Approximately 50% of cancer patients receive radiation treatment, either alone or in combination with other therapies. Tumor hypoxia has long been associated with resistance to radiation therapy. Moreover, the expression of hypoxia inducible factors HIF1␣ and/or HIF2␣ correlates with poor prognosis in many tumors. Recent evidence indicates that HIF1␣ expression can enhance radiation-induced apoptosis in cancer cells. We demonstrate here that HIF2␣ inhibition promotes tumor cell death and, in contrast to HIF1␣, enhances the response to radiation treatment. Specifically, inhibiting HIF2␣ expression augments p53 activity, increases apoptosis, and reduces clonogenic survival of irradiated and non-irradiated cells. Moreover, HIF2␣ inhibition promotes p53-mediated responses by disrupting cellular redox homeostasis, thereby permitting reactive oxygen species (ROS) accumulation and DNA damage. These results correlate with altered p53 phosphorylation and target gene expression in untreated human tumor samples and show that HIF2␣ likely contributes to tumor cell survival including during radiation therapy.M any cellular responses to hypoxia are mediated by the hypoxia inducible factors (HIFs). These transcription factors promote the expression of over 200 genes (1) and are heterodimers consisting of either HIF1␣ or HIF2␣ bound to the HIF/ARNT subunit. While ARNT is constitutively expressed, both HIF␣ subunits are regulated by O 2 availability. Under normoxia, the von Hippel-Lindau (VHL) E3 ligase complex targets HIF␣ subunits for proteasomal degradation (2). When O 2 levels decline, the HIF␣ subunits are stabilized, bind ARNT, and activate the expression of target genes providing hypoxic adaptations.Solid tumors are characterized by oncogenic signaling and hypoxic microenvironments that promote HIF␣ accumulation (3). Moreover, HIF1␣ and/or HIF2␣ expression has been associated with increased tumor vascularization and poor prognosis of numerous cancers such as breast, ovarian, and non-small cell lung cancer (2, 4). Of note, in mouse xenograft models, HIF2␣ (and not HIF1␣) expression is crucial for growth of clear cell renal cell carcinoma (ccRCC) (5, 6) and neuroblastoma (7) tumors.TP53 is a tumor suppressor that is mutated or silenced in a majority of human cancers (8). It coordinates many cellular stress responses by regulating genes involved in DNA repair, cell cycle arrest, and apoptosis. Following stress stimuli, p53 is activated through a variety of post-translational modifications, including phosphorylation on serine 15 (9). For example, the ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (Chk2) kinases directly phosphorylate p53 in response to DNA damage, resulting in its activation (9). Although many tumors select for TP53 mutations, p53 pathway inhibition can also contribute to tumor progression (10).With the emergence of HIF inhibitors (11,12) and their potential use in cancer therapy, it is important to accurately predict the response of HIF␣-expressing tumor cells to treatment. HIF1␣ appears to enh...
The neural and emotional impact of RPEs is intact in major depression. These results suggest that depression does not affect the expression of dopaminergic RPEs and that attenuated RPEs in previous reports may reflect downstream effects more closely related to aberrant behavior. The correlation between symptom severity and baseline mood parameters supports an association between depression and momentary mood fluctuations during cognitive tasks. These results demonstrate a potential for smartphones in large-scale computational phenotyping, which is a goal for computational psychiatry.
The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-1α (HIF-1α) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vhl R/R ). Vhl R/R mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2α isoform, was upregulated in ES cells and tissues from Vhl R/R mice. Furthermore, we observed a striking phenotype in Vhl R/R spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl R/R splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2α genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl R/R mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics.
The authors argue that there is a need to transcend conceptualizations of the hidden curriculum as antithetical to humanism and offer suggestions for future research that explores the necessity and value of humanism and the hidden curriculum in medical education and training.
The first orthogonal combinatorial synthesis of a high-purity triazine library was demonstrated. Novel triazine-based microtubule inhibitors were discovered by an efficient zebrafish embryo screening and in vitro microtubule polymerization assay.
IntroductionReduced motivation is an important symptom of major depression, thought to impair recovery by reducing opportunities for rewarding experiences. We characterized motivation for monetary outcomes in depressed outpatients (N = 39, 22 female) and controls (N = 22, 11 female) in terms of their effectiveness in seeking rewards and avoiding losses. We assessed motivational function during learning of associations between stimuli and actions, as well as when learning was complete. We compared the activity within neural circuits underpinning these behaviors between depressed patients and controls.MethodsWe used a Go/No-Go task that assessed subjects’ abilities in learning to emit or withhold actions to obtain monetary rewards or avoid losses. We derived motivation-relevant parameters of behavior (learning rate, Pavlovian bias, and motivational influence of gains and losses). After learning, participants performed the task during functional magnetic resonance imaging (fMRI). We compared neural activation during anticipation of action emission vs. action inhibition, and for actions performed to obtain rewards compared to actions that avoid losses.ResultsDepressed patients showed a similar Pavlovian bias to controls and were equivalent in terms of withholding action to gain rewards and emitting action to avoid losses, behaviors that conflict with well-described Pavlovian tendencies to approach rewards and avoid losses. Patients were not impaired in overall performance or learning and showed no abnormal neural responses, for example in bilateral midbrain or striatum. We conclude that basic mechanisms subserving motivated learning are thus intact in moderate depression.ImplicationsTherapeutically, the intact mechanisms identified here suggest that learning-based interventions may be particularly effective in encouraging recovery. Etiologically, our results suggest that the severe motivational deficits clinically observed in depression are likely to have complex origins, possibly related to an impairment in the representation of future states necessary for long-term planning.
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