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The PML::RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML::RARA binding on gene expression and regulation in an inducible PML::RARA cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML::RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a computational machine learning implementation called Regulatory Element Behavior Extraction Learning to deconvolute the complex, local transcription factor binding site environment at PML::RARA bound positions to reveal distinct signatures that modulate how PML::RARA directs the transcriptional response. The PML-RARA gene fusion is the characteristic driver of Acute Promyelocytic Leukaemia (APL) and is known to bind to the genome. Here, the authors characterise the impact of PML-RARA on gene regulation in APL cell lines and patient samples using transcriptomics, epigenomics, and machine learning.

Measurable residual disease (MRD) is a key predictor of relapse, the primary cause of treatment failure after allogeneic haematopoietic cell transplantation (allo-HCT) in acute myeloid leukaemia. This Policy Review, based on guidance from the European Society for Blood and Marrow Transplantation, provides practical recommendations for incorporating MRD assessment into clinical decision making during the transplantation process, the application of which remains challenging in acute myeloid leukaemia due to technical limitations and the limited availability of standardised, evidence-based approaches. Available methods include reverse transcription quantitative PCR, digital droplet PCR, next-generation sequencing, and multiparametric flow cytometry—chimerism-based approaches are under investigation. This Policy Review highlights the importance of MRD monitoring to enable timely, risk-adapted interventions that encompass both pre-transplantation and post-transplantation periods and can include tailoring conditioning intensity, donor selection, immunosuppression management, donor lymphocyte infusions, and pharmacological therapies such as FLT3 or IDH inhibitors, hypomethylating agents, venetoclax, or menin inhibitors. These recommendations aim to harmonise MRD-driven clinical practice and improve patient outcomes, while identifying key areas for future research.

Co-stimulation is critical to the function of chimeric antigen receptor (CAR) T-cells. Previously, we demonstrated that dual co-stimulation can be effectively harnessed by a parallel (p)CAR architecture in which a CD28-containing second generation CAR is co-expressed with a 4-1BB containing chimeric co-stimulatory receptor (CCR). When compared to linear CARs, pCAR-engineered T-cells elicit superior anti-tumor activity in a range of pre-clinical models. Since CD19 is the best validated clinical target for cellular immunotherapy, we evaluated a panel of CD19-specific CAR and pCAR T-cells in this study. First, we generated a panel of single chain antibody fragments (scFvs) by alanine scanning mutagenesis of the CD19-specific FMC63 scFv (V H domain) and these were incorporated into second generation CD28+CD3ζ CARs. The resulting panel of CAR T-cells demonstrated a broad range of CD19 binding ability and avidity for CD19-expressing tumor cells. Each scFv-modified CAR was then converted into a pCAR by co-expression of an FMC63 scFv-targeted CCR with a 4-1BB endodomain. When compared to second generation CARs that contained an unmodified or mutated FMC63 scFv, each pCAR demonstrated a significant enhancement of tumor re-stimulation potential and IL-2 release, reduced exhaustion marker expression and enhanced therapeutic efficacy in mice with established Nalm-6 leukemic xenografts. These data reinforce the evidence that the pCAR platform delivers enhanced anti-tumor activity through effective provision of dual co-stimulation. Greatest anti-tumor activity was noted for intermediate avidity CAR T-cells and derived pCARs, raising the possibility that effector to target cell avidity is an important determinant of efficacy.

Background For patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive healthcare costs and negatively impacts quality of life (QoL). Venetoclax with low-dose cytarabine (VEN + LDAC) is a novel, low-intensity treatment for AML patients who cannot receive IC. VEN + LDAC is given as an outpatient and toxicity appears significantly lower than with IC. Analysis of clinical trials performed to date are promising for patients with the genotype NPM1 mut FLT3 ITD neg , where remission and survival rates appear comparable to those achieved with IC. Methods VICTOR is an international, two-arm, open-label, multi-centre, non-inferiority, randomised-controlled phase II trial to assess VEN + LDAC compared to standard of care (IC) as first-line treatment in older patients (initially aged ≥ 60 years) with newly diagnosed AML. The trial will recruit patients with a NPM1 mut FLT3 ITD neg genotype; those with a favourable risk in relation to the experimental treatment. University of Birmingham is the UK co-ordinating centre, with national hubs in Aarhus University Hospital, Denmark, and Auckland District Health Board, New Zealand. The primary outcome is molecular event-free survival time where an event is defined as failure to achieve morphological complete response (CR) or CR with incomplete blood count recovery after two cycles of therapy; molecular persistence, progression or relapse requiring treatment change; morphological relapse, or; death. Secondary outcomes include cumulative resource use at 12- and 24-months, and QoL as assessed by EORTCQLQ-C30 and EQ-5D-3L at 3-, 6-, 12-, 18- and 24-months. The trial employs an innovative Bayesian design with target sample size of 156 patients aged > 60 years. Discussion The principle underpinning the VICTOR trial is that the chance of cure for patients in the experimental arm should not be compromised, therefore, an adaptive design with regular checks on accumulating data has been employed, which will allow for a staged expansion of the trial population to include younger patients if, and when, there is sufficient evidence of non-inferiority in older patients. Trial registration EudraCT: 2020–000,273-24; 21-Aug-2020. ISRCTN: 15,567,173; 08-Dec-2020.

The hoary hypothesis of a Baptist source underlying Luke 1–2 is ventured anew, to see if it might benefit from a narrative appraisal of John's Nativity. The dramatis personae, besides the obvious ones, include the alternately bewildered, fearful, and joyous onlookers, who, with the virtuous parents, represent faithful Israel, deprived of the traditional site and personnel of its worship and finding in the wondrous birth the opening to an eschatological restoration. Parents and observers are joined in the plural voicing of the Benedictus, their exultant celebration of deliverance arriving from on high.

Dillon examines the term \"new evangelization\" in Mark 1:1-15. Ever since the international Synod of Catholic Bishops found it possible, in the fall of 2012, to devote four weeks to discussion of \"the new evangelization,\" the phrase has become something of a passe-partout in Catholic ministerial and educational endeavors. It might cause some discomfort to biblical scholars, however, who are probably not numerous among Vatican phrase-makers. After all, every evangelization worthy of the name is new, so the phrase is tautological. The term expresses a privileged moment of the spoken word, since the \"evangel\"--the \"gospel\"--is primarily and essentially oral, involving a unique exchange between speaker and listener, initiated by the Holy Spirit, of which St. Paul wrote memorably in Rom 10:17: \"Faith comes from hearing, and hearing is of the word of Christ.\"