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In chronic lymphocytic leukemia (CLL), NOTCH1 mutations have been associated with clinical resistance to the anti-CD20 rituximab, although the mechanisms behind this peculiar behavior remain to be clarified. In a wide CLL series ( n =692), we demonstrated that CLL cells from NOTCH1 -mutated cases (87/692) were characterized by lower CD20 expression and lower relative lysis induced by anti-CD20 exposure in vitro . Consistently, CD20 expression by CLL cells was upregulated in vitro by γ-secretase inhibitors or NOTCH1-specific small interfering RNA and the stable transfection of a mutated (c.7541-7542delCT) NOTCH1 intracellular domain (NICD-mut) into CLL-like cells resulted in a strong downregulation of both CD20 protein and transcript. By using these NICD-mut transfectants, we investigated protein interactions of RBPJ, a transcription factor acting either as activator or repressor of NOTCH1 pathway when respectively bound to NICD or histone deacetylases (HDACs). Compared with controls, NICD-mut transfectants had RBPJ preferentially complexed to NICD and showed higher levels of HDACs interacting with the promoter of the CD20 gene. Finally, treatment with the HDAC inhibitor valproic acid upregulated CD20 in both NICD-mut transfectants and primary CLL cells. In conclusion, NOTCH1 mutations are associated with low CD20 levels in CLL and are responsible for a dysregulation of HDAC-mediated epigenetic repression of CD20 expression.

CD49d, the alpha-chain of the integrin heterodimer α4β1, was identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p chromosome involving TP53 . In addition to TP53 , the clinical relevance of NOTCH1 , SF3B1 and BIRC3 gene mutations has been recently emphasized. By analyzing a cohort of 778 unselected CLL patients, we assessed the clinical relevance of CD49d as an OS predictor in subgroups defined by mutation/deletion of the TP53 , NOTCH1 , SF3B1 and BIRC3 genes. In this context, CD49d emerged as an independent predictor of OS in multivariate Cox analysis (Hazard ratio =1.88, P< 0.0001). Consistently, high CD49d expression identified CLL subsets with inferior OS in the context of each category of a previously reported hierarchical risk stratification model. Moreover, by evaluating the relative importance of biological prognosticators by random survival forests, CD49d was selected among the top-ranked OS predictor (variable importance =0.0410), along with IGHV mutational status and TP53 abnormalities. These results confirmed CD49d as an independent negative OS prognosticator in CLL also in comprehensive models comprising the novel recurrent mutations. In this context, TP53 disruption and NOTCH1 mutations retained prognostic relevance, in keeping with their roles in CLL cell immuno-chemoresistance.

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m 2 ) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57–84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0–95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9–68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ⩾3 neutropenia was observed in 61.7% of patients; however, grade ⩾3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.

Reading is essentially a two-channel function, requiring the integration of intact visual and auditory processes both peripheral and central. It is essential for normal reading that these component processes go forward automatically. Based on this model, Boder described three main subtypes of dyslexia: dysphonetic dyslexia (DD), dyseidetic, mixed and besides a fourth group defined non-specific reading delay (NSRD). The subtypes are identified by an algorithm that considers the reading quotient and the % of errors in the spelling test. Chiarenza and Bindelli have developed the Direct Test of Reading and Spelling (DTRS), a computerized, modified and validated version to the Italian language of the Boder test. The sample consisted of 169 subjects with DD and 36 children with NSRD. The diagnosis of dyslexia was made according to the DSM-V criteria. The DTRS was used to identify the dyslexia subtypes and the NSRD group. 2–5 min of artefact-free EEG (electroencephalogram), recorded at rest with eyes closed, according to 10–20 system were analyzed. Stability based Biomarkers identification methodology was applied to the DTRS and the quantitative EEG (QEEG). The reading quotients and the errors of the reading and spelling test were significantly different in the two groups. The DD group had significantly higher activity in delta and theta bands compared to NSRD group in the frontal, central and parietal areas bilaterally. The classification equation for the QEEG, both at the scalp and the sources levels, obtained an area under the robust Receiver Operating Curve (ROC) of 0.73. However, we obtained a discrimination equation for the DTRS items which did not participate in the Boder classification algorithm, with a specificity and sensitivity of 0.94 to discriminate DD from NSRD. These results demonstrate for the first time the existence of different neuropsychological and neurophysiological patterns between children with DD and children with NSRD. They may also provide clinicians and therapists warning signals deriving from the anamnesis and the results of the DTRS that should lead to an earlier diagnosis of reading delay, which is usually very late diagnosed and therefore, untreated until the secondary school level.

Mediation analysis assesses whether an exposure directly produces changes in cognitive behavior or is influenced by intermediate “mediators”. Electroencephalographic (EEG) spectral measurements have been previously used as effective mediators representing diverse aspects of brain function. However, it has been necessary to collapse EEG measures onto a single scalar using standard mediation methods. In this article, we overcome this limitation and examine EEG frequency‐resolved functional connectivity measures as a mediator using the full EEG cross‐spectral tensor (CST). Since CST samples do not exist in Euclidean space but in the Riemannian manifold of positive‐definite tensors, we transform the problem, allowing for the use of classic multivariate statistics. Toward this end, we map the data from the original manifold space to the Euclidean tangent space, eliminating redundant information to conform to a “compressed CST.” The resulting object is a matrix with rows corresponding to frequencies and columns to cross spectra between channels. We have developed a novel matrix mediation approach that leverages a nuclear norm regularization to determine the matrix‐valued regression parameters. Furthermore, we introduced a global test for the overall CST mediation and a test to determine specific channels and frequencies driving the mediation. We validated the method through simulations and applied it to our well‐studied 50+‐year Barbados Nutrition Study dataset by comparing EEGs collected in school‐age children (5–11 years) who were malnourished in the first year of life with those of healthy classmate controls. We hypothesized that the CST mediates the effect of malnutrition on cognitive performance. We can now explicitly pinpoint the frequencies (delta, theta, alpha, and beta bands) and regions (frontal, central, and occipital) in which functional connectivity was altered in previously malnourished children, an improvement to prior studies. Understanding the specific networks impacted by a history of postnatal malnutrition could pave the way for developing more targeted and personalized therapeutic interventions. Our methods offer a versatile framework applicable to mediation studies encompassing matrix and Hermitian 3D tensor mediators alongside scalar exposures and outcomes, facilitating comprehensive analyses across diverse research domains. This study introduces a novel mediation analysis approach using EEG cross‐spectra to investigate whether malnourishment affects children's cognitive performance. The results indicate that brain function across delta, theta, alpha, and beta band frequencies mediates the impact of malnourishment on cognitive performance in specific brain regions.

In chronic lymphocytic leukemia (CLL), NOTCH1 1 mutations have been associated with clinical resistance to the anti-CD20 rituximab, although the mechanisms behind this peculiar behavior remain to be clarified. In a wide CLL series (n = 692), we demonstrated that CLL cells from NOTCH1-mutated cases (87/692) were characterized by lower CD20 expression and lower relative lysis induced by anti-CD20 exposure in vitro. Consistently, CD20 expression by CLL cells was upregulated in vitro by Y-secretase inhibitors or NOTCH1 -specific small interfering RNA and the stable transfection of a mutated (c.7541-7542delCT NOTCH1 intracellular domain (NICD-mut) into CLL-like cells resulted in a strong downregulation of both CD20 protein and transcript. By using these NICD-mut transfectants, we investigated protein interactions of RBPJ, a transcription factor acting either as activator or repressor of NOTCH1 pathway when respectively bound to NICD or histone deacetylases (HDACs). Compared with controls, NICD-mut transfectants had RBPJ preferentially complexed to NICD and showed higher levels of HDACs interacting with the promoter of the CD20 gene. Finally, treatment with the HDAC inhibitor valproic acid upregulated CD20 in both NICD-mut transfectants and primary CLL cells. In conclusion, NOTCH1 1 mutations are associated with low CD20 levels in CLL and are responsible for a dysregulation of HDAC-mediated epigenetic repression of CD20 expression. Leukemia (2016) 30, 182-189; doi:10.1038/leu.2015.182

The importance of early therapy intensification in B-cell CLL (B-CLL) patients remains to be defined. Even though several studies have been published, no randomized trials comparing directly autologous stem cell transplant (ASCT) and the accepted conventional therapy (that is, rituximab, fludarabine and CY; R-FC) have been reported so far. To assess the benefit of a first-line aggressive therapy, we designed a multicenter, randomized, phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL. Primary end point was CR: 96 patients were enrolled (48 in each arm). On an intent-to-treat basis, the CR rates in the ASCT and R-FC arms were 62.5% and 58%, respectively. After 5 years of follow-up, PFS was 60.4% in the ASCT arm and 65.1% in the R-FC arm, time to progression 65.8 and 70.5%, and overall survival 88% vs 88.1%, respectively. Our trial demonstrates, for the first time in a randomized manner, that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients; the possibility of its clinical benefit in certain subgroups remains uncertain.