Predicting Mid-Life Capital Formation with Pre-School Delay of Gratification and Life-Course Measures of Self-Regulation

How well do pre-school delay of gratification and life-course measures of self-regulation predict mid-life capital formation? We surveyed 113 participants of the 1967–1973 Bing pre-school studies on delay of gratification when they were in their late 40’s. They reported 11 mid-life capital formation outcomes, including net worth, permanent income, absence of high-interest debt, forward-looking behaviors, and educational attainment. To address multiple hypothesis testing and our small sample, we pre-registered an analysis plan of well–powered tests. As predicted, a newly constructed and pre-registered measure derived from preschool delay of gratification does not predict the 11 capital formation variables (i.e., the sign-adjusted average correlation was 0.02). A pre-registered composite self-regulation index, combining preschool delay of gratification with survey measures of self-regulation collected at ages 17, 27, and 37, does predict 10 of the 11 capital formation variables in the expected direction, with an average correlation of 0.19. The inclusion of the preschool delay of gratification measure in this composite index does not affect the index\u27s predictive power. We tested several hypothesized reasons that preschool delay of gratification does not have predictive power for our mid-life capital formation variables

LKB1 Inactivation Dictates Therapeutic Response of Non-Small Cell Lung Cancer to the Metabolism Drug Phenformin

SummaryThe LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors

Fast Metabolic Response to Drug Intervention Through Analysis on a Miniaturized, Highly Integrated Molecular Imaging System

We report on a radiopharmaceutical imaging platform designed to capture the kinetics of cellular responses to drugs. Methods: A portable in vitro molecular imaging system comprising a microchip and a β-particle imaging camera permitted routine cell-based radioassays of small numbers of either suspended or adherent cells. We investigated the kinetics of responses of model lymphoma and glioblastoma cancer cell lines to ^(18)F-FDG uptake after drug exposure. Those responses were correlated with kinetic changes in the cell cycle or with changes in receptor tyrosine kinase signaling. Results: The platform enabled direct radioassays of multiple cell types and yielded results comparable to those from conventional approaches; however, the platform used smaller sample sizes, permitted a higher level of quantitation, and did not require cell lysis. Conclusion: The kinetic analysis enabled by the platform provided a rapid (∼1 h) drug screening assay

Attention diversion improves response inhibition of immediate reward, but only when it is beneficial: An fMRI Study

Deficits of self-control are associated with a number of mental state disorders. The ability to direct attention away from an alluring stimulus appears to aid inhibition of an impulsive response. However, further functional imaging research is required to assess the impact of shifts in attention on self-regulating processes. We varied the level of attentional disengagement in an functional magnetic resonance imaging (fMRI)-based Go/No-go task to probe whether diversion of attention away from alluring stimuli facilitates response inhibition. We used the attention-grabbing characteristic of faces to exogenously direct attention away from stimuli and investigated the relative importance of attention and response inhibition mechanisms under different delayed reward scenarios [i.e., where forgoing an immediate reward ($1) led to a higher ($10) or no payoff in the future]. We found that diverting attention improved response inhibition performance, but only when resistance to an alluring stimulus led to delayed reward. Region of interest analyses indicated significant increased activity in posterior right inferior frontal gyrus during successful No-go trials for delayed reward trials compared to no delayed reward trials, and significant reduction in activity in the superior temporal gyri and left caudate in contexts of high attentional diversion. Our findings imply that strategies that increase the perceived benefits of response inhibition might assist individuals in abstaining from problematic impulsive behaviors

Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA

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

The Structure-Function Linkage Database

The Structure–Function Linkage Database (SFLD, http://sfld.rbvi.ucsf.edu/) is a manually curated classification resource describing structure–function relationships for functionally diverse enzyme superfamilies. Members of such superfamilies are diverse in their overall reactions yet share a common ancestor and some conserved active site features associated with conserved functional attributes such as a partial reaction. Thus, despite their different functions, members of these superfamilies ‘look alike’, making them easy to misannotate. To address this complexity and enable rational transfer of functional features to unknowns only for those members for which we have sufficient functional information, we subdivide superfamily members into subgroups using sequence information, and lastly into families, sets of enzymes known to catalyze the same reaction using the same mechanistic strategy. Browsing and searching options in the SFLD provide access to all of these levels. The SFLD offers manually curated as well as automatically classified superfamily sets, both accompanied by search and download options for all hierarchical levels. Additional information includes multiple sequence alignments, tab-separated files of functional and other attributes, and sequence similarity networks. The latter provide a new and intuitively powerful way to visualize functional trends mapped to the context of sequence similarity