Synergistic Strategies for KMT2A-Rearranged Leukemias: Beyond Menin Inhibitor.

KMT2A-rearranged leukemias are a highly aggressive subset of acute leukemia, characterized by poor prognosis and frequent relapses despite intensive treatment. Menin inhibitors, which target the critical KMT2A-menin interaction driving leukemogenesis, have shown promise in early clinical trials. However, resistance to these inhibitors, often driven by menin mutations or alternative oncogenic pathways, remains a significant challenge.

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.

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.

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

Introduction: The seeds of wild pea () 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.

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.

Long-term psychological outcomes following stroke: the OX-CHRONIC study.

Background: Stroke survivors rate longer-term (> 2 years) psychological recovery as their top priority, but data on how frequently psychological consequences occur is lacking. Prevalence of cognitive impairment, depression/anxiety, fatigue, apathy and related psychological outcomes, and whether rates are stable in long-term stroke, is unknown.

Methods: N = 105 long-term stroke survivors (M [SD] age = 72.

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML.

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown.

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction.

Advances in the clinical management of pediatric B-cell acute lymphoblastic leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases.

A human genome editing-based MLL::AF4 ALL model recapitulates key cellular and molecular leukemogenic features.

Cellular ontogeny and MLL breakpoint site influence the capacity of MLL-edited CD34+ hematopoietic cells to initiate and recapitulate infant patients' features in pro-B-cell acute lymphoblastic leukemia (B-ALL). We provide key insights into the leukemogenic determinants of MLL-AF4+ infant B-ALL.

Development and pilot of a community low-vision, service-specific Patient-Reported Experience Measure.

Purpose: Patient-Reported Experience Measures (PREMs) act to identify the patient's objective experience while receiving care. PREM data can provide feedback to professionals on patients' personal experience of care processes, quality of care and insight into patient expectations. This can support service improvements and person-centeredness of care.

An Automated, Home-Cage, Video Monitoring-based Mouse Frailty Index Detects Age-associated Morbidity in C57BL/6 and Diversity Outbred Mice.

Frailty indexes (FIs) provide quantitative measurements of nonspecific health decline and are particularly useful as longitudinal monitors of morbidity in aging studies. For mouse studies, frailty assessments can be taken noninvasively, but they require handling and direct observation that is labor-intensive to the scientist and stress inducing to the animal. Here, we implement, evaluate, and provide a refined digital FI composed entirely of computational analyses of home-cage video and compare it to manually obtained frailty scores in both C57BL/6 and genetically heterogeneous Diversity Outbred mice.

Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.

Background: Improving the poor prognosis of infant leukaemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven paediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity.

The genetic architecture of flowering time changes in pea from wild to crop.

Change in phenology has been an important component in crop evolution, and selection for earlier flowering through a reduction in environmental sensitivity has helped broaden adaptation in many species. Natural variation for flowering in domesticated pea (Pisum sativum L.) has been noted and studied for decades, but there has been no clear account of change relative to its wild progenitor.

Identification of a c-MYB-directed therapeutic for acute myeloid leukemia.

A significant proportion of patients suffering from acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, relapsed disease being a common problem. Molecular targeting of essential oncogenic mediators is an attractive approach to improving outcomes for this disease. The hematopoietic transcription factor c-MYB has been revealed as a central component of complexes maintaining aberrant gene expression programs in AML.

Accelerated decline in white matter microstructure in subsequently impaired older adults and its relationship with cognitive decline.

Little is known about a longitudinal decline in white matter microstructure and its associations with cognition in preclinical dementia. Longitudinal diffusion tensor imaging and neuropsychological testing were performed in 50 older adults who subsequently developed mild cognitive impairment or dementia (subsequently impaired) and 200 cognitively normal controls. Rates of white matter microstructural decline were compared between groups using voxel-wise linear mixed-effects models.

Long-term psychological consequences of stroke (OX-CHRONIC): A longitudinal study of cognition in relation to mood and fatigue after stroke: Protocol.

Background: The long-term psychological consequences of stroke and how cognitive problems change over time after the first-year following stroke remain unclear. Particularly, trajectories of domain-specific and domain-general cognitive functions and how cognition interacts with mood, fatigue and quality of life are not well described.

Aims: To determine the prevalence, trajectories and wider impact of domain-specific cognitive impairment in long-term stroke survivors, in relation to mood, fatigue and quality of life.

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.

KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs.

Unravelling the complex interactions between self-awareness, cognitive change, and mood at 6-months post-stroke using the Y-shaped model.

We investigated the relationships between cognitive change following stroke, awareness of cognitive impairments, and mood to further understanding of change processes influencing psychological outcomes post-stroke in line with the "Y-shaped" process model. Patients ( = 143;  = 73 years, SD = 13.73; 74 males) were assessed at 3-weeks (T1) and 6-months (T2) post-stroke and had completed the Oxford Cognitive Screen (T1 and T2), the Cognitive Failures Questionnaire (CFQ; T2), and the Hospital Anxiety and Depression Scale (HADS; T2).

Learning white matter subject-specific segmentation from structural MRI.

Purpose: Mapping brain white matter (WM) is essential for building an understanding of brain anatomy and function. Tractography-based methods derived from diffusion-weighted MRI (dMRI) are the principal tools for investigating WM. These procedures rely on time-consuming dMRI acquisitions that may not always be available, especially for legacy or time-constrained studies.

TractEM: Evaluation of protocols for deterministic tractography white matter atlas.

Reproducible identification of white matter pathways across subjects is essential for the study of structural connectivity of the human brain. One of the key challenges is anatomical differences between subjects and human rater subjectivity in labeling. Labeling white matter regions of interest presents many challenges due to the need to integrate both local and global information.

Drug Repurposing for Targeting Acute Leukemia With ()-Gene Rearrangements.

The treatment failure rates of acute leukemia with rearrangements of the Mixed Lineage Leukemia (MLL) gene highlight the need for novel therapeutic approaches. Taking into consideration the limitations of the current therapies and the advantages of novel strategies for drug discovery, drug repurposing offers valuable opportunities to identify treatments and develop therapeutic approaches quickly and effectively for acute leukemia with -rearrangements. These approaches are complimentary to de novo drug discovery and have taken advantage of increased knowledge of the mechanistic basis of MLL-fusion protein complex function as well as refined drug repurposing screens.

Default mode network connectivity and cognition in the aging brain: the effects of age, sex, and APOE genotype.

The default mode network (DMN) overlaps with regions showing early Alzheimer's Disease (AD) pathology. Age, sex, and apolipoprotein E ɛ4 are the predominant risk factors for developing AD. How these risk factors interact to influence DMN connectivity and connectivity-cognition relationships before the onset of impairment remains unknown.

Association of Depression and Anxiety With Cognitive Impairment 6 Months After Stroke.

Objective: To investigate the associations between general cognitive impairment and domain-specific cognitive impairment with depression and anxiety at 6 months poststroke.

Methods: Participants were patients with confirmed acute stroke from the OCS-Care Study who were recruited on stroke wards in a multisite study and followed up at a 6-month poststroke assessment. Depression and anxiety symptoms were assessed by the Hospital Anxiety and Depression Scale subscales, with scores greater than 7 indicating possible mood disorders.

Long-Term Consumption of Anthocyanin-Rich Fruit Juice: Impact on Gut Microbiota and Antioxidant Markers in Lymphocytes of Healthy Males.

Polyphenols are considered protective against diseases associated with oxidative stress. Short-term intake of an anthocyanin-rich fruit juice resulted in significantly reduced deoxyribonucleic acid (DNA) strand-breaks in peripheral blood lymphocytes (PBLs) and affected antioxidant markers in healthy volunteers. Consequently, effects of long-term consumption of fruit juice are of particular interest.