Management of Chronic Myeloid Leukemia in Advanced Phase

Management of chronic myeloid leukemia (CML) in advanced phases remains a challenge also in the era of tyrosine kinase inhibitors (TKIs) treatment. Cytogenetic clonal evolution and development of resistant mutations represent crucial events that limit the benefit of subsequent therapies in these patients. CML is diagnosed in accelerated (AP) or blast phase (BP) in <5% of patients, and the availability of effective treatments for chronic phase (CP) has dramatically reduced progressions on therapy. Due to smaller number of patients, few randomized studies are available in this setting and evidences are limited. Nevertheless, three main scenarios may be drawn: (a) patients diagnosed in AP are at higher risk of failure as compared to CP patients, but if they achieve optimal responses with frontline TKI treatment their outcome may be similarly favorable; (b) patients diagnosed in BP may be treated with TKI alone or with TKI together with conventional chemotherapy regimens, and subsequent transplant decisions should rely on kinetics of response and individual transplant risk; (c) patients in CP progressing under TKI treatment represent the most challenging population and they should be treated with alternative TKI according to the mutational profile, optional chemotherapy in BP patients, and transplant should be considered in suitable cases after return to second CP. Due to lack of validated and reliable markers to predict blast crisis and the still unsatisfactory results of treatments in this setting, prevention of progression by careful selection of frontline treatment in CP and early treatment intensification in non-optimal responders remains the main goal. Personalized evaluation of response kinetics could help in identifying patients at risk for progression

Improving building energy modelling by applying advanced 3D surveying techniques on agri-food facilities

Food industry is the production sector with the highest energy consumption. In Europe, the energy used to produce food accounts for 26% of total energy consumption. Over 28% is used in industrial processes. Recently, European food companies have increased their efforts to make their production processes more sustainable, also by giving preference to the use of renewable energy sources. In Italy, the total energy consumption in agriculture and food sectors decreased between 2013 and 2014, passing from 16.79 to 13.3 Mtep. Since energy consumption in food industry is nearly twice the one in agriculture (8.57 and 4.73 Mtep, respectively), it is very important to improve energy efficiency and use green technologies in all the phases of food processing and conservation. In Italy, a recent law (Legislative Decree 102, 04/07/2014) has made energy-use diagnosis compulsory for all industrial concerns, particularly for those showing high consumption levels. In the case of food industry buildings, energy is mainly used for indoor microclimate control, which is needed to ensure workers' wellbeing and the most favourable conditions for food processing and conservation. To this end, it is important to have tools and methods allowing for easy, rapid and precise energy performance assessment of agri-food buildings. The accuracy of the results obtainable from the currently available computational models depends on the grade of detail and information used in constructional and geometric modelling. Moreover, this phase is probably the most critical and time-consuming in the energy diagnosis. In this context, fine surveying and advanced 3D geometric modelling procedures can facilitate building modelling and allow technicians and professionals in the agri-food sector to use highly efficient and accurate energy analysis and evaluation models. This paper proposes a dedicated model for energy performance assessment in agri-food buildings. It also shows that using advanced surveying techniques, such as a terrestrial laser scanner and an infrared camera, it is possible to create a three-dimensional parametric model, while, thanks to the heat flow meter Accepted paper measurement method, it is also possible to obtain a thermophysical model. This model allows assessing the energy performance of agri-food buildings in order to improve the indoor microclimate control and the conditions of food processing and conservation

BCR-ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein

Patients with chronic myeloid leukemia in whom tyrosine kinase inhibitors (TKIs) fail often present mutations in the BCR-ABL catalytic domain. We noticed a lack of substitutions involving 4 amino acids (E286, M318, I360, and D381) that form hydrogen bonds with ponatinib. We therefore introduced mutations in each of these residues, either preserving or altering their physicochemical properties. We found that E286, M318, I360, and D381 are dispensable for ABL and BCR-ABL protein stability but are critical for preserving catalytic activity. Indeed, only a "conservative" I360T substitution retained kinase proficiency and transforming potential. Molecular dynamics simulations of BCR-ABLI360T revealed differences in both helix αC dynamics and protein-correlated motions, consistent with a modified ATP-binding pocket. Nevertheless, this mutant remained sensitive to ponatinib, imatinib, and dasatinib. These results suggest that changes in the 4 BCR-ABL residues described here would be selected against by a lack of kinase activity or by maintained responsiveness to TKIs. Notably, amino acids equivalent to those identified in BCR-ABL are conserved in 51% of human tyrosine kinases. Hence, these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.This work was supported by an investigator grant to P.V. from Associazione Italiana per la Ricerca sul Cancro (AIRC) and by funding from the Biotechnology and Biological Sciences Research Council (BB/I023291/1 and BB/H018409/1 to AP and FF). P.B. is the recipient of an AIRC - Marie Curie fellowship

Taxonomic remarks on Isatis tinctoria (Brassicaceae) from Pollino National Park (Basilicata, Italy)

Isatis L. (Brassicaceae) is an Eurasian genus including 79 species (1). It is one of the most difficult cruciferous genera (2). Some species, in fact, are highly polymorphic in fruit morphology, the structures that provide the most diagnostic characters (3). In addition, due to the extreme variability in all morphological characters, the limits of many species are uncertain (4). Most if not all diagnostic characters used in earlier classifications are very variable and because of the unreliability of vegetative and floral characters it is difficult or impossible to identify many specimens when mature fruits are missing (5). The patterns of variation suggest that hybridisation may be widespread (4). Moreover, intermediate specimens are rather frequent, even between some taxa that are morphologically easily recognisable (4). In Italy, according to Conti & al. (6), Isatis is represented by 3 species: I. apennina Grande (= I. allioni P.W.Ball), endemic to Italy and France (south-west Alps and central Apennine), I. praecox Kit., an European taxon restricted to Lombardia, and I. tinctoria L., an Asiatic species widespread in central and south Italy. Floristic investigations in the Pollino National Park (on the Lucanian side) led to the discovery of a little population referable to I. tinctoria. However, a comparative study of the plants showed that they differ in many relevant characters. The fact that this Lucanian population has morphological dissimilarities involves its critical revision that could bring to a new taxonomic delimitation

Bortezomib and Arsenic Trioxide Activity on a Myelodysplastic Cell Line (P39): a Gene Expression Study

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883 An anti-carcinoma monoclonal antibody (mAb) NEO-201 can also target human acute myeloid leukemia (AML) cell lines in vitro

BackgroundNEO-201 is an IgG1 mAb targeting variants of CEACAM5/6 and has demonstrated tumor sensitivity and specificity in epithelial cells. Functional analysis has revealed that NEO-201 can engage innate immune effector mechanisms including ADCC and CDC to directly kill tumor cells expressing its target. A recent Phase 1 clinical trial at the NCI has determined both safety and recommended Phase 2 dosing. We have also seen the expression of the NEO-201 target on hematologic cells, specifically Tregs and neutrophils. Due to epitope being expressed both on malignant epithelial cells as well as several hematologic cells, we designed this study to explore the reactivity of NEO-201 against hematological neoplastic cells in vitro.MethodsPhenotypic analysis was conducted by flow cytometry. Cell lines used were six AML (HL60, U937, MOLM13, AML2, IMS-M2 and OCL-AML3), two multiple myelomas (MM) (OPM2, MM1.S), two acute lymphoblastic leukemia (ALL) (SUP-B15, RPMI8402) and four mantle cell lymphoma (MCL) (Jeko-1, Z138, JVM2 and JVM13). Markers used for flow cytometry analysis were CD15, CD45, CD38, CD138, CD14, CD19 and NEO-201. Functional analysis was performed by evaluating the ability of NEO-201 to mediate ADCC activity against AML cell lines using human NK cells as effector cells.Results5 of 6 AML cell lines tested bind to NEO-201 and the% of positive cells were 47%, 99.5%,100%,100% and 97.8% for HL60, U937, MOLM13, AML3 and IMS-M2, respectively. The% of positive cells in the two MM cell line were 99% and 18% for OPM2 and MM1.S, respectively. NEO-201 binding was not detected in the two ALL and the four MCL cell lines tested. Functional analysis has demonstrated that NEO-201 can mediate ADCC activity against the AML cell line (HL60) tested.ConclusionsThis study demonstrates that NEO-201 mAb's target is expressed in most of the AML cell lines tested in vitro. In addition, we have shown it can mediate ADCC activity against HL60 cells (AML). Together, these findings provide a rationale for further investigation of the role of NEO-201 in AML as well as MM, further exploring patient PBMCs and bone marrow samples

Protective, Antioxidant and Antiproliferative Activity of Grapefruit IntegroPectin on SH-SY5Y Cells

Tested in vitro on SH-SY5Y neuroblastoma cells, grapefruit IntegroPectin is a powerful protective, antioxidant and antiproliferative agent. The strong antioxidant properties of this new citrus pectin, and its ability to preserve mitochondrial membrane potential and morphology, severely impaired in neurodegenerative disorders, make it an attractive therapeutic and preventive agent for the treatment of oxidative stress-associated brain disorders. Similarly, the ability of this pectic polymer rich in RG-I regions, as well as in naringin, linalool, linalool oxide and limonene adsorbed at the outer surface, to inhibit cell proliferation or even kill, at high doses, neoplastic cells may have opened up new therapeutic strategies in cancer research. In order to take full advantage of its vast therapeutic and preventive potential, detailed studies of the molecular mechanism involved in the antiproliferative and neuroprotective of this IntegroPectin are urgently needed