cssi/SciSciGPT-SciSciNet huggingface dataset:
Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial

Summary Background Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). Methods In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. Findings Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7–48) of 18 patients with melanoma and six (33%; 14–59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3–4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1–2 seizures (n=3 [17%]) in the melanoma cohort. Interpretation Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding Merck and the Yale Cancer Center.
The Effects of Structured Transfer Pathways in Community Colleges

Most of the students who set out to earn degrees in community colleges never do. Interventions that simplify the complex organizational structures of these schools are promising solutions to this p...
THE CONCEPT OF AUTONOMY

Despite the rise in prominence of the concept of autonomy, the concept remains vague at best. Joel Feinberg attributes this vagueness to the fact that autonomy is used in different contexts,1 although he admits the uses are closely related. Gerald Dworkin attributes the vagueness of the concept to the fact that ‘autonomy’ is a “term of art”,2 which will not repay an Austinian investigation into its uses. But the concept of autonomy is used in very concrete roles, and is a key issue in many practical debates. If the concept is to serve in this role, we must have an idea of just what the concept is about, if only in the abstract.
Understanding and Analyzing Human Error in Real-World Operations

Publisher Summary Given that human error plays such a central role in aviation accidents, it is crucial to understand the causes of error and the ways errors contribute to accidents. Furthering this understanding should be the foundation of any safety research program, and any operational safety program should be built on this foundation. Finding ways to improve safety and efficiency and to reduce costs are central aspects of the work of human factors experts, thus these experts require a deep and veridical understanding of the nature and context of human error. This chapter attempts to provide a foundation for that understanding and a framework for practical application. The way in which errors are analyzed and interpreted hinges on one's perspective on what causes error. The chapter presents a perspective on the nature of errors made by skilled professionals such as pilots and the roles those errors play in accidents. It discusses the types of information we need in order to understand why error-related accidents occur, examines sources of this information, and describes diverse approaches to analyzing errors and accidents. It illustrates some analytical approaches and concludes by examining the implications of these studies for developing countermeasures for reducing vulnerability to error.
Probing the validity of the diffuse mismatch model for phonons using atomistic simulations

Due to its simplicity the diffuse mismatch model (DMM) remains a popular description of phonon transmission across solid-solid boundaries. However, it remains unclear in which situations the DMM should be expected to be a valid model of the underlying physics. Here its validity is investigated mode-by-mode using a three-dimensional extension of the frequency domain, perfectly matched layer (FD-PML) method, to study the interface between face-centered cubic solids with interdiffused atoms. While submonolayer levels of interdiffusion are found to increase the number of available modes for transmission, consistent qualitatively with the DMM, we do not find quantitative or qualitative convergence toward the DMM at higher levels of interdiffusion. In particular, contrary to the fundamental assumption of the DMM, modes are not found to lose memory of their initial polarization and wave vector. The transmission coefficients of randomly interdiffused and smoothly graded interfaces are also compared. While smoothly graded interfaces show strong antireflection properties, selection rules still prohibit transmission of many modes, whereas interdiffused interfaces are not subject to such rules and achieve similar thermal interface conductance by transmitting with lower probability but using a wider range of modes.
Inhibition of colorectal tumorigenesis in azoxymethane (AOM)-treated rats by green tea polyphenols

A134 The cancer preventive activity of tea and its constituents has been demonstrated in different animal models. However, the results on colon cancer prevention by tea polyphenols in rats have not been consistent. Previously, our results showed that dietary administration of Polyphenon E (PPE, a standardized green tea polyphenol preparation) inhibited the formation of aberrant crypt foci in AOM-treated rats. Herein, we conducted a study with PPE as the preventive agent in the AOM-induced rat colon cancer model using the colorectal tumor as an endpoint. F344 rats were given two weekly injections of AOM (15 mg/kg), and then fed a 20% high fat diet with or without 0.24% PPE for 34 weeks. In the positive control group, 96% of rats developed colorectal tumors with multiplicity of 3.64 ± 0.31, and tumor tissues showed highly elevated levels of Akt and phospho-Akt, and decreased levels of caspase-3 activation, in comparison to the normal colorectal mucosa. Dietary PPE treatment did not change liver or kidney weight, but decreased body weight by 5% in the treated group compared to the control. The decrease in body weight may be due to inhibition of lipid absorption by tea polyphenols (as suggested by our study in a high fat diet-induced obesity mouse model). Dietary PPE treatment significantly decreased tumor multiplicity and tumor size by 55% (p
Martyrs for a just cause: The eulogies of Cesar Chavez

During his years as president of the United Farm Workers (UFW), Cesar Chavez delivered five eulogies for individuals who were killed while engaged in union activities. This paper argues that these “Accidental Martyrs” were rhetorically created by Chavez to serve as symbols for the union's cause. The eulogies helped Chavez to build a union community and to move the UFW's members to accept particular beliefs and to undertake specific acts. He also used the martyrs as models in his later speeches.
Should the Devil Wear Prada? Analyzing Consumers’ Responses to Luxury Branding

The chapter focuses on the analysis of luxury and the major definitional and conceptual issues involving luxury in the fashion industry. In the midst of rising globalization and a daily changing economy, luxury brands play a vital role in political, social, and business spheres by fulfilling people’s physical and psychological needs. This research provides a framework for an investigation into the consumption and management of luxury in today’s society. Further, it examines the different consumers’ perspectives of luxury, sometimes known as “semi-luxury,” and its impact on the market. The aim of this research is to give a sense of the characteristics of luxury and semi-luxury brands to academics and practitioners in the luxury fashion industry. These characteristics are derived from focus groups, one-to-one interviews, and online surveys. Finally, the chapter offers insights and pointers for future research.
CeNDR, the Caenorhabditis elegans natural diversity resource

Studies in model organisms have yielded considerable insights into the etiology of disease and our understanding of evolutionary processes. Caenorhabditis elegans is among the most powerful model organisms used to understand biology. However, C. elegans is not used as extensively as other model organisms to investigate how natural variation shapes traits, especially through the use of genome-wide association (GWA) analyses. Here, we introduce a new platform, the C. elegans Natural Diversity Resource (CeNDR) to enable statistical genetics and genomics studies of C. elegans and to connect the results to human disease. CeNDR provides the research community with wild strains, genome-wide sequence and variant data for every strain, and a GWA mapping portal for studying natural variation in C. elegans Additionally, researchers outside of the C. elegans community can benefit from public mappings and integrated tools for comparative analyses. CeNDR uses several databases that are continually updated through the addition of new strains, sequencing data, and association mapping results. The CeNDR data are accessible through a freely available web portal located at http://www.elegansvariation.org or through an application programming interface.
Incorporating a Pharmacist into the Discharge Process: A Unit-Based Transitions of Care Pilot:

Objective: To evaluate the impact of a multifaceted, pharmacy-driven, unit-based transitions of care (TOC) program on all-cause 30-day readmission rates and to assess readmission rates in predefined subgroup patient populations. Methods: This prospective study included adult patients who were discharged from the pilot unit from January 5 to January 30, 2015. Patients who expired during hospitalization, left the hospital against medical advice, or transferred to another unit or nonaffiliated hospital were excluded. Possible pharmacist interventions included daily medication profile review, delivery of discharge medications to the bedside, counseling, and communication of a discharge medication list to follow-up providers. Patients had a 30-day follow-up period from the date of discharge to assess for readmission. Results: A total of 131 patients were screened and 94 patients were included. The primary outcome evaluating 30-day readmission rates occurred in 12.8% of patients in the pilot group versus 18.8% of patients in the historical control group (p = .26). None of the patients who received all possible pharmacist interventions were readmitted. Secondary outcomes assessing readmission rates in predefined subgroup populations as well as length of stay were comparable between the 2 groups. All identified medication discrepancies were resolved prior to discharge. Conclusion: Readmission rates during the pilot were numerically lower but not statistically significant when compared with historical data. Enhancement of the pharmacy-driven TOC services through allocation of additional resources is in progress. Further investigation is warranted to determine the impact of a TOC pharmacist after the service is sustained.
Characteristic mode analysis of ground plane size in microstrip patch antennas

The Theory of Characteristic Modes is proposed as a systematic approach to antenna design to achieve the goal of finding the antenna structure with optimum broadband behavior. This theory provides a physical insight to the radiating nature of microstrip patch antennas and reduces the design optimization time. In this paper, the resonant behavior of different ground plane sizes are analyzed using this theory. The modal analysis concludes that the larger the ground plane the more resonant the antenna structure is. Hence, microstrip patch antennas with larger ground plane are a good candidate to achieve the highest impedance bandwidth.
Single-cell epigenomics maps the continuous regulatory landscape of human hematopoietic differentiation

Normal human hematopoiesis involves cellular differentiation of multipotent cells into progressively more lineage-restricted states. While epigenomic landscapes of this process have been explored in immunophenotypically-defined populations, the single-cell regulatory variation that defines hematopoietic differentiation has been hidden by ensemble averaging. We generated single-cell chromatin accessibility landscapes across 8 populations of immunophenotypically-defined human hematopoietic cell types. Using bulk chromatin accessibility profiles to scaffold our single-cell data analysis, we constructed an epigenomic landscape of human hematopoiesis and characterized epigenomic heterogeneity within phenotypically sorted populations to find epigenomic lineage-bias toward different developmental branches in multipotent stem cell states. We identify and isolate sub-populations within classically-defined granulocyte-macrophage progenitors (GMPs) and use ATAC-seq and RNA-seq to confirm that GMPs are epigenomically and transcriptomically heterogeneous. Furthermore, we identified transcription factors and cis-regulatory elements linked to changes in chromatin accessibility within cellular populations and across a continuous myeloid developmental trajectory, and observe relatively simple TF motif dynamics give rise to a broad diversity of accessibility dynamics at cis-regulatory elements. Overall, this work provides a template for exploration of complex regulatory dynamics in primary human tissues at the ultimate level of granular specificity - the single cell.
Getting my feet wet

After finishing my undergrad studies, I did what many newly minted electrical engineers do and moved to Silicon Valley. Working at Apple, I was living my dream of contributing to the very products I had always admired. Yet, after a couple of years, I began to feel as though something was missing. I
Aqueous cigarette tar extracts disrupt corticogenesis from human embryonic stem cells in vitro

Abstract Background Cigarette butts are the most common form of litter in the world, and approximately 4.5 trillion smoked cigarettes are discarded every year worldwide. Cigarette butts contain over 4000 chemicals, many of which are known to have neurotoxic effects. Stem cell neuronal differentiation provides an excellent cellular model with which to examine the impact of aqueous cigarette tar extracts (ACTEs) on neurodevelopment. Methods We have developed a neurosphere-based stem cell neuronal differentiation protocol that can recapitulate corticogenesis and produce cell types that are similar to upper and lower layer cortical projection neurons found in the germinal zone of the developing human cortex. In this study, ACTEs were generated from smoked cigarette butts and then applied at different concentrations to neuronal progenitors and cortical neurons derived from human embryonic stem cells. Results ACTEs reduced the expression of the cortical neuronal progenitor markers pax6, tbr2, and neuroD and decreased the number of cortical layer neurons (tbr1, satb2, foxp2, and brn2) after exposure to as low as 1.87% of the extract from one smoked cigarette butt. Furthermore, our results showed that ACTEs increased reactive oxygen species (ROS) production in cortical neurons, which caused a substantial loss of the synaptic proteins PSD95, synaptophysin, vesicular glutamate transporter1 (vGlut1), and the extracellular matrix molecule reelin; all of those molecules are important for the maintenance of cortical neuron identity and activity. Conclusion ACTEs from smoked cigarettes have significant effects on cortical neuron development and neurodegeneration. The stem cell neuronal differentiation model holds great promise as a potentially powerful tool for the assessment of ACTEs on neurotoxicity.
Assessment of the potential impact of dose rounding parenteral chemotherapy agents on cost savings and drug waste minimization.

BackgroundFiscally responsible utilization of anticancer treatments is necessary to combat their continually increasing cost. Dose rounding is one strategy that has been explored to minimize cost and waste without losing clinical effectiveness.ObjectivesTo determine if dose rounding chemotherapy agents is a feasible cost-containment strategy at an institution with a small oncology clinic.MethodsThis study is a retrospective chart review of all body surface area dosed parenteral chemotherapy prescribed for an oncological diagnosis over a 12-month period (1 October 2015–30 September 2016). Chemotherapy doses were rounded down by 5%. Doses for patients with metastatic diagnoses were also rounded down by 10%. Rounded doses were evaluated for a potential decrease in vial size. Cost was represented as dollar/milligram of drug. Potential for drug waste minimization was also calculated.ResultsThere were 877 total doses of chemotherapy administered to 70 unique patients throughout the 12-month duration of the stud...
Marine Photochemistry of Organic Matter: Processes and Impacts

Abstract Dissolved organic matter (DOM) is the strongest light-absorbing component of seawater, especially in coastal regions, and therefore it plays a dominant role in marine photochemical and photophysical processes in surface waters. This critical review focuses on the impact of DOM photochemistry on marine biogeochemical processes, highlighting and evaluating recent advances and areas for future work. Specific topics reviewed include: (1) coupling photochemical and microbial processes; (2) photochemical dissolved inorganic carbon (DIC) formation and oxygen consumption; (3) carbon monoxide photoproduction; (4) role of photochemistry in the sulfur, nitrogen, and phosphorus cycles; (5) mechanisms of DIC photoformation and DOM oxidation; (6) particle and sea-ice photochemistry; (7) photochemical transformations of siderophores and toxins; and (8) modeling photochemical rates. Finally, several avenues of future work are discussed including the need for mechanistic studies, photoproduction, and air-sea exchange of important atmospheric trace gases, DOM marine food web dynamics and trace metals, photodissolution, and photoflocculation of particles, and improved quantification of photochemical rates.
Gene Therapy: The Path Toward Becoming a Realistic Cure for Sickle Cell Disease

Unlike hydroxyurea or chronic blood transfusions to alleviate severity of sickle cell disease (SCD), hematopoietic stem cell transplantation (HSCT) is the only currently available curative option for patients with SCD. Data suggests an overall survival of >95% with a myeloablative regimen using HLA-matched sibling donors and >90% disease-free survival using a non-myeloablative regimen, yet less than 15% of patients with SCD have an appropriately matched donor. Allogeneic transplantation is further limited by morbidity and mortality from transplant conditioning, graft-versus-host disease (GVHD), and graft rejection; therefore other curative options are needed. The premise of gene therapy either by editing, modification, or gene insertion into autologous hematopoietic stem cells (HSCs) for the purpose of curative therapy for genetically based diseases raises the promise of a safer cure for SCD that is available to all patients. After decades of ongoing research, gene therapy for the cure of SCD is now a reality and is being investigated in multiple clinical trials.
Light induced reversible and irreversible mechanical responses in nanotube-polymer composites

Abstract It is shown that visible light irradiation of carbon nanotube (CNT) dispersed polymers may yield both reversible and irreversible changes in measured mechanical stress. While light irradiation of PDMS (polydimethylsiloxane)–CNT composite yields a change of stress level at a fixed strain, which reverts to the original value after the incident light is removed, the RET (reactive ethylene terpolymer)–CNT composite exhibits such reversible characteristics as well as an additional irreversible stress-relaxation response when the composite is first irradiated by light. A microscopic model is proposed to explain the mechanism of the dual photomechanical responses of the RET-CNT composites and quantitative predictions are compared with experimental measurements.
Semantic Models for Labeling Spectrum Data

With the increasing importance and demand for wireless communications, there is a spectrum crunch and there is no easy way to meet this increasing demand. Spectrum monitoring is a key enabler for understanding how the spectrum is currently used and identifying opportunities for spectrum sharing. This paper focuses on analysis of a large volume of complex spectrum measurements in the public safety band and involves modeling spectrum sensors, public safety domain knowledge and events involving public safety. The information models developed can be used to create labels for the complex spectrum data and facilitate the analysis of the data needed for spectrum sharing.
XXIX. On the photographic use of a silvered-glass reflecting telescope

(1864). XXIX. On the photographic use of a silvered-glass reflecting telescope. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science: Vol. 28, No. 189, pp. 249-255.
LY379268 Does Not Have Long-Term Procognitive Effects nor Attenuate Glutamatergic Signaling in AβPP/PS1 Mice.

Chronically elevated basal glutamate levels are hypothesized to attenuate detection of physiological signals thereby inhibiting memory formation and retrieval, while inducing excitotoxicity-mediated neurodegeneration observed in Alzheimer's disease (AD). However, current medication targeting the glutamatergic system, such as memantine, shows limited efficacy and is unable to decelerate disease progression, possibly because it modulates postsynaptic N-methyl-D-aspartate receptors rather than glutamate release or clearance. To determine if decreasing presynaptic glutamate release leads to long-term procognitive effects, we treated AβPP/PS1 mice with LY379268 (3.0 mg/kg; i.p.), a metabotropic glutamate receptor (mGluR)2/3 agonist from 2-6 months of age when elevated glutamate levels are first observed but cognition is unaffected. C57BL/6J genetic background control mice and another cohort of AβPP/PS1 mice received normal saline (i.p.) as vehicle controls. After 6 months off treatment, mice receiving LY379268 did not show long-term improvement as assessed by the Morris water maze (MWM) spatial learning and memory paradigm. Following MWM, mice were isoflurane anesthetized and a glutamate selective microelectrode was used to measure in vivo basal and stimulus-evoked glutamate release and clearance independently from the dentate, CA3, and CA1 hippocampal subregions. Immunohistochemistry was used to measure hippocampal astrogliosis and plaque pathology. Similar to previous studies, we observed elevated basal glutamate, stimulus evoked glutamate release, and astrogliosis in AβPP/PS1 vehicle mice versus C57BL/6J mice. Treatment with LY379268 did not attenuate these responses nor diminish plaque pathology. The current study builds upon previous research demonstrating hyperglutamatergic hippocampal signaling in AβPP/PS1 mice; however, long-term therapeutic efficacy of LY379268 in AβPP/PS1 was not observed.
Involvement of CHK1 pathway in protecting cells from taxotere-induced killing

5326 Taxotere is an anticancer agent with demonstrated activity in a variety of solid tumors. Taxotere affects tubulin polymerization and interferes with mitotic transition. These changes activate the apoptosis process and elicit cytotoxicity. However, these changes can also slow down cell cycle progression by activating checkpoints that provide time for repair and thus reduce the cytotoxicity. Therefore, the cellular response to taxotere-cytotoxicity can impact the expected therapeutic efficacy. To date, the mechanism by which cell cycle checkpoints impact taxotere cytotoxicity remains unclear. Here our preliminary data show that a CHK1 over-expressing cell line, A1-5 cells (JBC, 276:17693, 2001) were more resistant to taxotere cytotoxicity than its counterpart cell line, B4 cells. Validation of the gene-specific effect was obtained when CHK1 protein expression was suppressed by siRNA and the taxotere resistance was eliminated in A1-5 cells. These data suggest that CHK1 pathway-regulated checkpoint can be important in protecting cells from the taxotere cytotoxicity. This work was supported by a grant from Aventis.
Clientelism's Red Herrings: Dead Ends and New Directions in the Study of Nonprogrammatic Politics

Research on clientelism often starts from a shared puzzle: How can clientelism be a viable electoral strategy if voters can renege on their commitments to politicians? The standard solution propose...
A Machine Learning Platform for NLP in Big Data

The objective of this work is the design of an architecture for the management and storage of data that are exponentially increasing and coming from different sources. The main areas of intervention are focused on demonstrating how a solution of a service architecture is able to abstract itself from any software that produces or receives data and guarantees a correct flow of them regardless of the speed or quantity of input, also guaranteeing fault-tolerance. A case study is presented for processing and archiving natural language, ensuring fault tolerance, reliability, speed and a high storage capacity. The result of this paper is an architecture that is able to process text data and to obtain the subject from each of them.
Intrathecal Delivery of BDNF Into the Lumbar Cistern Re-Engages Locomotor Stepping After Spinal Cord Injury

Delivery of neurotrophins to the spinal injury site via cellular transplants or viral vectors administration has been shown to promote recovery of locomotion in the absence of locomotor training in adult spinalized animals. These delivery methods involved risks of secondary injury to the cord and do not allow for precise and controlled dosing making them unsuitable for clinical applications. The present study was aimed at evaluating the locomotor recovery efficacy and safety of the neurotrophin BDNF delivered intrathecally to the lumbar locomotor centers using an implantable and programmable infusion mini-pump. Results showed that BDNF treated spinal cats recovered weight-bearing plantar stepping at all velocities tested (0.3-0.8 m/s). Spinal cats treated with saline did not recover stepping ability, especially at higher velocities, and dragged their hind paws on the treadmill. Histological evaluation showed minimal catheter associated trauma and tissue inflammation, underlining that intrathecal delivery by an implantable/programmable pump is a safe and effective method for delivery of a controlled BDNF dosage; it poses minimal risks to the cord and is clinically translational.
Shakespeare on the Arabian Peninsula: KATHERINE HENNESSEY, (London: Palgrave Macmillan, 2018), 340 pages; £79.99 hardcover, £63.99 eBook.

In Shakespeare on the Arabian Peninsula, Katherine Hennessey provides an encyclopedic accounting of The Bard’s appearances in the Gulf Cooperation Council states and Yemen over the course of the 20...
Patient-reported outcomes in breast cancer FDA drug labels and review documents.

Background Patient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions. Methods We included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted. Results Of 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers' comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods. Conclusions Despite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.
Protocol for tissue slice cultures from human solid tumors to study therapeutic response.

Summary The impact of systemic therapy on the tumor microenvironment has been difficult to study in human solid tumors. Our protocol describes steps for establishing slice cultures to investigate response to chemotherapies, immunotherapies, or adoptive cell therapies. Endpoints include changes in viability, histology, live-cell imaging, and multi-omics analyses. The protocol has been applied to a broad array of gastrointestinal malignancies. Culture conditions and treatment parameters can be modified for specific experiments. The platform is highly flexible and easy to manipulate. For complete details on the use and execution of this protocol, please refer to Kenerson et al. (2020) , Jabbari et al. (2020) , Brempelis et al. (2020) , and Jiang et al. (2017) .
Orientalism and Islam: James Mill and John Stuart Mill: Despotism in India

One of the early English admirers of Alexis de Tocqueville was John Stuart Mill who immediately recognized the first volume of Democracy in America as “an excellent book, uniting considerable graphic power with the capacity of generalizing on the history of society.” After the publication of Tocqueville's second volume, Mill thought rather differently that the work was “really abstruse, by being so abstract and not sufficiently illustrating his propositions,” thus making it difficult to review. Nevertheless, Mill, in two, long admiring reviews, complimented Tocqueville on a great achievement that, he wrote, changed the face of political philosophy and the discussion on the tendencies of modern society. Like his French friend, John Stuart Mill was another public intellectual, forwarding ideas to influence politics and culture. In his discussion of Tocqueville, Mill concluded that the Frenchman's definition of democracy was not a particular form of government but equality of conditions, the absence of all aristocracy, whether constituted by political privilege or by superiority in individual importance and social power. More pointedly, in his May 11, 1840, letter, Mill praised one of Tocqueville's “great, general conclusions,” that the real danger in democracy, the real evil to be struggled against, was not anarchy or love of change but “Chinese stagnation” and immobility. John Stuart Mill in a number of his writings was to draw a similar conclusion on the issue of stagnation. He also took a similar position to that of Tocqueville about the possible tyranny of public opinion or collective mediocrity in democratic societies.
Radiation-Damage Considerations

The designs of nuclear-fission and fusion power plants do not, in general, appear to make unusual demands on materials in terms of mechanical-property requirements. Superficially, the needs of the designer can be met by commercially available alloys. However, the radiation environment produces unique effects on the composition, microstructure, and defect population of these alloys, resulting in time-dependent and time-independent changes in mechanical properties. These changes must be quantified for the designer.
Next‐Generation Sequencing RNA‐Seq Library Construction

This unit presents protocols for construction of next-generation sequencing (NGS) directional RNA sequencing libraries for the Illumina HiSeq and MiSeq from a wide variety of input RNA sources. The protocols are based on the New England Biolabs (NEB) small RNA library preparation set for Illumina, although similar kits exist from different vendors. The protocol preserves the orientation of the original RNA in the final sequencing library, enabling strand-specific analysis of the resulting data. These libraries have been used for differential gene expression analysis and small RNA discovery and are currently being tested for de novo transcriptome assembly. The protocol is robust and applicable to a broad range of RNA input types and RNA quality, making it ideal for high-throughput laboratories.
Images of Europe

How do Commission officials conceive the Commission’s role in the European Union? Should the Commission be the government of Europe or the servant of member states? Is there a third possibility, institutional pragmatism, whereby Commission and member states share authority? This article lays out jurisdictional options and role conceptions adopted by Commission officials, and estimates their relative incidence using a 2008 large-scale survey among Commission officials (N=1901). There is a plurality of views, though within relatively narrow parameters. In explaining variation, national background shapes views more than professional background.
Applications of the symmetric chain decomposition of the lattice of divisors

The symmetric chain decomposition of the lattice of divisors,D N, is applied to prove results about the strict unimodality of the Whitney numbers ofD N, about minimum interval covers for the union of consecutive rank-sets ofD N, and about the distribution of sums of vectors in which each vector can be included several times (an extension of the famous Littlewood-Offord problem)
Calcium Pyrophosphate Dihydrate Deposition Disease (Pseudogout) after Total Knee Arthroplasty

The authors report a case of calcium pyrophosphate dihydrate deposition disease (pseudogout) presenting in the early period after primary total knee arthroplasty. The patient's symptoms resolved with conservative management including colchicine and indomethacin. The presentation of pseudogout resembles septic arthritis and should be included in the differential diagnosis to prevent unnecessary surgery in these patients.
Simulating heat addition via mass addition in variable area compressible flows

The authors recently demonstrated the striking and potentially useful similarity between the influence of heat addition and mass addition (injected normal to the flow with the same total temperature and composition) on constant area compressible duct flows. This was primarily accomplished by means of closed-form, mathematical solutions for flows involving a single forcing function (e.g., heat or mass addition), commonly known as simple flows. The analyses were primarly based on the classical one-dimensional model of the steady, frictionless, constant throughflow area flow of a calorically perfect gas. The similarities were also found to exist when wall friction is present, including the estimated point of boundary-layer separation in supersonic flow. We extend the prior results to incorporate the influence of throughflow area variation
Global existence of large solutions to initial boundary value problems for a viscous, heat-conducting, one-dimensional real gas

Abstract The existence of global classical solutions to initial boundary value problems in the dynamics of a one-dimensional, viscous, heat-conducting gas is established. The nonlinear dissipative effects turn out to be sufficiently strong to prevent the development of singularities.
Plastic bronchitis in children: A case series and review of the medical literature

Plastic bronchitis is characterized by marked obstruction of the large airways by bronchial casts. We reviewed our experience and the literature to determine whether mortality rates are determined by underlying disease or cast type. We present 3 children with obstructive bronchial casts. One 3-year-old patient with Noonan's syndrome developed respiratory failure following surgery for tetralogy of Fallot requiring support with extracorporeal membrane oxygenation (ECMO) the first such case. There were 42 cases in the literature of children with plastic bronchitis. Casts may be divided into two types. Type I casts are inflammatory, consisting mainly of fibrin with cellular infiltrates, and occur in inflammatory diseases of the lung. Type II, or acellular casts, consist mainly of mucin with a few cells, and usually occur following surgery for congenital cardiac defects. Patients categorized by underlying disease included 31% with asthma or allergic disease, 40% with underlying cardiac defects, and 29% with other diseases. Mortality was 16%, but increased to 29% in patients with cardiac defects. Deaths occurred as long as 1 year after surgical repair for underlying defects. There were no deaths in patients with asthma. Life-threatening events were statistically higher in patients with cardiac defects (41%) than in those with asthma (0%, P = 0.02). Higher mortality in patients with type II casts compared to type I casts did not reach statistical significance (28% vs. 6%; P = 0.06). In conclusion, patients presenting with plastic bronchitis are at high risk for serious complications, especially with underlying cardiac disease.
The Means and Ends of Empire

Kennedy’s “The Means and Ends of Empires” offers a commentary on Julian Go’s stimulating comparative study of the British and American empires, Patterns of Empire . It argues that Go’s book is strongest in its analysis of the means by which the United States forged an empire, providing fresh insights into its strategies of expansion and control. By highlighting the ways those strategies built on—and diverged from—the ones employed by the British Empire, the book provides a bracing challenge to claims of American exceptionalism. It is less illuminating or original, however, in its assessment of Britain’s imperial experience, and when Go turns from the means by which these empires are made and maintained to how they come to an end, he advances an argument that falls short both on evidentiary and interpretive grounds. The latter part of Kennedy’s essay exposes the problems with Go’s assessment of the causes and chronology of British imperial collapse, and it challenges his claim that the United States entered a similar stage of inexorable decline in the 1970s. It notes that the preoccupation with imperial decline often says more about the political and intellectual anxieties of its purveyors than it does about the empires themselves. Empires are resilient, making it diffi cult to differentiate temporary setbacks from lasting losses.
Femtosecond laser dressing of the surfaces of porous alumina grinding wheels

The interaction of 180 fs, 775 nm laser pulses with the surfaces of alumina and glass under controlled gas atmospheres at ambient pressure has been investigated to study material redeposition, residual surface roughness and ablation rate. The effect of using various gases to protect the surface of the material appears to interfere with the effects of the plasma and can change the resulting microstructure of the dressed surface. By varying the combinations of fluence and laser scanning speed during ultra fast ablation at high repetition rates an optimum dressing condition can be reached. The process can be used to continuously dress porous vitrified cutting tools that are used for micro and nanogrinding processes.
Deletion of 12/15-Lipoxygenase Alters Macrophage and Islet Function in NOD-Alox15null Mice, Leading to Protection against Type 1 Diabetes Development

Aims Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. We showed previously that deletion of the 12/15-lipoxygenase enzyme (12/15-LO, Alox15 gene) in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D. Methods 12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD-Alox15null macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass. Results 12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15null mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass. Conclusions These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass.
Dynamic characterization of premature ventricular beats and ventricular tachycardias

Abstract The contraction patterns induced by ectopic ventricular premature beats and ventricular tachycardias occurring in man during left ventriculography were analyzed. These were compared with contraction patterns induced by ventricular premature beats and tachycardias produced in five dogs by epicardial left ventricular apical or basilar stimulation. Two patterns of contraction observed in the animals corresponded to two patterns observed in man. Apically stimulated left ventricular beats produced an “hourglass” type of contraction pattern and were hemodynamically more effective than beats arising from basilar stimulation, which produced an inverse “teardrop” pattern. The same patterns were reproduced by experimental ventricular tachycardias. These observations stress the importance of a normal sequence of ventricular contraction to optimal cardiac function in man and warn against the hazards of misinterpretation of the left ventricular contraction pattern if the beat originates ectopically during ventriculography.
Lunar Orbiter mission design.

The primary objectives of the Lunar Orbiter Program were to obtain photographic coverage of potential Apollo and Surveyor landing sites on the moon and to contribute to the scientific knowledge of the moon. An additional objective was to obtain information on the gravitational field of the moon. The landing site search at 1-m resolution was essentially completed by the end of the third flight; remaining flights provided a 100-m resolution map of the lunar front side and closeup views of scientifically interesting sites. The lunar back side was covered at about 1 km resolution. In this paper the lunar orbit design is developed in terms of mission requirements and predicted effects due to Earth and lunar gravitational fields. Errors experienced in predicting the spacecraft trajectory during the flight are indicated to be due to large irregularities in the lunar gravitational field.
Advances in the automated detection of metaphase chromosomes labeled with fluorescence dyes.

Applications of fluorescence in situ hybridization (FISH) for translocation studies and biological dosimetry would benefit substantially from reliable and efficient automatic detection of metaphase chromosomes labeled with fluorescent dyes. We replicated and evaluated a fluorescence metaphase finder previously developed at the Medical Research Council (MRC), Human Genetics Unit (Scotland) and at Lawrence Berkeley Laboratory (LBL; California). The MRC/LBL system seemed to detect nearly all of the metaphases on the test slides, but it presented an unacceptable number of false positives (about five false positives per one true positive). Furthermore, we determined that the system actually overcalled true detections by counting certain metaphase spreads twice (duplicates). Through modifications of the MRC/LBL system, we developed the Lawrence Livermore National Laboratory (LLNL) system, which minimizes the detection of duplicates, incorporates new detection features, uses a binary decision tree (BDT) for classification, and provides functionalities to improve scanning accuracy and improve the post-detection review. To test the new system, DAPI-stained preparations of metaphase chromosomes from blood lymphocytes of four unrelated donors were placed on slides in drops ranging from 7 mm to 20 mm in diameter. Drops contained between 5 and 200 scorable metaphases each. The LLNL system achieved ≈90% detection of non-duplicated metaphases as verified by an expert cytogeneticist, with typically less than one false positive per every one true positive detected. Cytometry 33:10–18, 1998. Published 1998 Wiley-Liss, Inc.
Synconvergent surface-breaking normal faults of Late Cretaceous age within the Sevier hinterland, east-central Nevada

The hinterland of the Sevier orogenic belt of western North America is widely interpreted as a Cretaceous to Paleogene orogenic plateau. Although evidence for mid-crustal extension of Late Cretaceous age within the Sevier hinterland is widespread, coeval surface-breaking normal fault systems have not been documented. New 1:12,000-scale mapping within the type section of the latest Cretaceous to Eocene Sheep Pass Formation of east-central Nevada suggests that deposition occurred in response to normal fault movement recording up to 4 km of Late Cretaceous and Paleogene stratigraphic throw. Intrabasinal normal faulting caused lateral thickness variations within the basal Sheep Pass Formation, although upper members are largely unaffected. An extensional basin setting best explains the fanning of bedding dips, the deposition of megabreccia, and the presence of syndepositional normal faults within the Sheep Pass Formation. Deposition of the basal member of the Sheep Pass Formation is bracketed between ca. 81.3 ± 3.7 Ma and 66.1 ± 5.4 Ma, based on the (U-Th)/He cooling ages of detrital zircons, and on a U-Pb carbonate age derived from the overlying lacustrine limestone member. These new data provide the strongest evidence to date for the existence of Late Cretaceous, surface-breaking normal faults in the Sevier hinterland. Normal faulting was coeval with mid-crustal hinterland extension and with continued contraction within the Sevier foreland to the east.