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Background: The CK12 expression signature consists of genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13 and was previously shown to associate with the presence of T and B cell rich tertiary lymphoid structures in melanoma and other cancers, and with better patient survival independent of tumor staging and treatment. I-SPY 2 is a biomarker-rich, phase II neoadjuvant platform trial for high risk early stage breast cancer. Here we leverage the I-SPY 2 biomarker program to test the hypothesis that this signature associates with sensitivity to neoadjuvant immunotherapies and potentially other classes cancer therapeutics in breast cancer. Methods: Data from 1130 patients across 12 arms of I-SPY2 (control (ctr): 210; veliparib/carboplatin (VC): 71; neratinib (N): 114; MK2206: 93; ganitumab: 106; ganetespib: 93; AMG386: 134; TDM1/pertuzumab(P): 52; H/P: 44; pembrolizumab (pembro): 69; durvalumab/olaparib (durva/olap): 71; pembro/SD101: 72) were available for analysis. Pre-treatment FF (n=987) or FFPE (n=143) biopsies were assayed using Agilent gene expression arrays. Signature scores were calculated as the average expression level across the 12 genes, after z-score normalization. We used logistic modeling to assess association with pCR in each arm in a model adjusting for HR and HER2 (likelihood ratio test, p Citation Format: Hatem Soliman, Denise Wolf, Jo Chien, Christina Yau, Michael Campbell, Mark Magbanua, Ruixiao Lu, Nicholas O'Grady, Lamorna Brown-Swigart, Gillian Hirst, Beverly Parker, Laura Sit, Smita Asare, Doug Yee, Angie DeMichele, Rita Nanda, Lajos Pusztai, Don Berry, Laura Esserman, Laura Van't Veer. Chemokine12 (CK12) tertiary lymphoid gene expression signature as a predictor of response in 3 immunotherapy arms of the neoadjuvant ISPY 2 TRIAL - pembrolizumab with and without SD101, and durvalumab combined with olaparib - and in 9 other arms of the trial including platinum-based and dual-anti-HER2 therapies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-07.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

A striking shape was recently observed for the endoplasmic reticulum, a cellular organelle consisting of stacked sheets connected by helical ramps [Terasaki et al., Cell 154, 285 (2013)]. This shape is interesting both for its biological function, to synthesize proteins using an increased surface area for ribosome factories, and its geometric properties that may be insensitive to details of the microscopic interactions. In the present work, we find very similar shapes in our molecular dynamics simulations of the nuclear pasta phases of dense nuclear matter that are expected deep in the crust of neutron stars. There are dramatic differences between nuclear pasta and terrestrial cell biology. Nuclear pasta is 14 orders of magnitude denser than the aqueous environs of the cell nucleus and involves strong interactions between protons and neutrons, while cellular-scale biology is dominated by the entropy of water and complex assemblies of biomolecules. Nonetheless, the very similar geometry suggests both systems may have similar coarse-grained dynamics and that the shapes are indeed determined by geometrical considerations, independent of microscopic details. Many of our simulations self-assemble into flat sheets connected by helical ramps. These ramps may impact the thermal and electrical conductivities, viscosity, shear modulus, and breaking strain of neutron star crust. The interaction we use, with Coulomb frustration, may provide a simple model system that reproduces many biologically important shapes.

Background: Exotic non-spherical nuclear pasta shapes are expected in nuclear matter at just below saturation density because of competition between short range nuclear attraction and long range Coulomb repulsion. Purpose: We explore the impact of nuclear pasta on nucleosynthesis, during neutron star mergers, as cold dense nuclear matter is ejected and decompressed. Methods: We perform classical molecular dynamics simulations with 51200 and 409600 nucleons, that are run on GPUs. We expand our simulation region to decompress systems from an initial density of 0.080 fm^{-3} down to 0.00125 fm^{-3}. We study proton fractions of Y_P=0.05, 0.10, 0.20, 0.30, and 0.40 at T =0.5, 0.75, and 1.0 MeV. We calculate the composition of the resulting systems using a cluster algorithm. Results: We find final compositions that are in good agreement with nuclear statistical equilibrium models for temperatures of 0.75 and 1 MeV. However, for proton fractions greater than Y_P=0.2 at a temperature of T = 0.5 MeV, the MD simulations produce non-equilibrium results with large rod-like nuclei. Conclusions: Our MD model is valid at higher densities than simple nuclear statistical equilibrium models and may help determine the initial temperatures and proton fractions of matter ejected in mergers., 13 pages

A former senior editorial executive at the Daily Telegraph explains why he thinks maintaining a superior news service is the way forward for the paper and delivers this message to the paper's new proprietors, the Barclay brothers: "I am not suggesting that the Telegraph should ditch or even reduce any of its non-news ingredients - no paper can live on news alone these days - but simply that it focuses its attention and best journalistic skills on news coverage. Yes, it is an old-fashioned idea, but sometimes those do work. During my decade on The Daily Telegraph I had to fight over and over again to preserve the paper's gothic titlepiece or masthead, which was highly distinctive and itself stood for integrity. It has survived, although slightly tweaked, and in my view the paper's reputation has benefited from this. If the Barclays drop the gothic, we will know the paper is heading for real trouble."

We present a series of high-resolution, three-dimensional hydrodynamics simulations of a gravitationally unstable solar nebula model. The influences of both azimuthal grid resolution and the treatment of thermal processes on the origin and evolution of gravitational instabilities are investigated. In the first set of simulations, we vary the azimuthal resolution for a locally isothermal simulation, doubling and quadrupling the resolution used in a previous study; the largest number of grid points is (256, 256, 64) in cylindrical coordinates (r, , z). At this resolution, the disk breaks apart into a dozen short-lived condensations. Although our previous calculations underresolved the number and growth rate of clumps in the disk, the overall qualitative, but fundamental, conclusion remains: fragmentation under the locally isothermal condition in numerical simulations does not in itself lead to the survival of clumps to become gaseous giant protoplanets. Since local isothermality represents an extreme assumption about thermal processes in the disk, we also present several extended simulations in which heating from an artificial viscosity scheme and cooling from a simple volumetric cooling function are applied to two different models of the solar nebula. The models are differentiated primarily by disk temperature: a high-Q model generated directly by our self-consistent field equilibrium code and a low-Q model generated by cooling the high-Q model in a two-dimensional version of our hydrodynamics code. Here, high-Q and low-Q refer to the minimum values of the Toomre stability parameter Q in each disk, Qmin = 1.8 and 0.9, respectively. Previous simulations, by ourselves as well as others, have focused on initial states that are already gravitationally unstable, i.e., models similar to the low-Q model. This paper presents for the first time the numerical evolution of an essentially stable initial equilibrium state (the high-Q model) to a severely unstable one by cooling. The additional heating and cooling are applied to each model over the outer half of the disk or the entire disk. The models are subject to the rapid growth of a four-armed spiral instability; the subsequent evolution of the models depends on the thermal behavior of the disk. The cooling function tends to overwhelm the heating included in our artificial viscosity prescription, and as a result the spiral structure strengthens. The spiral disturbances transport mass at prodigious rates during the early nonlinear stages of development and significantly alter the disk's vertical surface. Although dense condensations of material can appear, their character depends on the extent of the volumetric cooling in the disk. In the simulation of the high-Q model with heating and cooling applied throughout the disk, thin, dense rings form at radii ranging from 1 to 3 AU and steadily increase in mass; later companion formation may occur in these rings as cooling drives them toward instability. When heating and cooling are applied only over the outer radial half of the disk, however, a succession of single condensations appears near 5 AU. Each clump has roughly the mass of Saturn, and some survive a complete orbit. Since the clumps form near the artificial boundary in the treatment of the disk gas physics, the production of a clump in this case is a numerical artifact. Nevertheless, radially abrupt transitions in disk gas characteristics, for example, in opacity, might mimic the artificial boundary effects in our simulations and favor the production of stable companions in actual protostellar and protoplanetary disks. The ultimate survival of condensations as eventual stellar or substellar companions to the central star is still largely an open question.

In 1986, when Andrew Neil called Sunday Times journalists to a meeting around the corner from the paper's Grays Inn Road offices and commanded them to go to Fortress Wapping or else — the silence was broken by a mild-mannered, bespectacled senior editor. With 17 years' service behind him, Don Berry accused Neil of treating the journalists with contempt: they had been lied to, their house agreement had been flagrantly violated, and their herding to Wapping was a Murdoch ruse to evade redundancy payments. Though Berry was cheered to the rafters, it was the end of his career with the Sunday Times. But his talents and high prinicples were quickly seized by Max Hastings, newly appointed editor of The Daily Telegraph, whose reliance on Berry then was proven later when Hastings took him to the Evening Standard. Below me publish Berry's retirement speech describing his first days on five different papers.

Nuclear pasta, with non-spherical shapes, is expected near the base of the crust in neutron stars. Large scale molecular dynamics simulations of pasta show long lived topological defects that could increase electron scattering and reduce both the thermal and electrical conductivities. We model a possible low conductivity pasta layer by increasing an impurity parameter Q_{imp}. Predictions of light curves for the low mass X-ray binary MXB 1659-29, assuming a large Q_{imp}, find continued late time cooling that is consistent with Chandra observations. The electrical and thermal conductivities are likely related. Therefore observations of late time crust cooling can provide insight on the electrical conductivity and the possible decay of neutron star magnetic fields (assuming these are supported by currents in the crust)., 5 pages, 2 figures

The dense neutron-rich matter found in supernovae and neutron stars is expected to form complex nonuniform phases referred to as nuclear pasta. The pasta shapes depend on density, temperature and proton fraction and determine many transport properties in supernovae and neutron star crusts. We use two recently developed hybrid CPU/GPU codes to perform large scale molecular dynamics (MD) simulations with $51200$ and $409600$ nucleons of nuclear pasta. From the output of the MD simulations we characterize the topology and compute two observables, the radial distribution function $g(r)$ and the structure factor $S(q)$, for systems with proton fractions $Y_p=0.10, 0.20, 0.30$ and $0.40$ at about one third of nuclear saturation density and temperatures near $1.0$ MeV. We observe that the two lowest proton fraction systems simulated, $Y_p=0.10$ and $0.20$, equilibrate quickly and form liquid-like structures. Meanwhile, the two higher proton fraction systems, $Y_p=0.30$ and $0.40$, take a longer time to equilibrate and organize themselves in solid-like periodic structures. Furthermore, the $Y_p=0.40$ system is made up of slabs, lasagna phase, interconnected by defects while the $Y_p=0.30$ systems consist of a stack of perforated plates, the nuclear waffle phase. The periodic configurations observed in our MD simulations for proton fractions $Y_p\ge0.30$ have important consequences for the structure factors $S(q)$ of protons and neutrons, which relate to many transport properties of supernovae and neutron star crust. A detailed study of the waffle phase and how its structure depends on temperature, size of the simulation and the screening length showed that finite-size effects appear to be under control and, also, that the plates in the waffle phase merge at temperatures slightly above $1.0$ MeV and the holes in the plates form an hexagonal lattice at temperatures slightly lower than $1.0$ MeV., Comment: 16 pages, 12 figires, 6 tables, small changes with respect to previous version, Phys Rev C in press

As newspapers struggle to secure ad revenue advertisers are calling the tune by designing ads that dominate pages to the detriment of editorial. Don Berry laments the trend and asks, possibly with tongue in cheek: why don’t proprietors and chief executives unite to resist the ad agency bullies?

The formation of complex nonuniform phases of nuclear matter, known as nuclear pasta, is studied with molecular dynamics simulations containing 51200 nucleons. A phenomenological nuclear interaction is used that reproduces the saturation binding energy and density of nuclear matter. Systems are prepared at an initial density of 0.10fm$^{-3}$ and then the density is decreased by expanding the simulation volume at different rates to densities of 0.01 fm$^{-3}$ or less. An originally uniform system of nuclear matter is observed to form spherical bubbles ("swiss cheese"), hollow tubes, flat plates ("lasagna"), thin rods ("spaghetti") and, finally, nearly spherical nuclei with decreasing density. We explicitly observe nucleation mechanisms, with decreasing density, for these different pasta phase transitions. Topological quantities known as Minkowski functionals are obtained to characterize the pasta shapes. Different pasta shapes are observed depending on the expansion rate. This indicates non equilibrium effects. We use this to determine the best ways to obtain lower energy states of the pasta system from MD simulations and to place constrains on the equilibration time of the system., Comment: 14 pages, 8 figures

The neutron-rich isotope ${}^{22}$Ne may be a significant impurity in carbon and oxygen white dwarfs and could impact how the stars freeze. We perform molecular dynamics simulations to determine the influence of ${}^{22}$Ne in carbon-oxygen-neon systems on liquid-solid phase equilibria. Both liquid and solid phases are present simultaneously in our simulation volumes. We identify liquid, solid, and interface regions in our simulations using a bond angle metric. In general we find good agreement for the composition of liquid and solid phases between our MD simulations and the semianalytic model of Medin and Cumming. The trace presence of a third component, neon, does not appear to strongly impact the chemical separation found previously for two-component carbon and oxygen systems. This suggests that small amounts of ${}^{22}$Ne may not qualitatively change how the material in white dwarf stars freezes. However, we do find systematically lower melting temperatures (higher $\ensuremath{\Gamma}$) in our MD simulations compared to the semianalytic model. This difference seems to grow with impurity parameter ${Q}_{\text{imp}}$ and suggests a problem with simple corrections to the linear mixing rule for the free energy of multicomponent solid mixtures that is used in the semianalytic model.

A molecular dynamics code simulating the diffusion in dense nuclear matter in white dwarf stars is analyzed in this collaboration between PTI (Indiana University) and ZIH (Technische Universitat Dresden). The code is highly configurable allowing MPI, OpenMP, or hybrid runs and additional fine-tuning with a range of parameters. The first step in the code analysis is to identify the best performing parameter set of the serial version. This configuration represents the most promising candidate for further studies. Aim of the parallel analysis is then to measure the scalability limits of the different parallel code implementations and to detect bottlenecks possibly preventing higher parallel efficiency. This work has been done with the parallel analysis framework Vampir.

We determine the liquid-solid phase diagram for carbon-oxygen and oxygen-selenium plasma mixtures using two-phase molecular dynamics simulations. We identify liquid, solid, and interface regions using a bond angle metric. To study finite-size effects, we perform 27,648- and 55,296-ion simulations. To help monitor nonequilibrium effects, we calculate diffusion constants D(i). For the carbon-oxygen system we find that D(O) for oxygen ions in the solid is much smaller than D(C) for carbon ions and that both diffusion constants are 80 or more times smaller than diffusion constants in the liquid phase. There is excellent agreement between our carbon-oxygen phase diagram and that predicted by Medin and Cumming. This suggests that errors from finite-size and nonequilibrium effects are small and that the carbon-oxygen phase diagram is now accurately known. The oxygen-selenium system is a simple two-component model for more complex rapid proton capture nucleosynthesis ash compositions for an accreting neutron star. Diffusion of oxygen, in a predominantly selenium crystal, is remarkably fast, comparable to diffusion in the liquid phase. We find a somewhat lower melting temperature for the oxygen-selenium system than that predicted by Medin and Cumming. This is probably because of electron screening effects.

We determine the phase diagram for dense carbon/ oxygen mixtures in White Dwarf (WD) star interiors using molecular dynamics simulations involving liquid and solid phases. Our phase diagram agrees well with predictions from Ogata et al. and Medin and Cumming and gives lower melting temperatures than Segretain et al. Observations of WD crystallization in the globular cluster NGC 6397 by Winget et al. suggest that the melting temperature of WD cores is close to that for pure carbon. If this is true, our phase diagram implies that the central oxygen abundance in these stars is less than about 60%. This constraint, along with assumptions about convection in stellar evolution models, limits the effective S factor for the $^{12}$C($\alpha,\gamma$)$^{16}$O reaction to S_{300}, Comment: 4 pages, 2 figures, Phys. Rev. Lett. in press

Using molecular dynamics simulations, we determine the structure of neutron star crust made of rapid proton capture nucleosynthesis material. We find a regular body centered cubic lattice, even with the large number of impurities that are present. Low charge $Z$ impurities tend to occupy interstitial positions, while high $Z$ impurities tend to occupy substitutional lattice sites. We find strong attractive correlations between low $Z$ impurities that could significantly increase the rate of pycnonuclear (density driven) nuclear reactions. The thermal conductivity is significantly reduced by electron impurity scattering. Our results will be used in future work to study the effects of impurities on mechanical properties such as the shear modulus and breaking strain., 7 pages, 9 figures, added A values to table I, version as published

Fusion reactions in the crust of an accreting neutron star are an important source of heat, and the depth at which these reactions occur is important for determining the temperature profile of the star. Fusion reactions depend strongly on the nuclear charge $Z$. Nuclei with $Z\le 6$ can fuse at low densities in a liquid ocean. However, nuclei with Z=8 or 10 may not burn until higher densities where the crust is solid and electron capture has made the nuclei neutron rich. We calculate the $S$ factor for fusion reactions of neutron rich nuclei including $^{24}$O + $^{24}$O and $^{28}$Ne + $^{28}$Ne. We use a simple barrier penetration model. The $S$ factor could be further enhanced by dynamical effects involving the neutron rich skin. This possible enhancement in $S$ should be studied in the laboratory with neutron rich radioactive beams. We model the structure of the crust with molecular dynamics simulations. We find that the crust of accreting neutron stars may contain micro-crystals or regions of phase separation. Nevertheless, the screening factors that we determine for the enhancement of the rate of thermonuclear reactions are insensitive to these features. Finally, we calculate the rate of thermonuclear $^{24}$O + $^{24}$O fusion and find that $^{24}$O should burn at densities near $10^{11}$ g/cm$^3$. The energy released from this and similar reactions may be important for the temperature profile of the star., Comment: 7 pages, 4 figs, minor changes, to be published in Phys. Rev. C

Recently, crust cooling times have been measured for neutron stars after extended outbursts. These observations are very sensitive to the thermal conductivity $\kappa$ of the crust and strongly suggest that $\kappa$ is large. We perform molecular dynamics simulations of the structure of the crust of an accreting neutron star using a complex composition that includes many impurities. The composition comes from simulations of rapid proton capture nucleosynthesys followed by electron captures. We find that the thermal conductivity is reduced by impurity scattering. In addition, we find phase separation. Some impurities with low atomic number $Z$ are concentrated in a subregion of the simulation volume. For our composition, the solid crust must separate into regions of different compositions. This could lead to an asymmetric star with a quadrupole deformation that radiates gravitational waves. Observations of crust cooling can constrain impurity concentrations., Comment: 8 pages, 8 figures, minor changes, PRE in press

We calculate the shear viscosity $\eta$ and thermal conductivity $\kappa$ of a nuclear pasta phase in neutron star crusts. This involves complex non-spherical shapes. We use semiclassical molecular dynamics simulations involving 40,000 to 100,000 nucleons. The viscosity $\eta$ can be simply expressed in terms of the height $Z^*$ and width $\Delta q$ of the peak in the static structure factor $S_p(q)$. We find that $\eta$ increases somewhat, compared to a lower density phase involving spherical nuclei, because $Z^*$ decreases from form factor and ion screening effects. However, we do not find a dramatic increase in $\eta$ from non-spherical shapes, as may occur in conventional complex fluids., Comment: 8 pages, 7 figures, minor changes, Phys. Rev. C in press

Nucleosynthesis, on the surface of accreting neutron stars, produces a range of chemical elements. We perform molecular dynamics simulations of crystallization to see how this complex composition forms new neutron star crust. We find chemical separation, with the liquid ocean phase greatly enriched in low atomic number elements compared to the solid crust. This phase separation should change many crust properties such as the thermal conductivity and shear modulus. The concentration of carbon, if present, is enriched in the ocean. This may allow unstable thermonuclear burning of the carbon and help explain the ignition of the very energetic explosions known as superbursts., Comment: 8 pages, 6 figures, minor changes, Physical Review E in press

The nuclear pasta -- a novel state of matter having nucleons arranged in a variety of complex shapes -- is expected to be found in the crust of neutron stars and in core-collapse supernovae at subnuclear densities of about $10^{14}$ g/cm$^3$. Due to frustration, a phenomenon that emerges from the competition between short-range nuclear attraction and long-range Coulomb repulsion, the nuclear pasta displays a preponderance of unique low-energy excitations. These excitations could have a strong impact on many transport properties, such as neutrino propagation through stellar environments. The excitation spectrum of the nuclear pasta is computed via a molecular-dynamics simulation involving up to 100,000 nucleons. The dynamic response of the pasta displays a classical plasma oscillation in the 1-2 MeV region. In addition, substantial strength is found at low energies. Yet this low-energy strength is missing from a simple ion model containing a single-representative heavy nucleus. The low-energy strength observed in the dynamic response of the pasta is likely to be a density wave involving the internal degrees of freedom of the clusters., Comment: 4 pages, 3 figures, Phys Rev C in press

This paper describes the parallel implementation of fastDNAml, a program for the maximum likelihood inference of phylogenetic trees from DNA sequence data. Mathematical means of inferring phylogenetic trees have been made possible by the wealth of DNA data now available. Maximum likelihood analysis of phylogenetic trees is extremely computationally intensive. Availability of computer resources is a key factor limiting use of such analyses. fastDNAml is implemented in serial, PVM, and MPI versions, and may be modified to use other message passing libraries in the future. We have developed a viewer for comparing phylogenies. We tested the scaling behavior of fastDNAml on an IBM RS/6000 SP up to 64 processors. The parallel version of fastDNAml is one of very few computational phylogenetics codes that scale well. fastDNAml is available for download as source code or compiled for Linux or AIX.

The liquid-solid phase-diagram of dense carbon-oxygen plasma mixtures found in white dwarf stars interiors is determined from molecular dynamics (MD) simulations. Our MD simulations consist of boxes with 55296 ions with different carbon to oxygen ratios. Finite size effects are estimated comparing the new MD simulations results to previous smaller simulations. We use bond angle metric to identify whether an ion is in the solid, liquid or interface and study non-equilibrium effects by obtaining the diffusion coefficients in the different phases. Our phase diagram agrees with predictions from Medin and Cumming obtained by an independent method.