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INTRODUCTION: Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling. METHODS: Patients had intermediate- or high-risk smoldering multiple myeloma. Patients with QT interval corrected by Fridericias formula (QTcF) > 470 ms, QRS interval ≥ 110 ms, or PR interval ≥ 200 ms were excluded. Triplicate ECGs were collected at screening, Dose 1, and Dose 8. Analyses of on-treatment ECGs were conducted with a time-matched baseline (primary analysis). By time-point, pharmacokinetic-pharmacodynamic (PK/PD), and outlier analyses were conducted. RESULTS: Of 123 patients in CENTAURUS, 31 were enrolled in the QTc substudy. Daratumumab produced a small increase in heart rate (5-12 beats per minute) of unclear significance. There was a small but clinically insignificant effect on QTc, as measured by both time-matched time-point and PK/PD analyses. The primary analysis demonstrated a maximum mean increase in QTcF of 9.1 ms (90% 2-sided upper confidence interval [CI], 14.1 ms). The primary PK/PD analysis predicted a maximum QTcF increase of 8.5 ms (90% 2-sided upper CI, 13.5 ms). No patient had an abnormal U wave, a new QTcF > 500 ms, or > 60 ms change from baseline for QTcF. CONCLUSION: Analysis of ECG intervals and concentration-QTc relationships showed a small but clinically insignificant effect of daratumumab. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02316106.

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014-0.096), 0.102 (80% CI, 0.044-0.160), and 0.206 (80% CI, 0.118-0.295), respectively, translating to a median PFS ≥24 months in all arms (P

The increasing usage of electrical energy storage solutions demands for cost effective, scalable and sustainable manufacturing technologies. Deposition of functional inks, carrying electrochemically active materials is a suitable technique as it delivers material with selected properties only to required locations. However, the production of stable dispersions featuring high concentrations of active material ‐ necessary for effective deposition ‐ is challenging. Here we present an approach to print supercapacitor electrodes with onion‐like carbon as active material, using a simple, cost‐effective process as well as a water‐based ink. The ink is highly stable and can be deposited by spray and inkjet techniques. The fabricated electrodes offer a capacitance of up to 14 mF cm−2 (27 F g−1) and retained 97 % of their initial capacitance after 5000 cycles, demonstrating excellent performance and stability of the coating. [ABSTRACT FROM AUTHOR]

Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Because of their unique biology, developing effective methods to eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic overexpression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential. Further, we report that the central metabolic stress regulator AMPK is also intrinsically activated in LSC populations and is upstream of FIS1. Inhibition of AMPK signaling recapitulates the biological effect of FIS1 loss. These data suggest a model in which LSCs co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation.

Lithium‐ion batteries are widely used in various industrial and consumer applications. One key point is the thermal stability of these batteries regarding safety. Thermogravimetric analysis and differential scanning calorimetry (DSC) are ideal methods to study the thermal properties of differently charged electrode materials without safety issues associated with thermal runaway tests of the complete cell. This study shows a significant relationship between state of charge (SOC) and power released by the electrode material during the heating process. For the utilized cathode material LixCoO2, a linear relationship is apparent between the decomposition temperature and the decomposition energy, enabling estimation of the SOC. The decomposition temperature of differently charged anode material strongly correlates with the selected heating rate. This study reveals substantial dependencies of the measured power on the utilized crucibles, providing a systematic approach to benchmark the impact of crucible type on observed DSC signals during battery component analysis. [ABSTRACT FROM AUTHOR]

Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meisl as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either Mill or Dotll in MN1-expressing cells abrogated the cell of origin-derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mill or Dotll impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical [MN1.sup.hi] leukemia, and human [MN1.sup.hi]/[HOXA9.sup.hi] leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in [MN1.sup.hi] AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML., Introduction The meningioma-1 (MN1) gene is frequently overexpressed in acute myeloid leukemia (AML) and is associated with a poor prognosis (1-5). High MN1 expression occurs across multiple cytogenetic and molecular [...]