Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.

Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in MLL-FP leukaemia. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy.

Epigenetic Therapies.

Epigenetic therapies are emerging for pediatric cancers. Due to the relatively low mutational burden in pediatric tumors, epigenetic dysregulation and differentiation blockade is a hallmark of oncogenesis in some childhood cancers. By targeting epigenetic regulators that maintain tumor cells in a primitive developmental state, epigenetic therapies may induce differentiation.

Labor Status at Delivery and Lung Function in Extremely Prematurely Born Young Adults.

Background: There has been conflicting evidence regarding the impact of mode of delivery on respiratory outcomes in later childhood and adulthood. It is possible labor status, rather than mode of delivery, influences later respiratory morbidity. We hypothesized that extremely premature infants born to mothers in labor would have better lung function at follow-up than those born to mothers not in labor.

Increased BMI Velocity is Associated with Elevated Patient Health Questionnaire-9 Scores in Adolescents with Obesity.

Existing studies that have demonstrated a positive association between obesity and depression have been among adults, did not utilize the Patient Health Questionnaire (PHQ), or were conducted in a homogenous patient population. In this retrospective longitudinal cohort study of patients >11 and <18 years old with obesity in one health system we analyzed associations between change in BMI between two BMI measurements and PHQ-9 scores using chi-square and Kruskal-Wallis tests. We used PHQ-9 scores dichotomized at View Article and Find Full Text PDF

PD-1 and CD73 on naive CD4 T cells synergistically limit responses to self.

Vaccination with self- and foreign peptides induces weak and strong expansion of antigen-specific CD4 T cells, respectively, but the mechanism is not known. In the present study, we used computational analysis of the entire mouse major histocompatibility complex class II peptidome to test how much of the naive CD4 T cell repertoire specific for self-antigens was shaped by negative selection in the thymus and found that negative selection only partially explained the difference between responses to self and foreign. In naive uninfected and unimmunized mice, we identified higher expression of programmed cell death protein 1 (PD-1) and CD73 mRNA and protein on self-specific CD4 T cells compared with foreign-specific CD4 T cells.

NUP98 fusion proteins and KMT2A-MENIN antagonize PRC1.1 to drive gene expression in AML.

Control of stem cell-associated genes by Trithorax group (TrxG) and Polycomb group (PcG) proteins is frequently misregulated in cancer. In leukemia, oncogenic fusion proteins hijack the TrxG homolog KMT2A and disrupt PcG activity to maintain pro-leukemogenic gene expression, though the mechanisms by which oncofusion proteins antagonize PcG proteins remain unclear. Here, we define the relationship between NUP98 oncofusion proteins and the non-canonical polycomb repressive complex 1.

Point-of-care procalcitonin trends in suspected neonatal late-onset infection: a prospective observational study.

Background: Procalcitonin-guided antimicrobial decision-making has been shown to be safe in adult intensive care settings. Most antimicrobial exposure in neonatal units is in culture-negative conditions. We hypothesise that Procalcitonin aids antimicrobial stewardship efforts in suspected Late-Onset Neonatal Sepsis.

Pediatric Obesity Pharmacotherapy: State of the Science, Research Gaps, and Opportunities.

Pediatric obesity is a major public health problem, affecting nearly 20% of children and adolescents living in the United States. In 2023, the American Academy of Pediatrics released its first clinical practice guideline for the evaluation and management of child and adolescent obesity and recommended integrating health behavior and lifestyle interventions with pharmacological treatment when medically indicated. However, there is a limited evidence base to guide antiobesity medication treatment decisions in clinical practice and limited data on long-term safety during this critical period of growth and development in youth.

Psychedelic research at a crossroads.

There is an urgent need to develop better treatments for mental health conditions that affect one in every eight people in the world. To combat this concern, psychedelic drugs have been combined with psychotherapy and studied in clinical trials in the United States and Europe. Psychedelics are hallucinogenic drugs that alter brain activity and facilitate altered states of consciousness.

3D-printed surfaces of titanium implant: the fibroblasts response.

Ti-6Al-4V (wt%) is the most widely used titanium alloy and its additive manufactured (or 3D printed) parts with near net-shape have provided great advantages for biomedical applications. While the impact of surface roughness on the biocompatibility of 3D-printed Ti-6Al-4V part is recognized, further exploration is needed to fully understand this complex relationship. Hence, this study presents a comprehensive evaluation of as-printed Ti-6Al-4V structures, both with and without surface texturing, with particular focus on the fibroblast response.

The Epidemiology of Psychedelic Use Among United States Military Veterans.

We sought to identify patterns of psychedelic use among United States military veterans, compare demographic variables and perspectives of those who did and did not report use, and characterize benefits and adverse outcomes associated with use. Respondents ( = 426) were recruited to complete an online cross-sectional survey. Approximately one-half (51%) reported using psychedelics.

Chronic consequences of accidental dural puncture and postdural puncture headache in obstetric anaesthesia - sieving through the evidence.

Purpose Of Review: Accidental dural puncture (ADP) and postdural puncture headache (PDPH) are relatively common complications of neuraxial anaesthesia and analgesia in obstetrics. Both may result in acute and chronic morbidity. This review intends to discuss the chronic implications of ADP and PDPH and raise awareness of severe and potentially life-threatening conditions associated with them.

Nurse-delivered sleep restriction therapy to improve insomnia disorder in primary care: the HABIT RCT.

Background: Insomnia is a prevalent and distressing sleep disorder. Multicomponent cognitive-behavioural therapy is the recommended first-line treatment, but access remains extremely limited, particularly in primary care where insomnia is managed. One principal component of cognitive-behavioural therapy is a behavioural treatment called sleep restriction therapy, which could potentially be delivered as a brief single-component intervention by generalists in primary care.

Precision medicine for Defence?

Proteins control individual patient's response to pharmaceutical medication, be they receptors, transporters or enzymes. These proteins are under the control of genes. The study of these genes and the interplay between multiple genes is pharmacogenomics, with individual genes being termed pharmacogenes.

Obesity in Adolescents: A Review.

Importance: Obesity affects approximately 21% of US adolescents and is associated with insulin resistance, hypertension, dyslipidemia, sleep disorders, depression, and musculoskeletal problems. Obesity during adolescence has also been associated with an increased risk of mortality from cardiovascular disease and type 2 diabetes in adulthood.

Observations: Obesity in adolescents aged 12 to younger than 18 years is commonly defined as a body mass index (BMI) at the 95th or greater age- and sex-adjusted percentile.

Bioregenerative dietary supplementation in space: Brassica rapa var. nipposinica and other Brassica cultivars.

Despite the precise environmental manipulation enabled by controlled environment agriculture (CEA), plant genotype remains a key factor in producing desirable traits. Brassica rapa var. nipposinica (mizuna) is a leading candidate for supplementing deficiencies in the space diet, however, which cultivar of mizuna will respond best to the environment of the international space station (ISS) is unknown.

Comparative Proteomics and Interactome Analysis of the SARS-CoV-2 Nucleocapsid Protein in Human and Bat Cell Lines.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19 and responsible for the global coronavirus pandemic which started in 2019. Despite exhaustive efforts to trace its origins, including potential links with pangolins and bats, the precise origins of the virus remain unclear. Bats have been recognized as natural hosts for various coronaviruses, including the Middle East respiratory coronavirus (MERS-CoV) and the SARS-CoV.

Patient perceptions of nurses' cultural competence in public sector hospitals in Gauteng.

Background: Healthcare institutions are increasingly receiving patients from diverse cultural backgrounds because of migration, rapid urbanisation, and easier access to healthcare. Because the satisfaction of these patients is linked to their perceptions of appropriate cultural care, understanding patient perspectives about cultural competence is imperative. Additionally, patient perceptions about nurses' cultural competence are largely unexplored in South Africa.