High-dose carfilzomib achieves superior anti-tumor activity over lowdose and recaptures response in relapsed/refractory multiple myeloma resistant to low-dose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex

The optimal carfilzomib dosing is a matter of debate. We analyzed the inhibition profiles of proteolytic proteasome subunits β5, β2 and β1 after low-dose (20/27 mg/m2) versus high-dose (≥36 mg/m2) carfilzomib in 103 pairs of peripheral blood mononuclear cells from patients with relapsed/refractory (RR) multiple myeloma (MM). β5 activity was inhibited (median inhibition >50%) in vivo by 20 mg/m2, whereas β2 and β1 were co-inhibited only by 36 and 56 mg/m2, respectively. Co-inhibition of β2 (P=0.0001) and β1 activity (P=0.0005) differed significantly between high-dose and low-dose carfilzomib. Subsequently, high-dose carfilzomib showed significantly more effective proteasome inhibition than low-dose drug in vivo (P=0.0003). We investigated the clinical data of 114 patients treated with carfilzomib combinations. High-dose carfilzomib demonstrated a higher overall response rate (P=0.03) and longer progression-free survival (PFS) (P=0.007) than low-dose carfilzomib. Therefore, we escalated the carfilzomib dose to ≥ 36 mg/m2 in 16 patients who progressed during low-dose carfilzomib-containing therapies. High-dose carfilzomib recaptured response (≥ partial remission) in 9 (56%) patients with a median PFS of 4.4 months. Altogether, we provide the first in vivo evidence in RRMM patients that the molecular activity of high-dose carfilzomib differs from that of low-dose carfilzomib by co-inhibition of β2 and β1 proteasome subunits and, consequently, high-dose carfilzomib achieves a superior anti-MM effect than low-dose and recaptures response in RRMM being resistant to low-dose carfilzomib. The optimal carfilzomib dose should be ≥ 36 mg/m2 to reach a sufficient anti-tumor activity, while the balance between efficacy and tolerability should be considered in each patient.Bio-organic Synthesi

Vibronic state specific predissociation rates from excited electronic states

It is shown that predissociation can be perceived as a primary process due to the continuum part of a Morse oscillator potential. In the model proposed here internal conversion to the ground state is thus not necessarily the primary process of a consecutive dissociation but may be a simultaneous decay. As a consequence, dissociation rates should show strong variations from specific (ro-) vibrational states of the first excited electronic states that are similar to those known from “pure” internal conversion rates. This behaviour is demonstrated by calculating predissociation rates for the $\rm C_6H_6 \rightarrow C_6H_5 + H$ process. Especially the out-of-plane modes seem to play an extraordinary role in the excess energy behaviour of the predissociation rate. At lower excess energies, rates from single vibronic levels with out-of-plane mode characteristics may show an increase by several orders of magnitude

12. Februar 1917

Stadtarchiv Solingen, Bergische Arbeiterstimme 12. Februar 1917 Die Geschäftsleitung der „Freien Presse“ in Elberfeld setzt ein neue Redaktion ein. Damit wird aus dem Organ der Minderheit eine Zeitung der Mehrheitssozialdemokratie              Aus der Partei.              Die „Freie Presse“.    An der Spitze der „Freien Presse“ in Elberfeld lesen wir folgendes:                       An unsere Leser!    Der Kriegszustand und seine Begleiterscheinungen bringen, wie für fast alle Staatsbür..