Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that have either been recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.

Many large-scale studies revealed that exogenous erythropoietin, erythropoie-sis-stimulating agents, have no renoprotective effects. We investigated the effects of en-dogenous erythropoietin on renal function in ischemic reperfusion injury (IRI) of kidney using prolyl hydroxylase domaine (PHD) inhibitor, Roxadustat (ROX). 4 hr hypoxia (7% O2) and 4 hr treatment by ROX prior to IRI did not improve renal function. In contrast, 24-72 hr pre-treatment by ROX largely improved the decline of renal function by IRI. Hy-poxia and 4 hr ROX increased interstitial cells-derived Epo production by 75 and 6-fold, respectively, before IRI and worked as exogenous Epo. 24-72 hr ROX treatment increased Epo production during IRI by 9-fold. Immunohistochemistry revealed that 24 hr ROX caused Epo production in proximal and distal tubules and worked as endogenous Epo. Our data show that 24-72 hr ROX-induced tubular endogenous Epo production results in renoprotection but peritubular exogenous Epo production by interstitial cells-derived in-duced by hypoxia and 4 hr ROX did not. Stimulation of tubular but not peritubular Epo production may link to renoprotection.

The doctoral defense is an important step in the doctoral journey and an essential requirement for obtaining the doctoral degree. Past research on the doctoral defense has focused solely on national practices. In this work, I investigate the potential link between the doctoral defense format based on its major and minor elements and the perception of the defense by the student. For this purpose, I first reviewed the different defense formats used internationally to extract the different elements of the doctoral defense, as well as the literature on students’ perceptions of the doctoral defense. Then, I carried out an international survey which received 297 responses, of which 204 completed surveys which I used for the analysis in this article. I first analyzed the outcomes of the survey using qualitative and quantitative methods, and then cross-correlated the outcomes of defense format to the outcomes of student perception. From this analysis, I observe that the defense elements that positively impact the students’ perception are: publication of the thesis before the defense, receiving committee feedback before the defense, knowing the recommendation of one or more committee members in advance, having the supervisor present in the audience or as part of the committee, using a dress code, and including a laudatio. The final conclusion of this work is threefold. The first conclusion is that the details of the defense format impact most the students’ perception. The second conclusion is that doctoral students on average value the defense as a positive experience. The third conclusion is that the defense format cannot influence two important aspects of how a student perceives the defense: the student’s inner life and lived experience during the defense, and the behavior of the committee members.