Relationship of Driver Oncogenes to Long-Term Pemetrexed Response in Non--Small-Cell Lung Cancer.

BackgroundPemetrexed is approved in the treatment of advanced stage nonsquamous non-small-cell lung cancer (NSCLC). The length of response is variable, and we thus sought to identify which clinicopathologic characteristics are associated with long-term disease control with pemetrexed.Patients and methodsPatients with metastatic NSCLC received pemetrexed (with or without bevacizumab) for 12 months or longer, either as maintenance treatment after first-line platinum-based chemotherapy or as subsequent treatment. Clinical and pathologic characteristics were collected.ResultsOf a total of 196 patients who received pemetrexed starting in 2007, 25 patients were identified who received pemetrexed for over 1 year. Of these, 15 patients received pemetrexed with or without bevacizumab as maintenance treatment and 10 patients received pemetrexed as subsequent treatment. Fifteen (60%) of 25 patients had an oncogenic driver mutation as follows: 5 (20%) had ROS1 gene rearrangements, 4 (16%) had ALK gene rearrangements, 3 (12%) had KRAS mutations, 2 (8%) had epidermal growth factor receptor (EGFR) mutations, and 1 (4%) had an NRAS mutation. The median overall survival was 42.2 months (95% confidence interval, 37.4-61.3) and median progression-free survival was 22.1 months (95% confidence interval, 15.1-29.1). Patients with an oncogenic driver mutation had significantly better progression-free survival (P = .006) and overall survival (P = .001).ConclusionAmong patients with NSCLC who received pemetrexed for an extended time, those with ALK and ROS1 gene rearrangements were proportionally overrepresented compared with that anticipated in a general nonsquamous NSCLC population, and patients with oncogenic driver mutations had improved outcomes

The Fisheries of the North Sea

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The Message in Our Music : What Popular Congregational Songs Say about Our Beliefs

Congregational singing is a source of basic theological instruction, both reflecting and shaping what we believe. It is crucial, therefore, that we say what we believe when we sing. In this study, the authors focused on the songs most accessed by users of the Christian Copyright Licensing, Inc. (CCLI) service between 2006-2012. Twenty songs were identified as having received significant usage during this time period. The results of this study found that a representative sampling of the lyrics of the most popular congregational songs did not sufficiently express foundational concepts of the Christian faith. Although individual congregations may have a systematic plan for teaching Christian theology in other parts of the church service than congregational singing, the high comparative use of the top songs listed suggests that very few systematic plans are used for congregational singing; that instead, a random selection of songs are used, with little regard to any formal theological training for the congregation, or to even attempt to more comprehensively reflect a specific doctrinal teaching in any single service. It is incumbent on pastors to avoid treating congregational singing as the “warm-up” for the “real” teaching time. It is also incumbent on church music leaders to either choose or compose songs that connect to a specific theological concept in a comprehensive, systematic, and not haphazard way

Deconstruction and Gauge Theories in AdS_5

On a slice of AdS_5, despite having a dimensionful coupling, gauge theories can exhibit logarithmic dependence on scale. In this paper, we utilize deconstruction to analyze the scaling behavior of the theory, both above and below the AdS curvature scale, and shed light on position-dependent regularizations of the theory. We comment on applications to geometries other than AdS.Comment: 15 pages, 1 figur

Role of arginase 2 in systemic metabolic activity and adipose tissue fatty acid metabolism in diet-induced obese mice

Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(−/−) or A1(+/−) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2−/−, but not A1+/−, mice. Additionally, A2−/− HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1α, PPAR-γ, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-α, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2−/− mice, but more prominently maintained in A1+/− mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction

Dendritic and axonal targeting patterns of a genetically-specified class of retinal ganglion cells that participate in image-forming circuits.

BackgroundThere are numerous functional types of retinal ganglion cells (RGCs), each participating in circuits that encode a specific aspect of the visual scene. This functional specificity is derived from distinct RGC morphologies and selective synapse formation with other retinal cell types; yet, how these properties are established during development remains unclear. Islet2 (Isl2) is a LIM-homeodomain transcription factor expressed in the developing retina, including approximately 40% of all RGCs, and has previously been implicated in the subtype specification of spinal motor neurons. Based on this, we hypothesized that Isl2+ RGCs represent a related subset that share a common function.ResultsWe morphologically and molecularly characterized Isl2+ RGCs using a transgenic mouse line that expresses GFP in the cell bodies, dendrites and axons of Isl2+ cells (Isl2-GFP). Isl2-GFP RGCs have distinct morphologies and dendritic stratification patterns within the inner plexiform layer and project to selective visual nuclei. Targeted filling of individual cells reveals that the majority of Isl2-GFP RGCs have dendrites that are monostratified in layer S3 of the IPL, suggesting they are not ON-OFF direction-selective ganglion cells. Molecular analysis shows that most alpha-RGCs, indicated by expression of SMI-32, are also Isl2-GFP RGCs. Isl2-GFP RGCs project to most retino-recipient nuclei during early development, but specifically innervate the dorsal lateral geniculate nucleus and superior colliculus (SC) at eye opening. Finally, we show that the segregation of Isl2+ and Isl2- RGC axons in the SC leads to the segregation of functional RGC types.ConclusionsTaken together, these data suggest that Isl2+ RGCs comprise a distinct class and support a role for Isl2 as an important component of a transcription factor code specifying functional visual circuits. Furthermore, this study describes a novel genetically-labeled mouse line that will be a valuable resource in future investigations of the molecular mechanisms of visual circuit formation

Robust Maximum- Likelihood Position Estimation in Scintillation Cameras

The classical maximum-likelihood (ML) estimator for the position of a scintillation event in a gamma camera, as derived by Gray and Macovski in 1976, requires exact knowledge of the light-spread function (LSF) of each photomultiplier tube. In practice, one must determine each LSF from noisy measurements corrupted by Poisson noise, quantization error, and electronic noise and bias. Since the ML position estimator involves derivatives of each LSF, even small measurement errors can result in degraded estimator performance. In this paper we derive a robust ML position estimator that accounts for the statistical uncertainty in LSF measurements. The form of the robust estimator diminishes contributions from the tails of the LSF, where the relative measurement errors are the largest.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85879/1/Fessler117.pd