Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease

Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S. Food and Drug Administration-approved glucosylceramide synthase inhibitor, reduced osteoclast-driven bone loss in preclinical in vivo models of myeloma. In combination with zoledronic acid, a bisphosphonate that treats myeloma bone disease, eliglustat provided further protection from bone loss. Autophagic degradation of TRAF3, a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. Eliglustat blocked autophagy by altering glycosphingolipid composition whilst restoration of missing glycosphingolipids rescued autophagy markers and TRAF3 degradation thus restoring osteoclastogenesis in bone marrow cells from myeloma patients. This work delineates both the mechanism by which glucosylceramide synthase inhibition prevents autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the clinical translational potential of eliglustat for the treatment of myeloma bone disease

Effects of hypoxaemia and bradycardia on neonatal cerebral haemodynamics.

Near infrared spectroscopy has been used to assess the effects of bradycardia and hypoxia on the cerebral circulation in the premature neonate. The technique is well tolerated and can be applied in almost any infant. Continuous monitoring of changes in cerebral oxygenated, deoxygenated, and total haemoglobin is possible. Total haemoglobin is analogous to cerebral blood volume; thus information on circulatory changes as well as oxygenation state can be obtained. Twenty five babies had cerebral monitoring carried out using this technique. During episodes of hypoxia, both spontaneous and induced, impairment of haemoglobin oxygenation within the brain was detected together with an overall increase in the total mean haemoglobin concentration, which was 0.8 x 10(-2) mmol/l. Bradycardia with apnoea also led to impairment of cerebral oxygenation, and to a rapid fall in the concentration of total mean haemoglobin to 1.4 x 10(-2) mmol/l, which was followed in some cases by an increase to above the resting value on recovery of the heart rate to a mean of 0.7 x 10(-2) mmol/l. These disturbances to total haemoglobin concentration represent abnormalities of cerebral blood volume that may be implicated in the pathogenesis of neonatal cerebral injury

Determination of the number of J/ψ events with inclusive J/ψ decays

A measurement of the number of J/ψ events collected with the BESIII detector in 2009 and 2012 is performed using inclusive decays of the J/ψ. The number of J/ψ events taken in 2009 is recalculated to be (223.7 ± 1.4) × 106, which is in good agreement with the previous measurement, but with significantly improved precision due to improvements in the BESIII software. The number of J/ψ events taken in 2012 is determined to be (1086.9 ± 6.0) × 106. In total, the number of J/ψ events collected with the BESIII detector is measured to be (1310.6 ± 7.0) × 106, where the uncertainty is dominated by systematic effects and the statistical uncertainty is negligible

Measurements of the center-of-mass energies at BESIII via the di-muon process

From 2011 to 2014, the BESIII experiment collected about 5 fb-1 data at center-of-mass energies around 4 GeV for the studies of the charmonium-like and higher excited charmonium states. By analyzing the di-muon process e+e- → γISR/FSRμ+μ-, the center-of-mass energies of the data samples are measured with a precision of 0.8 MeV. The center-of-mass energy is found to be stable for most of the time during data taking