Dose Reduction versus Dose-interval Prolongation in Eribulin Mesilate Monotherapy in Patients with Metastatic Breast Cancer: A Retrospective Comparative Study.

It is often necessary to modify the dose or schedule of eribulin mesilate (Eri) because of adverse events. Therefore, we retrospectively investigated the optimal approach for Eri dose adjustment and/or dosage interval adjustment. Patients who received Eri at the institutions affiliated with the Division of Oncology of the Aichi Prefectural Society of Hospital Pharmacists between July 2011 and November 2013 were enrolled in this study. We compared the group that underwent dose reduction without changes to their dosage interval (dose reduction group) with the group that had a change in their dosage interval (dose-interval prolongation group). The primary end-point was time to treatment failure (TTF), and the secondary end-points were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and adverse events. The TTF and OS of the dose reduction group were approximately two times longer than those of the dose-interval prolongation group. In addition, the dose reduction group had significantly improved ORR and CBR, which together indicate an antitumor effect (p=0.013 and 0.002, respectively). Although peripheral neuropathy occurred significantly more frequently in the patients in the dose reduction group (p=0.026), it was grade 1 and controllable in most of the cases. There were no differences in the occurrence of other adverse effects between the two groups. Therefore, we suggest that dose reduction with maintenance of the dosage interval is the preferred treatment approach in cases where Eri dose or schedule modification is necessary.

Evidence for a stable association of Psb30 (Ycf12) with photosystem II core complex in the cyanobacterium Synechocystis sp. PCC 6803.

Ycf12 (Psb30) is a small hydrophobic subunit of photosystem II (PS II) complexes found in the cyanobacterium, Thermosynechococcus elongatus. However, earlier intense proteomic analysis on the PS II complexes from the cyanobacterium, Synechocystis 6803, could not detect Psb30. In this work, we generated a mutant of Synechocystis 6803 in which a hexa-histidine tag was fused to the C-terminus of Synechocystis Psb30. The mutant accumulated fully functional PS II complexes. Purification of Psb30 by metal affinity chromatography from thylakoid extracts resulted in co-purification of an oxygen-evolving PS II complex with normal subunit composition. This result indicates that Psb30 is expressed and stably associated with the PS II complex in Synechocystis. The histidine-tagged Psb30 in the purified PS II complex was not detected by staining or anti-polyhistidine antibodies. We also generated a mutant in which ycf12 was disrupted. The mutant grew photosynthetically and showed no significant phenotype under moderate growth conditions. Purified PS II complexes from the disruptant showed an oxygen-evolving activity comparable to wild type under low irradiance. However, it showed a remarkably lower activity than wild type under high irradiance. Thus Psb30 is required for the efficient function of PS II complexes, particularly under high irradiance conditions.

Ycf12 is a core subunit in the photosystem II complex.

The latest crystallographic model of the cyanobacterial photosystem II (PS II) core complex added one transmembrane low molecular weight (LMW) component to the previous model, suggesting the presence of an unknown transmembrane LMW component in PS II. We have investigated the polypeptide composition in highly purified intact PS II core complexes from Thermosynechococcus elongatus, the species which yielded the PS II crystallographic models described above, to identify the unknown component. Using an electrophoresis system specialized for separation of LMW hydrophobic proteins, a novel protein of approximately 5 kDa was identified as a PS II component. Its N-terminal amino acid sequence was identical to that of Ycf12. The corresponding gene is known as one of the ycf (hypothetical chloroplast reading frame) genes, ycf12, and is widely conserved in chloroplast and cyanobacterial genomes. Nonetheless, the localization and function of the gene product have never been assigned. Our finding shows, for the first time, that ycf12 is actually expressed as a component of the PS II complex in the cell, revealing that a previously unidentified transmembrane protein exists in the PS II core complex.