Inside the biology of early T-cell precursor acute lymphoblastic leukemia: the perfect trick

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare, distinct subtype of T-ALL characterized by genomic instability, a dismal prognosis and refractoriness to standard chemotherapy. Since its first description in 2009, the expanding knowledge of its intricate biology has led to the definition of a stem cell leukemia with a combined lymphoid-myeloid potential: the perfect trick. Several studies in the last decade aimed to better characterize this new disease, but it was recognized as a distinct entity only in 2016. We review current insights into the biology of ETP-ALL and discuss the pathogenesis, genomic features and their impact on the clinical course in the precision medicine era today

Can the new and old drugs exert an immunomodulatory effect in acute myeloid leukemia?

Acute myeloid leukemia (AML) is considered an immune-suppressive neoplasm capable of evading immune surveillance through cellular and environmental players. Increasing knowledge of the immune system (IS) status at diagnosis seems to suggest ever more attention of the crosstalk between the leukemic clone and its immunologic counterpart. During the last years, the advent of novel immunotherapeutic strategies has revealed the importance of immune dysregulation and suppression for leukemia fitness. Considering all these premises, we reviewed the “off-target” effects on the IS of different drugs used in the treatment of AML, focusing on the main advantages of this interaction. The data reported support the idea that a successful therapeutic strategy should consider tailored approaches for performing leukemia eradication by both direct blasts killing and the engagement of the IS

FLT3 mutational analysis in acute myeloid leukemia: Advantages and pitfalls with different approaches

FMS-like tyrosine kinase 3 (FLT3) is one of the most closely studied genes in blood diseases. Numerous methods have been adopted for analyses, mainly in acute myeloid leukemia (AML) diagnostic work-up. According to international recommendations, the current gold standard approach allows FLT3 canonical mutations to be investigated, providing the main information for risk assessment and treatment choice. However, the technological improvements of the last decade have permitted “black side” gene exploration, revealing numerous hidden aspects of its role in leukemogenesis. The advent of the next-generation sequencing era emphasizes lights and shadows of FLT3 conventional mutational analysis, highlighting the need for a more comprehensive study of the gene. However, more extensive analysis is opening new, unexplored questions whose impact on clinical outcomes is still unknown. The present work is focused on the main topics regarding FLT3 mutational analysis in AML, debating the strengths and weaknesses of the current gold standard approach. The rights and wrongs of NGS introduction in clinical practice will be discussed, showing that a more extensive knowledge of FLT3 mutational status could lead to reconsidering its role in AML management

Nanopore Sequencing in Blood Diseases: A Wide Range of Opportunities

The molecular pathogenesis of hematological diseases is often driven by genetic and epigenetic alterations. Next-generation sequencing has considerably increased our genomic knowledge of these disorders becoming ever more widespread in clinical practice. In 2012 Oxford Nanopore Technologies (ONT) released the MinION, the first long-read nanopore-based sequencer, overcoming the main limits of short-reads sequences generation. In the last years, several nanopore sequencing approaches have been performed in various “-omic” sciences; this review focuses on the challenge to introduce ONT devices in the hematological field, showing advantages, disadvantages and future perspectives of this technology in the precision medicine era

Epitranscriptomics in normal and malignant hematopoiesis

Epitranscriptomics analyze the biochemical modifications borne by RNA and their downstream influence. From this point of view, epitranscriptomics represent a new layer for the control of genetic information and can affect a variety of molecular processes including the cell cycle and the differentiation. In physiological conditions, hematopoiesis is a tightly regulated process that produces differentiated blood cells starting from hematopoietic stem cells. Alteration of this process can occur at different levels in the pathway that leads from the genetic information to the phenotypic manifestation producing malignant hematopoiesis. This review focuses on the role of epitranscriptomic events that are known to be implicated in normal and malignant hematopoiesis, opening a new pathophysiological and therapeutic scenario. Moreover, an evolutionary vision of this mechanism will be provided

Genomic segmental duplications on the basis of the t(9;22) rearrangement in chronic myeloid leukemia

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Ecosystem functioning and ecological status in the Venice lagoon, which relationships?

The implementation of management measures for improving the ecological status within an Ecosystem Based Management approach represents one the of the main challenges in coastal and transitional water environments. In general terms, ecological status and ecosystem functioning are expected to be positively associated, being good ecological processes a sort of prerequisite for the ecosystem health, but often relationships between ecosystem functioning indicators and the metrics used to define ecological status resulted to be rather puzzling. Moreover, the Biological Quality Elements (BQEs) do not show a consistent response to the changes in the ecosystem. This situation does not allow to recognize where interventions are really needed, hindering the definition of effective management strategies. In the present paper, a spatially explicit food web model of the Venice lagoon (with the resolution of 300 m) is used to simulate changes in the ecological status and related them to different management scenarios. Functional changes in the food web were investigated by comparing values of a set of 12 indicators derived by the ecological network analysis. In general, results highlighted on one hand the need for more discussion about the implementation of the WFD, at least in complex and spatially heterogeneous transitional waters environments, as the Venice lagoon; on the other, results remark the opportunity to support the BQEs monitoring with an ecological modelling approach. These models are certainly not the panacea for addressing questions about the environmental management, as they have inherent uncertainties (on parameters, structure, processes etc.); however, they can prove useful for selecting among different policy choices, since they offer the opportunity to simulate the mean effects, preliminarily verifying the efficacy of the proposed interventions

Measurement of neutron detection efficiency between 22 and 174 MeV using two different kinds of Pb-scintillating fiber sampling calorimeters

We exposed a prototype of the lead-scintillating fiber KLOE calorimeter to neutron beam of 21, 46 and 174 MeV at The Svedberg Laboratory, Uppsala, to study its neutron detection efficiency. This has been found larger than what expected considering the scintillator thickness of the prototype. %To check our method, we measured also the neutron %detection efficiency of a 5 cm thick NE110 scintillator. We show preliminary measurement carried out with a different prototype with a larger lead/fiber ratio, which proves the relevance of passive material to neutron detection efficiency in this kind of calorimeters

Tailoring the Transport Properties of Mesoporous Doped Cerium Oxide for Energy Applications

Hard-template nanocasted mesoporous cerium oxide possesses a unique combination of thermal stability, high surface area, and short diffusion lengths for mass and gas transport, which makes it relevant for high-temperature catalysis, sensing, and electrochemical applications. Here, we present an in-depth study of a number of mesoporous doped ceria systems, and we assess their fundamental structure and functionalities by complementary transmission electron microscopy imaging and spectroscopy, electron tomography reconstructions, and electrochemical impedance spectroscopy. We employed surface chemical modifications for increasing the ionic conductivity of as-synthesized mesoporous Gd-doped ceria by 2 orders of magnitude, enabling the ionic pathway across mesoporous particles. Complementary bulk doping strategies (by the addition of Pr) result in the easy tuning of the electrical transport mechanisms converting pure ionic mesoporous ceria into a mixed ionic-electronic conductor. The results obtained here are rationalized in light of local charge accumulation and mobility effects, providing a potential tool for engineering transport properties in nanocasted ceria and similar nanostructured materials for use in energy applications in the form of functional composites, infiltrated structures, or catalytic layers

Effects of Alpha-Lipoic Acid and Myoinositol Supplementation on the Oocyte Enviroment of Obese Infertile Women

INTRODUCTION Obesity is characterized by increased inflammation and oxidative stress, resulting in adverse effects on women reproductive potential. Antioxidant supplementation may exert a positive effect on the obese ovarian environment. Indeed, we preliminarily observed a reduction of mitochondrial (mt) DNA content, a marker of oxidative stress, in granulosa cells of obese infertile women supplemented with Sinopol\uae (Laborest SpA), composed by alpha-lipoic acid (ALA) 800 mg, myoinositol (MYO) 2 g, folic acid (FA) 400 ug. This suggested a potential role of Sinopol\uae in reducing oxidative stress in the obese ovarian environment. Here we analyzed Total Antioxidant Capacity (TAC) in follicular fluid and mtDNA levels in granulosa cells, in a larger population of infertile women undergoing in vitro fertilization (IVF). METHODS 19 normal weight (NW) and 24 obese (OB) infertile women were enrolled in our IVF center. Infertility was investigated and a non-ovarian diagnosis was made. Patients did not present any additional pathology. All women were provided with FA and among them 15 OB (OB-SIN) were also supplemented with ALA and MYO, for 2 months before ovarian stimulation. Follicular fluid (FF) and granulosa cells (GC) were collected after oocyte retrieval. TAC was measured in FF by enzymatic assay, mtDNA levels evaluated in GC by Real-time PCR. Results were compared by ANOVA and correlations assessed by Pearson\u2019s correlation (SPSS; IBM). RESULTS OB groups had similar BMI (OB patients supplemented with only folic acid (OB-F): 30.2 \ub1 0.7; OB-SIN: 32.7 \ub1 1.1 kg/m2). Women age was similar in all groups (NW: 36.7 \ub1 0.6; OB-F: 37.6 \ub1 1.7; OB-SIN: 35.9 \ub1 1.1 years). Among OB women, antioxidant capacity was significantly higher in OB-SIN than in OB-F. mtDNA levels showed an opposite trend, being decreased in OB-SIN and increased in OB-F compared to NW, though not reaching statistical significance. mtDNA levels were significantly and inversely correlated with the number of total oocytes and metaphase II (mature) oocytes. Pregnancy rate was similar in NW (36.8%) and OB-SIN (33.3%) women, while it was lower in OB-F patients (11.1%). CONCLUSION We analyzed molecular markers in granulosa cells and follicular fluid as indicators of oocytes oxidative state. Our results suggest that supplementation with a compound of ALA -a natural antioxidant, cofactor in the mt respiratory chain- and MYO -an insulin-sensitizer- might increase antioxidant defenses and reduce oxidative stress in the obese ovarian environment, possibly contributing at restoring physiological conditions. This might improve IVF pregnancy rates in obese infertile women. Further studies are needed to clarify the synergic action of ALA, MYO and FA on the oocyte oxidative environment. Supported by Laborest Sp