Late chronotypes are associated with neoadjuvant chemotherapy-induced nausea and vomiting in women with breast cancer

Neoadjuvant chemotherapy, that is, the administration of chemotherapy before surgery, has been commonly used for locally advanced breast cancer to improve the surgical outcomes and increase the opportunity for breast-conserving therapy. Women with breast cancer often receive an anthracycline-based regimen as the neoadjuvant chemotherapy, which is associated with a high risk of emesis. Despite the development of novel antiemetics, chemotherapy-induced nausea and vomiting (CINV) has been commonly reported as a major adverse effect, affecting the quality of life of the patients. However, the factors predicting CINV in women with breast cancer undergoing neoadjuvant chemotherapy remain unclear. In this single-institution, prospective, observational study conducted at an outpatient cancer centre in the Republic of Korea from November 2013 to March 2016, we analysed women with breast cancer who planned to be treated with neoadjuvant chemotherapy before surgery. Candidate factors associated with CINV were assessed before neoadjuvant chemotherapy using the Munich Chronotype Questionnaire, Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale. CINV was assessed after chemotherapy by using the Multinational Association of Supportive Care in Cancer Antiemesis Tool. Of a total of 143 participants, 7 patients were lost to follow-up and 2 patients were excluded due to changes in their treatment plan; thus, 134 patients were finally included in the analyses. Overall, 48.5% of the participants experienced CINV, with delayed CINV prevalence (42.5%) being more common than acute (39.6%). In the univariate analyses, overall CINV was significantly associated with late chronotypes (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.37–8.87; p = 0.009), a history of nausea/vomiting (OR, 2.19; 95% CI, 1.10–4.37; p = 0.026) and anxiety (OR, 2.25; 95% CI, 1.05–4.81; p = 0.036). In the multivariate analyses, late chronotypes (OR, 3.53; 95% CI, 1.27–9.79; p = 0.015) and a history of nausea/vomiting (OR, 2.83; 95% CI, 1.31–6.13; p = 0.008) remained significantly associated with CINV. In conclusion, in women with breast cancer undergoing neoadjuvant chemotherapy before surgery, late chronotypes were found to have an increased risk of CINV; these data suggest that clinicians need to assess and consider the chronotype in the management of CINV.     

Control of the pericentrosomal H2O2 level by peroxiredoxin I is critical for mitotic progression

Proteins associated with the centrosome play key roles in mitotic progression in mammalian cells. The activity of Cdk1-opposing phosphatases at the centrosome must be inhibited during early mitosis to prevent premature dephosphorylation of Cdh1—an activator of the ubiquitin ligase anaphase-promoting complex/cyclosome—and the consequent premature degradation of mitotic activators. In this paper, we show that reversible oxidative inactivation of centrosome-bound protein phosphatases such as Cdc14B by H₂O₂ is likely responsible for this inhibition. The intracellular concentration of H₂O₂ increases as the cell cycle progresses. Whereas the centrosome is shielded from H₂O₂ through its association with the H₂O₂-eliminating enzyme peroxiredoxin I (PrxI) during interphase, the centrosome-associated PrxI is selectively inactivated through phosphorylation by Cdk1 during early mitosis, thereby exposing the centrosome to H₂O₂ and facilitating inactivation of centrosome-bound phosphatases. Dephosphorylation of PrxI by okadaic acid–sensitive phosphatases during late mitosis again shields the centrosome from H₂O₂ and thereby allows the reactivation of Cdk1-opposing phosphatases at the organelle.     

Lack of Significant Elevation of Myeloid-Derived Suppressor Cells in Peripheral Blood of Chronically Hepatitis C Virus-Infected Individuals

Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive function. Compared to the level in healthy controls (HC), no elevation of MDSC in chronic hepatitis C (cHEP-C) patients was found, and there was no difference in MDSC based on genotype or viral load (P > 0.25). Moreover, MDSC of cHEP-C patients inhibited CD8 T cell function as efficiently as MDSC of HC did. Since we detected neither quantitative nor qualitative differences in MDSC of cHEP-C patients relative to those of HC, we postulate that MDSC in peripheral blood are most likely not significant regarding immune dysfunction in cHEP-C.     

Regulation of c-Myc Expression by Ahnak Promotes Induced Pluripotent Stem Cell Generation

We have previously reported that Ahnak-mediated TGFβ signaling leads to down-regulation of c-Myc expression. Here, we show that inhibition of Ahnak can promote generation of induced pluripotent stem cells (iPSC) via up-regulation of endogenous c-Myc. Consistent with the c-Myc inhibitory role of Ahnak, mouse embryonic fibroblasts from Ahnak-deficient mouse (Ahnak^−/− MEF) show an increased level of c-Myc expression compared with wild type MEF. Generation of iPSC with just three of the four Yamanaka factors, Oct4, Sox2, and Klf4 (hereafter 3F), was significantly enhanced in Ahnak^−/− MEF. Similar results were obtained when Ahnak-specific shRNA was applied to wild type MEF. Of note, expressionof Ahnak was significantly induced during the formation of embryoid bodies from embryonic stem cells, suggesting that Ahnak-mediated c-Myc inhibition is involved in embryoid body formation and the initial differentiation of pluripotent stem cells. The iPSC from 3F-infected Ahnak^−/− MEF cells (Ahnak^−/−-iPSC-3F) showed expression of all stem cell markers examined and the capability to form three primary germ layers. Moreover, injection of Ahnak^−/−-iPSC-3F into athymic nude mice led to development of teratoma containing tissues from all three primary germ layers, indicating that iPSC from Ahnak^−/− MEF are bona fide pluripotent stem cells. Taken together, these data provide evidence for a new role for Ahnak in cell fate determination during development and suggest that manipulation of Ahnak and the associated signaling pathway may provide a means to regulate iPSC generation.