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FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols BACKGROUND: Genomic signatures, such as the 70-gene MammaPrint, provide additional prognostic information for early-stage breast cancer (EBC), such as tumor metastatic potential, and expand the available information clinicians and patients require for shared treatment decision making beyond the standard clinicopathologic factors. EBC tumors are further stratified into clinically actionable subtypes by molecular assays such as the 80-gene molecular profiling assay BluePrint, improving pathological complete response rates (pCR) and outcomes as evidenced by a number of recent trials. The ongoing FLEX Study (NCT03053193) is designed to expand the genomic information available for EBC cases, and to increase the speed of data generation for rare and underserved research areas. To date, FLEX is the largest international multicenter real-world evidence (RWE) EBC registry, with more than 10,000 patients enrolled in fewer than five years since opening. FLEX pairs full genome data with more than 800 clinical data points collected over 10 years of follow up to provide the most comprehensive big data database available for early-stage breast cancer. The FLEX enrollment has a goal of a minimum of 30,000 patients within 10 years. METHODS: The FLEX study is a multicenter, prospective, observational trial for patients ≥18 years old with histologically proven stage I-III invasive breast cancer that is node negative or positive (up to three nodes) who receive MammaPrint, with or without BluePrint as standard of care management. Patients consent to the collection of clinically annotated full transcriptome data. Additionally, this study protocol allows physicians to investigate targeted populations or clinical trial investigator-initiated studies (IIS) upon approval by a peer-driven Scientific Review Committee. As patients enrolled in the FLEX study meet all eligibility criteria for inclusion no additional consent is required. The FLEX enrollment has already surpassed 1/3 of set target goal. As of April 2022, the trial has surpassed 10,000 patients enrolled at nearly 100 trial sites across the US and Europe, Middle East and Africa (EMEA). To date, there have been 36 publications in international scientific congresses with 39 FLEX IIS and in progress. With over 250 active and collaborating physicians leveraging the shared infrastructure, the IIS have enabled the ability to address disparities in treatment to underrepresented populations, rare subtypes, age, and patient centered specific topics. Current and future questions investigated via this platform will continue to strive to improve outcomes for early-stage breast cancer patients. Citation Format: Alejandra Perez, Hannah Linden, Nathalie Johnson, Sami Diab, Chirag Jani, Chelsea D. Gawryletz, Richard Fine, Laura Lawson, Megan Baker, Victoria Poillucci, Lisa E. Blumencranz, William Audeh. FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-05-01.

In May 1945, journalist Edward Kennedy famously bypassed military censorship to break the news of Germany's surrender. No action by an American correspondent during World War II proved more controversial. Disaccredited by the Army and denounced by many of his colleagues, at year's end, Kennedy's career at the Associated Press was over and his reputation in a shambles. Historians have considered the episode a rare instance of an otherwise cooperative media defying military censorship. However, reconstructing Kennedy's career reveals just how fraught media–military relations actually were during that war, and it calls into question the conventional wisdom that the media's relationship with the military was generally amicable during the war, only to break down a generation later in Vietnam.

In 1937, the American Foreign Correspondents Association in London denied membership to Edward R. Murrow, CBS's European director. As a broadcaster, it reasoned, he was not actually a journalist. Less than seven years later Murrow was elected the organizations president. This reversal of fortune dramatizes how quickly broadcast news gained legitimacy during World War II, and media historians have emphasized how the war itself actually stimulated this growth. Richard W. Steele, for one, has documented the Roosevelt administration's use of radio and radio news to build support for entry into the war, while Michele Hilmes has detailed the role radio played in sustaining American unity during the war itself.1 Similarly, Gerd Horton has examined the government's role in producing radio programing in service of the war effort.2 Nearly fifty years ago, Eric Barnouw wrote in his History of Broadcasting in the United States that as the war began, "the nation's attention was increasingly on radio. News broadcasts were winning a growing audience-and stirring increasing controversy."3 Historians continue to stress this link, as when Susan J. Douglas recently titled her chapter on this period "World War II and the Invention of Broadcast Journalism."4Historians frequently highlight Murrow's own dramatic reporting from England as the crucial event in the acceptance of broadcast journalism. When Murrow had arrived in London in 1937, broadcast journalists resided at the margins of newsgathering. This was largely the result of the close and conflicted relationship between the newspaper industry and radio as the latter developed in the 1930s, a time when, in Michael Stamm's phrase, the newspaper industry became the news industry.4 As a consequence of the tangled relationship with the newspapers, for much of the thirties news was barely a presence on radio, little more than periodic bulletins of wire service copy intended to steer listeners to their newspapers, supplemented by short commentaries by policy analysts such as Dorothy Thompson, Elmer Davis, and H.V. Kaltenborn.6In Europe, Murrow was initially little more than a glorified booking agent, arranging for various politicians, public figures, and print journalists to discuss current events on the air. Beginning with his work orchestrating live broadcasts from various European capitals during the Munich crisis in 1938, Murrow expanded the possibilities of broadcast news, exploiting its natural advantages in speed and immediacy. Through his eyewitness reporting of the Battle of Britain and especially his dramatic rooftop accounts of the subsequent bombing campaign against London and other major British cities now known as the Blitz, Murrow brought the European conflict vividly into American homes.Such reporting leads most historians to focus on Murrow to the exclusion of other wartime broadcast journalists. In the words of his biographer Joseph Persico, "over 120 correspondents covered the Blitz. The words that best captured the feel and sense of it for America were Edward R. Murrow's."7 Christopher Daly echoes this sentiment in his recent history of American journalism: "Although NBC and the much smaller Mutual network also had correspondents in London, none of them matched Murrow. . . . Murrow proved that radio news could be accurate, responsible, even soulful. And it could run rings around newspapers and magazines."8 Douglas Gomery concedes that "many students of broadcast history believe radio journalism and war coverage were invented in the late 1930s and early 1940s by Edward R. Murrow" even as he suspects some mythmaking in assessments of Murrow.'1However consequential Murrow's reporting from London was for American audiences at the time and has proven ever since, a closer inspection of the historical record suggests a different story. A comprehensive search of military and other governmental records in the National Archives of both the United States and the United Kingdom (many of which have never before been examined in this context); the unpublished papers of several broadcasters, government officials, and news organizations; and subsequent published accounts of other broadcasters reveals that this exclusive focus on Murrow, and especially of Murrow's work during the Blitz, is misplaced. …

The War Beat, Europe, an intensively researched and comprehensive study of how American journalists covered the American army's campaigns in Europe during World War II, is a welcome addition to the...

By Philip WoodsNew York: Oxford University Press, 2016, 206 pp.During World War II, the campaign in Burma was often referred to as the “Forgotten War.” Thus it makes sense that reporting from this ...

This article recounts the media's role in one of the more controversial military and diplomatic actions of the Second World War, the American decision to install Admiral Jean Darlan as head of the Vichyite administration in North Africa in the wake of the Allied landings in 1942. Darlan's administration continued to enforce anti-Jewish directives, persecute political enemies, and indeed lock up many of those who had—at great personal risk—aided the Allies. Journalists learned of these actions, but their initial attempts to report on them were spiked by military censors. Eventually several correspondents were able to get word of these injustices into their reports from the field, and American policy began to change. Drawing on the published memoirs of several of the main actors, as well as State Department, U.S. Army and other archival material, this article traces these events in more detail as reported by four correspondents on the scene—A.J. Liebling, Ernie Pyle, John MacVane, and Drew Middleto...

The history of the author’s moral rights doctrine in the laws of France and the United States opens productive inquiry into the nature of American authorship, the functions of authorship more widely, and ultimately, the direction of print culture studies as a field. Such moral rights have never been a coherent feature of American law, and this “ghost” of moral rights clarifies the difference between American and French intellectual property regimes as they treat authors, as well as reveals the materialist emphasis in most historiography of American authorship itself.

The orphan nuclear receptor estrogen-related receptor alpha (ERRalpha) has been implicated in the development of various human malignancies, including breast, prostate, ovary, and colon cancer. ERRalpha, bound to a co-activator protein (e.g., peroxisome proliferator receptor gamma co-activator-1alpha, PGC-1alpha), regulates cellular energy metabolism by activating transcription of genes involved in various metabolic processes, such as mitochondrial genesis, oxidative phosphorylation, and fatty acid oxidation. Accumulating evidence suggests that ERRalpha is a novel target for solid tumor therapy, conceivably through effects on the regulation of tumor cell energy metabolism associated with energy stress within solid tumor microenvironments. This report describes a novel steroidal antiestrogen (SR16388) that binds selectively to ERRalpha, but not to ERRbeta or ERRgamma, as determined using a time-resolved fluorescence resonance energy transfer assay. SR16388 potently inhibits ERRalpha's transcriptional activity in reporter gene assays, and prevents endogenous PGC-1alpha and ERRalpha from being recruited to the promoters or enhancers of target genes. Representative in vivo results show that SR16388 inhibited the growth of human prostate tumor xenografts in nude mice as a single agent at 30mg/kg given once daily and 100mg/kg given once weekly. In a combination study, SR16388 (10mg/kg, once daily) and paclitaxel (7.5mg/kg, twice weekly) inhibited the growth of prostate tumor xenografts in nude mice by 61% compared to untreated xenograft tumors. SR16388 also inhibited the proliferation of diverse human tumor cell lines after a 24-h exposure to the compound. SR16388 thus has utility both as an experimental antitumor agent and as a chemical probe of ERRalpha biology.

A method based on free energy perturbation is introduced for calculation of the dielectric constant of bulk liquids by molecular simulation. Its application to the TIP4P water model gives a result in good agreement with that obtained using a previously described method based on induced polarization. Both estimates are obtained in a single Monte Carlo simulation of a sample of water in a uniform applied electric field. Two simulations were performed yielding four estimates for the dielectric constant. The resulting values were in the range 56-64 with (statistical) standard errors of ∼3 for the polarization method and ∼9 for the free energy method

Left atrial or pulmonary capillary wedge pressure V waves are used immediately after mitral valve replacement to evaluate valve competence. However, their correlation with hemodynamically significant regurgitation has not been established. Transesophageal echocardiography (TEE) was used to prospectively examine whether left atrial V waves represented significant mitral regurgitation in 11 patients undergoing mitral valve replacement. Left atrial pressure V waves were measured in the immediate postcardiopulmonary bypass period by direct cannulation of the right superior pulmonary vein and recorded on a paper chart recorder. In each patient, three evaluations of mitral regurgitation by Doppler TEE were made at 15-minute intervals. In 22 of 33 evaluations, left atrial V waves with peak V wave height more than 5 mm Hg above the mean left atrial pressure were present. However, only in 3 of these periods did transesophageal echocardiography show evidence of more than trace mitral regurgitation by pulsed Doppler and color flow mapping. As indicators of mild-to-severe mitral regurgitation diagnosed by TEE, left atrial V waves had a specificity for the three evaluation periods of 40%, 30%, and 40%. Left atrial V waves with peak height greater than 5 mm Hg above mean left atrial pressure frequently appear following mitral valve replacement, but these V waves are nonspecific signs of mitral regurgitation.

Quantum-mechanical electron density calculations reveal that a significant polarization is induced in the cofactor NADPH (reduced nicotinamide adenine dinucleotide phosphate) on binding to the enzyme dihydrofolate reductase. The calculations indicate that electron density corresponding to approximately 0.7 electron charges is shifted within the molecule, extending over more than 20 A. Further calculations on proposed enzyme mutants show that the polarization of NADPH on binding to DHFR is, in large part, induced by a motif of three positively charged residues. This motif was also identified to be directly responsible for the positive electrostatic potential surrounding the cofactor binding site in the enzyme. The possibility of this long-range polarization of NADPH was originally proposed based on a previous study of ligand binding to DHFR where a conserved structural motif of three positively charged residues was found to play a major role in polarizing the substrate folate over its entire length of 18 A.

Tryptamine-4,5-dione protected as the carbamate was prepared in excellent overall yield by the oxidation of serotonin carbamate with benzeneseleninic anhydride. This o -quinone, which was potently neurotoxic, readily added sulfur nucleophiles under basic conditions including cysteine and glutathione in 1,4-fashion, a reactivity pattern which may reflect the mechanism of the neurotoxicity.

Cet article présente le travail de juristes qui ont récemment élaboré une critique des présupposés sous-jacents à la théorie et à la législation sur le copyright. Cette reconceptualisation des notions d'auteur, de propriété intellectuelle et de copyright amène à réviser les conclusions de chercheurs qui ont, depuis vingt ans, étudié les conditions de travail (matérielles en particulier) des auteurs américains., Fine Richard. Authorship Cross-Examined by Critical Legal Studies. In: Revue Française d'Etudes Américaines, N°78, octobre 1998. L'édition américaine en mouvement. pp. 60-72.

A model for an antibody specific for the carcinoembryonic antigen (CEA) has been constructed using a method which combines the concept of canonical structures with conformational search. A conformational search technique is introduced which couples random generation of backbone loop conformations to a simulated annealing method for assigning side chain conformations. This technique was used both to verify conformations selected from the set of known canonical structures and to explore conformations available to the H3 loop in CEA ab initio. Canonical structures are not available for H3 due to its variability in length, sequence, and observed conformation in known antibody structures. Analysis of the results of conformational search resulted in three equally probable conformations for H3 loop in CEA. Force field energies, solvation free energies, exposure of charged residues and burial of hydrophobic residues, and packing of hydrophobic residues at the base of the loop were used as selection criteria. The existence of three equally plausible structures may reflect the high degree of flexibility expected for an exposed loop of this length. The nature of the combining site and features which could be important to interaction with antigen are discussed.

We describe the design, construction, and performance of a special purpose, hardwired accelerator for molecular mechanical calculations called FASTRUN. The processor was designed at Columbia University in 1984, constructed in the Instrumentation Division of Brookhaven National Laboratory, and delivered to Columbia in final form in 1989. It was rendered functional for molecular mechanics in early 1990. Together with its host Star array processor, FASTRUN has a measured performance for molecular dynamics simulations which compares favorably with present day supercomputers. The hardware replication cost of FASTRUN is on the order of $100,000.00.

Tryptamine-4,5-dione protected as the carbamate was prepared in excellent overall yield by the oxidation of serotonin carbamate with benzeneseleninic anhydride. This o -quinone, which was potently neurotoxic, readily added sulfur nucleophiles under basic conditions including cysteine and glutathione in 1,4-fashion, a reactivity pattern which may reflect the mechanism of the neurotoxicity.

La technique de la perturbation de l'energie libre est utilisee avec les simulations de Monte Carlo pour calculer la contribution electrostatique de l'energie libre d'hydratation d'un cation hypothetique dont la charge varie entre 0 et 3 au

In this paper we present a classical treatment of electrostatic interactions in proteins. The protein is treated as a region of low dielectric constant with spherical charges embedded within it, surrounded by an aqueous solvent of high dielectric constant, which may contain a simple electrolyte. The complete analysis includes the effects of solvent screening, polarization forces, and self energies, which are related to solvation energies. Formulae, and sample calculations of forces and energies, are given for the special case of a spherical protein. Our analysis and model calculations point out that any consistent treatment of electrostatic interactions in proteins should account for the following. (1) Solvent polarization is an important factor in the calculation of pairwise electrostatic interactions. Solvent polarization substantially affects both electrostatic energies and forces acting upon charges. (2) No simple expression for the effective dielectric constant, Deff, can generally be valid, since Deff is a sensitive function of position. (3) Solvent screening of pairwise interactions involving dipolar groups is less effective than the screening of charges. In fact for many interactions involving dipoles, solvent screening can be essentially ignored. (4) The self energy of charges makes a large contribution to the total electrostatic energy of a protein. This must be compensated by specific interactions with other groups in the protein. Strategies for applying our analysis to proteins whose structures are known are discussed.

We describe a method for predicting the conformations of loops in proteins and its application to four of the complementarity determining regions [CDRs] in the crystallographically determined structure of MCPC603. The method is based on the generation of a large number of randomly generated conformations for the backbone of the loop being studied, followed by either minimization or molecular dynamics followed by minimization starting from these random structures. The details of the algorithm for the generation of the loops are presented in the first paper in this series (Shenkin et al. [submitted]). The results of minimization and molecular dynamics applied to these loops is presented here. For the two shortest CDRs studied (H1 and L2, which are five and seven amino acids long), minimizations and dynamics simulations which ignore interactions of the loop amino acids beyond the carbon beta replicate the conformation of the crystal structure closely. This suggests that these loops fold independently of sequence variation. For the third CDR (L3, which is nine amino acids), those portions of the CDR near its base which are hydrogen bonded to framework are well replicated by our procedures, but the top of the loop shows significant conformational variability. This variability persists when side chain interactions for the MCPC603 sequence are included. For a fourth CDR (H3, which is 11 amino acids long), new low-energy backbone conformations are found; however, only those which are close to the crystal are compatible with the sequence when side chain interactions are taken into account. Results from minimization and dynamics on single CDRs with all other CDRs removed are presented. These allow us to explore the extent to which individual CDR conformations are determined by interactions with framework only.

One approach to finding the conformation of minimum energy for a complicated molecule is to perform energy minimization, perhaps coupled to more exhaustive search procedures such as dynamics or Monte Carlo sampling, from many starting conformation. Where there are geometric constraints on the conformations, as in a ring molecule, or a variable loop starting and ending in known constant regions of one of a series of homologous proteins, rapidly generating many such starting conformations, all satisfying the constraints, has been a problem in the past. We have devised an algorithm, which we call random tweak, which performs this task in the context of a torsional description of a molecule, and have used it to model the backbones of the six CDRs (complementarity determining regions) of the immunoglobulin MCPC603. These range in size from 5 to 19 residues, and have from 8 to 36 variable dihedral angles. Ensembles of 100 properly closed backbone structures for each CDR were generated under several conditions of van der Waals screening internally and against the rest of the molecule, and ensembles of 1000 were generated for selected CDRs. These structure “libraries” reveal how the geometry at the base of a CDR and the topography of the surrounding protein surface restrict the region of space that a given CDR can occupy. In accord with simple notions of chain molecule statistics, the more highly extended a CDR at its base, the more similar the possible structures and the fewer that are necessary to span the conformational space. Energy minimization and molecular dynamics studies (reported elsewhere) using these libraries to furnish starting conformations show that, as the number of residues in a CDR goes from five to nine, the number of randomly generated structures necessary to ensure that low-lying energetic minima, such as the native conformation, will be found several times goes from a few tens to a few hundred. Some of the spatial features of an ensemble of random conformations are implicit in the histogram of the rms atomic displacements calculated for all the pairs in the ensemble. The random tweak method is carried out by setting each dihederal angle on the main chain of the variable fragment to a random value, then using an iterated linearized Lagrange multiplier technique to enforce the geometric constraints with the minimal conformational perturbation. The time required for the algorithm is linear in fragment length, and the resulting ability of the method to handle large loops makes it especially applicable to the modeling of homologous proteins. In most cases, hundreds of acceptable structures could be generated in a few hours on a VAX 11/780. Where van der Waals screening against fixed atoms need not be performed, as for isolated ring molecules, generation times go down by an order of magnitude or more.