Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

The current shift of therapy of chronic lymphocytic leukemia (CLL) towards novel targeted agents mandates the identification of molecular predictors to inform on who can still benefit from chemoimmunotherapy and who can be instead early considered for novel targeted agents. Fludarabine, cyclophosphamide, and rituximab (FCR) is the most effective chemoimmunotherapy regimen for the management of CLL and represents the current standard of care for young and fit patients devoid of TP53 disruption. A retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients failing FCR (median progression free survival: 2.2 years, p < 0.001) similar to cases harboring TP53 mutations (median progression free survival: 2.6 years, p < 0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, p = 0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. The functional implications of BIRC3 mutations are largely unexplored and little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first line FCR. By immunoblotting analysis, we showed that the non-canonical NF-kB pathway is active in BIRC3 mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3 mutated primary CLL cells are less sensitive to fludarabine. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches

An update on: molecular genetics of high-risk chronic lymphocytic leukemia

ABSTRACTIntroduction: During the past few years, new genomic approaches have elucidated the molecular genetics of chronic lymphocytic leukemia (CLL) to a large extent. As a consequence, specific hi..

Assessing prognosis of chronic lymphocytic leukemia using biomarkers and genetics

Chronic lymphocytic leukemia (CLL) is a clinically and genetically heterogenous disease. Genomic studies have deciphered the pathogenesis of CLL and has allowed the identification of prognostic and..

Stiffer Spleen Predicts Higher Bone Marrow Fibrosis and Higher JAK2 Allele Burden in Patients With Myeloproliferative Neoplasms

A total of 63 myeloproliferative neoplasms [MPN; 9 polycythemia vera (PV), 32 essential thrombocythemia (ET), and 22 myelofibrosis (MF)] underwent spleen stiffness (SS) measurement by vibration-controlled transient elastography equipped with a novel spleen-dedicated module. Higher SS values significantly correlated with grade 2-3 bone marrow (BM) fibrosis (p=0.035), with hemoglobin level <10 g/dl (p=0.014) and with white blood cells 6510,000/ml (p=0.008). Median SS was significantly higher in MF patients compared to ET and PV (p=0.015). SS also correlated with higher JAK2 variant allele frequency (p=0.02). This study identifies SS as a potential noninvasive tool that reflects BM fibrosis and the mutational burden in MPN

Predictors and outcomes associated with the growth curves of self-efficacy beliefs in regard to anger and sadness regulation during adolescence: a longitudinal cross-cultural study

IntroductionThis longitudinal study examined unique and joint effects of parenting and negative emotionality in predicting the growth curves of adolescents’ self-efficacy beliefs about regulating two discrete negative emotions (anger and sadness) and the association of these growth curves with later maladjustment (i.e., internalizing and externalizing problems).MethodsParticipants were 285 children (T1: Mage = 10.57, SD = 0.68; 53.3% girls) and their parents (mothers N = 286; fathers N = 276) from Colombia and Italy. Parental warmth, harsh parenting, and internalizing and externalizing problems were measured in late childhood at T1, whereas early adolescents’ anger and sadness were measured at T2 (T2: Mage = 12.10, SD = 1.09). Adolescent self-efficacy beliefs about anger and sadness regulation were measured at five time-points from T2 to T6 (T6: Mage = 18.45, SD = 0.71), and internalizing and externalizing problems were measured again at T6.ResultsMulti-group latent growth curve models (with country as the grouping variable) demonstrated that in both countries there was on average a linear increase in self-efficacy about anger regulation and no change or variation in self-efficacy about sadness regulation. In both countries, for self-efficacy about anger regulation (a) T1 harsh parenting and T1 externalizing problems were negatively associated with the intercept, (b) T2 anger was negatively associated with the slope, and (c) the intercept and the slope were associated with lower T6 internalizing and externalizing problems, controlling for T1 problems. For self-efficacy about sadness regulation, (a) T1 internalizing problems were negatively associated with the intercept only in Italy, (b) T2 sadness was negatively associated with the intercept only in Colombia, and (c) the intercept negatively predicted T6 internalizing problems.DiscussionThis study advances knowledge of the normative development of self-efficacy beliefs about anger and sadness regulation during adolescence across two countries, highlighting the predictive value of pre-existing family and individual characteristics on this development and prediction by the development of self-efficacy beliefs on later adjustment

A systematic method to construct mimetic finite-difference schemes for incompressible flows

We present a general procedure to construct a non-linear mimetic finite-difference operator. The method is very simple and general: it can be applied for any order scheme, for any number of grid points and for any operator constraints. In order to validate the procedure, we apply it to a specific example, the Jacobian operator for the vorticity equation. In particular we consider a finite difference approximation of a second order Jacobian which uses a 9x9 uniform stencil, verifies the skew-symmetric property and satisfies physical constraints such as conservation of energy and enstrophy. This particular choice has been made in order to compare the present scheme with Arakawa’s renowned Jacobian, which turns out to be a specific case of the general solution. Other possible generalizations of Arakawa’s Jacobian are available in literature but only the present approach ensures that the class of solutions found is the widest possible. A simplified analysis of the general scheme is proposed in terms of truncation error and study of the linearised operator together with some numerical experiments. We also propose a class of analytical solutions for the vorticity equation to compare an exact solution with our numerical results

Insecure attachment and technology addiction among Italian young adults: the mediating role of impulsivity, alexithymia and general psychological distress

Introduction: The majority of previous studies (Schimmenti et al., 2014) have investigated the direct effect of insecurity attachment with youth's internet and smartphone addiction. However, the potential mediators of this relation have been understudied. In this contribution, we examined the mediating role of some psychological risk factors (i.e., impulsivity, psychological distress and alexithymia) in the relation between insecure attachment dimensions (i.e., attachment anxiety and attachment avoidance) and technology addiction (i.e. problematic Internet use, smartphone addiction and Internet addiction). In addition, we also tested the moderating role of gender. Materials and Methods: Data were collected from 539 Italian adolescents and young adults, mostly females (N = 378; 70.1%), aged 19.76 ± 1.99 years. Participants completed self-report measures of attachment insecurity, psychological risk factors and technology addiction. Results: Main results from multi-group path analysis model showed that attachment anxiety had no direct effect on technology addiction,whereas attachment avoidance had a small negative direct effect, but only among women. Anxiety and avoidant attachment dimensions were significantly and positively associated with technology addiction only through the increase of all psychological risk factors. Finally, no moderation effect of gender was found. Discussion: Findings suggested that higher levels of insecure attachment dimensions are associated with higher levels of impulsivity, psychological distress and alexithymia that in turn contribute to the increase of technology addiction. Such findings might have relevant implications to inform any treatment plan for young adults who are overinvolved with technology activities and so to deliver patient-tailored interventions

Atypical Chronic Myeloid Leukemia: Where Are We Now?

Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (&gt;20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (&lt; 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options

The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition.

Curcumin, a natural polyphenol, has been described to exhibit effects on signaling pathways, leading to induction of apoptosis. In this study, we observed that curcumin inhibited Hsp90 activity causing depletion of client proteins implicated in survival pathways. Based on this observation, this study was designed to investigate the cellular effects of curcumin combination with the pan-HDAC inhibitors, vorinostat and panobinostat, which induce hyperacetylation of Hsp90, resulting in inhibition of its chaperone function. The results showed that, at subtoxic concentrations, curcumin markedly sensitized tumor cells to vorinostat- and panobinostat-induced growth inhibition and apoptosis. The sensitization was associated with persistent depletion of Hsp90 client proteins (EGFR, Raf-1, Akt, and survivin). In conclusion, our findings document a novel mechanism of action of curcumin and support the therapeutic potential of curcumin/HDAC inhibitors combination, because the synergistic interaction was observed at pharmacologically achievable concentrations, which were ineffective when each drug was used alone