cssi/SciSciGPT-SciSciNet huggingface dataset:
The value of pharmaceutical representative visits and medication samples in community-based family practices

Background Interactions between the pharmaceutical industry and physicians have been discussed in numerous publications; however, most articles are limited to surveys and self-report data and often focus on academic or training contexts. We describe the role of pharmaceutical representatives and the use of samples in community-based family practices, using data obtained by directly observing clinical encounters. Methods We collected detailed descriptive field notes of the direct observations of 53 primary care clinicians and 1588 patient encounters in 18 purposefully selected Nebraska family practices. We used a comparative case study design, that used depth interviews of clinicians and office staff, and included details of the interactions with pharmaceutical representatives and the use of samples in clinical encounters. Results Individual providers and practices displayed noticeable variation in their approaches to drug representatives and samples. We found formal strategies and policies in a minority of practices. Generally there was little structure in the organization and distribution of sample medications at the office level, and detailed patient education regarding these drugs was rarely observed in patient encounters. Nevertheless, samples were used in almost 20% of observed encounters, at times as starter dosages, but often as complete courses of treatment. The benefits derived from contact with the pharmaceutical industry varied substantially, but most often included free medication samples, meals, and patient education materials. Conclusions Clinicians have a complex symbiosis with the pharmaceutical industry and need to critically evaluate their handling of samples and their contact with pharmaceutical representatives to optimize this relationship and ensure quality patient care. Clinics with specific policies for interactions with drug companies appear to derive more satisfaction from their encounters.
Projection-based two-phase minimum and maximum length scale control in topology optimization

Length scale control in topology optimization is an important area of research with direct implications on numerical stability and solution manufacturability. Projection-based algorithms for continuum topology optimization have received considerable attention in recent years due to their ability to control minimum length scale in a flexible and computationally efficient manner. In this paper, we propose a new projection-based algorithm that embeds minimum length scale control on two material phases (e.g., solid and void) as well as optional maximum length scale on one material phase (e.g., solid or void) into the projection methodology used for material distribution approaches to topology optimization. The proposed algorithms are demonstrated on benchmark problems and are shown to satisfy the length scale constraints imposed.
Targeting intrinsic cell death pathways to control fungal pathogens

Fungal pathogens pose an increasing threat to public health. Limited clinical drug regimens and emerging drug-resistant isolates challenge infection control. The global burden of human fungal pathogens is estimated at 1 billion infections and 1.5 million deaths annually. In addition, plant fungal pathogens increasingly threaten global food resources. Novel strategies are needed to combat emerging fungal diseases and pan-resistant fungi. An untapped mechanistically novel approach is to pharmacologically activate the intrinsic cell death pathways encoded by pathogenic fungi. This strategy is analogous to new anti-cancer therapeutics now entering the clinic. Here we summarize the best understood examples of cell death mechanisms encoded by pathogenic fungi, contrast these to mammalian cell death pathways, and highlight the gaps in knowledge towards identifying potential death effectors as druggable targets.
Accelerated Design Methodology for Dual-Input Doherty Power Amplifiers

A novel design theory and the methodology are presented for dual-input Doherty power amplifiers (DPAs) in which the auxiliary transistor does not fully turn off at backoff power. Given the input parameters selected by the PA designer, a Doherty load modulation behavior is exactly implemented at the current-source reference planes of the transistors by solving for the characteristic impedance of the Doherty quarter-wave transformer and the common load. The Doherty output combiner at the package reference plane that sustains the desired dual-input DPA performance is then synthesized using nonlinear embedding and exactly implemented with a lossless and reciprocal circuit. The new analytic DPA design theory also provides an expanded design space, which facilitates the selection of the optimal design based on the gain, linearity, and efficiency tradeoff. The design methodology is implemented in a software program to enable the automatic design of a dual-input DPA prototype at the package reference planes within 24 s. To validate the theory and the design methodology, a 2-GHz dual-input asymmetric DPA is fabricated and measured. When excited with a 20-MHz local thermal equilibrium (LTE) signal with 9.55-dB peak-to-average power ratio (PAPR), the DPA achieves an average power-added efficiency (PAE) of 51.6% with an adjacent-channel-power-leakage ratio (ACLR) of −47.1 dBc after linearization.
Natural hazards and mineral commodity supply: Quantifying risk of earthquake disruption to South American copper supply

Abstract Mineral resources, and their mining and enrichment operations, are not equally distributed across Earth. The concentration of mineral supply in certain regions, owing to the geology or geography of the mineral resource, raises the level of risk related to supply disruption. Where mineral production coincides with areas prone to natural hazards, supply may be especially at risk. However, the level of risk that natural hazards pose to mineral supply has yet to be quantified on a global or regional scale. Using copper in South America as a case study, this paper offers methods for quantifying (i) the coincidence of mineral production and seismic hazards, and (ii) the Expected Annual Disruption (EAD) of the mineral supply from earthquakes. The first of these methods indicates that, of the 101 copper producing facilities in South America considered, 76 are located within an area of high seismic hazard, taken here as the area with >85% chance of exceeding Modified Mercalli Intensity VI earthquake shaking in 50 years. Collectively, the 76 facilities comprise 82%, 87%, and 91% of the 2015 South American mine production, smelter capacity, and refinery capacity, respectively. For each of the 101 facilities, the second method calculates the EAD using a full earthquake shaking hazard forecast at the location, the annualized copper production of the facility, and models of the vulnerability of that production to shaking. The EADs are summed by country, here within South America, as a demonstration of how supply risk could eventually be quantified globally. Consideration of two illustrative vulnerability models shows that future work is needed to determine percentages of disruption to mineral production for different levels of earthquake shaking. Ultimately, the methods presented herein could be applied to other mineral commodities and/or adapted for other natural hazards, and the resulting EADs could be summed. Results from these methods could be used to focus more detailed risk assessments where the risk is highest.
Flexible Electrochemical Bioelectronics: The Rise of In Situ Bioanalysis

The amalgamation of flexible electronics in biological systems has shaped the way health and medicine are administered. The growing field of flexible electrochemical bioelectronics enables the in situ quantification of a variety of chemical constituents present in the human body and holds great promise for personalized health monitoring owing to its unique advantages such as inherent wearability, high sensitivity, high selectivity, and low cost. It represents a promising alternative to probe biomarkers in the human body in a simpler method compared to conventional instrumental analytical techniques. Various bioanalytical technologies are employed in flexible electrochemical bioelectronics, including ion-selective potentiometry, enzymatic amperometry, potential sweep voltammetry, field-effect transistors, affinity-based biosensing, as well as biofuel cells. Recent key innovations in flexible electrochemical bioelectronics from electrochemical sensing modalities, materials, systems, fabrication, to applications are summarized and highlighted. The challenges and opportunities in this field moving forward toward future preventive and personalized medicine devices are also discussed.
Economically disadvantaged communities: a solution-based study through education and information communication technology

North Carolina ranked 40th out of the 50 states in the USA in a new report card on public education. Generally, schools are graded A, B, C, D and F grades where 80% of school grades are based on the percentage of student tests scores that are at or above grade-level performance. In Economically Disadvantaged communities, specifically, those in one large county in Central North Carolina, schools there tend to perform poorly, scoring 'D' and 'F' grades in the state schools' report cards. The main research question was: Do students in low performing schools also score low on the Incoming Readiness scale? A survey and secondary data (North Carolina School Report Cards for 2016-2017) were collected and analysed. The key finding was low performing schools had higher percentage of students with low Incoming Readiness. The study covers issues of social justice and the need to improve school performance.
A review of the application of 2D isotropic-anisotropic correlation NMR spectroscopy in structural studies of chalcogenide glasses

Abstract The application of solid-state high-resolution NMR spectroscopy in the structural investigation of chalcogenide glasses in Ge/As/P/Si-X (X = S, Se,Te) systems has remained challenging even for the spin-1/2 nuclides (29Si, 31P, 77Se, 125Te), owing to their low natural abundance (except for 31P), slow spin-lattice relaxation rate and large CSA and chemical shift distribution induced line broadening effects. However, most of these deleterious effects can be successfully overcome in two-dimensional (2D) isotropic-anisotropic correlation NMR experiments, especially when performed at high magnetic field and in conjunction with the Car-Purcell-Meiboom-Gill (CPMG) echo train acquisition. In this contribution we present a short introduction to the basic principles of such experiments and review their applications over the last decade in deciphering various short- and intermediate- range structural characteristics of chalcogenide glasses in S-Se, Se-Te, Ge-Se, As-Se and Si-Se systems as well as in investigating the molecular dynamics in a P-Se supercooled liquid. We anticipate possible future applications of these 2D isotropic-anisotropic correlation NMR experiments, particularly in conjunction with density functional theory-based calculations of NMR chemical shift tensor parameters and additional signal enhancement schemes, in addressing complex structural correlations and distributions in chalcogenide glasses.
Physostigmine in Anticholinergic Poisoning: An Old Antidote With Resurgence

Physostigmine is a cholinesterase inhibitor used therapeutically in patients with anticholinergic delirium that is so severe that intubation may be required for airway protection. Given that a wide variety of medications have anticholinergic properties, and the current standard of care is typically a central nervous system depressant, hospitalizations are often lengthy and normally require a critical-care level of attention. Despite this, physostigmine is often underutilized and poorly understood in the clinical setting. We report a case of a 43-year-old female who presented to the emergency department one hour after ingesting approximately 150 tablets of diphenhydramine in a suicide attempt. She was treated with benzodiazepines with minimal success, and airway protection became imminent as her mentation continued to decline. Through the use of physostigmine, we were able to save this patient from endotracheal intubation and the potential complications of mechanical ventilation.
Simulated filament shapes in embedded 3D printing.

Embedded 3D printing, wherein fluid inks are extruded into support baths, has enabled the manufacture of complex, custom structures ranging from cell-laden tissue analogues to soft robots. This method encompasses two techniques: embedded ink writing (EIW), where filaments are extruded, and embedded droplet printing (EDP), where droplets are suspended. Materials for embedded 3D printing can be Newtonian, but often both the ink and the support bath are yield stress fluids, following elastic behavior below the yield stress and shear-thinning, viscous behavior above the yield stress. The effect of surface tension on print quality has been debated, as inks have been printed into supports at high and low surface tensions. In order to guide material selection for embedded 3D printing and identify key scaling relationships that influence print quality, this study investigates the role of ink rheology, support rheology, and surface tension on the morphology of single filaments. Numerical simulations in OpenFOAM demonstrate that at low viscosities, surface tension controls the filament morphology. Where capillarity is suppressed, the ratio of the local ink and support viscosities and the shape of the yield surface in the support control the filament shape. Herschel–Bulkley support fluids (yield stress fluids) produce more stable, accurately positioned filaments than Newtonian supports. In the short term, non-zero surface tensions can suppress filament shape defects in EIW and are essential for producing droplets in EDP.
Advancements in Thermal Comfort Modeling Using Modern Sensing and Computational Technologies

Despite numerous technical efforts to enhance thermal comfort in multiple building typologies, thermal stress has been reported as the most serious problem among building users for several decades. Many advanced thermal comfort prediction models have been investigated and applied, but there are still significant limitations to meet the individual occupants’ thermal satisfaction while minimizing their thermal stress. One main reason is the limited technical parameters that are considered in thermal comfort prediction models. In addition, while many indoor and outdoor environmental attributes dynamically change almost every second, the current thermal comfort prediction models often assume many of these attributes to be constant over time.
Exploiting user activeness for data retention in HPC systems

HPC systems typically rely on the fixed-lifetime (FLT) data retention strategy, which only considers temporal locality of data accesses to parallel file systems. However, our extensive analysis based on the leadership-class HPC system traces suggests that the FLT approach often fails to capture the dynamics in users' behavior and leads to undesired data purge. In this study, we propose an activeness-based data retention (ActiveDR) solution, which advocates considering the data retention approach from a holistic activeness-based perspective. By evaluating the frequency and impact of users' activities, ActiveDR prioritizes the file purge process for inactive users and rewards active users with extended file lifetime on parallel storage. Our extensive evaluations based on the traces of the prior Titan supercomputer show that, when reaching the same purge target, ActiveDR achieves up to 37% file miss reduction as compared to the current FLT retention methodology.
Evaluations of a noise control for roof bolting machines

In collaboration with Kennametal Inc. and Corry Rubber Corporation, the U.S. National Institute for Occupational Safety and Health (NIOSH) developed a drill bit isolator to address noise overexposures associated with roof bolting machines in underground coal mines. NIOSH laboratory studies confirmed that the drill bit isolator reduces noise during drilling. Field studies were needed to confirm that a noise reduction could be obtained under working conditions and that the device was sufficiently durable. This paper reports results of field tests of the device conducted at five underground coal mines. Noise reduction was assessed by comparing the operator's noise exposure during drilling with and without the drill bit isolator. Durability was assessed by recording the number of holes and total feet drilled with each bit isolator until either the test period ended or the device failed. The results from these tests showed that the device is an effective noise control in a mine environment. The field-tested drill bit isolators provided a noise reduction of 3-5 dB(A). Of nine devices tested for durability, five exceeded 610 m (2,000 ft) drilled and two exceeded 762 m (2,500 ft) drilled before failure. Durability issues found in the field tests led to final production optimizations that have resulted in a commercially available product for drilling with 35-mm- (1.3-in.-) diameter roof bits and hexagonal drill steels.
The epsilon-(gamma-glutamyl)lysine crosslink and the catalytic role of transglutaminases.

Publisher Summary The production of functional protein units in many cases requires the formation of covalent bonds, and prevalent among these are crosslinks within and between molecules that play a major role in maintaining gross forms of structure and limiting degrees of extensibility. This chapter describes the current knowledge of the distribution, formation, and function of the ɛ-(γ-glutamyl)lysine crosslink, and focuses largely on the crosslink known to be or believed to be formed by the catalytic action of transglutaminases. These enzymes catalyze a calcium-dependent acyl-transfer reaction in which the γ-carboxamide groups of peptide-bound glutamine residues are the acyl donors. Participation of ɛ-amino groups of peptide-bound lysine residues as acyl acceptors yields ɛ-(γ-glutamyl)lysine crosslinks. Although, there is a little doubt that the enzymes described in the chapter are capable of catalyzing crosslink formation, individualities of substrate preference notwithstanding, current data do not prove that this is the biological function of each. The chapter is believed to permit critical evaluation of the information available, suggest areas that hold the greatest opportunity for advances, and will, as a consequence, stimulate further investigations of the synthesis, distribution, and function of the ɛ-(γ-glutamyl)lysine crosslink.
Tribute to Andy Sage, and a new taxonomy of model attributes

First let me render some recollections about Andy Sage, a wonderful human being to whom those of us calling ourselves system engineers owe a great deal. My first connection with Andy was in regard to IEEE Transactions. I had been Editor of IEEE Transactions on Human Factors in Electronics, starting around 1966. That publication changed its name in 1970 to IEEE Transactions on Man-Machine Systems. There was also an IEEE Transactions of Systems Science and Cybernetics existing from about 1964. In the early 1970s it was decided to combine the two IEEE Groups and hence their transactions as well, the combined publication being IEEE Transactions on Systems Man and Cybernetics. Andy Sage was chosen Editor of that new Transactions and served in that role for many years, doing an outstanding job. As is no doubt mentioned in other papers in this volume Andy took on a great many other editing and book-writing tasks, in addition to becoming the founding Dean of the School of Engineering at George Mason University. I always held Andy in the greatest esteem in terms of his energy, organizational skills and fairness. The results of his efforts were always of the highest quality.
Micro‐Situational Antecedents of Violent Atrocity1

This article presents an analysis of video recordings showing micro-situational events that preceded the 1995 Srebrenica massacre in which more than 7,000 Bosnian-Muslim men were killed by troops of the Bosnian Serb Army. The article focuses on the sequential unfolding of micro interactions and emotional dynamics that preceded the atrocity. Micro interactions constitute situational turning points toward, or away from, atrocities. Even if there are preplanned plots or macro-structural background conditions that lead particular persons to be motivated to commit violence, a micro-situational, emotional momentum is needed for atrocities to occur. The article brings together the analysis of video material of violent situations with Ekman’s research tools for emotional cues and Collins’s micro-sociological theory of violence.
GaN HEMT PA with over 84% power added efficiency

Described are the design procedure and measured performance of a PA targeted for the W-CDMA downlink band exhibiting over 84% PAE at 2.14%GHz. The PA is designed with an uncharacterised GaN HEMT. A measurement-based design approach is used to optimise the source and load impedance at the fundamental frequency with class-F -1 harmonic terminations enforced. S -parameters extracted from a full-wave EM model characterising the impedance transformation from the virtual drain of the GaN HEMT to an output matching circuit are used to design class-F -1 second- and third-harmonic terminations. The highest efficiency for the final PA occurred 10 MHz off the design frequency, exhibiting 84.9 PAE, 8.2 W output power and 18.4 dB of gain at 2.15 GHz.
Metastatic melanoma to the upper aerodigestive tract: A Systematic Review of the Literature

This study is a systematic review of the literature that was performed to clarify the natural history and treatment outcomes of upper aerodigestive tract metastases from cutaneous melanoma. A search of the MEDLINE database was undertaken from 1950 to 2013 to identify relevant manuscripts for this review. Article inclusion required cases with documentation of previous cutaneous melanoma primary lesions, adequate survival data, and description of metastatic treatment. Individual patient data were extracted from source articles for analysis of survival outcomes. A systematic search revealed 34 relevant articles with 37 cases for inclusion. Metastases were identified throughout the upper aerodigestive tract with a predilection for the oropharynx, larynx, and oral cavity. Treatment outcomes were estimated with the Kaplan-Meier method, with survival of 37% and 16% at 1 and 5 years, respectively. As expected from previous reports, 73% presented with disseminated disease burden with almost universally poor prognosis despite locoregional or systemic therapy. Conversely, a group of patients with limited metastatic burden had improved treatment response with a 1-year survival of 90%, denoting a hazard ratio of 9.7332 (95% confidence interval, 4.5-21.1) for disseminated disease in comparison. Upper aerodigestive tract metastases of melanoma thus are rare clinical entities that in general present in the setting of disseminated disease and evidently necessitate a focus on palliation. In contrast, for those with a limited metastatic burden, aggressive multimodality therapy including complete metastectomy can produce a significant survival advantage.
Keeping Up With the Quants: Your Guide to Understanding and Using Analytics by Thomas H. Davenport and Jinho Kim

You don't need to be an expert winemaker to be a connoisseur of fine wine. Similarly, you don't need to be an expert in statistics to be able to make good decisions based on data. The analogy to wi...
The Effects of Large-Scale Economic Change and Policies on Children's Developmental Contexts and Developmental Outcomes

Abstract— In the current era of rapid economic change in societies worldwide, it is vital to examine how large-scale societal changes might affect children’s development. This article summarizes existing evidence on 3 types of large-scale economic change and policies that theory and empirical evidence suggest affect children’s development: economic growth and downturns, changes in demand for worker skills, and employment policies and regulations. It also summarizes evidence regarding the community- and family-level mechanisms through which these effects may be conveyed, focusing where possible on empirical studies that can identify causality. It concludes with recommendations for future research.
A Stochastic Model for Hedge Fund Relative Returns

A stochastic difference equation of the form X_n = A_n X_{n-1}+B_n is proposed to model the annual returns X_n of a hedge fund relative to other funds in the same strategy group in year n, and is fit to data from the TASS database over the period 2000 to 2004. In the proposed model, {A_n} and {B_n} are independent sequences of independent and identically distributed random variables, allowing general distributions, with A_n and B_n independent of X_{n-1}, E[B_n] = 0 and E[A_n] = gamma, 0
A Puzzle-Based Seminar for Computer Engineering Freshmen

We observe that recruitment efforts aimed at alleviating the shortage of skilled workforce in computer engineering must be augmented with strategies for retaining and motivating the students after they have enrolled in our educational programmes. At the University of California, Santa Barbara, we have taken a first step in this direction by offering a required freshman seminar entitled “Ten Puzzling Problems in Computer Engineering”. This one-unit pass/not-pass gateway course, which is graded based solely on attendance, introduces our students to some of the most challenging problems faced by computer engineers in their daily professional endeavors and at the frontiers of research. To accomplish this feat in a manner that is both understandable and appealing to freshmen, the problems are related to popular mathematical and logical puzzles. Each 1-hour class session begins by introducing the students to puzzles of a particular kind and letting them participate in formulating solutions. Historical context, ...
Twenty-first century behavioral medicine: A context for empowering clinicians and patients with diabetes: A consensus report

In the past decades, the sophistication of treatments for diabetes has increased dramatically, and evidence for effective interventions has proliferated. As a result, it is now possible to achieve excellent glucose control and reduce the risk of many of the complications associated with the disease. Despite these advances, however, many people with diabetes have less than optimal metabolic control and continue to suffer from preventable complications. The gap between optimal evidence-based medicine and actual practice can be great, dependent not only on the ability of the clinician to make changes in practice patterns but also on the central role of the patient in implementing optimal management plans in daily life. With recognition of the centrality of patients’ actions to achieve optimal outcomes must come awareness that those actions reflect much more than simple “self-control.” In addition to individual characteristics, the environment in which behaviors are enacted has great influence, from family eating patterns to the design of neighborhoods to workplace and national health policies. For patients and clinicians, these factors create the context or environment in which behaviors are enacted. Diabetes provides a prime example of this fundamental interaction of individual characteristics with the ecological or contextual factors. For example, Pima Indians living in the U.S. have the highest prevalence of type 2 diabetes of any population in the world, yet Pimas living traditional lifestyles in Mexico have relatively low levels of diabetes. Ample evidence links genetics to diabetes within the Pima population, but exposure to an obesogenic environment is critical to expression of this very strong genetic propensity (1). This interplay between the individual and the context in which he or she behaves is commonly cited in discussions of personal health choices and health and social policies. These perspectives have shifted in …
The bizarre mnemonic: The effect of retention interval and mode of presentation

Two experiments are reported, in which subjects were told to use visual images to help them remember lists of words. Both experiments yielded the typical results with immediate free recall: In mixed lists, words in bizarre contexts are remembered better than those in common contexts, but no such advantage exists for pure lists. In Experiment 1, memory was also tested after 48 h, and no evidence was found to suggest that the advantage for bizarre contexts continued to increase during this longer retention interval, or that it is even present for groups tested only after this delay. That is, the bizarre context effect (BCE) appears to be limited to brief retention intervals. In Experiment 2, words presented with pictures were found to be remembered better than those presented with sentences, but there was no interaction of this picture advantage with the BCE. In Experiment 1 no correlation between extroversion and BCE magnitude was found, and Experiment 2 yielded no correlation between mental image ability and BCE magnitude. However, subjects with high mental-image ability scores remembered more from pure bizarre lists than did those with low mental-image scores.
Plasminogen-mediated matrix invasion and degradation by macrophages is dependent on surface expression of annexin II

Genetic evidence demonstrates the importance of plasminogen activation in the migration of macrophages to sites of injury and inflammation, their removal of necrotic debris, and their clearance of fibrin. These studies identified the plasminogen binding protein annexin II on the surface of macrophages and determined its role in their ability to degrade and migrate through extracellular matrices. Calcium-dependent binding of annexin II to RAW264.7 macrophages was shown using flow cytometry and Western blot analysis of EGTA eluates. Ligand blots demonstrated that annexin II comigrates with one of several proteins in lysates and membranes derived from RAW264.7 macrophages that bind plasminogen. Preincubation of RAW264.7 macrophages with monoclonal anti–annexin II IgG inhibited (35%) their binding of 125I-Lys-plasminogen. Likewise, plasmin binding to human monocyte-derived macrophages and THP-1 monocytes was inhibited (50% and 35%, respectively) when cells were preincubated with anti–annexin II IgG. Inhibition of plasminogen binding to annexin II on RAW264.7 macrophages significantly impaired their ability to activate plasminogen and degrade [3H]-glucosamine–labeled extracellular matrices. The migration of THP-1 monocytes through a porous membrane, in response to monocyte chemotactic protein-1, was blocked when the membranes were coated with extracellular matrix. The addition of plasminogen to the monocytes restored their ability to migrate through the matrix-coated membrane. Preincubation of THP-1 monocytes with anti–annexin II IgG inhibited (60%) their plasminogen-dependent chemotaxis through the extracellular matrix. These studies identify annexin II as a plasminogen binding site on macrophages and indicate an important role for annexin II in their invasive and degradative phenotype.
Integrating incompatible hardware and software systems

Integration of existing physical systems and hardware controlled systems such as machinery, HVAC, door locks, power distribution, pumps, etc, with newly developed software designed to control these systems presents interesting problems. Many of these large systems cannot be replaced with newer systems to enable integrated software control, or such replacement is not feasible, leading to the need to bridge the gap between the existing hardware system and the software which will control it. Consideration of this problem, a paradigm for design and development of such a system to bridge the gap, and a case study involving a robot arm and the SR4 robot will be used to illustrate and present the problem.
Abstract 3049: Development of novel survivin inhibitors to target mitotic machinery in cancers

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Survivin, a member of the inhibitor of apoptosis (IAP) protein family has essential roles in cell division and inhibition of apoptosis. Over-expression of survivin is observed in most human cancers, but survivin expression is not detectable in non-proliferating normal adult tissues. In dividing cells, survivin is detected as an integral component of the chromosomal passenger complex (CPC). In the CPC, survivin is organized as a homodimer, associated with Aurora B-kinase and plays a critical role in the recruitment of a number of proteins to the kinetochore and centromere, which are essential for mitotic progression. Several clinical correlative studies in cancer patients have shown that elevated levels of survivin decreases overall survival and leads to resistance to radiation and chemotherapeutic treatments. Thus, disruption of functional survivin along its dimer interface is hypothesized to inhibit the proliferation of cancer cells by further sensitizing them to therapeutic agents and radiation. Recently, through HTS-NMR and AS/MS affinity based screenings, compound 1 (C1) was identified to bind to the dimerization interface of survivin monomers. Further development of this compound was accomplished by computational modeling of inhibitor interactions along the dimerization interface, which has lead to the design of a panel of promising compounds analogous to compound 1. Two of the most potent inhibitors included LLP3 and LLP9, which showed significant levels of activity between 50 and 100 nM. In proliferating human umbilical vein endothelial cells (HUVEC) as well as in prostate cancer cells (PC3) cells, the compounds caused a delay in mitotic progression and major mitotic defects. These cells expressed physiological levels of GFP-tagged survivin, which were used for visualization in automated fluorescent time-lapse videomicroscopy to investigate how the survivin dimerization inhibitors affected cell cycle progression. The same microscopy methods were used for understanding the specificity and activity of each respective compound. The investigation of cells treated with each of the compounds allowed for resolution of subcellular level effects on mitotic progression and CPC organization/movement during mitosis. The qualitative microscopy data was enumerated in order to quantify effects the compounds had on cells. The cells were enumerated in triplicate and tracked for changes in their proliferation, cell death, changes in ploidy, and other mitotic defects. The relationships between structure and activity of the compounds will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3049. doi:1538-7445.AM2012-3049
Etiocholanolone receptor in rat liver and Novikoff rat hepatoma cell culture.

Abstract The binding of tritiated etiocholanolone to rat liver and Novikoff hepatoma cells has been investigated. Cytosols obtained from rat liver and Novikoff hepatoma contain high affinity-low capacity binding macromolecules (Kd = 9.6 × 10−10 M for rat liver and 1.1 × 10−9 M for Novikoff hepatoma and the number of binding sites was 64 fmol/mg protein for rat liver and 76 fmol/mg protein for Novikoff hepatoma). Cytosols labelled with [3H]-etiocholanolone had a sedimentation coefficient of 4.6 under low and high salt concentration. Preincubation of rat liver slices and Novikoff hepatoma cells with unlabelled etiocholanolone followed by exchange of nuclear receptor complex with [3H]-etiocholanolone showed the presence of a single peak sedimenting at 4.6 S. Extraction of nuclear receptor peak sedimenting at 4.6 S and identification of the steroid showed that 86% of the radioactivity was associated with etiocholanolone and 14% with 5β-androstane-3α,17β-diol. Competition studies showed that steroids with 5β-H configuration were very effective in displacing etiocholanolone from cytoplasmic receptors while steroids with the 5α-configuration were not. These studies show that etiocholanolone receptor present in mammalian liver is essentially similar to that obtained from chick embryo liver.
Theory-based screening for prevention: Focusing on mediating processes in children of divorce

Prevention programs in mental health theoretically can benefit from selecting participants who have a greater likelihood of developing psychological problems because of their exposure to the putative mediators targeted for change in an intervention. Screening on mediators may increase statistical power to detect program effects, enhance the cost-effectiveness of intervention trials, and decrease the possibility of iatrogenic effects. The circumstances that optimize the strategy of screening on the basis of mediating variables are discussed, and data are presented to illustrate the development of a mediational selection strategy to identify families who might best benefit from a preventive intervention for children of divorce. In addition, we present evidence that adjustment problems for children experiencing a divorce, as with most mental health problems, are not the result of one specific factor, but are jointly determined by several mediating processes that occur subsequent to the divorce. The mediational selection strategy developed illustrates the utility of measuring a set of mediational processes central to conferring risk for mental health problems to children of divorce.
HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch functions

Mutations in the human mismatch repair (MMR) gene hMSH2 have been linked to approximately 40% of hereditary nonpolyposis colorectal cancers (HNPCC). While the consequences of deletion or truncating mutations of hMSH2 would appear clear, the detailed functional defects associated with missense alterations are unknown. We have examined the effect of seven single amino acid substitutions associated with HNPCC that cover the structural subdomains of the hMSH2 protein. We show that alterations which produced a known cancer-causing phenotype affected the mismatch-dependent molecular switch function of the biologically relevant hMSH2-hMSH6 heterodimer. Our observations demonstrate that amino acid substitutions within hMSH2 that are distant from known functional regions significantly alter biochemical activity and the ability of hMSH2-hMSH6 to form a sliding clamp.
Enediynes: Exploration of microbial genomics to discover new anticancer drug leads

The enediyne natural products have been explored for their phenomenal cytotoxicity. The development of enediynes into anticancer drugs has been successfully achieved through the utilization of polymer- and antibody–drug conjugates (ADCs) as drug delivery systems. An increasing inventory of enediynes would benefit current application of ADCs in many oncology programs. Innovations in expanding the enediyne inventory should take advantage of the current knowledge of enediyne biosynthesis and post-genomics technologies. Bioinformatics analysis of microbial genomes reveals that enediynes are underexplored, in particular from Actinomycetales. This digest highlights the emerging opportunities to explore microbial genomics for the discovery of novel enediyne natural products.
Brain neuronal chromatin responses in acute soman intoxicated rats.

Male Sprague-Dawley rats (200 g) were injected subcutaneously with soman, a potent neuronal acetylcholinesterase (AChE) inhibitor, at doses of 0.5, 0.8 and 1.0 LD50 (1 LD50=135 μg/kg) before decapitation at 1 and 24 h post-exposure. Correlative data were obtained on the severity of brain AChE inactivation and physicochemical changes in nuclear chromatin of cerebrocortical (layer V) and striatal neurons using Feulgen-DNA (F-DNA) cytophotometry and ocular filar micrometry. Decreased lability of neurons to F-DNA acid hydrolysis (reduced F-DNA yield), nuclear shrinkage and chromatin aggregation (decreased chromophore area) were used as indices of suppression of genomic template activity; conversely, increases in F-DNA yield and chromophore area signify enhanced neuroexcitation. At 1 hr post-soman there was a dose-dependent inactivation of AChE with a moderate increase in chromatin activation, i.e., nuclear hypertrophy and chromatin dispersion. At 24 hr post-soman there was a partial restoration of AChE activity, notably in striatal neurons, with a suppression in chromatin template activity. These data indicate that actions of soman on neuronal functioning are time-dependent. The absence of any dose-related neuronal chromatin changes may signify existence of non-cholinergic mediated events.
PTEL: capable file transfer package

The main purpose of PTEL is to perform transfers of files between computer systems. For this use it is a reliable, well functioning package. PTEL is also able to perform automatic dialling, control automatic logons and emulate a DEC VT‐102 terminal. PTEL lacks the exploding menus, screen windows and colour graphics offered by some other packages. What it offers are sound basic operation and reliability in file transfers.
Friends and foes

Nationalism and Internationalism in Science, 1880–1939: Four Studies of the Nobel Population. By Elisabeth Crawford. Cambridge University Press: 1992. Pp. 157. £27.95, $44.95.
Selective immobilization of proteins to self-assembled monolayers presenting active site-directed capture ligands

This paper describes a method for the selective and covalent immobilization of proteins to surfaces with control over the density and orientation of the protein. The strategy is based on binding of the serine esterase cutinase to a self-assembled monolayer presenting a phosphonate ligand and the subsequent displacement reaction that covalently binds the ligand to the enzyme active site. Surface plasmon resonance (SPR) spectroscopy showed that cutinase binds irreversibly to a monolayer presenting the capture ligand at a density of 1% mixed among tri(ethylene glycol) groups. The covalent immobilization is specific for cutinase, and the glycol-terminated monolayer effectively prevents unwanted nonspecific adsorption of proteins. To demonstrate that the method could be used to immobilize proteins of interest, a cutinase-calmodulin fusion protein was constructed and immobilized to the monolayer. SPR showed that calcineurin selectively associated with the immobilized calmodulin. This capture ligand immobilization method combines the advantages that the immobilization reaction is highly selective for the intended protein, the tether is covalent and, hence, stable, and the method avoids the need for synthetic modification and rigorous purification of proteins before immobilization. These characteristics make the method well suited to a range of applications and, in particular, for constructing protein microarrays.
Atmospheric parameterization of evaporation from non-plant-covered surfaces

Abstract A new atmospheric parameterization formulation of evaporation from a nonplant-covered surface was derived by combining the previous two types of widely used formulations, the so-called “α method” and the “β method.” The study indicates that the “α method” cannot provide a reasonable estimation of evaporation from bare soil, while the “β method” does provide reasonable predictions during the daytime. However, the evaporation rate differences, estimated by the β method from that by the new parameterization, is evident at night. The deviation rises while increasing the atmospheric stability and reducing the soil wetness. The impact of atmospheric stability, soil wetness at the top or inside the soil, and soil type on evaporation rate is also discussed in detail.
Translational medicine: mitigating risks for investigators.

Although investigators are encouraged to translate their laboratory research to impact the care of patients, there is an unappreciated downside to participating in “T1 translation” from the standpoint of the investigator if their translational efforts do not yield positive results in pivotal clinical trials.
Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin

Thirteen patients with carcinomas of major and minor salivary gland origin (nine adenoid cystic carcinomas and four adenocarcinomas) were treated with cyclophosphamide (500 mg/m2), doxorubicin (50 mg/m2), and cisplatin (50 mg/m2) (CAP) by intravenous injections on the first day of a 28-day regimen. Sixty-one cycles of CAP were administered (mean, 4.7 cycles per patient). Eleven patients were treated for palliation of recurrent disease (locoregional, ten; lung, ten; liver, three; and bone, three). Two patients untreated previously, one with extensive local disease involving the base of the skull and one with a solitary lung metastasis (resected with a positive margin) and an initially unappreciated base of tongue primary, received two cycles of CAP followed by local treatment and adjuvant CAP. Previous therapy for the 11 patients with recurrent disease included surgery (ten), radiotherapy [RT(11)], chemotherapy (three), or hormonal therapy (two). Three complete and three partial responses to chemotherapy were noted for an overall response rate of 46%. The median duration of response in palliative patients was 5 months (range, 2 to 9). Of the two patients receiving induction CAP, one relapsed with distant disease 26 months after treatment, and the other remains disease-free after 60 months of follow-up examination. Chemotherapy was well tolerated generally, and no chemotherapy-related deaths occurred. One hypertensive patient suffered a stroke after 3 cycles of therapy. CAP is an active regimen against salivary gland carcinomas and deserves further study. Also, it may be of value as induction or adjuvant treatment for patients with advanced disease untreated previously.
Family-to-work Spillover Stress: Coping Communicatively in the Workplace

One career path that sheds light on the relationship between work and family for women is that of care-giving professionals. Because of the stressful nature of their socialized roles as caregivers at work and at home, these women constitute a unique population. This interpretive study investigated female care-giving professionals' family-to-work spillover stress and revealed eight communication strategies the women used to cope with it in the workplace. Insight is also provided into the organizational factors that facilitated and inhibited supportive communication in the workplace. Practical implications regarding how “family friendly” communication may enhance the work environment for employees are also discussed.
The Hostess Project

In an effort to further inhabit my grandmother's memories as a young wife, I began an autobiographical, photographic record of my experiences with her recipe journal. The Hostess Project is as much a social experiment as a nostalgic experience. I dress in her clothing, prepare meals based on her hand-written recipes, serve invited guests, and perform the role of hostess. I prepare dishes based on her hand-written instruction: her recipes. Aspics, croquettes, meatloaf with pickle and egg garnish . . . And I photograph the results. This article describes the origins of The Hostess Project and explores the relationship between time and memory, photography and memory, and food and memory.