B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with ...B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC t(MYC) (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.
•B-PLL is tightly linked to MYC aberrations (translocation or gain) and 17p (TP53) deletion.•Cases of B-PLL with MYC aberration and 17p (TP53) deletion have the worst prognosis.
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Abstract The maintenance of information in auditory short-term memory (ASTM) is accompanied by a sustained anterior negativity (SAN) in the event-related potential measured during the retention ...interval of simple auditory memory tasks. Previous work on ASTM showed that the amplitude of the SAN increased in negativity as the number of maintained items increases. The aim of the current study was to measure the SAN and observe its behavior beyond the point of saturation of auditory short-term memory. We used atonal pure tones in sequences of 2, 4, 6, or 8 t. Our results showed that the amplitude of SAN increased in negativity from 2 to 4 items and then levelled off from 4 to 8 items. Behavioral results suggested that the average span in the task was slightly below 3, which was consistent with the observed plateau in the electrophysiological results. Furthermore, the amplitude of the SAN predicted individual differences in auditory memory capacity. The results support the hypothesis that the SAN is an electrophysiological index of brain activity specifically related to the maintenance of auditory information in ASTM.
•Impact of masking on electrophysiological components in an AB paradigm.•Masking reduces the effectiveness of the deployment and engagement of attention.•Backward masking slows downstream processing, ...and limits conscious perception.
The attentional blink (AB) is a difficulty in correctly processing a target when it follows one or more other targets after a short delay. When no backward mask is presented after the last critical target, there is no or little behavioral AB deficit. The mask plays an important role in limiting conscious access to target information. In this electrophysiological study, we tested the impact of masking on the deployment and engagement of attention by measuring the N2pc and P3 components in an RSVP paradigm. We found that the presence of a mask in an AB paradigm reduced the amplitude of the N2pc, P3a, and P3b components. In addition to reducing encoding in memory, masking also reduced the effectiveness of the deployment and engagement of attention on the last target. We discuss the role of these findings in the context of current masking, consciousness, and AB models.
Background
ETAP‐1 was created to evaluate the quality of services trajectory from families’ perspective. The items of ETAP‐1 were developed from previous studies on integrated care, existing quality ...assessments, and consultations with families and experts in evaluation and in autism spectrum disorder (ASD).
Method
The questionnaire was completed by 200 parents of children aged 5 and under who were recently diagnosed with ASD or intellectual disability. Of these, 183 received diagnostic evaluation through a clinic specialized in ASD; the other 17 underwent diagnostic evaluation in hospital settings.
Results
Factor analysis supported the a priori dimensions of quality and distinctions between experiences before and during diagnostic evaluation. The instrument had high internal consistency, convergent and discriminant validity with other measures and was sensitive to differences in service delivery models.
Discussion
ETAP‐1 is useful in organizing information on families’ experiences throughout their services trajectories and according to a dynamic perspective.
Summary
Follicular lymphomas (FLs) with MYC rearrangements (MYC‐R) and extra copies of MYC (MYC‐EC) are rare and the prognosis impact is uncertain. We conducted a retrospective study including 321 FL ...patients, among whom 259 (81%) had no 8q24 alterations and 62 (19%) were assigned to 8qAlt. Forty‐five cases were classified as MYC‐EC and six as MYC‐R. MYC‐R patients were significantly older (P = 0·008), had higher follicular lymphoma international prognostic index (FLIPI) stage (P = 0·05) and β2‐microglobulin (β2m; P = 0·05). Among patients treated with immuno‐chemotherapy, four presented a MYC‐R and 25 a MYC‐EC. Univariate analysis showed the absence of significant difference between MYC‐EC and normal MYC (MYC‐NL) regarding progression‐free survival (PFS; HR1·3; 95% CI 0·4–1·6) and specific overall survival (SOS; HR 1·6; 95% CI 0·4–5·7). Those results were compared to data from the PRIMA trial. This confirmed that MYC‐EC had no impact on PFS (P = 0·86) or SOS (P = 0·9). Conversely, MYC‐R was associated with a trend to inferior outcome regarding PFS (HR : 6·1; 95% CI 2·2–17·1; P = 0·00026), lymphoma‐related death (SOS; HR 13·6; 95% CI 2·9–65; P = 0·00014) and risk of transformation (transformation‐free survival (TFS); HR 82·7; 95% CI 14·8–463·4; P < 0·0001). In conclusion, MYC‐EC has no prognostic impact in FL but MYC‐R FL tended to be associated with an increased risk of transformation and poorer outcome.
We compared the electrophysiological correlates for the maintenance of non-musical tones sequences in auditory short-term memory (ASTM) to those for the short-term maintenance of sequences of ...coloured disks held in visual short-term memory (VSTM). The visual stimuli yielded a sustained posterior contralateral negativity (SPCN), suggesting that the maintenance of sequences of coloured stimuli engaged structures similar to those involved in the maintenance of simultaneous visual displays. On the other hand, maintenance of acoustic sequences produced a sustained negativity at fronto-central sites. This component is named the Sustained Anterior Negativity (SAN). The amplitude of the SAN increased with increasing load in ASTM and predicted individual differences in the performance. There was no SAN in a control condition with the same auditory stimuli but no memory task, nor one associated with visual memory. These results suggest that the SAN is an index of brain activity related to the maintenance of representations in ASTM that is distinct from the maintenance of representations in VSTM.
•We study auditory short-term memory via electrophysiology.•We identified the Sustained Anterior Negativity (SAN).•The SAN is a new electrophysiological index of auditory short-term memory.•We dissociated the SAN from the maintenance of visual items in short-term memory.•Our results provide evidence in favour of a decentralised vision of short-term memory.
Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. ...However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.
Anemia is a frequent cytopenia in myelodysplastic syndromes (MDS) and most patients require red blood cell transfusion resulting in iron overload (IO). Deferasirox (DFX) has become the standard ...treatment of IO in MDS and it displays positive effects on erythropoiesis. In low risk MDS samples, mechanisms improving erythropoiesis after DFX treatment remain unclear. Herein, we addressed this question by using liquid cultures with iron overload of erythroid precursors treated with low dose of DFX (3μM), which corresponds to DFX 5 mg/kg/day, an unusual dose used for iron chelation. We highlight a decreased apoptosis rate and an increased proportion of cycling cells, both leading to higher proliferation rates. The iron chelation properties of low dose DFX failed to activate the Iron Regulatory Proteins and to support iron depletion, but low dose DFX dampers intracellular reactive oxygen species. Furthermore low concentrations of DFX activate the NF-κB pathway in erythroid precursors triggering anti-apoptotic and anti-inflammatory signals. Establishing stable gene silencing of the Thioredoxin (TRX) 1 genes, a NF-κB modulator, showed that fine-tuning of reactive oxygen species (ROS) levels regulates NF-κB. These results justify a clinical trial proposing low dose DFX in MDS patients refractory to erythropoiesis stimulating agents.
PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the ...frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.
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