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Innovative therapeutic strategies have emerged over the past decade to improve outcomes for most lymphoma patients. Nevertheless, the aggressive presentation seen in high-risk mantle cell lymphoma (MCL) patients remains an unmet medical need. The highly proliferative cells that characterize these tumors depend on nucleotide synthesis to ensure high DNA replication and RNA synthesis. To take advantage of this vulnerability, STP-B, a clinically available small molecule selectively targeting CTP synthase 1 (CTPS1) has been recently developed. CTPS1 is a key enzyme of the pyrimidine synthesis pathway mediated through its unique ability to provide enough CTP in highly proliferating cells. Herein, we demonstrated that CTPS1 was expressed in all MCL cells, and that its high expression was associated with unfavorable outcomes for patients treated with chemotherapy. Using aggressive MCL models characterized by blastoid morphology, TP53 mutation or polyresistance to targeted therapies, we showed that STP-B was highly effective at nanomolar concentrations in vitro and in vivo, irrespective of these high-risk features. Inhibition of CTPS1 rapidly leads to cell cycle arrest in early S-phase accompanied by inhibition of translation, including of the anti-apoptotic protein MCL1. Consequently, CTPS1 inhibition induced synergistic cell death in combination with the selective BCL2 inhibitor venetoclax, both in vitro and in vivo. Overall, our study identified CTPS1 as a promising target for MCL patients and provided a mechanism-based combination with the BCL2 inhibitor venetoclax for the design of future chemotherapy-free treatment regimens to overcome resistance.

Background/objective: Inhibition is crucial for controlling behavior and is impaired in various psychopathologies. Neurofeedback holds promise in addressing cognitive deficits, and experimental research is essential for identifying its functional benefits. This study aimed to investigate whether boosting sensorimotor activity (SMR) improves inhibitory control in a final sample of healthy individuals ( N = 53), while exploring the underlying neurophysiological mechanism., Method: Participants were randomly divided into two groups: one receiving SMR neurofeedback training to enhance sensorimotor activity within the 12-15 Hz frequency range, and the other receiving sham feedback. Inhibition performance and neural correlates were evaluated with a Go-NoGo task before (T0) and after (T1) 10 neurofeedback sessions using event-related potentials. Data were analyzed via ANOVAs and regression analyses., Results: Compared to placebo, the active group demonstrated higher absolute SMR power ( p = 0.040) and improvements in inhibitory control, including faster response times and fewer inhibition errors ( p < 0.001, d = 6.06), associated with a larger NoGoP3d amplitude ( p < 0.001, d = 3.35). A positive correlation between the increase in SMR power and the rise in NoGoP3d amplitude (β=0.46, p = 0.015) explains 21 % of the observed variance., Conclusions: Uptraining SMR power is linked to heightened utilization of neural resources for executing optimal inhibition responses. These results uphold its effectiveness in cognitive rehabilitation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that they do not practice clinically with neurofeedback but have received blueprint certification training and supervision in preparation for the neurofeedback entry-level certification from the Biofeedback Certification International Alliance (BCIA)., (© 2024 The Authors. Published by Elsevier B.V.)

Abstract: To establish a strict p53-dependent gene-expression profile, TP53-/- clones were derived from TP53+/+ and TP53-/mut t(4;14) human myeloma cell lines (HMCLs) using CRISPR/Cas9 technology. From the 17 dysregulated genes shared between the TP53-/- clones from TP53+/+ HMCLs, we established a functional p53 score, involving 13 genes specifically downregulated upon p53 silencing. This functional score segregated clones and myeloma cell lines as well as other cancer cell lines according to their TP53 status. The score efficiently identified samples from patients with myeloma with biallelic TP53 inactivation and was predictive of overall survival in Multiple Myeloma Research Foundation-coMMpass and CASSIOPEA cohorts. At the functional level, we showed that among the 13 genes, p53-regulated BAX expression correlated with and directly affected the MCL1 BH3 mimetic S63845 sensitivity of myeloma cells by decreasing MCL1-BAX complexes. However, resistance to S63845 was overcome by combining MCL1 and BCL2 BH3 mimetics, which displayed synergistic efficacy. The combination of BH3 mimetics was effective in 97% of patient samples with or without del17p. Nevertheless, single-cell RNA sequencing analysis showed that myeloma cells surviving the combination had lower p53 score, showing that myeloma cells with higher p53 score were more sensitive to BH3 mimetics. Taken together, we established a functional p53 score that identifies myeloma cells with biallelic TP53 invalidation, demonstrated that p53-regulated BAX is critical for optimal cell response to BH3 mimetics, and showed that MCL1 and BCL2 BH3 mimetics in combination may be of greater effectiveness for patients with biallelic TP53 invalidation, for whom there is still an unmet medical need., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

A strategy combining targeted therapies is effective in B-cell lymphomas (BCL), such as mantle cell lymphoma (MCL), but acquired resistances remain a recurrent issue. In this study, we performed integrative longitudinal genomic and single-cell RNA-sequencing analyses of patients with MCL who were treated with targeted therapies against CD20, BCL2, and Bruton tyrosine kinase (OAsIs trial). We revealed the emergence of subclones with a selective advantage against OAsIs combination in vivo and showed that resistant cells were characterized by B-cell receptor (BCR)-independent overexpression of NF-κB1 target genes, especially owing to CARD11 mutations. Functional studies demonstrated that CARD11 gain of function not only resulted in BCR independence but also directly increased the transcription of the antiapoptotic BCL2A1, leading to resistance against venetoclax and OAsIs combination. Based on the transcriptional profile of OAsIs-resistant subclones, we designed a 16-gene resistance signature that was also predictive for patients with MCL who were treated with conventional chemotherapy, underlying a common escape mechanism. Among druggable strategies to inhibit CARD11-dependent NF-κB1 transduction, we evaluated the selective inhibition of its essential partner MALT1. We demonstrated that MALT1 protease inhibition led to a reduction in the expression of genes involved in OAsIs resistance, including BCL2A1. Consequently, MALT1 inhibition induced synergistic cell death in combination with BCL2 inhibition, irrespective of CARD11 mutational status, both in vitro and in vivo. Taken together, our study identified mechanisms of resistance to targeted therapies and provided a novel strategy to overcome resistance in aggressive BCL. The OAsIs trial was registered at www.clinicaltrials.gov #NCT02558816., (© 2023 by The American Society of Hematology.)

Aggressive B-cell malignancies, such as mantle cell lymphoma (MCL), are microenvironment-dependent tumors and a better understanding of the dialogs occurring in lymphoma-protective ecosystems will provide new perspectives to increase treatment efficiency. To identify novel molecular regulations, we performed a transcriptomic analysis based on the comparison of circulating MCL cells (n=77) versus MCL lymph nodes (n=107) together with RNA sequencing of malignant (n=8) versus normal B-cell (n=6) samples. This integrated analysis led to the discovery of microenvironment-dependent and tumor-specific secretion of interleukin-32 beta (IL32β), whose expression was confirmed in situ within MCL lymph nodes by multiplex immunohistochemistry. Using ex vivo models of primary MCL cells (n=23), we demonstrated that, through the secretion of IL32β, the tumor was able to polarize monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. We highlighted that while IL32β-stimulated macrophages secreted several protumoral factors, they supported tumor survival through a soluble dialog, mostly driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFkB inhibition to counteract microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells. These data uncovered the IL32β/BAFF axis as a previously undescribed pathway involved in lymphoma-associated macrophage polarization and tumor survival, which could be counteracted through selective NIK inhibition.

Recent global data indicates a worldwide increase in polydrug use associated with a shift from recreational to productive habits of consumption. Such non-responsible abuse of substances (alcohol, cocaine, heroin, etc.) is likely to lead to addictive disorders that are characterized by various neuropsychopharmacological effects. A main cognitive function involved in the onset and long-term maintenance of addiction is reactive inhibition, i.e., the ability to withhold a prepotent motor dominant response. In the present study, 63 (poly)drug user patients who were undergoing a detoxification program, in addition to 19 healthy controls matched for gender, age, and education, were subjected to a "contextual Go/No-Go task" with concomitant electroencephalography. Stimuli were superimposed on three contextual backgrounds: control (black screen), drug-unrelated (neutral pictures), or drug-related (pictures related to drug consumption). Of these patients, 23 were cocaine users (CU), 21 were heroin users (HU), and 19 were polydrug users (PDU). The main results showed that (1) at the behavioral level, more commission errors occurred with the PDU patients compared to the healthy controls; (2) at the neurophysiological level, specific alterations were found on classical event-related potentials that index reactive inhibition. Indeed, the higher rate of errors in the PDU group was subtended by both reduced amplitude and latency on the ∆N2 component and increased ∆P3 latency compared to controls. These data clearly suggest a more deleterious impact of polydrug use on inhibitory functions. In addition, our results provide evidence of reduced ERN amplitude in cocaine users, suggesting that impaired performance monitoring and error-processing may support impaired awareness, thereby preventing these patients from changing their behaviors.

Background: Approximately half of all people with alcohol use disorder (AUD) relapse into alcohol reuse in the next few weeks after a withdrawal treatment. Brain stimulation and cognitive training represent recent forms of complementary interventions in the context of AUD., Objective: To evaluate the clinical efficacy of five sessions of 2 mA bilateral transcranial direct current stimulation (tDCS) for 20 min over the dorsolateral prefrontal cortex (DLPFC) (left cathodal/right anodal) combined with alcohol cue inhibitory control training (ICT) as part of rehabilitation. The secondary outcomes were executive functioning (e.g. response inhibition) and craving intensity, two mechanisms strongly related to abstinence., Methods: A randomized clinical trial with patients (n = 125) with severe AUD at a withdrawal treatment unit. Each patient was randomly assigned to one of four conditions, in a 2 [verum vs. sham tDCS] x 2 [alcohol cue vs. neutral ICT] factorial design. The main outcome of treatment was the abstinence rate after two weeks or more (up to one year)., Results: Verum tDCS improved the abstinence rate at the 2-week follow-up compared to the sham condition, independently of the training condition (79.7% [95% CI = 69.8-89.6] vs. 60.7% [95% CI = 48.3-73.1]; p = .02). A priori contrasts analyses revealed higher abstinence rates for the verum tDCS associated with alcohol cue ICT (86.1% [31/36; 95% CI = 74.6-97.6]) than for the other three conditions (64% [57/89; 95% CI = 54-74]). These positive clinical effects on abstinence did not persist beyond two weeks after the intervention. Neither the reduction of craving nor the improvement in executive control resulted specifically from prefrontal-tDCS and ICT., Conclusions: AUD patients who received tDCS applied to DLPFC showed a significantly higher abstinence rate during the weeks following rehabilitation. When combined with alcohol specific ICT, brain stimulation may provide better clinical outcomes., Trial Registration: ClinicalTrials.gov number NCT03447054 https://clinicaltrials.gov/ct2/show/NCT03447054., Competing Interests: Declaration of competing interest This study is part of Macha Dubuson Ph.D thesis. Dr Kornreich reported receiving grants from the King Baudouin Foundation and the CHU Brugmann Foundation during the study. Dubuson reported receiving salary support through grants of the King Baudouin Foundation and the Brugmann Foundation during the study. There are no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: We investigated whether the mid-term impact (1 week posttraining) of a "combined cognitive rehabilitation (CRP)/transcranial direct current stimulation (tDCS) program" on the performance of a Go/No-go task was enhanced compared with isolated CRP and whether it varied according to the stimulation site (right inferior frontal gyrus [rIFG] vs right dorsolateral prefrontal cortex [rDLPFC])., Methods: A total of 150 healthy participants were assigned to (1) an Inhibition Training (IT) group, (2) a group receiving active tDCS over the rIFG in combination with IT (IT + IF), (3) a group receiving active tDCS over the rDLPFC in combination with IT (IT + DL), (4) a group receiving IT with sham tDCS (ITsham), and (5) a No-Training (NT) group to control for test-retest effects. Each group undertook 3 sessions of a Go/No-go task concomitant with the recording of event-related potentials (T0, before training; T1, at the end of a 4-day training session [20 minutes each day]; T2, 1 week after T1)., Results: With the exception of the NT participants, all the groups exhibited improved performances at T2. The IT + DL group exhibited the best improvement profile, indexed by faster response times (RTs) (T0 > T1 = T2), with a reduced rate of errors at the posttraining sessions compared with both T0 and T1. This "inhibitory learning effect" was neurophysiologically indexed by shorter No-go N2d latencies and enhanced No-go P3d amplitudes., Conclusion: CRP combined with active tDCS over the rDLPFC appears to be optimal for boosting long-term (one week) inhibitory skills as it induced specific and robust neural changes.

Cognitive training results in significant, albeit modest, improvements in specific cognitive functions across a range of mental illnesses. Inhibitory control, defined as the ability to stop the execution of an automatic reaction or a planned motor behavior, is known to be particularly important for the regulation of health behaviors, including addictive behaviors. For example, several studies have indicated that inhibitory training can lead to reduced alcohol consumption or a loss of weight/reduced energy intake. However, the exact neurocognitive mechanisms that underlie such behavioral changes induced by training are still matter of debate. In the present study, we investigated the long-term impact (ie, at 1 week posttraining) of an inhibitory training program (composed of 4 consecutive daily training sessions of 20 minutes each) on the performance of a Go/No-go task. Healthy participants were randomly assigned to 1 of 3 designated groups: (1) an Inhibition Training (IT) group that received training based on a hybrid flanker Go/No-go task; (2) a group that received a noninhibition-based (ie, episodic memory; EM) training; and (3) a No-Training (NT) group to control for test-retest effects. Each group underwent 3 sessions of a Go/No-go task concomitant with the recording of event-related potentials. Our results revealed a specific impact of the Inhibitory Training on the Go/No-go task, indexed by a faster process compared with the other 2 groups. This effect was neurophysiologically indexed by a faster N2 component on the difference NoGo-Go waveform. Importantly, effects at both the behavioral and at the neural level were still readily discernible 1 week posttraining. Thus, our data clearly corroborate the notion that cognitive training is effective, while also indicating that it may persist over time.

Alcohol Use Disorder (AUD) has a disconcertingly high relapse rate (70-80% within a year following withdrawal). Preventing relapse or minimizing its extent is hence a challenging goal for long-term successful management of AUD. New perspectives that rely on diverse neuromodulation tools have been developed in this regard as care supports. This paper focuses on electroencephalogram-neurofeedback (EEG-NF), which is a tool that has experienced renewed interest in both clinical and research areas. We review the literature on EEG-based neurofeedback studies investigating the efficacy in AUD and including at least 10 neurofeedback training sessions. As neurofeedback is a form of biofeedback in which a measure of brain activity is provided as feedback in real-time to a subject, the high degree of temporal resolution of the EEG interface supports optimal learning. By offering a wide range of brain oscillation targets (alpha, beta, theta, delta, gamma, and SMR) the EEG-NF procedure increases the scope of possible investigations through a multitude of experimental protocols that can be considered to reinforce or inhibit specific forms of EEG activity associated with AUD-related cognitive impairments. The present review provides an overview of the EEG-NF protocols that have been used in AUD and it highlights the current paucity of robust evidence. Within this framework, this review presents the arguments in favor of the application of EEG-NF as an add-on tool in the management of alcohol disorders to enhance the cognitive abilities required to maintain abstinence more specifically, with a focus on inhibition and attentional skills., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Despite equated behavioral performance levels, hazardous drinkers generally exhibited increased neural activity while performing simple cognitive tasks compared to light drinkers. Here, 49 participants (25 hazardous and 24 light drinkers) participated in an event-related potentials (ERPs) study while performing an n -back working memory task. In the control zero-back (N0) condition, the subjects were required to press a button when the number "2" or "6" was displayed. In the two-back and three-back (N2; N3) conditions, the subjects had to press a button when the displayed number was identical to the number shown two/three trials earlier. To assess for the impact of alcohol consumption on the updating of working memory processes under various cognitive loads, difference waveforms of "N2 minus N0" and "N3 minus N0" were computed by subtracting waveforms in the N0 condition from waveforms in the N2 and N3 conditions, for the light and the hazardous drinkers. Three main ERP components were noted for both groups: a P200/N200 complex, a P300 component, and an N400/P600 activity. The results show that, to perform the task at the same level as the light drinkers, the hazardous drinkers exhibited larger amplitude differences, mainly around the P300 and P600 components. These data may be considered, at the preventive level, as vulnerability factors for developing adult substance use disorders, and they stress the importance, at a clinical level, to consider such working memory processes in the management of alcohol dependence.

Prima-1 Met (APR-246) was previously shown to be dependent on glutathione inhibition and on ROS induction in cancer cells with mutated or deleted TP53 . Because this ROS induction was, at least in part, due to a direct interference with the thioredoxin reductase enzyme, we investigated whether activity of Prima-1 Met could be mimicked by auranofin, an inhibitor of the thioredoxin reductase. We thus compared the activity of auranofin and Prima-1 Met in 18 myeloma cell lines and in 10 samples from patients with multiple myeloma or plasma cell leukemia. We showed that, similar to Prima-1 Met , the activity of auranofin was not dependent on either TP53 status or p53 expression; was inhibited by N-acetyl-L-cysteine, a ROS scavenger; displayed a dramatic synergy with L-buthionine sulfoximine, an irreversible inhibitor of glutathione synthesis; and induced cell death that was not dependent on Bax/Bak expression. These data showed that auranofin and Prima-1 Met similarly overcome cell death resistance in myeloma cells due to either p53 deficiency or to mitochondrial dysfunction.

Mantle cell lymphoma (MCL) accumulates in lymphoid organs, but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (insulin-like growth factor-1, B-cell activating factor, interleukin-6, interleukin-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures (ie, proliferation, NF-κB, and survival signatures). We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression, leading to a consequent loss of mitochondrial priming. Of interest, this loss of priming was overcome by the type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-x L induction through NF-κB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche., (© 2016 by The American Society of Hematology.)

The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD50 < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD50 < 10 nM). Mcl-1 and Bcl-xL both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x(L) up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.