Immunomodulatory drugs in acute myeloid leukemia treatment

Immunomodulatory drugs (IMiDs) are analogs of thalidomide. They have immunomodulatory, antiangiogenic and proapoptotic properties and exert a role in regulating the tumor microenvironment. Recently IMiDs have been investigated for their pleiotropic properties and their therapeutic applications in both solid tumors (melanoma, prostate carcinoma and differentiated thyroid cancer) and hematological malignancies. Nowadays, they are applied in de novo and relapsed/ refractory multiple myeloma, in myelodysplastic syndrome, in del5q syndrome with specific use of lenalidomide and B-cell lymphoma. Several studies have been conducted in the last few years to explore IMiDs possible use in acute myeloid leukemia treatment. Here we report the mechanisms of action of IMiDs in acute myeloid leukemia and their potential future therapeutic application in this disease

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

n/

Direct Alcohol Fuel Cells: A Comparative Review of Acidic and Alkaline Systems

In the last 20 years, direct alcohol fuel cells (DAFCs) have been the subject of tremendous research efforts for the potential application as on-demand power sources. Two leading technologies respectively based on proton exchange membranes (PEMs) and anion exchange membranes (AEMs) have emerged: the first one operating in an acidic environment and conducting protons; the second one operating in alkaline electrolytes and conducting hydroxyl ions. In this review, we present an analysis of the state-of-the-art acidic and alkaline DAFCs fed with methanol and ethanol with the purpose to support a comparative analysis of acidic and alkaline systems, which is missing in the current literature. A special focus is placed on the effect of the reaction stoichiometry in acidic and alkaline systems. Particularly, we point out that, in alkaline systems, OH- participates stoichiometrically to reactions, and that alcohol oxidation products are anions. This aspect must be considered when designing the fuel and when making an energy evaluation from a whole system perspective

Hsp90 depletion goes wild

Hsp90 reveals phenotypic variation in the laboratory, but is Hsp90 depletion important in the wild? Recent work from Chen and Wagner in BMC Evolutionary Biology has discovered a naturally occurring Drosophila allele that downregulates Hsp90, creating sensitivity to cryptic genetic variation. Laboratory studies suggest that the exact magnitude of Hsp90 downregulation is important. Extreme Hsp90 depletion might reactivate transposable elements and/or induce aneuploidy, in addition to revealing cryptic genetic variation

Microenvironment expression in diffuse large B-cell lymphomas

Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, is recognized as a heterogeneous disease with distinct molecular subtypes derived from different stages of B-cell differentiation. The contribution of the tumor microenvironment to the pathogenesis and tumor survival of DLBCL is poorly understood. However, several recent studies have yielded intriguing findings and shed some light on the possible roles of the microenvironment. In this retrospective study, data from 29 patients diagnosed with DLBCL between 2009 and 2013 were reviewed. All patients had pathologically confirmed DLBCL and had been treated with the R-CHOP regimen. In these patients, we correlated the expression of CD3 staining for T cells, tryptase staining for mast cells, CD68 for tumor-associated macrophages (TAMs), and CD31 staining for blood vessels. CD68 and tryptase expression, as well as MVD, were increased in chemo-resistant patients compared to chemosensitive patients. Tryptase expression showed a positive correlation with MVD, supporting a role for mast cells in DLBCL tumor angiogenesis, while the CD68 correlation with MVD was not significant, indicating a different role for TAMs rather than angiogenesis in DLBCL. A statistically significant difference was observed in the expression of CD3 in patients with bulky disease. Specifically, a higher expression of CD3 was observed in nonbulky disease patients (mean expression 52.91%, n = 20) compared to bulky disease patients (mean expression 34.9%, n = 9), P value < .05. The reduction in T cells in bulky disease patients contributes to loosen the immune control over the tumor, resulting in an increased cell proliferation, leading to large tumor cell masses, which are predictive of poor prognostic and clinical outcomes. CD3 showed a positive correlation with tryptase and MVD, while multiple regression analysis efficaciously predicted MVD depending on CD3 and tryptase as predictors, supporting a complex interplay between these cells in sustaining tumor angiogenesis in DLBCL patients. The improved understanding of tumor biology and of the role of the tumor microenvironment has led to advances in the diagnosis, classification, prognostics, as well as novel treatments of patients with hematologic malignancies. In particular, translational research, leading to drugs that target the interaction between the tumor microenvironment and malignant cells, has provided many promising new approaches to cancer therapy. Ongoing dynamic and correlation studies of tumor biology and the contribution of the tumor microenvironment should be promoted in the context of novel drug development in order to identify optimal therapies for various lymphomas and improve the curability of these diseases

Stress da radiazione RF a 900 MHz ed attivazione di elementi trasponibili in tessuti germinali di Drosophila melanogaster

Nel mondo naturale gli individui, le popolazioni e le specie si devono confrontare con variazioni delle condizioni ambientali. Gli organismi e le loro cellule mettono in atto un adattamento fisiologico attraverso risposte che sono immediate e reversibili. Condizioni di stress però, possono causare modificazioni a livello genomico che possono alterare processi biologici fondamentali conducendo a trasformazioni cellulari. È noto da tempo che fattori ambientali provocano condizioni di stress che possono indurre in vari organismi l’attivazione di elementi genetici mobili o elementi trasponibili (TEs) il cui movimento è tra le cause di instabilità genomica. In questo lavoro, individui di Drosophila melanogaster sono stati sottoposti a stress da radiazione RF a 900 MHz ed esaminati per l’attivazione di TEs nei tessuti germinali di entrambi i sessi. Tale stress ha causato un significativo incremento dell’attivazione di tali elementi, confermando che diversi stress ambientali possono avere come conseguenza l’instabilità dei genomi e la comparsa di mutazioni de novo dovute all’inserzione di elementi trasponibili in geni codificanti

The future of biotic indices in the ecogenomic era: Integrating (e)DNA metabarcoding in biological assessment of aquatic ecosystems

The bioassessment of aquatic ecosystems is currently based on various biotic indices that use the occurrence and/ or abundance of selected taxonomic groups to define ecological status. These conventional indices have some limitations, often related to difficulties inmorphological identification of bioindicator taxa. Recent development of DNA barcoding and metabarcoding could potentially alleviate some of these limitations, by using DNA sequences instead of morphology to identify organisms and to characterize a given ecosystem. In this paper,we review the structure of conventional biotic indices, andwe present the results of pilotmetabarcoding studies using environmental DNA to infer biotic indices. We discuss the main advantages and pitfalls of metabarcoding approaches to assess parameters such as richness, abundance, taxonomic composition and species ecological values, to be used for calculation of biotic indices.We present some future developments to fully exploit the potential of metabarcoding data and improve the accuracy and precision of their analysis. We also propose some recommendations for the future integration of DNA metabarcoding to routine biomonitoring program

A multicenter study on the appropriateness of hospitalization in obstetric wards: application of Obstetric Appropriateness Evaluation Protocol (Obstetric AEP)

The cross-sectional study has been based on the implementation of the Obstetric Appropriateness Evaluation Protocol (OAEP) in seven hospitals to determine inappropriate hospital admissions and days of stay. The outcomes were: inappropriateness of admission and "percentage of inappropriateness" for one hospitalization. A total number of 2196 clinical records were reviewed. The mean percentage of inappropriateness for hospitalization was 22%. The percentage of inappropriateness for the first 10 d of hospitalization peaked in correspondence of the fourth (42%). The logistic regression model on inappropriated admission reported that emergency admission was a protective factor (OR = 0.4) and to be hospitalized in wards with 6530 beds risk factor (OR = 5.12). The second linear model on "percentage of inappropriateness" showed that inappropriated admission and wards with 6530 beds increased the percentage (p < 0.001); whereas the admission in Teaching Hospitals was inversely associated (p < 0.001). The present study suggests that the percentage of inappropriate admission depends especially on the inappropriate admission and the large number of beds in obstetric wards. This probably indicates that management of big hospitals, which is very complex, needs improving the processes of support and coordination of health professionals. The OAEP tool seems to be an useful instrument for the decision-makers to monitor and manage the obstetric wards. \ua9 2014 Informa UK Ltd. All rights reserved

Autosomal Recessive Atrial Dilated Cardiomyopathy With Standstill Evolution Associated With Mutation of Natriuretic Peptide Precursor A

n/

Targeted whole exome sequencing and Drosophila modelling to unveil the molecular basis of primary ovarian insufficiency

STUDY QUESTION: Can a targeted whole exome sequencing (WES) on a cohort of women showing a primary ovarian insufficiency (POI) phenotype at a young age, combined with a study of copy number variations, identify variants in candidate genes confirming their deleterious effect on ovarian function? SUMMARY ANSWER: This integrated approach has proved effective in identifying novel candidate genes unveiling mechanisms involved in POI pathogenesis. WHAT IS KNOWN ALREADY: POI, a condition occurring in 1% of women under 40 years of age, affects women’s fertility leading to a premature loss of ovarian reserve. The genetic causes of POI are highly heterogeneous and several determinants contributing to its prominent oligogenic inheritance pattern still need to be elucidated. STUDY DESIGN, SIZE, DURATION: WES screening for pathogenic variants of 41 Italian women with non-syndromic primary and early secondary amenorrhoea occurring before age 25 was replicated on another 60 POI patients, including 35 French and 25 American women, to reveal statistically significant shared variants. PARTICIPANTS/MATERIALS, SETTING, METHODS: The Italian POI patients’ DNA were processed by targeted WES including 542 RefSeq genes expressed or functioning during distinct reproductive or ovarian processes (e.g. DNA repair, meiosis, oocyte maturation, folliculogenesis and menopause). Extremely rare variants were filtered and selected by means of a Fisher Exact test using several publicly available datasets. A case-control Burden test was applied to highlight the most significant genes using two ad-hoc control female cohorts. To support the obtained data, the identified genes were screened on a novel cohort of 60 Caucasian POI patients and the same case-control analysis was carried out. Comparative analysis of the human identified genes was performed on mouse and Drosophila melanogaster by analysing the orthologous genes in their ovarian phenotype, and two of the selected genes were fruit fly modelled to explore their role in fertility. MAIN RESULTS AND THE ROLE OF CHANCE: The filtering steps applied to search for extremely rare pathogenic variants in the Italian cohort revealed 64 validated single-nucleotide variants/Indels in 59 genes in 30 out of 41 screened women. Burden test analysis highlighted 13 ovarian genes as being the most enriched and significant. To validate these findings, filtering steps and Burden analysis on the second cohort of Caucasian patients yielded 11 significantly enriched genes. Among them, AFP, DMRT3, MOV10, FYN and MYC were significant in both patient cohorts and hence were considered strong candidates for POI. Mouse and Drosophila comparative analysis evaluated a conserved role through the evolution of several candidates, and functional studies using a Drosophila model, when applicable, supported the conserved role of the MOV10 armitage and DMRT3 dmrt93B orthologues in female fertility. LARGE SCALE DATA: The datasets for the Italian cohort generated during the current study are publicly available at ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/): accession numbers SCV001364312 to SCV001364375. LIMITATIONS, REASONS FOR CAUTION: This is a targeted WES analysis hunting variants in candidate genes previously identified by different genomic approaches. For most of the investigated sporadic cases, we could not track the parental inheritance, due to unavailability of the parents’ DNA samples; in addition, we might have overlooked additional rare variants in novel candidate POI genes extracted from the exome data. On the contrary, we might have considered some inherited variants whose clinical significance is uncertain and might not be causative for the patients’ phenotype. Additionally, as regards the Drosophila model, it will be extremely important in the future to have more mutants or RNAi strains available for each candidate gene in order to validate their role in POI pathogenesis. WIDER IMPLICATIONS OF THE FINDINGS: The genomic, statistical, comparative and functional approaches integrated in our study convincingly support the extremely heterogeneous oligogenic nature of POI, and confirm the maintenance across the evolution of some key genes safeguarding fertility and successful reproduction. Two principal classes of genes were identified: (i) genes primarily involved in meiosis, namely in synaptonemal complex formation, asymmetric division and oocyte maturation and (ii) genes safeguarding cell maintenance (piRNA and DNA repair pathways). STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Italian Ministry of Health grants ‘Ricerca Corrente’ (08C621_2016 and 08C924_2019) provided to IRCCS Istituto Auxologico Italiano, and by ‘Piano Sostegno alla Ricerca’ (PSR2020_FINELLI_LINEA_B) provided by the University of Milan; M.P.B. was supported by Telethon-Italy (grant number GG14181). There are no conflicts of interest