cssi/SciSciGPT-SciSciNet huggingface dataset:
Phase I trial using patupilone (epothilone B) and concurrent radiotherapy for central nervous system malignancies.

Purpose Based on preclinical data indicating the radiosensitizing potential of epothilone B, the present study was designed to evaluate the toxicity and response rate of patupilone, an epothilone B, with concurrent radiotherapy (RT) for the treatment of central nervous system malignancies. Methods and Materials The present Phase I study evaluated the toxicities associated with patupilone combined with RT to establish the maximal tolerated dose. Eligible patients had recurrent gliomas ( n = 10) primary ( n = 5) or metastatic ( n = 17) brain tumors. Dose escalation occurred if no dose-limiting toxicities, defined as any Grade 4-5 toxicity or Grade 3 toxicity requiring hospitalization, occurred during treatment. Results Of 14 patients, 5 were treated with weekly patupilone at 1.5 mg/m 2 , 4 at 2.0 mg/m 2 , 4 at 2.5 mg/m 2 , and 1 at 4 mg/m 2 . Of 18 patients, 7 were treated in the 6-mg/m 2 group, 6 in the 8-mg/m 2 group, and 5 in the 10-mg/m 2 group. Primary central nervous system malignancies received RT to a median dose of 60 Gy. Central nervous system metastases received whole brain RT to a median dose of 37.4 Gy, and patients with recurrent gliomas underwent stereotactic RT to a median dose of 37.5 Gy. One dose-limiting toxicity (pneumonia) was observed in group receiving 8-mg/m 2 every 3 weeks. At the subsequent dose level (10 mg/m 2 ), two Grade 4 dose-limiting toxicities occurred (renal failure and pulmonary hemorrhage); thus, 8 mg/m 2 every 3 weeks was the maximal tolerated dose and the recommended Phase II dose. Conclusion Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone was well tolerated and safe, with a maximal tolerated dose of 8 mg/m 2 every 3 weeks.
Generalized gridding reconstruction from nonuniformly sampled data

Gridding reconstruction is a method to derive data on a Cartesian grid from a set of non-uniformly sampled measurements. This method is appreciated for being robust and computationally fast. However, it lacks solid analysis and design tools to quantify or minimize the reconstruction error. Least squares reconstruction, on the other hand, is another method which is optimal in the sense that it minimizes the reconstruction error. This method is computationally intensive and, in many cases, sensitive to measurement noise; hence it is rarely used in practice. Despite the seemingly different approaches of reconstruction, the gridding and least squares reconstruction methods are shown to be closely related. The similarity between these two methods is accentuated when they are properly expressed in a common matrix form. It is shown that the gridding algorithm can be considered an approximation to the least squares method. The optimal gridding parameters are defined as ones yielding the least approximation error. These parameters are calculated by minimizing the norm of an approximation error matrix. This method is used to find the optimal density compensation factors which minimize the weighted approximation error. An iterative method is also proposed for joint optimization of the interpolating kernel and the deapodization function. Some applications in magnetic resonance imaging are presented.
Relationship between Lipophilic Character and Anesthetic Activity

Abstract The structure‐activity relationships in the anesthetic action of a set of 26 aliphatic ethers were found to be parabolic functions of their octanol‐water partition coefficients. The results obtained with the gaseous anesthetics were compared with correlations obtained for various hypnotics acting from solution. It was found that optimum lipophilic character (defined as log P 0 from the octanol‐water system) is about 2.0 for general anesthetics, which is the same as that found for barbiturates, ureas, alcohols, etc .
Escape and avoidance responding in the toad

Southern toads, Bufo terrestris terrestris, were given 20 daily trials in a one-way avoidance box for five days. The frequency of no responses decreased, avoidance responses increased, and escape responses remained essentially the same. There was an increase in the number of avoidance responses in each daily session of trials, followed by a lower initial level of avoidance responding on the following day. An improvement in performance as measured by response latency was also observed. The pattern of response latencies was consistent with that of the avoidance responses in that there was a decline in response latency over daily trials with higher initial levels on the early trials of the following day.
Studies on malate dehydrogenases and aspartate aminotransferases from Neurospora crassa

Abstract Both mitochondrial and cytoplasmic forms of malic dehydrogenase and aspartate aminotransferase have been demonstrated in extracts of Neurospora crassa . The mitochondrial and cytoplasmic malic dehydrogenases can readily be distinguished from each other, and from the two forms of aminotransferase, by starch gel electrophoresis. Coenzyme analogs were used to demonstrate differences in the catalytic properties of the two forms of malic dehydrogenases. Resolution of Neurospora aspartate aminotransferase and malic dehydrogenase activities was obtained by gel filtration, and the two types of activity showed differing behavior during ammonium sulfate fractionation. The present data strongly implies that in N. crassa aspartate aminotransferase and malic dehydrogenase activities reside in distinct proteins. This is in marked contrast to previous reports that both types of enzymic activity in Neurospora extracts are associated with a single mitochondrial protein.
Influence of Spider Silk on Refugia Preferences of the Recluse Spiders Loxosceles reclusa and Loxosceles laeta (Araneae: Sicariidae)

In a previous experimental study, recluse spiders Loxosceles reclusa Gertsch and Mulaik and Loxosceles laeta (Nicolet) (Araneae: Sicariidae) preferred small cardboard refugia covered with conspecific silk compared with never-occupied refugia. Herein, we investigated some factors that might be responsible for this preference using similar cardboard refugia. When the two Loxosceles species were given choices between refugia previously occupied by their own and by the congeneric species, neither showed a species-specific preference; however, each chose refugia coated with conspecific silk rather than those previously inhabited by a distantly related cribellate spider, Metaltella simoni (Keyserling). When L. laeta spiders were offered refugia that were freshly removed from silk donors compared with heated, aged refugia from the same silk donor, older refugia were preferred. Solvent extracts of L. laeta silk were chosen approximately as often as control refugia when a range of solvents (methylene chloride:methanol, water, and hexane) were used. However, when acetone was used on similar silk, there was a statistical preference for the control, indicating that there might be a mildly repellent aspect to acetone-washed silk. Considering the inability to show attraction to chemical aspects of fresh silk, it seems that physical attributes may be more important for selection and that there might be repellency to silk of a recently vacated spider. These findings are discussed in regard to pest management strategies to control recluse spiders.
Frequency-selective MEMS for miniaturized communication devices

With Q's in the tens to hundreds of thousands, micromachined vibrating resonators are proposed as IC-compatible tanks for use in the low phase noise oscillators and highly selective filters of communications subsystems. To date, LF oscillators have been fully integrated using merged CMOS+microstructure technologies, and bandpass filters consisting of spring-coupled micromechanical resonators have been demonstrated in the HF range. In particular, two-resonator micromechanical bandpass filters have been demonstrated with frequencies up to 14.5 MHz, percent bandwidths on the order of 0.2%, and insertion losses less than 1 dB. Higher-order three-resonator filters with frequencies near 455 kHz have also been achieved, with equally impressive insertion losses for 0.09% bandwidths, and with more than 64 dB of passband rejection. Evidence suggests that the ultimate frequency range of this high-Q tank technology depends upon material limitations, as well as design constraints-in particular, to the degree of electromechanical coupling achievable in micro-scale resonators.
Moral kinematics: the role of physical factors in moral judgments.

Harmful events often have a strong physical component—for instance, car accidents, plane crashes, fist fights, and military interventions. Yet there has been very little systematic work on the degree to which physical factors influence our moral judgments about harm. Since physical factors are related to our perception of causality, they should also influence our subsequent moral judgments. In three experiments, we tested this prediction, focusing in particular on the roles of motion and contact. In Experiment 1, we used abstract video stimuli and found that intervening on a harmful object was judged as being less bad than intervening directly on the victim, and that setting an object in motion was judged as being worse than redirecting an already moving object. Experiment 2 showed that participants were sensitive not only to the presence or absence of motion and contact, but also to the magnitudes and frequencies associated with these dimensions. Experiment 3 extended the findings from Experiment 1 to verbally presented moral dilemmas. These results suggest that domain-general processes play a larger role in moral cognition than is currently assumed.
Changing the Lens A Position Paper on the Value of Qualitative Research Methodology as a Mode of Inquiry in the Education of the Deaf

A case study of a young deaf child's conversation development is used to explore the relationship between mode of inquiry and findings resulting from the use of qualitative research methodology. Data were collected through participant observation, videotaping, and interviews in the participants' natural settings. The breadth of findings from thematic analysis of descriptive data and discourse analysis of language samples led to the discovery of the child's language competencies in a field where research usually focuses on language deficits. Additionally, data revealed the contextual features that contributed to the child's conversation development. Scope of findings and implications for educators and researchers provide evidence of the value of qualitative methodology as a mode of inquiry in the field of education of the Deaf.
The 3-D Prefrontal Cortex: Hemispheric Asymmetries in Prefrontal Activity and Their Relation to Memory Retrieval Processes

Neuroimaging results have raised interest in characterizing hemispheric asymmetries in prefrontal activity during different types of memory retrieval tasks. In this issue, Dobbins et al. and Mitchell et al. report results suggesting that the two hemispheres of the prefrontal cortex may indeed make different contributions to memory retrieval. Here, I discuss these findings within the context of studies characterizing more general processing differences between the cerebral hemispheres and studies characterizing prefrontal organization along the dorsal–ventral and anterior–posterior dimensions.
Localization of Capping Protein in Chicken Epithelial Cells by Immunofluorescence and Biochemical Fractionation

We have localized capping protein in epithelial cells of several chicken tissues using affinity-purified polyclonal antibodies and immunofluorescence. Capping protein has a distribution in each tissue coincident with proteins of the cell-cell junctional complex, which includes the zonula adherens, zonula occludens, and desmosome. "En face" views of the epithelial cells showed capping protein distributed in a polygonal pattern coincident with cell boundaries in intestinal epithelium, sensory epithelium of the cochlea, and the pigmented epithelium of the retina and at regions of cell-cell contact between chick embryo kidney cells in culture. "Edge-on" views obtained by confocal microscopy of intact single intestinal epithelial cells and of retinal pigmented epithelium showed that capping protein is located in the apical region of the epithelial cells coincident with the junctional complexes. These images do not resolve the individual types of junctions of the junctional complex. Immunolabeling of microvilli or stereocilia was faint or not detectable. Capping protein was also detected in the cytoplasm of intact intestinal epithelial cells and in nuclei of cells in the pigmented retina and in the kidney cell cultures, but not in nuclei of cells of the intestinal epithelium or sensory epithelium. Biochemical fractionation of isolated intestinal epithelial cells shows capping protein in the brush border fraction, which contains the junctional complexes, and in the soluble fraction. These results are consistent with the results of the immunolabeling experiments. Highly purified microvilli of the brush borders also contained capping protein; this result was unexpected based on the low intensity of immunofluorescence staining of microvilli and stereocilia. The microvilli were not contaminated with junctional complexes, as defined by the absence of several markers for cell junctions. The cause and significance of this discrepancy is not certain at this time. Since capping protein binds the barbed end of actin filaments in vitro, we hypothesize that capping protein is bound to the barbed ends of actin filaments associated with one or more of the junctions of the junctional complex.
Notch Ligands Are Substrates for Protein O-Fucosyltransferase-1 and Fringe*

O-Fucose has been identified on epidermal growth factor-like (EGF) repeats of Notch, and elongation of O-fucose has been implicated in the modulation of Notch signaling by Fringe. O-Fucose modifications are also predicted to occur on Notch ligands based on the presence of the C2XXGG(S/T)C3 consensus site (where S/T is the modified amino acid) in a number of the EGF repeats of these proteins. Here we establish that both mammalian and Drosophila Notch ligands are modified withO-fucose glycans, demonstrating that the consensus site was useful for making predictions. The presence of O-fucose on Notch ligands raised the question of whether Fringe, anO-fucose specific β1,3-N-acetylglucosaminyltransferase, was capable of modifying O-fucose on the ligands. Indeed, O-fucose on mammalian Delta1 and Jagged1 can be elongated with Manic Fringe in vivo, and Drosophila Delta and Serrate are substrates for Drosophila Fringe in vitro. These results raise the interesting possibility that alteration of O-fucose glycans on Notch ligands could play a role in the mechanism of Fringe action on Notch signaling. As an initial step to begin addressing the role of the O-fucose glycans on Notch ligands in Notch signaling, a number of mutations in predicted O-fucose glycosylation sites onDrosophila Serrate have been generated. Interestingly, analysis of these mutants has revealed that O-fucose modifications occur on some EGF repeats not predicted by the C2XXGGS/TC3 consensus site. A revised, broad consensus site, C2X3–5S/TC3 (whereX3–5 are any 3–5 amino acid residues), is proposed.
Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction

Background—Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with multiple pathophysiologic abnormalities, including left ventricular (LV) diastolic dysfunction, longitudinal LV systolic dysfunction, abnormal ventricular-arterial coupling, pulmonary hypertension, and right ventricular (RV) remodeling/dysfunction. However, the relative prognostic significance of each of these pathophysiologic abnormalities in HFpEF is unknown. Methods and Results—We prospectively studied 419 patients with HFpEF using echocardiography and sphygmomanometry to assess HFpEF pathophysiologic markers. Cox proportional hazards analyses were used to determine the associations between pathophysiologic markers and outcomes. Mean age was 65±12 years; 62% were women; 39% were black; comorbidities were common; and study participants met published criteria for HFpEF. RV abnormalities were frequent: 28% had abnormal tricuspid annular plane systolic excursion, 15% had reduced RV fractional area ...
Protective Role of Smad6 in Inflammation‐Induced Valvular Cell Calcification

Calcific aortic vascular and valvular disease (CAVD) is associated with hyperlipidemia, the effects of which occur through chronic inflammation. Evidence suggests that inhibitory small mothers against decapentaplegic (I-Smads; Smad6 and 7) regulate valve embryogenesis and may serve as a mitigating factor in CAVD. However, whether I-Smads regulate inflammation-induced calcific vasculopathy is not clear. Therefore, we investigated the role of I-Smads in atherosclerotic calcification. Results showed that expression of Smad6, but not Smad7, was reduced in aortic and valve tissues of hyperlipidemic compared with normolipemic mice, while expression of tumor necrosis factor alpha (TNF-α) was upregulated. To test whether the effects are in response to inflammatory cytokines, we isolated murine aortic valve leaflets and cultured valvular interstitial cells (mVIC) from the normolipemic mice. By immunochemistry, mVICs were strongly positive for vimentin, weakly positive for smooth muscle α actin, and negative for an endothelial cell marker. TNF-α upregulated alkaline phosphatase (ALP) activity and matrix mineralization in mVICs. By gene expression analysis, TNF-α significantly upregulated bone morphogenetic protein 2 (BMP-2) expression while downregulating Smad6 expression. Smad7 expression was not significantly affected. To further test the role of Smad6 on TNF-α-induced valvular cell calcification, we knocked down Smad6 expression using lentiviral transfection. In cells transfected with Smad6 shRNA, TNF-α further augmented ALP activity, expression of BMP-2, Wnt- and redox-regulated genes, and matrix mineralization compared with the control cells. These findings suggest that TNF-α induces valvular and vascular cell calcification, in part, by specifically reducing the expression of a BMP-2 signaling inhibitor, Smad6.
Recombinant Human Bone Morphogenetic Protein-2 in Spine Surgery

The era of using bone morphogenetic protein (BMP) to augment spinal arthrodesis has been noteworthy in a number of ways. Since the U.S. Food and Drug Administration (FDA) approved the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in a titanium cage for anterior lumbar interbody arthrodesis in 2002, the widespread effects of its use have been well publicized, both in the evidence-based literature and in the lay press, with a variety of connotations. Initially perceived as a revolutionary, fail-safe bone-graft substitute that obviated the need for iliac crest bone graft, rhBMP-2 is now perceived as a potentially high-risk material and has been vilified in academic circles, the media, and conversations between surgeons and patients. This review will highlight the important historical milestones in the clinical and basic-science research on BMP and will assess the current state of its use in spine surgery. The use of iliac crest bone graft has long been the so-called gold standard for the augmentation of spinal arthrodesis. With the ability to obtain large amounts of graft through either an anterior or a posterior approach, the technique has evolved greatly to …
Bringing multi-antenna gain to energy-constrained wireless devices

Leveraging the redundancy and parallelism from multiple RF chains, MIMO technology can easily scale wireless link capacity. However, the high power consumption and circuit-area cost prevents MIMO from being adopted by energy-constrained wireless devices. In this paper, we propose Halma, that can boost link capacity using multiple antennas but a single RF chain, thereby, consuming the same power as SISO. While modulating its normal data symbols, a Halma transmitter hops between multiple passive antennas on a per-symbol basis. The antenna hopping pattern implicitly carriers extra data, which the receiver can decode by extracting the index of the active antenna using its channel pattern as a signature. We design Halma by intercepting the antenna switching and channel estimation modules in modern wireless systems, including ZigBee and WiFi. Further, we design a model-driven antenna hopping protocol to balance a tradeoff between link quality and dissimilarity of channel signatures. Remarkably, by leveraging the inherent packet structure in ZigBee, Halma's link capacity can scale well with the number of antennas. Using the WARP software radio, we have implemented Halma along with a ZigBee- and WiFi-based PHY layer. Our experiments demonstrate that Halma can improve ZigBee's throughput and energy efficiency by multiple folds under realistic network settings. For WiFi, it consumes similar power as SISO, but boosts throughput across a wide range of link conditions and modulation levels.
The Economic Impacts of Dirty Bomb Attacks on the Los Angeles and Long Beach Ports: Applying the Supply-Driven NIEMO (National Interstate Economic Model)

As homeland security policy makers seek to funnel scarce resources to the most vulnerable areas, geographic impact studies have become ever more crucial since the events of Sep.11, 2001. In a sense that the Los Angeles and Long Beach ports are among the largest in the world, service interruptions there would have nation-wide economic impacts. Because foreign and domestic imports are in greater volumes than exports, the interruption of imports should be examined with a supply-side MRIO-type model. Hence, a new supply-side National Interstate Economic Model (NIEMO) yields extra information with important political implications – in addition to the previously estimated demand-side results, because both simulations show that terrorist attacks in one state have significant economic impacts in other states. Especially in the U.S. Senate where political power is evenly distributed among the states, the supplyand demand-side results could help garner nationwide support for prevention measures in specific places, often distant from the states where the measures are taken.
DRIVERS OF CUSTOMER LOYALTY IN A RETAIL STORE ENVIRONMENT

The determinants of customer loyalty are identified for a large U.S. retailer based on a survey of 972 customers. An ordered logistic regression is used to estimate the proportion of a retailers customers who are willing to recommend the retailers products to others based on survey results. Statistical results document that service quality, product quality and brand image drive customer loyalty as measured by a customers willingness to recommend the retailers products to other people. Service management managers can improve these drivers of customer loyalty by better training, recognition and reward programs, day-to-day store operations, and job, product, process and store design. Given the general research objective of defining a universal model of what drives customer loyalty in a diverse set of industries, this research provides additional statistical evidence to support the theory that brand image, product quality, and service quality determine customer loyalty.
Patient Centered Primary Care (PCPC): An Overview

There is no doubt that we face major problems both in health care quality and costs. The crucial question for the Employer (Buyer) is how to respond to these issues. There is a solution. Simply stated, the failure we are experiencing today is, basically, a failure in our primary care system. Therefore, any initiative that strives to improve the overall quality and cost of care must focus on primary care.
The Informational Content of Implied Volatility Around Stock Splits

Previous research has been mixed with respect to whether option implied volatility reflects market expectations about future realized volatility for the underlying asset. This paper uses a previously documented volatility increasing event, the stock split, to investigate the informational content in implied volatility around stock split announcements. We find that the time series profile of implied volatility around stock splits is consistent with the predictions of standard option pricing theory. Option market participants appear to revise their forecasts of future realized volatility permanently upward at the split announcement. In addition, we find that changes in implied volatility at the split announcement provide informative forecasts of changes in realized stock volatility at the ex-date. However, these forecasts are biased and inefficient as other known, firm-specific variables improve the forecasts of changes in realized volatility. The use of intra-daily realized volatility estimates rather than those based on daily observations significantly reduces the bias in predictive regressions.
Accelerating Drug Development for the Field: Building Clinical Trial Recruitment Infrastructure in Parkinson’s

There is no “department of cures.”[1][1] There are many diverse players involved in drug development, each of whom brings critical financial, intellectual, and human resources to the process. However, no one is in charge of the overall direction the field takes—charting the course and
A New Class of Renewable Thermoplastics with Extraordinary Performance from Nanostructured Lignin-Elastomers

A new class of thermoplastic elastomers has been created by introducing nanoscale-dispersed lignin (a biomass-derived phenolic oligomer) into nitrile rubber. Temperature-induced controlled miscibility between the lignin and the rubber during high shear melt-phase synthesis allows tuning the material's morphology and performance. The sustainable product has unprecedented yield stress (15–45 MPa), strain hardens at large deformation, and has outstanding recyclability. The multiphase polymers developed from an equal-mass mixture of a melt-stable lignin fraction and nitrile rubber with optimal acrylonitrile content, using the method described here, show 5–100 nm lignin lamellae with a high-modulus rubbery interphase. Molded or printed elastomeric products prepared from the lignin-nitrile material offer an additional revenue stream to pulping mills and biorefineries.
Interventions for Increasing Physical Activity: From “Ingenious Toys” to mHealth∗

The ABC ’s of primary and secondary cardiovascular disease prevention are not complete without D (diet and weight management) and certainly without E (exercise) [(1)][1]. Although coming in last in the helpful mnemonic, exercise certainly is not the least important. The benefits of increased
Larvicidal Efficacy of Bacillus thuringiensis Serotype H-14 Against Stagnant-Water Mosquitoes and Its Effects on Nontarget Organisms

Five formulations of Bacillus thuringiensis var. israelensis (serotype H-14) were evaluated against larvae of eight mosquito species. In the laboratory, most species essentially showed similar levels of susceptibility to a given formulation. The range of activity of the various formulations against a given species was on the order of two- to sixfold. In general, the LC90 against fourth-stage larvae ranged from 0.13 to 0.45 ppm, for high-potency formulations, to 0.45 to 0.9 ppm for low-potency formulations. Second instars were two to six times more susceptible than 4th instars to the various formulations. Under field conditions, the various formulations showed different activity levels. In clear, shallow, and nonvegetated water, the high-potency formulations yielded excellent control of larvae at rates as low as 112 to 280 g/ha. Formulations with low potency were needed at rates as high as 280 to 560 g/ha to yield effective control of larvae in these biotypes. None of the commercial formulations at mosquitocidal and fivefold these rates induced short-term effects on the dominant nontarget fauna. Mayfly and dragonfly naiads, diving beetle larvae and adults, and ostracods were not affected at the rates of 0.56 to 2.24 kg/ha of the formulations employed.
Acceleration of groundwater remediation by deep sweeps and vortex ejections induced by rapidly pulsed pumping

One key limiting factor to groundwater remediation is contaminant sequestered in pores whose contents do not mix well with the bulk flow. Mixing between well-connected (pores whose volume is flushed as water flows through the aquifer) and poorly connected pores (pores whose volume does not exchange readily when water flows through the aquifer) is of primary concern. Under steady flow, contaminants are effectively trapped in the poorly connected pores and are transferred only by molecular diffusion. This slow mixing process between pore types is a bottleneck to remediation. We present a novel rapidly pulsed pumping method that increases the mixing between these pore types. We do it in the context of pump-and-treat remediation because it is the most common remediation practice. In rapidly pulsed pumping, the increase in flow causes a deep sweep, which pushes the flow into poorly connected pores and sweeps out sequestered contaminants. The decrease in flow causes a vortex ejection, which causes the vortex within the poorly connected pore to emerge with contaminant. These actions are modeled with computational fluid mechanics to elucidate the individual mechanisms and determine how they function and interact. Cleanup of single and multiple poorly connected pore systems were simulated and show the acceleration possible. This technique can decrease the time and cost needed to remediate contaminated aquifers, which in the United States has been estimated to exceed $1 trillion. Since our rapidly pulsed pumping method enhances mixing between well-connected and poorly connected pores, it can be applied to other remediation schemes such as in situ methods.
Management countermeasure and fuzzy judgement on internal marketing

Along with the economical development,the enterprise for the adaption time development step,more and more realizes the internal marketing the unimportance.This article has first carried on the brief introduction to the internal marketing,and applies in the fuzzy mathematics in this foundation the synthetic judgment method,carries on the whole to internal marketing the judgment;Finally is to the essential essential factor which studies has the question summary and the countermeasure analysis.
Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.
Staged Stereotactic Radiosurgery for Large Brain Metastases: Local Control and Clinical Outcomes of a One-Two Punch Technique.

Background Treatment options are limited for large, unresectable brain metastases. Objective To report a single institution series of staged stereotactic radiosurgery (SRS) that allows for tumor response between treatments in order to optimize the therapeutic ratio. Methods Patients were treated with staged SRS separated by 1 mo with a median dose at first SRS of 15 Gy (range 10-21 Gy) and a median dose at second SRS of 14 Gy (range 10-18 Gy). Overall survival was evaluated using the Kaplan-Meier method. Cumulative incidences were estimated for neurological death, radiation necrosis, local failure (marginal or central), and distant brain failure. Absolute cumulative dose-volume histogram was created for each treated lesion. Logistic regression and competing risks regression were performed for each discrete dose received by a certain volume. Results Thirty-three patients with 39 lesions were treated with staged radiosurgery. Overall survival at 6 and 12 mo was 65.0% and 60.0%, respectively. Cumulative incidence of local failure at 6 and 12 mo was 3.2% and 13.3%, respectively. Of the patients who received staged therapy, 4 of 33 experienced local failure. Radiation necrosis was seen in 4 of 39 lesions. Two of 33 patients experienced a Radiation Therapy Oncology Group toxicity grade > 2 (2 patients had grade 4 toxicities). Dosimetric analysis revealed that dose (Gy) received by volume of brain (ie, VDose(Gy)) was associated with radiation necrosis, including the range V44.5Gy to V87.8Gy. Conclusion Staged radiosurgery is a safe and effective option for large, unresectable brain metastases. Prospective studies are required to validate the findings in this study.
A Commencement for Eye Commensals.

"Paucibacterial" levels of the normal eye surface have left immunologists wondering whether a true microbiome exists there. In this issue of Immunity, St. Leger et al. (2017) address this head-on, discovering a naturally existing commensal in mice that induces γδT cell-mediated protection from opportunistic infection.
A Simplicity Criterion for Physical Computation

AbstractThe aim of this article is to offer a formal criterion for physical computation that allows us to objectively distinguish between competing computational interpretations of a physical syste...
Sidelobe Exploitation for Beam Discovery in Line of Sight Millimeter Wave Systems

Exhaustive search methods for optimum beamforming directions result in high computational complexity and increased time delays. Hence, this letter presents a novel initial beam discovery technique for codebook-based designs which leverages the presence of sidelobes as adjacent patterns to the main beamforming lobes. Namely, once a signal is detected in the direction of a sidelobe during beam scanning, the main lobe is shifted toward that direction and the scan is terminated. Simulation results show that the proposed scheme gives significant performance gains versus existing methods.
Marathon Group Therapy with Illicit Drug Users

Marathon group therapy offers the skilled therapist a means of creating a therapeutic environment in which illicit drug users can work to resolve their personal problems and to improve the quality of their interpersonal relationships. It is the purpose of this paper to describe how marathons operate to help illicit drug users and to summarize research conducted on the group process and the resulting attitude changes occurring among marathon group participants.
Guided Physical Exertion in Sports-Related Concussion Patients (P6.309)

Objective: To determine if guided sub-symptomatic threshold physical exertion hastens recovery from sports-related concussion. Background: The management of sports-related concussion (SRC) has evolved over time. The most recent consensus statement suggests return of light activity after a period of 24–48 hours of relative physical and cognitive rest. The amount and timing of activites, and effects of cognitive and physical activity on recovery after SRC are not determined. In this study, we reviewed the use of guided sub-symptomatic threshold physical exertion after SRC in the University of Michigan NeuroSport Clinic to determine if it affects symptom improvement and return to sport outcomes. Design/Methods: This is a retrospective chart review of SRC patients from September 2016 through January 2017. Patients who underwent controlled physical exertion while symptomatic within 15 days of their concussion were included in the intervention group. Those who did not undergo this testing, were asymptomatic at time of testing, or who underwent testing after 15 days from their concussion were included in the non-intervention group. Statistical analysis was performed using a Cox regression model and controlled for multiple co-variates: age, provider, previous concussions, neck pain, neurologic exam abnormalities (vestibular and oculomotor), co-morbidities (migraines, depression/anxiety, ADHD/learning disability), treatments (physical and vestibular therapy), and the relationship between time to clinic presentation and exertional testing. Results: 121 patients were included in the analysis. Population characteristics were similar between intervention and non-intervention groups. There was a statistically significant association between the intervention and time to return to sport (p=0.031, HR=2.07). Conclusions: Guided sub-symptomatic exercise testing performed in the early stages of a sports-related concussion was associated with more rapid symptom resolution, and return to sport. Early physical activity was not associated with prolong recovery or worsened symptoms. Disclosure: Dr. Popovich has nothing to disclose. Dr. Almeida has nothing to disclose. Dr. Lorincz has nothing to disclose. Dr. Sas has nothing to disclose.
Broadening the utilitarian epistemology of agritourism research through children and families

The genesis of agritourism is rooted in diversifying income for farmers, and accordingly, epistemological framing of agritourism research has focused on understanding the direct economic value of f...
Abstraction, imagery, and control in cognitive architecture

This dissertation presents a theory describing the components of a cognitive architecture supporting intelligent behavior in spatial tasks. In this theory, an abstract symbolic representation serves as the basis for decisions. As a means to support abstract decision-making, imagery processes are also present. Here, a concrete (highly detailed) representation of the state of the problem is maintained in parallel with the abstract representation. Perceptual and action systems are decomposed into parts that operate between the environment and the concrete representation, and parts that operate between the concrete and abstract representations. Control processes can issue actions as a continuous function of information in the concrete representation, and actions can be simulated (imagined) in terms of it. The agent can then derive useful abstract information by applying perceptual processes to the resulting concrete state. This theory addresses two challenges in architecture design that arise due to the diversity and complexity of spatial tasks that an intelligent agent must address. The perceptual abstraction problem results from the difficulty of creating a single perception system able to induce appropriate abstract representations in each of the many tasks an agent might encounter, and the irreducibility problem arises because some tasks are resistant to being abstracted at all. Imagery works to mitigate the perceptual abstraction problem by allowing a given perception system to work in more tasks, as perception can be dynamically combined with imagery. Continuous control, and the simulation thereof via imagery, works to mitigate the irreducibility problem. The use of imagery to address these challenges differs from other approaches in AI, where imagery is considered as an alternative to abstract representation, rather than as a means to it. A detailed implementation of the theory is described, which is an extension of the Soar cognitive architecture. Agents instantiated in this architecture are demonstrated, including agents that use reinforcement learning and imagery to play arcade games, and an agent that performs sampling-based motion planning for a car-like vehicle. The performance of these agents is discussed in the context of the underlying architectural theory. Connections between this work and psychological theories of mental imagery are also discussed.
Amyloidoses of the Kidney and Genitourinary Tract

While most systemic amyloidoses can affect the genitourinary system, apart from renal, adrenal, and testicular amyloid deposits, other sites are usually silent or clinically less prominent. Systemic amyloidosis, presenting with lower urinary symptoms, is exceedingly rare, but it has been reported. Clinically, however, small fiber neuropathy and endocrine involvement are increasingly recognized. The former, which typically occurs in ATTR, but also in AL, may be responsible for lower urinary dysfunction, including dysuria, incontinence, and erectile dysfunction. The latter may be associated with functional impairment of the testes and adrenal glands. In general, most patients who present with urinary tract symptoms (painless hematuria, flank pain, hydronephrosis, mass, and irritative bladder symptoms) are diagnosed with localized amyloid deposits, which affect the urinary tract in the absence of visceral involvement. Testicular involvement is not uncommon in systemic amyloidoses, in particular in AA, AL, AApolipo A-I, ATTR, and dialysis-associated amyloidosis. In systemic AA and AApolipo A-I amyloidosis, in particular, testicular involvement is frequently seen and, since it may affect young adults, its clinical relevance is increasingly recognized.
Rural business programs and business performance: The impact of the USDA's Business and Industry (B&I) Guaranteed Loan Program

The USDA's Rural Development (RD) has implemented several loan and grant programs to support businesses located in rural areas and the Business and Industry (B&I) Guaranteed Loan Program is the largest among them. The focus of the present study is to estimate the impact of B&I program participation and the amount of loans received on the probability of survival and employment growth of recipient businesses over the period of 1990–2013. Using administrative data on B&I loans from RD and business‐level data from the National Establishment Time‐Series (NETS), we utilize a matched difference‐in‐difference estimation strategy to assess the impact of the B&I program on establishment‐level outcomes. We find that the receipt of a B&I loan helps recipient businesses to reduce the risk of failure and grow slightly faster, compared with a similar control group of businesses. We also test if the impacts vary with the loan size and find that while increasing the size of loans has an increasing effect to reduce the risk of failure, it shows no statistically significant effect on employment growth.
Price Indexes for US Medical Care Spending, 1980–2006

We construct price indexes for medical care spending in the US economy for the period 1980–2006. Our indexes show slower price growth than the official deflator from 1987–2001, consistent with the fact that indexes that improve on the official statistics typically find slower price growth than the official indexes. However, the result is reversed for the 2001–2006 time period. We develop a decomposition that parses out the numerical differences in these indexes into three factors that are held constant in the official price indexes but are not in our indexes: changes in the type of provider supplying care, changes in the type of insurance plan used by the patients, and changes in the bundle of procedures used to treat patients. Our results suggest that using the official price measures may provide misleading conclusions about spending trends and productivity growth in this important sector over this time period.
Rat Class 3 Aldehyde Dehydrogenase: Crystals and Preliminary Analysis

Class 3 aldehyde dehydrogenase (A1DH) from rat liver has been expressed in native form by E. coli from the pTALDH vector (Harper et al., 1988). This A1DH differs substantially from the class 1 and 2 AlDHs both in catalytic properties and in primary and quaternary structure. However, secondary structural predictions suggest that the subunit tertiary structures of all three A1DH classes are largely similar (Lindahl and Evces, 1984; Hempel et al., 1989). Although functional residues have been identified from chemical modification and sequence comparisons, no tertiary structure of an A1DH has yet been determined.
Teacher Candidates’ Sense of Self-Efficacy Toward Classroom Management:

The authors examined differences in self-efficacy regarding classroom management practices between alternative teacher candidates (alternative certification [AC]) and traditional teacher candidates...
Perception of contrastive stress in alaryngeal speech

Abstract: This project was a perceptual investigation of contrastive stress in alaryngeal speech. The ability to signal contrastive stress in American English was assessed by obtaining high quality tape recordings of sentence production from four normal and sixteen laryngectomized speakers using four different types of alaryngeal speech. The recordings of these sentences, paired on the basis of differences in the location of contrastive stress, were presented to forty listeners for perceptual evaluation of stress location using a two-interval-forced-choice procedure. As expected, the four normal speakers achieved high (95% or above) levels of stress contrast. Contrastive stress patterns were also realized in a highly effective manner (93% or above) by three esophageal speakers, three tracheoesophageal (Blom-Singer) speakers, and three users of the Western Electric # 5 artificial larynx. Contrastive stress patterns were realized in a lower (86–88%), but reasonably effective manner by two users of the Servox artificial larynx. The findings were interpreted to highlight the contributions that study of clinical samples may make to questions about linguistic theory, speech production and speech perception.
Narciclasine, an isocarbostyril alkaloid, has preferential activity against primary effusion lymphoma

Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin lymphoma associated with infection by Kaposi sarcoma-associated herpes virus (KSHV). PEL is an aggressive disease with extremely poor prognosis when treated with conventional chemotherapy. Narciclasine, a natural product present in Amaryllidaceae family of flowering plants including daffodils, belongs to a class of molecules termed 'isocarbostyril alkaloid'. We have found that narciclasine displays preferential cytotoxicity towards PEL at low nanomolar concentrations and is approximately 10 and 100-fold more potent than its structural analogs lycoricidine and lycorine, respectively. Narciclasine arrested cell-cycle progression at the G1 phase and induced apoptosis in PEL, which is accompanied by activation of caspase-3/7, cleavage of PARP and increase in the surface expression of Annexin-V. Although narciclasine treatment resulted in a marked decrease in the expression of MYC and its direct target genes,time-course experiments revealed that MYC is not a direct target of narciclasine. Narciclasine treatment neither induces the expression of KSHV-RTA/ORF50 nor the production of infectious KSHV virions in PEL. Finally, narciclasine provides dramatic survival advantages to mice in two distinct mouse xenograft models of PEL. In conclusion, our results suggest that narciclasine could be a promising agent for the treatment of PEL.
Use of the Change in Weaning Parameters as a Predictor of Successful Re-Extubation:

Objective:Weaning parameters are well studied in patients undergoing first time extubation. Fewer data exists to guide re-extubation of patients who failed their first extubation attempt. It is rea...