes. Subcutaneous fat from green hams had higher \u3b1-linolenic acid content (P<0.01) in the group reared at greater space allowance. Green hams from this group lost less weight at trimming (P<0.01) and the resulting cured hams received better sensory evaluations (P<0.05). No difference was observed in fatty acid composition and unsaturation levels of the subcutaneous fat from cured hams. Our data suggest that heavy pigs intended for Parma ham would benefit from the adoption of higher individual floor space allowances, both in terms of animal welfare (increased possibility to rest) and of productive parameters, without having any detrimental effect on the suitability of the thighs for dry-curing or on the quality of the final product

Literature Review on the Pre-Slaughter Welfare of Italian Heavy Pigs

This work provides a narrative review of the available information on the welfare of Italian heavy pigs in the pre-slaughter phase (transport, lairage, and stunning). The meat from these pigs is used for specific PDO (Protected Designation of Origin) products, and the production rules for these specialties require higher body weight (160–170 kg) and age (in general more than 9 months) at slaughter than in most other countries. This may lead to specific behavioral and physiological needs of pigs. The present paper summarizes the main research findings and knowledge gaps for each of the pre-slaughter phases. Studies are presented according to the four principles of the Welfare Quality assessment protocol (good feeding, good housing, good health, and appropriate behavior). The results of the literature review indicate a lack of knowledge on several aspects. Most of studies were carried out in a single slaughterhouse, making it difficult to identify risk factors and confounding effects. Moreover, animal-based measures were assessed using different protocols, reducing the possibility of comparison across studies. These findings may serve as a basis for the development of specific research studies and policies aimed at enhancing the animal welfare level and the ethical attributes of this renowned production, also in accordance with consumers’ expectations

Redistribution of DNA topoisomerase II beta after in vitro stabilization of human erythroleukemic nuclei by heat or Cu++ revealed by confocal microscopy.

Using confocal laser scanning microscope and a monoclonal antibody we have examined by means of indirect immunofluorescence techniques the distribution of DNA topoisomerase II beta (the 180-kDa nucleolar isoform of topoisomerase II) following stabilization of isolated nuclei by exposure to moderate heat (37 degrees or 42 degrees C) or Cu++. In intact cells the antibody specifically decorated the nucleoli. The same pattern was maintained if nuclei were incubated at 0 degree C in a buffer containing spermine/spermidine/KCl or stabilized by means of 0.5 mM Cu++ for 10 minutes at 0 degree C in the same buffer. On the contrary, if stabilization was performed by incubating the nuclei either at 37 degrees or 42 degrees C, the immunoreactivity dispersed all over the nucleus, forming numerous speckles. This phenomenon was not detected if, in addition to spermine/spermidine/KCl, the incubation buffer also contained 5 mM Mg++ and the temperature was 37 degrees C. If the stabilization was performed at 42 degrees C, Mg++ failed to maintain the original distribution of DNA topoisomerase II beta, as seen in intact cells. The analysis on 2-D optical section showed the alteration of the nucleolar profile, particularly at 37 degrees C, even when the samples were treated with Mg++. The 3-D reconstruction figured out the irregularity of the surface at 37 degrees C and the variations of the volume occupied by the fluorescent figures. These were in close proximity to each other both in intact cells and in 0 degree C incubated nuclei; they showed a certain degree of shrinkage in 0 degree C plus Cu++ exposed samples (-20\% of the volume), and, on the contrary, the labeled structures were scattered in a volume increased two- or threefold when exposed to 37 degrees or 42 degrees C, respectively. The addition of Mg++ restored the original spatial relationship and volume at 37 degrees C, but not at 42 degrees C, where the volumetric analysis showed an increase of about 50\%. Our results demonstrate that heat stabilization of isolated nuclei in a buffer without Mg++ (i.e., a technique often employed to prepare the nuclear matrix or scaffold) cannot be considered an optimal procedure to maintain the original distribution of protein within the nucleus

Dynamic Simulation of Outdoor Swimming Pool Solar Heating

Abstract This paper presents a dynamic model of a "passive" solar heating system composed by horizontal solar flat collectors coupled to an outdoor swimming pool. The numerical model has been developed by using the Matlab/Simulink environment and it allows to predict on a hourly basis the thermal energy collected by the solar panels, the inlet/outlet collector working fluid temperature, the pool water temperature and the system efficiency. As a case study, three different pools characterized by different dimensions and three different flat solar collectors (unglazed, glazed and evacuated collectors) have been considered. The Simulink model allows to estimate the warm-up period of the swimming pool as a function of the characteristics of the pool and of the solar collectors. It has been demonstrated that, by using the model, the designer can make the optimal sizing of the solar heating system in order to obtain a water pool temperature ranging within a fixed interval. The results demonstrate that unglazed collectors are appropriate for this kind of use and evacuated collectors can be useful just in case of very big swimming pools in order to reduce the absorbing area of the solar panels

Rapid prototyping for enhanced dynamic positioning systems

The paper aims to show the design procedure for a Class-2 dynamic positioning system, from initial conceptualisation to factory assessment test. The approach involves the use of simulation-based design combined with hardware in the loop testing. This kind of approach involves a detailed knowledge of the investigated ship but gives significant well-known advantages. The main are: the reduction of the design duration, the optimisation of the system performance, the debug of the control logics before the installation onboard, the reduction of the sea trial costs. Finally, the result of this process is a product ready to be installed onboard. Moreover, over the years, the interest of the classification societies in simulation results for certifying such systems is increased. This study shows both the approach and the results of designing a dynamic positioning system for a Platform Supply Vessel. A custom simulation platform has been developed to have realistic feedbacks of the case-study ship. The DP controller structure, including regulator, force and thrust allocation; have been conceptualised, and then, after the porting procedure, the DP software has been downloaded in the real PCL. Several HIL tests have been carried out to fine-tune the controller parameters. The results show, under different environmental conditions, the respect of the design criteria

Geology of the ‘Coltre della Val Marecchia’ (Romagna-Marche Northern Apennines, Italy)

A detailed geological map at 1:50,000 scale of the Marecchia Valley and adjoining areas (Northern Apennines, NA, Italy) is presented here. The Marecchia Valley represents a geological ‘unicum’ for the NA and it has been the focus of scientific debate for a long time, due to the occurrence in the area of the ‘Coltre della Val Marecchia (CVM)’, a complex stack of allochthonous and semi-allochthonous units emplaced in a foredeep basin during the Late Miocene to Early Pliocene. In order to clarify the geological evolution for this area, the lithostratigraphic relationships and the tectonic framework have been studied, allowing better understanding of the complex relationships between tectonics and sedimentation. The main result has been a new evolutionary framework for this sector of the orogen during the Late Miocene-Early Pliocene. Several new findings about the geological-structural setting and stratigraphy, result from the geological map presented here. These are overall supported by stratigraphic and tectonic evidence, which suggest time and modes of the CVM allochthonous emplacement within the Messinian-early Pliocene foredeep successions. Relationships between the allochthonous and autochthonous formations allowed recognition of two different bodies in the CVM, gravitationally emplaced following different trajectories and timing

Nuclear Diacylglycerol Produced by Phosphoinositide-specific Phospholipase C Is Responsible for Nuclear Translocation of Protein Kinase C-α

It is well established that an independent inositide cycle is present within the nucleus, where it is involved in the control of cell proliferation and differentiation. Previous results have shown that when Swiss 3T3 cells are treated with insulin-like growth factor-I (IGF-I) a rapid and sustained increase in mass of diacylglycerol (DAG) occurs within the nuclei, accompanied by a decrease in the levels of both phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate. However, it is unclear whether or not other lipids could contribute to this prolonged rise in DAG levels. We now report that the IGF-I-dependent increase in nuclear DAG production can be inhibited by the specific phosphatidylinositol phospholipase C inhibitor 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine or by neomycin sulfate but not by the purported phosphatidylcholine-phospholipase C specific inhibitor D609 or by inhibitors of phospholipase D-mediated DAG generation. Treatment of cells with 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine or neomycin sulfate inhibited translocation of protein kinase C-alpha to the nucleus. Moreover, exposure of cells to 1-O-octadeyl-2-O-methyl-sn-glycero-3-phosphocholine, but not to D609, dramatically reduced the number of cells entering S-phase upon stimulation with IGF-I. These results suggest that the only phospholipase responsible for generation of nuclear DAG after IGF-I stimulation of 3T3 cells is PI-PLC. When this activity is inhibited, neither DAG rise is seen nor PKC-alpha translocation to the nucleus occurs. Furthermore, this PI-PLC activity appears to be essential for the G0/G1 to S-phase transition

The effects of clinoptilolite on piglet and heavy pig production

To evaluate the effects of clinoptilolite on piglet and heavy pig production two separated trials have been performed. In the first trial 40 pigs of the initial body weight of 55 kg were used. Animals were homogeneously allocated to two groups: a control group traditionally fed and a clinoptilolite group in which feed contained the additive at 2%. Pigs were slaugh- tered at about 160 kg body weight. Blood samples were taken to determine blood urea nitrogen (BUN). In the second trial a total of 116 piglets from 12 litters was used. Six litters were fed from the 7th day of life a diet containing clinoptilolite at 2%. According to the dietary treatment of the suckling period, 84 weaned piglets were homogeneously allocated to two groups fed up to 33 kg body weight a diet containing or not clinoptilolite at 2%. In both trials daily weight gain, feed intake and pigs' health were regularly recorded. The dietary inclusion of clinoptilolite at 2% did not resulted in any modification either of growing performances or of uraemia. Piglets on clinoptilolite diet showed a significant (P<0.05) improvement of faecal dry matter content. At slaughtering the dietary inclusion of clinoptilolite resulted in a trend towards an improvement of lean cuts yield and in a significant increase (P<0.05) of the ratio between lean and fat cuts. From our data it is sug- gested that clinoptilolite does not impair pig growing performances, determines a higher dry matter content of piglet fae- ces and improves carcass quality of heavy pigs with particular regard to lean cuts yield and lean to fat cuts ratio