Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia

High frequencies of blasts in primary acute lymphoblastic leukaemia (ALL) samples have the potential to induce leukaemia and to engraft mice. However, it is unclear how individual ALL cells each contribute to drive leukaemic development in a bulk transplant and the extent to which these blasts vary functionally. We used cellular barcoding as a fate mapping tool to track primograft ALL blasts in vivo. Our results show that high numbers of ALL founder cells contribute at similar frequencies to leukaemic propagation over serial transplants, without any clear evidence of clonal succession. These founder cells also exhibit equal capacity to home and engraft to different organs, although stochastic processes may alter the composition in restrictive niches. Our findings enhance the stochastic stem cell model of ALL by demonstrating equal functional abilities of singular ALL blasts and show that successful treatment strategies must eradicate the entire leukaemic cell population

The MLL-Menin Interaction is a Therapeutic Vulnerability in <em>NUP98</em>-rearranged AML

\ua9 2023 Wolters Kluwer Health. All rights reserved. Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors

Measurement of the electron electric dipole moment using GdIG

A new method for the detection of the electron edm using a solid is described. The method involves the measurement of a voltage induced across the solid by the alignment of the samples magnetic dipoles in an applied magnetic field, H. A first application of the method to GdIG has resulted in a limit on the electron edm of 5E-24 e-cm, which is a factor of 40 below the limit obtained from the only previous solid-state edm experiment. The result is limited by the imperfect discrimination of an unexpectedly large voltage that is even upon the reversal of the sample magnetization.Comment: 10 pages, 5 figures, v2:references corrected, submitted to PRL, v3:added labels to figure

Asymptomatic cardiac disease following mediastinal irradiation

AbstractObjectivesThis study was designed to evaluate the potential benefit of screening previously irradiated patients with echocardiography.BackgroundMediastinal irradiation is known to cause cardiac disease. However, the prevalence of asymptomatic cardiac disease and the potential for intervention before symptom development are unknown.MethodsWe recruited 294 asymptomatic patients (mean age 42 ± 9 years, 49% men, mean mantle irradiation dose 43 ± 0.3 Gy) treated with at least 35 Gy to the mediastinum for Hodgkin's disease. After providing written consent, each patient underwent electrocardiography and transthoracic echocardiography.ResultsValvular disease was common and increased with time following irradiation. Patients who had received irradiation more than 20 years before evaluation had significantly more mild or greater aortic regurgitation (60% vs. 4%, p < 0.0001), moderate or greater tricuspid regurgitation (4% vs. 0%, p = 0.06), and aortic stenosis (16% vs. 0%, p = 0.0008) than those who had received irradiation within 10 years. The number needed to screen to detect one candidate for endocarditis prophylaxis was 13 (95% confidence interval [CI] 7 to 44) for patients treated within 10 years and 1.6 (95% CI 1.3 to 1.9) for those treated at least 20 years ago. Compared with the Framingham Heart Study population, mildly reduced left ventricular fractional shortening (<30%) was more common (36% vs. 3%), and age- and gender-adjusted left ventricular mass was lower (90 ± 27 g/m vs. 117 g/m) in irradiated patients.ConclusionsThere is a high prevalence of asymptomatic heart disease in general, and aortic valvular disease in particular, following mediastinal irradiation. Screening echocardiography should be considered for patients with a history of mediastinal irradiation

Critical and Non-Critical Einstein-Weyl Supergravity

We construct N=1 supersymmetrisations of some recently-proposed theories of critical gravity, conformal gravity, and extensions of critical gravity in four dimensions. The total action consists of the sum of three separately off-shell supersymmetric actions containing Einstein gravity, a cosmological term and the square of the Weyl tensor. For generic choices of the coefficients for these terms, the excitations of the resulting theory around an AdS_4 background describe massive spin-2 and massless spin-2 modes coming from the metric; massive spin-1 modes coming from a vector field in the theory; and massless and massive spin-3/2 modes (with two unequal masses) coming from the gravitino. These assemble into a massless and a massive N=1 spin-2 multiplet. In critical supergravity, the coefficients are tuned so that the spin-2 mode in the massive multiplet becomes massless. In the supersymmetrised extensions of critical gravity, the coefficients are chosen so that the massive modes lie in a "window" of lowest energies E_0 such that these ghostlike fields can be truncated by imposing appropriate boundary conditions at infinity, thus leaving just positive-norm massless supergravity modes.Comment: 29 page

Localized helium excitations in 4He_N-benzene clusters

We compute ground and excited state properties of small helium clusters 4He_N containing a single benzene impurity molecule. Ground-state structures and energies are obtained for N=1,2,3,14 from importance-sampled, rigid-body diffusion Monte Carlo (DMC). Excited state energies due to helium vibrational motion near the molecule surface are evaluated using the projection operator, imaginary time spectral evolution (POITSE) method. We find excitation energies of up to ~23 K above the ground state. These states all possess vibrational character of helium atoms in a highly anisotropic potential due to the aromatic molecule, and can be categorized in terms of localized and collective vibrational modes. These results appear to provide precursors for a transition from localized to collective helium excitations at molecular nanosubstrates of increasing size. We discuss the implications of these results for analysis of anomalous spectral features in recent spectroscopic studies of large aromatic molecules in helium clusters.Comment: 15 pages, 5 figures, submitted to Phys. Rev.

Third Order Renormalization Group applied to the attractive one-dimensional Fermi Gas

We consider a Callan-Symanzik and a Wilson Renormalization Group approach to the infrared problem for interacting fermions in one dimension with backscattering. We compute the third order (two-loop) approximation of the beta function using both methods and compare it with the well known multiplicative Gell-Mann Low approach. We point out a previously unnoticed qualitative dependence of the third order fixed point on an arbitrary dimensionless parameter, which strongly suggest the spurious nature of the fixed point.Comment: 16 pages, Revised version, added comment

Managing Nonmetastatic Castration-resistant Prostate Cancer.

CONTEXT:Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation. OBJECTIVE:To review current nmCRPC management practices and identify opportunities for improving care of nmCRPC patients. EVIDENCE ACQUISITION:A literature search up to July 2018 was conducted, including clinical trials and clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, European Association of Urology, Prostate Cancer Clinical Trials Working Group, Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence). Keywords included prostate cancer, nonmetastatic, castration resistance, rising PSA, and biochemical relapse. EVIDENCE SYNTHESIS:Recommendations regarding indications for, and frequency of, imaging and PSA testing, as well as for initiating systemic therapy in nmCRPC are based on PSA rise kinetics and symptoms. Both enzalutamide and apalutamide have been shown to significantly increase metastasis-free survival in phase III placebo-controlled randomised trials in nmCRPC patients with PSA doubling time (DT) ≤10 mo. The expected impact of new imaging techniques in the assessment of nmCRPC is also reviewed. CONCLUSIONS:nmCRPC is a heterogeneous disease; while observation may be an option for some patients, enzalutamide and apalutamide may be appropriate to treat nmCRPC patients with PSA-DT ≤10 mo. The emergence of more accurate imaging modalities as well as circulating tumour biomarker assays will likely redefine the assessment of nmCRPC in the near future. PATIENT SUMMARY:Herein, we review key literature and clinical practice guidelines to summarise the optimal management of patients with prostate cancer and rising prostate-specific antigen despite castrate testosterone levels, but with no evidence of distant metastasis on traditional imaging. New drugs are being developed for this disease setting; novel imaging and tumour biomarker blood tests are likely to define this disease state more accurately

Case Report:Immune dysregulation associated with long-lasting regression of a (pre)leukemic clone

Regression of leukemia in the absence of disease-modifying therapy remains poorly understood, although immunological mechanisms are thought to play a role. Here, we present a unique case of a 17-year-old boy with immune dysregulation and long-lasting regression of a (pre)leukemic clone in the absence of disease-modifying therapy. Using molecular and immunological analyses, we identified bone marrow features associated with disease control and loss thereof. In addition, our case reveals that detection of certain fusion genes with hardly any blasts in the bone marrow may be indicative of an accompanying oncogenic fusion gene, with implications for disease surveillance- and management in future patients.</p