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Uma das complicações mais impactantes do diabetes mellitus (DM) é o pé diabético, que ocorre tanto em pacientes diabetes mellitus tipo 1 (DM1) quanto em diabetes mellitus tipo 2 (DM2). Este é um processo crônico relacionado a diversos fatores que acarretam o surgimento de úlcera nos pés. Ademais, infecções no pé diabético são de difícil controle, tornando a amputação uma possibilidade real, devendo esta, portanto, ser discutida antecipadamente com o paciente. Nesse contexto, o presente artigo, tem como questão norteadora: quais as principais complicações relacionadas a recidiva de amputações não traumáticas em pacientes com presença do pé diabético? Portanto, o objetivo deste trabalho foi descrever e evidenciar as principais complicações, recidiva e necessidade de reabordagem cirúrgica em pacientes diabetes mellitus (DM) com presença do pé diabético. Como metodologia, realizou-se uma revisão bibliográfica do tipo integrativa com abordagem qualitativa de caráter retrospectivo. Como resultados, os estudos originais demonstraram o grau de repercussão das amputações e a dependência individual elevada daqueles que são submetidos ao procedimento de amputação. Além disso, alguns outros estudos puderam propor medidas assistenciais para a redução de desfechos indesejados. Ademais, de acordo com os estudos e com a literatura vigente, é possível reafirmar o quão oneroso é para o Sistema de saúde as complicações do diabetes, uma vez que os custos com internações, tratamento, manejo e a prevenção do pé diabético são altos. Por fim, concluiu-se que muitas das complicações pós-cirúrgicas estão relacionadas ao nível de dependência do membro amputado, destacando a importância da prevenção desta complicação, além de infecção pós-operatória, necrose e trombose venosa profunda.

Sara De Santis,1 Cecilia Monaldi,1 Manuela Mancini,2 Samantha Bruno,1 Michele Cavo,1,2 Simona Soverini1 1Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, UO Ematologia ‘Lorenzo e Ariosto Seràgnoli’, Università di Bologna, Bologna, Italy; 2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, ItalyCorrespondence: Sara De SantisInsitute of Hematology “Lorenzo e Ariosto Seràgnoli”, Via Massarenti 9, Bologna, 40138, ItalyTel +39 051 2143791Fax +39 051 2144037Email sara.desantis9@unibo.itAbstract: Protein kinases (PKs) play crucial roles in cellular proliferation and survival, hence their deregulation is a common event in the pathogenesis of solid and hematologic malignancies. Targeting PKs has been a promising strategy in cancer treatment, and there are now a variety of approved anticancer drugs targeting PKs. However, the phenomenon of resistance remains an obstacle to be addressed and overcoming resistance is a goal to be achieved. Chronic myeloid leukemia (CML) is the first as well as one of the best examples of a cancer that can be targeted by molecular therapy; hence, it can be used as a model disease for other cancers. This review aims to summarize up-to-date knowledge on the main mechanisms implicated in resistance to PK inhibitory therapies and to outline the main strategies that are being explored to overcome resistance. The importance of molecular diagnostics and disease monitoring in counteracting resistance will also be discussed.Keywords: protein kinases, chronic myeloid leukemia, tyrosine kinase inhibitors, synthetic lethality

The European chestnut characterizes both the landscape and economy of mountainous Italian areas. In recent years, new canopy disorders have been reported: “chestnut yellows”, often ascribed to phytoplasma and/or nutrient deficiency, and “chestnut mosaic”, associated with a virus (ChMV). Therefore, research was carried out in four Italian regions to describe the two symptomatic frames and assess their etiology. Surveys were conducted on 101 chestnut trees (23 with mosaic, 38 with yellowing, and 40 without symptoms). The phytosanitary status was monitored, and the new canopy disorders were detected, distinguishing between yellowing and mosaic. Moreover, leaf samples were collected for molecular and nutrient analyses. No phytoplasma infection was recorded, while ChMV was detected in 91.3% of samples with mosaic symptoms, 31.6% of yellowing samples, and 30.0% of asymptomatic samples. Yellowing was associated with Mn deficiency. On the other hand, ChMV-infected and healthy leaves had similar mineral contents, showing that mosaic symptoms are induced by the virus. Both disorders negatively affected photosynthesis efficiency. These phytosanitary problems are present in Italian chestnut woods and cause local effects, and a relationship with other biotic and abiotic factors can be hypothesized. Considering the increase in new records, these symptoms represent an emerging issue whose impact and spread need to be further monitored.

One of the indications for BCR::ABL1 mutation testing in chronic myeloid leukemia (CML) is when tyrosine kinase inhibitor therapy (TKI) needs to be changed for unsatisfactory response. In this study, we evaluated a droplet digital PCR (ddPCR)-based multiplex strategy for the detection and quantitation of transcripts harbouring mutations conferring resistance to second-generation TKIs (2GTKIs). Parallel quantitation of e13a2, e14a2 and e1a2 BCR::ABL1 fusion transcripts enables to express results as percentage of mutation positive- over total BCR::ABL1 transcripts. We determined the limit of blank in 60 mutation-negative samples. Accuracy was demonstrated by further analysis of 48 samples already studied by next generation sequencing (NGS). Mutations could be called down to 0.5% and across 3-logs of BCR::ABL1 levels. Retrospective review of BCR::ABL1 NGS results in 513 consecutive CML patients with non-optimal response to first- or second-line TKI therapy suggested that a ddPCR-based approach targeted against 2GTKI-resistant mutations would score samples as mutation-negative in 22% of patients with warning response to imatinib but only in 6% of patients with warning response to 2GTKIs. We conclude ddPCR represents an attractive method for easy, accurate and rapid screening for 2GTKI-resistant mutations impacting on TKI selection, although ddPCR cannot identify compound mutations.

Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated. Evidence from the literature suggests that AKA may confer cancer cell chemo-resistance, inhibit p53, and enhance Polo-like kinase 1 (Plk1), CDK1, and cyclin B1 to promote cell cycle progression. In this study, we aimed to investigate the pathogenetic role of AKA and Plk1 in the advanced forms of SM. We demonstrate here, for the first time, that SM cell lines display hyper-phosphorylated AKA and Plk1. Danusertib (Aurora kinase inhibitor) and volasertib (Plk1 inhibitor) inhibited growth and induced apoptotic cell death in HMC-1.1 and -1.2 cells. Their growth-inhibitory effects were associated with cell cycle arrest and the activation of apoptosis. Cell cycle arrest was associated with increased levels of phospho-Wee1. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM.

BackgroundIn chronic myeloid leukemia (CML), Aurora kinase A and Polo like kinase 1 (Plk1), two serine-threonine kinases involved in the maintenance of a functional G2/M checkpoint, may cooperate with the constitutive tyrosine-kinase (TK) activity of the BCR-ABL1 fusion protein increasing DNA damage, promoting the occurrence of additional genomic alterations ultimately driving resistance to TK inhibitors (TKIs) and progression from chronic phase to blast crisis (BC). MethodsIn this study, we propose a new therapeutic strategy based on the combination of Aurora kinase A or Plk1 inhibition with danusertib or volasertib, respectively, and WEE1 inhibition with AZD1775. Apoptotic cell death was quantified by annexin V/propidium iodide staining and flow cytometry. Cell cycle distribution was assessed by PI staining and flow cytometry. Protein expression and activation was assessed by Western Blotting (WB) and Immunofluorescence. Clonogenic assays were performed to evaluate cells sensitivity to the different drugs.ResultsDanusertib and volasertib used as single drugs induced apoptosis and G2/M-phase arrest, associated with accumulation of phospho-WEE1. Subsequent addition of the WEE1 inhibitor AZD1775 in combination significantly enhanced the induction of apoptotic cell death in TKI-sensitive and -resistant cell lines as compared to both danusertib and volasertib alone and to the simultaneous combination. This schedule indeed induced a significant increase of the DNA double-strand break marker γH2AX, forcing the cells through successive replication cycles ultimately resulting in apoptosis. Finally, combination of danusertib or volasertib+AZD1775 significantly reduced the clonogenic potential of CD34+ CML progenitors. ConclusionsOur results may have implications for the development of innovative therapeutic approaches based on Aurora kinase A or Plk1 inhibition associated with WEE1 blocking, aimed to improve the outcomes of patients with multi-TKI-resistant or BC CML.

The European target of ensuring reliable and sustainable energy has led to the increase in biofuel demand. This growth makes necessary the check of the product quality in order to prevent environmental and technical problems during combustion. Technical standard EN ISO 17225 divided the different biofuels into quality classes on the basis of their chemico-physical characteristics and the origin and source. In addition, they define the laboratory methodologies to be performed. These conventional analyses can determine these quality parameters but they are lengthy and expensive compared to the real need of the market. In this study, Vis-NIR spectroscopy coupled with partial least squares regression was used to predict the most important chemical-physical parameters of woodchip and pellet samples as a possible alternative to the conventional laboratory analysis. The results showed the possibility to use spectroscopy to obtain information about biofuel quality. In detail, moisture content and net calorific value of woodchip samples were predicted with RMSEP of 3.78% (r2(pred) = 0.97) and RMSECV of 0.37 MJ/kg (r2(CV) = 0.92), respectively. Ash content and gross calorific value of pellet samples were predicted with RMSECV of 0.44% (r2(CV) = 0.81) and 0.20 MJ/kg (r2(CV) = 0.78), respectively, while ash content and gross calorific value on ground pellet samples were predicted with RMSECV of 0.47% (r2(CV) = 0.78) and 0.19 MJ/kg (r2(CV) = 0.80), respectively. The best results were obtained considering only the near infrared region of the electromagnetic spectrum, suggesting that the visible part is not influential for the prediction of the parameters of this study. Having such a rapid and economic tool will be fundamental for the biofuel processors in order to check different quality characteristics of the products directly in real time without the time delay of the laboratory analysis and complications of sampling representation.

Context: Genetic/genomic instability is a hallmark of CML. SETD2, a histone methyltransferase that trimethylates histone H3 on K36 (H3K36me3), has recently demonstrated a crucial role in preserving genomic integrity by modulating DNA Mismatch Repair (MMR) and Homologous Recombination (HR) repair. By Western blotting (WB), we previously observed SETD2 and H3K36me3 loss (resulting from aberrant SETD2 turnover) in 85% of blast crisis (BC) CML patients but not in newly diagnosed chronic phase (CP) patients who will achieve optimal responses. Objectives: 1. To investigate whether SETD2 is involved in the maintenance of genetic/genomic stability in CML. 2. To assess whether SETD2 loss precedes or follows progression from CP to blast crisis BC. Materials: SETD2-proficient (LAMA84) and -deficient (KCL22) CML cell lines and primary patient samples (n=86) were studied. Results: To investigate whether SETD2/H3K36me3 loss impinges on the activation and proficiency of HR, we used UV rays to induce DNA damage in SETD2 siRNA-depleted LAMA 84 (SETD2-proficient) cells. Compared to control cells, cells silenced for SETD2 displayed a marked increase in γH2AX (a marker of DNA damage) and fewer RAD51 foci (markers of ongoing HR). Assessment of MMR proficiency is ongoing. To further confirm the role of SETD2 as a tumor suppressor implicated in maintaining genomic stability in CML, we transfected KCL22 (SETD2-deficient) cells with an ectopic SETD2 plasmid. Preliminary results showed that SETD2 re-expression induced a reduction in cell doubling time, an accumulation of cells at G1/S checkpoint and a significant reduction in clonogenic potential. Studies are ongoing to assess the effects on DNA damage repair pathways. We next wondered when during disease history SETD2/H3K36me3 loss occurs. WB analysis ofpaired (diagnosis/progression) samples from four CML patients suggested that patients who will progress still have intact and functional SETD2 at diagnosis. Additional analyses are ongoing to assess whether SETD2/H3K36me3 loss precedes, hence allows to predict, progression to BC. Conclusion: Loss of SETD2/H3K36me3 is a novel, BCR-ABL1-independent mechanism of genetic instability in CML. Further investigations are needed to establish to what extent SETD2/H3K36me3 loss contributes to (and may be predictive of) disease progression. Supported by AIRC project 23001.

Context: Constitutively active KIT tyrosine kinase harboring the D816V mutation is the major driver of systemic mastocytosis (SM) pathogenesis. We have previously reported that the loss of function of SETD2 histone methyltransferase due to reduced protein stability is a common cooperating event in advanced SM (advSM). Objective: To dissect the mechanisms of action of midostaurin in advSM and to explore the potential of SETD2 as a marker of response to therapy. Materials: The mast cell (MC) leukemia cell line HMC-1 (negative for SETD2) and primary neoplastic MCs from 10 advSM patients, collected at regular time points during midostaurin treatment. Results: This study started from our preliminary observations indicating that aurora kinase A (AKA) is overexpressed and hyperactivated in advSM and is implicated in SETD2 proteasomal degradation. The new gold standard of therapy in advSM is midostaurin, which targets KIT andseveral other kinases, including AKA. We, thus, investigated whether midostaurin treatment may result in efficient AKA inhibition and subsequent SETD2 rescue. To this purpose, the HMC-1 cell line was treated with 5 µM midostaurin for 24 h, and phospho-AKA (T288), SETD2, and H3K36me3 (surrogate marker of SETD2 activity) were evaluated by WB. Midostaurin reduced AKA phosphorylation by 60%, partially restoring SETD2 expression and activity. We next wondered whether the same happens in patients treated with midostaurin. We, thus, collected and performed WB analysis on neoplastic mast cells from advSM patients before and during midostaurin treatment. We found that midostaurin may target AKA and rescue SETD2 expression and function in vivo and that SETD2/H3K36me3 rescue correlates with the clinical response to midostaurin and the reduction of KIT D816V allele burden, as assessed by digital PCR at 3, 6, and 12 months. In 8 patients who responded to midostaurin, SETD2/H3K36me3 rescue was detected by WB as early as 3 months after treatment onset, whereas 2 refractory patients did not show any increase in SETD2/H3K36me3 and maintained an unaltered KIT allele burden. Conclusions: Midostaurin treatment induces AKA partial dephosphorylation and consequent rescue of SETD2 expression and function in vitro and in vivo SETD2/H3K36me3 may serve as a biomarker of response to midostaurin. Supported by AIRC project 23001

Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting BCR-ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell-intrinsic and -extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML.

Moisture content is the most relevant quality parameter for wood fuels. Effective and fast determination of moisture of incoming feedstock is essential in the management of bioenergy facilities. The availability of fast and reliable moisture meters based on innovative technologies simplifies this task. However, in Mediterranean conditions the inherent variability of wood fuels calls for a careful sampling strategy if representative results are required while facing acceptable analytic costs. The present study is aimed at measuring the fuel heterogeneity and defining accordingly the appropriate number of samples to be analyzed in order to get reliable moisture-content results. A total of 70 truckloads (about 2270 t of woodchips) were sampled during commercial operations in two different seasons. Five samples were collected from each load and measured with standard method and magnetic resonance gauge. Results show that the variability of moisture content is influenced by mixing of species and storage of biomass. Heterogeneity can vary greatly also within single truckloads, to the point that three samples are needed to achieve about 90% of estimates within the desired precision limits. In the case of larger lots, such as barge or ship loads, 20 samples can provide sufficient precision in most scenarios.

Near infrared spectroscopy is a non-invasive and rapid technique to support the analysis of solid biofuels such as woodchip, which is considered as a suitable alternative for energy production, according to European goals for fossil fuel reduction. Chemical and physical properties of the woodchip influence combustion performance, so the most discriminant parameters such as moisture and ash content and gross calorific value were constantly monitored. The aim of this study was the development of prediction models for these three parameters with the use of a hand-held NIR spectrometer. Laboratory analyses were carried out to evaluate the quality of several Italian samples from a power plant, and PLS regression models were developed to test prediction accuracy. Moreover, the most relevant wavelengths were investigated to discriminate chemical compounds influence. Prediction models demonstrated the capacity of handheld MicroNIR instrument to be considered a practical tool for solid biofuel quality assessment. As a consequence, NIR spectroscopy improved real-time analysis and made it suitable for practical and industrial applications, as supported by the recent Italian standard UNI/TS 11765.

The determination of strawberry fruit quality through the traditional destructive lab techniques has some limitations related to the amplitude of the samples, the timing and the applicability along all phases of the supply chain. The aim of this study was to determine the main qualitative characteristics through traditional lab destructive techniques and Near Infrared Spectroscopy (NIR) in fruits of five strawberry genotypes. Principal Component Analysis (PCA) was applied to search for spectral differences among all the collected samples. A Partial Least Squares regression (PLS) technique was computed in order to predict the quality parameters of interest. The PLS model for the soluble solids content prediction was the best performing&mdash, in fact, it is a robust and reliable model and the validation values suggested possibilities for its use in quality applications. A suitable PLS model is also obtained for the firmness prediction&mdash, the validation values tend to worsen slightly but can still be accepted in screening applications. NIR spectroscopy represents an important alternative to destructive techniques, using the infrared region of the electromagnetic spectrum to investigate in a non-destructive way the chemical&ndash, physical properties of the samples, finding remarkable applications in the agro-food market.

No abstract available

In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for KIT D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing for patient screening; allele burden has prognostic implications and may be used to monitor therapeutic efficacy. Progress in genetic profiling of KIT, together with the use of next-generation sequencing panels for the characterization of associated gene mutations, have allowed the stratification of patients into three subgroups differing in terms of pathogenesis and prognosis: i) patients with mast cell-restricted KIT D816V; ii) patients with multilineage KIT D816V-involvement; iii) patients with “multi-mutated disease”. Thanks to these findings, new prognostic scoring systems combining clinical and molecular data have been developed. Finally, non-genetic SETD2 histone methyltransferase loss of function has recently been identified in advanced SM. Assessment of SETD2 protein levels and activity might provide prognostic information and has opened new research avenues exploring alternative targeted therapeutic strategies. This review discusses how progress in recent years has rapidly complemented previous knowledge improving the molecular characterization of SM, and how this has the potential to impact on patient diagnosis and management.

At the scale of human life, soil is a non-renewable resource, and forests, one of the major land-cover types of the Planet, are a multipurpose, complex and self-regenerating type of ecosystem. The comprehension of soil related processes, soil-tree relationships, forest dynamics and management in different environments is fundamental, especially in the context of global change, to guarantee a sustainable use of forest products (i.e., timber or wood energy) and to provide a broad range of ecosystem services. A reliable economic assessment of sustainable forest management and of ecosystem services is useful to setup state or intergovernmental policies promoting habitat conservation and/or increasing people’s socio-economic perspectives. Here we blend different research experiences on forest and environmental sectors. Future challenges should direct forest research focusing on non-renewable resources (soil, water, air), their functional changes due to forest management and product use, and on the externalization of those ecosystem services not yet accounted for.

Vine is one of the most widespread crop cultivated in Italy. The management of these residues is linked to an additional cost for the operator and determines environmental issues mainly due to open field combustion. A better exploitation of these residues could be the use for thermal energy production in residential heating devices fuelled with pellet. In the present work vineyard pruning residues were collected, pelletised, then characterised according to the standard for solid biofuels. Combustion tests were performed in a 150 kWth boiler fuelled with pruning pellet and the related TSP, CO, NOx emissions were measured. In order to make a comparison with the open field combustion emissions of the vineyard pruning residues, simulation tests were conducted at lab scale. Open field emissions are up to 120 times for CO emission and 30 times for TSP more than the boiler emission. Results highlighted that by avoiding open field combustion and using this residual biomass for energy production, a significant reduction of environmental pollution together with an increase in renewable energy production can be obtained. The results can be useful as support for policy makers engaged in developing the strategy for the promotion of renewable energy and air quality improvement.

The increasing concern regarding energy supply and the consequent rapid growth of the pellet market lead to the need to classify the product quality. To this aim, chemical-physical parameters and qualitative attributes are defined by the technical standards EN ISO 17,225 to classify the quality of biofuels, but, while the former can be determined by traditional chemical analysis, no methodologies have been set for the latter one. Hence, near-infrared spectroscopy was tested to obtain information about the origin and the source of the pellet, at the moment only declared by the producers and difficult to be achieved by conventional analysis. In fact, the great strength of the technique is based on the fact that biomass features could be read simultaneously with a rapid and cheap NIR measurement. Checking the presence of treated wood (e.g. residues from wood processing industry) especially in densified products, such as pellets and briquettes, is particular important since in several European countries, e.g. Italy, these materials are considered as waste. In this study more than a hundred samples of virgin and treated wood (residues from wood processing industries) were analysed by means of FT-NIR. Partial Least Square regression – Discriminant Analysis was used in order to classify samples between the two classes and different variables selection methods were tested in order to improve the classification performance of the models. The results obtained demonstrated that near infrared analysis coupled with multivariate analysis can be used in screening applications to classify virgin wood from glue-laminated wood and treated wood. In particular, the model for the discrimination of treated wood (except glue-laminated samples) from virgin wood performs 100% correct classification and the model for the discrimination between virgin wood and glue-laminated wood only has a 3.6% misclassification rate. The methodology can be considered as the first one able to provide information about the origin of the biomass in a rapid and cheap way.

Biomass is an important renewable energy source, in particular if obtained by residues it becomes even more sustainable. In Italy, residual biomass coming from olive oil industry, i.e. olive pomace, is produced in a significant amount and is concentrated in olive oil extraction sites, making interesting a possible valorisation of these residues. The different extraction processes employed influence the pomace quality and, consequently, it is fundamental to find a rapid technique to assess its physical and chemical characteristics for a correct valorisation. The aim of the work was to develop a NIR-based methodology to obtain in a fast and cheap way information about olive pomace. Several samples (n = 104) were collected in Marche region and analysed according to standards methods. NIR spectra were acquired using both fiberoptic probe and integrating sphere and subsequently were elaborated with multivariate techniques, i.e. principal component analysis (PCA) and partial least square regression (PLS). Results show that information on extraction process and composition of the pomace can be obtained. Prediction models with performance suitable for quality control applications were obtained for moisture and ash contents, whereas gross calorific value model was suitable only for screening application.

Deregulated activity of BCR-ABL1, a nonreceptor tyrosine kinase encoded by the fusion gene resulting from the t(9;22)(q34;q11) chromosomal translocation, is thought to be the driver event responsible for initiation and maintenance of chronic myeloid leukemia (CML). BCR-ABL1 was one of the first tyrosine kinases to be implicated in a human malignancy and the first to be successfully targeted. Imatinib mesylate, the first tyrosine kinase inhibitor (TKI) to be approved for therapeutic use, was hailed as a magic bullet against cancer and remains one of the safest and most effective anticancer agents ever developed. Second- and third-generation TKIs were later introduced to prevent or counteract the problem of drug resistance, that may arise in a small proportion of patients. They are more potent molecules, but have been associated to more serious side effects and complications. Patients achieving stable optimal responses to TKI therapy are predicted to have the same life expectancy of the general population. However, TKIs do not ‘cure’ CML. Only a small proportion of cases may attempt therapy discontinuation without experiencing subsequent relapse. The great majority of patients will have to assume TKIs indefinitely – which raises serious pharmacoeconomic concerns and is now shifting the focus from efficacy to compliance and quality of life issues. Here we retrace the steps that have led from the biological acquisitions regarding BCR-ABL1 structure and function to the development of inhibitory strategies and we discuss drug resistance mechanism and how they can be addressed. Electronic supplementary material The online version of this article (10.1186/s12943-018-0780-6) contains supplementary material, which is available to authorized users.

The use of woodchip, and biofuels in general, is a fundamental step towards the transition from fossil fuel to renewable energy. The growth in the demand for wood fuels and the inherent variability in the properties of woody material lead to the need to verify its quality. EN ISO 17225-4 divides woodchip in different quality classes according to chemical-physical parameters and quality attributes. In this study, we have coupled near infrared spectroscopy with Partial Least Square regression to model gross calorific value and ash content of woodchip samples. Moreover, variables selection methods were tested in order to improve the models and get better prediction. Gross calorific value and ash content were predicted with a standard error of 234 J/g and 0.44%, respectively. The results indicate that the models could be used in screening applications and near infrared spectroscopy is a promising tool in the evaluation of biomass quality.

Context: The hypoxic bone marrow microenvironment plays a crucial role in acute myeloid leukemia (AML) development and progression, acting as a sanctuary for leukemic stem cells (LSCs). Hypoxia drives transcriptomic and metabolomic changes that enhance the fitness of LSCs, reducing their susceptibility to drug treatment. Aurora kinases A and B are crucial actors during mitosis and their overexpression has been described in AML, making them promising therapeutic targets. Phase II studies of Aurora kinase inhibitors combined with induction chemotherapy have demonstrated good tolerability and efficacy in patients with high-risk AML. Objective: We aimed to investigate the influence of hypoxia on AML sensitivity to Aurora kinase inhibition. Materials: AML cell lines (NOMO-1: t(9;11), p53 mutated; MOLM-13: FLT3-ITD; MV-4-11: t(4;11), +8, +19, FLT3-ITD; KASUMI-1 t(8;21), c-KIT and p53 mutated) were treated under either normoxia or hypoxia (1% O2) with the pan-Aurora inhibitor tozasertib (100 and 250 nM for 24 and 48 hours). Annexin V and propidium iodide (PI) staining were performed to evaluate the induction of apoptosis and proliferation capacity. Protein level alterations were analyzed by Western blotting (WB). Results: Hypoxia strongly influenced the anti-leukemic effects of tozasertib, reducing its ability to inhibit growth and proliferation in AML cells. In particular, all tested AML cell lines cultured under hypoxia showed reduced sensitivity to tozasertib compared to those under normoxia, with a significant reduction of apoptotic death after 48h of treatment. AnnexinV+ cells ranged between 32 and 60% under hypoxia vs 47-70% under normoxia (p Conclusion: Our study shows that, irrespective of the genetic background, cellular responses to Aurora inhibition in AML are markedly impaired by hypoxia. This suggests that AML LSCs might not be eradicated by tozasertib treatment.