Management of drug resistance in mantle cell lymphoma

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell hemopathy characterized by the translocation t(11;14)(q13;q32) that leads to the overexpression of the cell cycle regulatory protein cyclin D1. This translocation is the initial event of the lymphomagenesis, but tumor cells can acquire additional alterations allowing the progression of the disease with a more aggressive phenotype and a tight dependency on microenvironment signaling. To date, the chemotherapeutic-based standard care is largely inefficient and despite the recent advent of different targeted therapies including proteasome inhibitors, immunomodulatory drugs, tyrosine kinase inhibitors, relapses are frequent and are generally related to a dismal prognosis. As a result, MCL remains an incurable disease. In this review, we will present the molecular mechanisms of drug resistance learned from both preclinical and clinical experiences in MCL, detailing the main tumor intrinsic processes and signaling pathways associated to therapeutic drug escape. We will also discuss the possibility to counteract the acquisition of drug refractoriness through the design of more efficient strategies, with an emphasis on the most recent combination approaches

Du sport perçu comme un phénomène de sous-culture délinquante. Les jeunes Inuit à la recherche d’un impossible compromis

À la fin des années quatre-vingt, parents et responsables politiques du Nunavut, territoire des Inuit du Nord du Québec, durent se saisir d’un problème grave. Malgré l’existence depuis quelque dix ans d’une commission scolaire spécifique, ils faisaient face à un échec massif. Les enfants allaient à l’école avec plus ou moins d’assiduité, mais un infime pourcentage arrivait à terminer le secondaire. De cette minorité de finissants n’émergeaient que les meilleurs, qui tentaient de s’inscrire au..

Differential Attacks Against SPN: A Thorough Analysis

International audienceThis work aims at determining when the two-round maximum expected differential probability in an SPN with an MDS diffusion layer is achieved by a differential having the fewest possible active Sboxes. This question arises from the fact that minimum-weight differentials include the best differentials for the AES and several variants. However, we exhibit some SPN for which the two-round MEDP is achieved by some differentials involving a number of active Sboxes which exceeds the branch number of the linear layer. On the other hand, we also prove that, for some particular families of Sboxes, the two-round MEDP is always achieved for minimum-weight differentials

Pharmacological targeting of bet bromodomain proteins in acute myeloid leukemia and malignant lymphomas : From molecular characterization to clinical applications

Altres ajuts: G.R. acknowledges supports from European Regional Development Fund (ERDF) "Una manera de hacer Europa".A25in25proarENG-pr910210011and DNA-protein interactions and abnormal chromatin remodeling are a major cause of uncontrolled gene transcription and constitutive activation of critical signaling pathways in cancer cells. Multiple epigenetic regulators are known to be deregulated in several hematologic neoplasms, by somatic mutation, amplification, or deletion, allowing the identification of specific epigenetic signatures, but at the same time providing new therapeutic opportunities. While these vulnerabilities have been traditionally addressed by hypomethylating agents or histone deacetylase inhibitors, pharmacological targeting of bromodomain-containing proteins has recently emerged as a promising approach in a number of lymphoid and myeloid malignancies. Indeed, preclinical and clinical studies highlight the relevance of targeting the bromodomain and extra-terminal (BET) family as an efficient strategy of target transcription irrespective of the presence of epigenetic mutations. Here we will summarize the main advances achieved in the last decade regarding the preclinical and clinical evaluation of BET bromodomain inhibitors in hematologic cancers, either as monotherapies or in combinations with standard and/or experimental agents. A mention will finally be given to the new concept of the protein degrader, and the perspective it holds for the design of bromodomain-based therapies

On the behaviors of affine equivalent Sboxes regarding differential and linear attacks

This paper investigates the effect of affine transformations of the Sbox on the maximal expected differential probability MEDP and linear potential MELP over two rounds of a substitution-permutation network, when the diffusion layer is linear over the finite field defined by the Sbox alphabet. It is mainly motivated by the fact that the 2-round MEDP and MELP of the AES both increase when the AES Sbox is replaced by the inversion in $GF(2^8)$. Most notably, we give new upper bounds on these two quantities which are not invariant under affine equivalence. Moreover, within a given equivalence class, these new bounds are maximal when the considered Sbox is an involution. These results point out that different Sboxes within the same affine equivalence class may lead to different two-round MEDP and MELP. In particular, we exhibit some examples where the basis chosen for defining the isomorphism between $GF(2)^m$ and $GF(2^m)$ affects these values. For Sboxes with some particular properties, including all Sboxes of the form $A(x^s)$ as in the AES, we also derive some lower and upper bounds for the 2-round MEDP and MELP which hold for any MDS linear layer

Recent advances in the targeting of epigenetic regulators in b-cell non-hodgkin lymphoma

In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies

Phenyl 2,3,4-tri-O-benzyl-1-thio-α-d-mannopyran­oside monohydrate

In the title compound, C33H34O5S·H2O, the mannopyran­oside ring adopts a chair conformation with the 2-α-thio­phenyl group occupying an axial position. One of the pendant benzyl groups is disordered over two sets of sites in a 0.5:0.5 ratio. In the crystal, the water mol­ecule makes two O—H⋯O hydrogen bonds to an adjacent sugar mol­ecule with the O atoms of the primary alcohol and ether groups acting as acceptors. At the same time, the OH group of the sugar makes a hydrogen bond to a water mol­ecule

Listening to the parent voice to inform person-centred neonatal care.

Family integrated care (FIC), where parents are an integral part of their baby’s care and decision-making can enhance parental involvement and empowerment, contributing to decreased parental separation and stress. It follows that parents can also be a central part of neonatal education for staff in the neonatal speciality. This paper focuses on what students and staff can learn from parents about what they feel is important to make their experience better. A narrative, interpretive approach was undertaken to collect and analyse parent interview narratives. A specific question was posed to a purposive sample of parents who have had premature babies about what health professionals can learn from them. Thematic analysis revealed five key themes relating to the importance of: communicating; listening; empathising; acknowledging (the parent’s role); realising (what matters to parents). These elements were incorporated into a framework named by the mnemonic, ‘CLEAR’. This highlights what parents want staff to be cognisant of when caring for them and their babies. Learning from the parents in our care enables a greater understanding of their experiences at difficult and challenging times. Having a deeper understanding of parents’ experiences can contribute to enhanced empathic learning.Peer reviewedFinal Accepted Versio

IgG4 Valency Modulates the Pathogenicity of Anti-Neurofascin-155 IgG4 in Autoimmune Nodopathy

Altres ajuts: Agence Nationale pour la Recherche; Association Française contre les Myopathies (23593).Background and Objective s : IgG4 autoantibodies to neurofascin-155 (Nfasc155) are associated with a subgroup of patients with chronic inflammatory demyelinating polyneuropathy (CIDP), currently named autoimmune nodopathy. We previously demonstrated that those antibodies alter conduction along myelinated axons by inducing Nfasc155 depletion and paranode destruction. In blood, IgG4 have the potency to exchange their moiety with other unrelated IgG4 through a process called Fab-arm exchange (FAE). This process results in functionally monovalent antibodies and may affect the pathogenicity of autoantibodies. Here, we examined this issue and whether FAE is beneficial or detrimental for Nfasc155 autoimmune nodopathy. Methods : The bivalency and monospecificity of anti-Nfasc155 were examined by sandwich ELISA in 10 reactive patients, 10 unreactive CIDP patients, and 10 healthy controls. FAE was induced in vitro using reduced glutathione and unreactive IgG4, and the ratio of the : light chain was monitored. To determine the pathogenic potential of bivalent anti-Nfasc155 IgG4, autoantibodies derived from patients were enzymatically cleaved into monovalent Fab and bivalent F(ab')2 or swapped with unreactive IgG4 and then were injected in neonatal animals. Results : Monospecific bivalent IgG4 against Nfasc155 were detected in the serum of all reactive patients, indicating that a fraction of IgG4 have not undergone FAE in situ. These IgG4 were, nonetheless, capable of engaging into FAE with unreactive IgG4 in vitro, and this decreased the levels of monospecific antibodies and modulated the ratio of the : light chain. When injected in animals, monovalent anti-Nfasc155 Fab did not alter the formation of paranodes; by contrast, both native anti-Nfasc155 IgG4 and F(ab')2 fragments strongly impaired paranode formation. The promotion of FAE with unreactive IgG4 also strongly diminished the pathogenic potential of anti-Nfasc155 IgG4 in animals and decreased IgG4 clustering on Schwann cells. Discussion : Our findings demonstrate that monospecific and bivalent anti-Nfasc155 IgG4 are detected in patients and that those autoantibodies are the pathogenic ones. The transformation of anti-Nfasc155 IgG4 into monovalent Fab or functionally monovalent IgG4 through FAE strongly decreases paranodal alterations. Bivalency thus appears crucial for Nfasc155 clustering and paranode destruction