A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer.

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m2 iv, on day one of a 28 days-cycle until progression. The Kaplan-Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects.Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016.

The transformation of targeted killing and international order.

This article introduces the special issue's question of whether and how the current transformation of targeted killing is transforming the global international order and provides the conceptual ground for the individual contributions to the special issue. It develops a two-dimensional concept of political order and introduces a theoretical framework that conceives the maintenance and transformation of international order as a dynamic interplay between its behavioral dimension in the form of violence and discursive processes and its institutional dimension in the form of ideas, norms, and rules. The article also conceptualizes targeted killing and introduces a typology of targeted-killing acts on the basis of their legal and moral legitimacy. Building on this conceptual groundwork, the article takes stock of the current transformation of targeted killing and summarizes the individual contributions to this special issue.

Antiprotozoal polyacetylenes from the Tanzanian medicinal plant Cussonia zimmermannii.

From the petroleum ether extract of the root bark of Cussonia zimmermannii four polyacetylenes, 1- 4, were isolated, three of which ( 1- 3) were active against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Plasmodium falciparum, and Leishmania donovani.

Novel plant substances acting as beta subunit isoform-selective positive allosteric modulators of GABAA receptors.

GABAA receptors are modulated by a large variety of compounds. A common chemical characteristic of most of these modulators is that they contain a cyclic entity. Three linear molecules of a polyacetylene structure were isolated from the East African medicinal plant Cussonia zimmermannii Harms and shown to allosterically stimulate GABAA receptors. Stimulation was not abolished by the absence of the gamma2 subunit, the benzodiazepine antagonist Ro15-1788 (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester), or the point mutation beta2N265S that abolishes effects by loreclezole. At a concentration of 30 microM, the substances by themselves elicited only tiny currents. Maximal stimulation at alpha1beta2gamma2 amounted to 110 to 450% for the three substances, and half-maximal stimulation was observed at concentrations of 1 to 2 muM. Stimulation was subunit composition-dependent and was for the substance MS-1, alpha1beta2gamma2 approximately alpha1beta2 approximately alpha3beta2gamma2 > alpha2beta2gamma2 > alpha5beta2gamma2 approximately alpha1beta3gamma2 approximately alpha6beta2gamma2 > alpha1beta1gamma2, for MS-2 alpha1beta2gamma2 approximately alpha3beta2gamma2 approximately alpha1beta2 > alpha2beta2gamma2 approximately alpha6beta2gamma2 approximately alpha5beta2gamma2 > alpha1beta1gamma2, and for MS-4, alpha1beta2gamma2 approximately alpha1beta2 approximately alpha5beta2gamma2 approximately alpha3beta2gamma2 approximately alpha2beta2gamma2 > alpha6beta2gamma2 >> alpha1beta1gamma2. Maximal stimulation by MS-1 was 450% at alpha1beta2gamma2, 80% at alpha1beta1gamma2, and 150% at alpha1beta3gamma2. MS-1 was thus specific for receptors containing the beta2 subunit. The reversal potential was unaffected by 10 microM MS-1, whereas apparent picrotoxin affinity for current inhibition was increased approximately 3-fold. In summary, these positive allosteric modulators of GABAA receptors of plant origin have a novel unusual chemical structure and act at a site independent of that of benzodiazepines and loreclezole.