Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes.

Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias. Loss of MLL-fusion protein appeared to result from inhibition of global protein translation by NSM. Importantly, combination of DSF with NSM enhanced MLL-fusion protein depletion. This led to more profound inhibition of downstream transcriptional leukemogenic programs regulated by MLL-fusion proteins and more effective killing of both MLL-rearranged AML and ALL cells. In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia.

Exploring access to community neurorehabilitation for people with progressive neurological conditions: a qualitative study.

PURPOSE: Community neurorehabilitation enables people with progressive neurological conditions (PNCs) to manage their symptoms to live an active, fulfilling life; however, it is not accessible to all. This study explored the factors influencing access to community neurorehabilitation in Northern Ireland from the perspective of people with PNCs and their carers. METHODS: Eleven people living with a PNC and three carers took part in virtual focus groups. Data was thematically analysed using the framework method. RESULTS: Access to neurorehabilitation was described as a staged journey, driven by people with PNCs, and impacted by interactions with others. Four themes were identified: the person in the driving seat, describing the value of person-centred care and the need for proactivity; the traffic lights, depicting the role and influence of health care professionals (HCPs); the need for direction; and roadworks and roadblocks, identifying additional barriers to access. In addition, six fundamentals of good access were identified. CONCLUSIONS: This study adds depth to our understanding of the complexity, and the roles and needs of people with PNCs and HCPs, in accessing community neurorehabilitation. Further research is needed to determine how best to empower people to access rehabilitation.

Access to community neurorehabilitation is dependent on personal factors including patient activation level and health care professional knowledge.People need to be empowered to access rehabilitation services.A single point of contact for advice and triaging concerns related to progressive neurological conditions is desirable.There is a need to understand the experiences and needs of people with low levels of patient activation to ensure equitable access to community-based neurorehabilitation.

Physical seed dormancy in pea is genetically separable from seed coat thickness and roughness.

Introduction: The seeds of wild pea (Pisum) exhibit marked physical dormancy due to impermeability of the seed coat to water, and the loss of this dormancy is thought to have been critical for domestication. Wild pea seed coats are also notably thick and rough, traits that have also reduced during domestication and are anecdotally linked to increased permeability. However, how these traits specifically interact with permeability is unclear. Methods: To investigate this, we examined the genetic control of differences in seed coat characteristics between wild P. sativum ssp. humile and a non-dormant domesticated P. s. sativum accession in a recombinant inbred population. QTL effects were confirmed and their locations refined in segregating F4/5 populations. Results: In this population we found a moderate correlation between testa thickness and permeability, and identified loci that affect them independently, suggesting no close functional association. However, the major loci affecting both testa thickness and permeability collocated closely with Mendel's pigmentation locus A, suggesting flavonoid compounds under its control might contribute significantly to both traits. We also show that seed coat roughness is oligogenic in this population, with the major locus independent of both testa thickness and permeability, suggesting selection for smooth seed was unlikely to be due to effects on either of these traits. Discussion: Results indicate loss of seed coat dormancy during domestication was not primarily driven by reduced testa thickness or smooth seededness. The close association between major permeability and thickness QTL and Mendel's 'A' warrant further study, particularly regarding the role of flavonoids.

FDA-approved disulfiram as a novel treatment for aggressive leukemia.

Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound. This study assessed the biological effects of disulfiram on leukemia cells and evaluated its potential as a treatment strategy. We found that disulfiram inhibits the viability of a diverse panel of acute lymphoblastic and myeloid leukemia cell lines (n = 16) and patient-derived xenograft cells from patients with poor outcome and treatment-resistant disease (n = 15). The drug induced oxidative stress and apoptosis in leukemia cells within hours of treatment and was able to potentiate the effects of daunorubicin, etoposide, topotecan, cytarabine, and mitoxantrone chemotherapy. Upon combining disulfiram with auranofin, a drug approved for the treatment of rheumatoid arthritis that was previously shown to exert antileukemic effects, strong and consistent synergy was observed across a diverse panel of acute leukemia cell lines, the mechanism of which was based on enhanced ROS induction. Acute leukemia cells were more sensitive to the cytotoxic activity of disulfiram than solid cancer cell lines and non-malignant cells. While disulfiram is currently under investigation in clinical trials for solid cancers, this study provides evidence for the potential of disulfiram for acute leukemia treatment. KEY MESSAGES: Disulfiram induces rapid apoptosis in leukemia cells by boosting oxidative stress. Disulfiram inhibits leukemia cell growth more potently than solid cancer cell growth. Disulfiram can enhance the antileukemic efficacy of chemotherapies. Disulfiram strongly synergises with auranofin in killing acute leukemia cells by ROS induction. We propose testing of disulfiram in clinical trial for patients with acute leukemia.

T cell-related memory

Immunological memory is embodied in the rapid and enhanced immune responsiveness to antigens that have been previously encountered. In this work we have analyzed the development of humoral immunological memory to a conventional antigen (TNP-BSA) and a superantigen (staphylococcal enterotoxin B (SEB) in T cell-reconstituted athymic or euthymic mice. It was demonstrated that T cell reconstituded athymic mice, which lack recent thymic emigrants, mount a primary response to a T cell dependent antigen, but do not develop memory or the capacity to produce specific anti-TNP IgG1 antibodies during the secondary immune response. On the other hand, if thymocytes were continously provided during the secondary response a typical memory response was achieved, with the presence of high levels of specific IgG1. In addition, we have shown that immunization of mice with staphylococcal enterotoxin B (SEB) resulted in a detectable anti-SEB antibody response, which was further increased upon boosting. The typical secondary response do SEB was mainly composed of IgG1, thus suggesting the involvement of interleukin-4 (IL-4)-producing T cells. These results led us to propose that the development of humoral immunological memory can not be solely explained by the long lifespan of primed T lymphocytes, and a novel dynamic and systemic hypothesis is given to explain memory development.

Coevolution of hosts and microorganisms: an analysis of the involvment of cytokines in host-parasite interactions

Parasites may employ particular strategies of eluding an immune response by taking advantage of those mechanisms that normally guarantee immunological self-tolerance. Much in the way as it occurs during the establishment of self-tolerance, live pathogens may induce clonal deletion, functional inactivation(anergy) and immunosupression. At this latter level, it appears that certain pathogens produce immunosupresive cytokine-like mediators or provoke like host the secrete cytokines that will compromise the anti-parasite immune response. It appears that immune responses that preferentially involve T helper l cells (secretors of interleukin-2-and interferon-y) tend to be protective, whereas T helper 2 cells (secretors of IL-4, IL5, IL-6, and IL-10), a population that antagonizes T helper cells, mediate disease susceptibility and are immunopathological reactions. Cytokines produced by T helper 2 cells mediate many symptoms of infection, including eosinophilia, mastocytosis, hyperimmunoglobulinemia, and elevated IgE levels. Administration of IL-2 and IFN-y has beneficial effects in many infections mediated by viruses, bacteria, and protozoa. The use of live vaccinia virus might be an avenue for the treatment of or vaccination against infection. We have found that a vaccinia virus expressing the gene for human IL-2, though attenuated, precipitates autoimmune disease in immunodeficient athymic mice. Thus, although T helper l cytokines may have desired immunostimulatory properties, they also may lead to unwarranted autoaggressive responses