Really Trying or Merely Trying

We enjoy first-person authority with respect to a certain class of actions: for these actions, we know what we are doing just because we are doing it. This paper first formulates an epistemological principle that captures this authority in terms of trying to act in a way that one has the capacity to act. It then considers a case of effortful action – running a middle distance race – that threatens this principle. And proposes the solution of changing the metaphysics of action: one can keep hold of the idea that we have first-person authority over what we are doing by adopting a disjunctive account of action

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors

Glioblastoma multiforme (GBM) remains refractory to conventional therapy. CD133+ GBM cells have been recently isolated and characterized as chemo-/radio-resistant tumor-initiating cells and are hypothesized to be responsible for post-treatment recurrence. In order to explore the molecular properties of tumorigenic CD133+ GBM cells that resist treatment, we isolated CD133+ GBM cells from tumors that are recurrent and have previously received chemo-/radio-therapy. We found that the purified CD133+ GBM cells sorted from the CD133+ GBM spheres express SOX2 and CD44 and are capable of clonal self-renewal and dividing to produce fast-growing CD133− progeny, which form the major cell population within GBM spheres. Intracranial injection of purified CD133+, not CD133− GBM daughter cells, can lead to the development of YKL-40+ infiltrating tumors that display hypervascularity and pseudopalisading necrosis-like features in mouse brain. The molecular profile of purified CD133+ GBM cells revealed characteristics of neuroectoderm-like cells, expressing both radial glial and neural crest cell developmental genes, and portraying a slow-growing, non-differentiated, polarized/migratory, astrogliogenic, and chondrogenic phenotype. These data suggest that at least a subset of treated and recurrent GBM tumors may be seeded by CD133+ GBM cells with neural and mesenchymal properties. The data also imply that CD133+ GBM cells may be clinically indolent/quiescent prior to undergoing proliferative cell division (PCD) to produce CD133− GBM effector progeny. Identifying intrinsic and extrinsic cues, which promote CD133+ GBM cell self-renewal and PCD to support ongoing tumor regeneration may highlight novel therapeutic strategies to greatly diminish the recurrence rate of GBM

Hollow Victories: The Crisis in Collecting Unpaid Wages for California's Workers

This report exposes a surprising, but unfortunately common problem facing low-wage workers in California and nationwide. Workers whose employers have failed to pay them face serious challenges in recovering their hard-earned wages — even after state authorities have found in the workers’ favor and have issued a legally binding judgment ordering employers to pay. To a worker who has lost hundreds, if not thousands of dollars in unpaid wages, winning a judgment is often at best a hollow victory. Non-payment or underpayment of wages, moreover, remains rampant nationwide. As a landmark survey of low-wage workers found in 2008, 26 percent of low-wage workers were paid less than the minimum wage in the prior week; 76 percent of those who worked more than 40 hours were not paid the legally required overtime rate. More than two-thirds of low-wage workers have experienced at least one payrelated violation in the previous work week—leading workers to lose an average of $2,634 annually due to workplace violations

Hollow Victories: The Crisis in Collecting Unpaid Wages for California's Workers

This report exposes a surprising, but unfortunately common problem facing low-wage workers in California and nationwide. Workers whose employers have failed to pay them face serious challenges in recovering their hard-earned wages — even after state authorities have found in the workers’ favor and have issued a legally binding judgment ordering employers to pay. To a worker who has lost hundreds, if not thousands of dollars in unpaid wages, winning a judgment is often at best a hollow victory. Non-payment or underpayment of wages, moreover, remains rampant nationwide. As a landmark survey of low-wage workers found in 2008, 26 percent of low-wage workers were paid less than the minimum wage in the prior week; 76 percent of those who worked more than 40 hours were not paid the legally required overtime rate. More than two-thirds of low-wage workers have experienced at least one payrelated violation in the previous work week—leading workers to lose an average of $2,634 annually due to workplace violations

Probability and delay in commitment

In the first stage of a two-stage choice, human subjects chose between probabilistic access to a second choice (between a small high-probability reward and a large low-probability reward) and commitment to the large low-probability reward. When confronted with the second-stage choice, subjects strongly preferred the small high-probability reward. When the first-stage probability (of access to the second stage) was high, subjects strongly preferred the path leading to the choice in the second stage. But when the first-stage probability was low, subjects committed themselves to the large low-probability reward. These results parallel those obtained by Rachlin and Green (1972) with pigeons and constitute some evidence that probabilities may be interpreted as delays

Activation of ERBB4 in Glioblastoma Can Contribute to Increased Tumorigenicity and Influence Therapeutic Response

Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the juxtamembrane JM-a and cytoplasmic CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11% of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0 ± 3.2 months) than was no p-ERBB4 (22.5 ± 9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target