Dendrite fragmentation: an experiment-driven simulation.

The processes leading to the fragmentation of secondary dendrite arms are studied using a three-dimensional Sn dendritic structure that was measured experimentally as an initial condition in a phase-field simulation. The phase-field model replicates the kinetics of the coarsening process seen experimentally. Consistent with the experiment, the simulations of the Sn-rich dendrite show that secondary dendrite arm coalescence is prevalent and that fragmentation is not. The lack of fragmentation is due to the non-axisymmetric morphology and comparatively small spacing of the dendrite arms. A model for the coalescence process is proposed, and, consistent with the model, the radius of the contact region following coalescence increases as t1/3 We find that small changes in the width and spacing of the dendrite arms can lead to a very different fragmentation-dominated coarsening process. Thus, the alloy system and growth conditions of the dendrite can have a major impact on the fragmentation process.This article is part of the theme issue 'From atomistic interfaces to dendritic patterns'.

Self-consistent modeling of anisotropic interfaces and missing orientations: Derivation from phase-field crystal.

Highly anisotropic interfaces play an important role in the development of material microstructure. Using the diffusive atomistic phase-field crystal (PFC) formalism, we determine the capability of the model to quantitatively describe these interfaces. Specifically, we coarse grain the PFC model to attain both its complex amplitude formulation and its corresponding phase-field limit. Using this latter formulation, in one-dimensional calculations, we determine the surface energy and the properties of the Wulff shape. We find that the model can yield Wulff shapes with missing orientations, the transition to missing orientations, and facet formation. We show that the corresponding phase-field limit of the complex amplitude model yields a self-consistent description of highly anisotropic surface properties that are a function of the surface orientation with respect to the underlying crystal lattice. The phase-field model is also capable of describing missing orientations on equilibrium shapes of crystals and naturally includes a regularizing contribution. We demonstrate, in two dimensions, how the resultant model can be used to study growth of crystals with varying degrees of anisotropy in the phase-field limit.

Direct Observation of "Pac-Man" Coarsening.

We report direct observation of a "Pac-Man" like coarsening mechanism of a self-supporting thin film of nickel oxide. The ultrathin film has an intrinsic morphological instability due to surface stress leading to the development of local thicker regions at step edges. Density functional theory calculations and continuum modeling of the elastic instability support the model for the process.

Phase-field model of oxidation: Equilibrium.

A phase-field model of an oxide relevant to corrosion resistant alloys for film thicknesses below the Debye length L_{D}, where charge neutrality in the oxide does not occur, is formulated. The phase-field model is validated in the Wagner limit using a sharp interface Gouy-Chapman model for the electrostatic double layer. The phase-field simulations show that equilibrium oxide films below the Wagner limit are charged throughout due to their inability to electrostatically screen charge over the length of the film, L. The character of the defect and charge distribution profiles in the oxide vary depending on whether reduced oxygen adatoms are present on the gas-oxide interface. The Fermi level in the oxide increases for thinner films, approaching the Fermi level of the metal in the limit L/L_{D}→0, which increases the driving force for adsorbed oxygen reduction at the gas-oxide interface.

Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma.

New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen for daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM.

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

The Three-Dimensional Morphology of Growing Dendrites.

The processes controlling the morphology of dendrites have been of great interest to a wide range of communities, since they are examples of an out-of-equilibrium pattern forming system, there is a clear connection with battery failure processes, and their morphology sets the properties of many metallic alloys. We determine the three-dimensional morphology of free growing metallic dendrites using a novel X-ray tomographic technique that improves the temporal resolution by more than an order of magnitude compared to conventional techniques. These measurements show that the growth morphology of metallic dendrites is surprisingly different from that seen in model systems, the morphology is not self-similar with distance back from the tip, and that this morphology can have an unexpectedly strong influence on solute segregation in castings. These experiments also provide benchmark data that can be used to validate simulations of free dendritic growth.

Critical nucleus composition in a multicomponent system.

The properties of a critical nucleus are derived using the capillarity theory in the framework of classical nucleation. An analytical solution for the composition of a critical nucleus is given for low supersaturation. The theory is valid for any multicomponent systems. It is found that the deviation in nucleus composition from the equilibrium tie-line is mainly due to the difference in the Hessian of the Gibbs energy of the phases and the magnitude of the deviation in composition from equilibrium is order of the supersaturation. Despite our analysis strictly holds for low supersaturation, this suggests strong deviations near the spinodal line.

Management of treatment-emergent peripheral neuropathy in multiple myeloma.

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.

Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a Wisconsin Oncology Network study.

Arsenic trioxide (As(2)O(3)) has established clinical activity in acute promyelocytic leukaemia and has pre-clinical data suggesting activity in lymphoid malignancies. Cell death from As(2)O(3) may be the result of oxidative stress. Agents which deplete intracellular glutathione, such as ascorbic acid (AA), may potentiate arsenic-mediated apoptosis. This multi-institution phase II study investigated a novel dosing schedule of As(2)O(3) and AA in patients with relapsed or refractory lymphoid malignancies. Patients received As(2)O(3) 0.25 mg/kg iv and AA 1000 mg iv for five consecutive days during the first week of each cycle followed by twice weekly infusions during weeks 2-6. Cycles were repeated every 8 weeks. The primary end point was objective response. In a subset of patients, sequential levels of intracellular glutathione and measures of Bcl-2 and Bax gene expression were evaluated in peripheral blood mononuclear cells during treatment. Seventeen patients were enrolled between March 2002 and February 2004. The median age was 71, and the majority of enrolled patients had non-Hodgkin's lymphoma (12/17). Sixteen patients were evaluable, and one patient with mantle cell lymphoma achieved an unconfirmed complete response after five cycles of therapy for an overall response rate of 6%. The trial, which had been designed as a two-stage study, was closed after the first stage analysis due to lack of activity. Haematologic toxicities were the most commonly reported events in this heavily pre-treated population, and comprised the majority of grade 3 and 4 toxicities. Intracellular depletion of glutathione was not consistently observed during treatment. As(2)O(3) and AA in this novel dosing strategy was generally well tolerated but had limited activity in patients with relapsed and refractory lymphoid malignancies.

Size-dependent nucleation kinetics at nonplanar nanowire growth interfaces.

In nanowire growth, kinetic processes at the growth interface can play an important role in governing wire compositions, morphologies, and growth rates. Molecular-dynamics simulations have been undertaken to probe such processes in a system featuring a solid-liquid interface shape characterized by a facet bounded by rough orientations. Simulated growth rates display a dependence on nanowire diameter consistent with a size-dependent barrier for facet nucleation. A theory for the interface mobility is developed, establishing a source for size-dependent growth rates that is an intrinsic feature of systems possessing growth interfaces with faceted and rough orientations.

Orientation dependence of strained-Ge surface energies near (001): role of dimer-vacancy lines and their interactions with steps.

Recent experiments and calculations have highlighted the important role of surface-energy (gamma) anisotropy in governing island formation in the Ge/Si(001) system. To further elucidate the factors determining this anisotropy, we perform atomistic and continuum calculations of the orientation dependence of gamma for strained-Ge surfaces near (001), accounting for the presence of dimer-vacancy lines (DVLs). The net effect of DVLs is found to be a substantial reduction in the magnitude of the slope of gamma vs orientation angle, relative to the highly negative value derived for non-DVL, dimer-reconstructed, strained-Ge(001) surfaces. The present results thus point to an important role of DVLs in stabilizing the (001) surface orientation of a strained-Ge wetting layer.

Role of strain-dependent surface energies in Ge/Si(100) island formation.

Formation energies for Ge/Si(100) pyramidal islands are computed combining continuum calculations of strain energy with first-principles-computed strain-dependent surface energies. The strain dependence of surface energy is critically impacted by the presence of strain-induced changes in the Ge {100} surface reconstruction. The appreciable strain dependencies of rebonded-step {105} and dimer-vacancy-line-reconstructed {100} surface energies are estimated to give rise to a significant reduction in the surface contribution to island formation energies.

Topological complexity and the dynamics of coarsening.

Coarsening or Ostwald ripening occurs in a vast array of two-phase systems. Coarsening results in a decrease in the interfacial area per unit volume and a concomitant increase in the size scale of the interfacial morphology. Much is known about the coarsening process in two-phase mixtures consisting of a polydisperse array of spherical particles. In contrast, in many two-phase mixtures, such as those found in two-phase polymers, ceramics, dendritic solid-liquid mixtures and order-disorder transformations, the interfaces are both interconnected and have a spatially varying mean curvature. Here we show that the morphological evolution of these topologically complex systems during coarsening can be quantified by measuring the probability of finding a patch of interface with a given curvature tensor. We find that the morphological evolution is described by the flow of probability density in this curvature space that is induced by the coarsening process. The hallmark of our approach is a close coupling between experiment and theory; we use the experimentally measured three-dimensional microstructure as an input to a phase-field calculation that then determines the flow in curvature space. The methodology is general, and applicable to many systems undergoing coarsening, regardless of their topology.

Self-organization of quantum dots in epitaxially strained solid films.

A nonlinear evolution equation for surface-diffusion-driven Asaro-Tiller-Grinfeld instability of an epitaxially strained thin solid film on a solid substrate is derived in the case where the film wets the substrate. It is found that the presence of a weak wetting interaction between the film and the substrate can substantially retard the instability and modify its spectrum in such a way that the formation of spatially regular arrays of islands or pits on the film surface becomes possible. It is shown that the self-organization dynamics is significantly affected by the presence of the Goldstone mode associated with the conservation of mass.

Faceting of a growing crystal surface by surface diffusion.

Consider faceting of a crystal surface caused by strongly anisotropic surface tension, driven by surface diffusion and accompanied by deposition (etching) due to fluxes normal to the surface. Nonlinear evolution equations describing the faceting of 1+1 and 2+1 crystal surfaces are studied analytically, by means of matched asymptotic expansions for small growth rates, and numerically otherwise. Stationary shapes and dynamics of faceted pyramidal structures are found as functions of the growth rate. In the 1+1 case it is shown that a solitary hill as well as periodic hill-and-valley solutions are unique, while solutions in the form of a solitary valley form a one-parameter family. It is found that with the increase of the growth rate, the faceting dynamics exhibits transitions from the power-law coarsening to the formation of pyramidal structures with a fixed average size and finally to spatiotemporally chaotic surfaces resembling the kinetic roughening.

Quantitative serial sectioning analysis.

A method for serial sectioning is presented that allows one to take about 20 sections per hour with spacings in the range 1-20 microm between sections. The alignment of the cross-sections is done with a linear variable differential transformer; it is thus independent of the microstructure of the sample and does not rely upon markers implanted in the sample. The alignment errors as well as tilts and rotation errors between sections associated with the new method are found to be negligible. Once all the sections are captured in a computer a three-dimensional image can be constructed. This image can be viewed interactively and rotated, thus allowing the direct observation of three-dimensional shapes. It can further be used to determine a vast array of microstructural parameters including those that cannot be determined from planar sections. The technique is illustrated through the reconstruction of the microstructure of a cast standard aluminium alloy specimen.

Dynamics of late-stage phase separation in crystalline solids.

The dynamics of Ostwald ripening in elastically stressed crystalline solids is determined through large-scale numerical simulations. Using the insight provided by the simulations, a theory for the dynamics of late-stage phase separation in elastically anisotropic homogeneous solids is developed. Both the theory and simulations show that for the systems considered elastic stress does not alter the exponent of the temporal power law for the average particle size but does affect the amplitude of the power law in a manner that is only a function of the symmetry of the particle morphology.

An acidic sequence within the cytoplasmic domain of furin functions as a determinant of trans-Golgi network localization and internalization from the cell surface.

The mammalian endopeptidase, furin, is predominantly localized to the trans-Golgi network (TGN) at steady state. The localization of furin to this compartment seems to be the result of a dynamic process in which the protein undergoes cycling between the TGN and the plasma membrane. Both TGN localization and internalization from the plasma membrane are mediated by targeting information contained within the cytoplasmic domain of furin. Here, we report the results of a mutagenesis analysis aimed at identifying the source(s) of targeting information within the furin cytoplasmic domain. Our studies show that there are at least two cytoplasmic determinants that contribute to the steady-state localization and trafficking of furin. The first determinant corresponds to a canonical tyrosine-based motif, YKGL (residues 758-761), that functions mainly as an internalization signal. The second determinant consists of a strongly hydrophilic sequence (residues 766-783) that contains a large cluster of acidic residues (E and D) and is devoid of any tyrosine-based or di-leucine-based motifs. This second determinant is capable of conferring localization to the TGN as well as mediating internalization from the plasma membrane. Thus, these observations establish the existence of a novel, autonomous determinant distinct from sorting signals described previously.