Bioinspired Ultrastrong Solid Electrolytes with Fast Proton Conduction along 2D Channels

Solid electrolytes have attracted much attention due to their great prospects in a number of energy- and environment-related applications including fuel cells. Fast ion transport and superior mechanical properties of solid electrolytes are both of critical significance for these devices to operate with high efficiency and long-term stability. To address a common tradeoff relationship between ionic conductivity and mechanical properties, electrolyte membranes with proton-conducting 2D channels and nacre-inspired architecture are reported. An unprecedented combination of high proton conductivity (326 mS cm⁻¹ at 80 °C) and superior mechanical properties (tensile strength of 250 MPa) are achieved due to the integration of exceptionally continuous 2D channels and nacre-inspired brick-and-mortar architecture into one materials system. Moreover, the membrane exhibits higher power density than Nafion 212 membrane, but with a comparative weight of only ≈0.1, indicating potential savings in system weight and cost. Considering the extraordinary properties and independent tunability of ion conduction and mechanical properties, this bioinspired approach may pave the way for the design of next-generation high-performance solid electrolytes with nacre-like architecture.

The advancement of solid electrolytes is severely impeded by the strong tradeoff relationship between ion-conduction and mechanical properties. Through integrating 2D channels and "brick-and-mortar" architecture into one materials system, an unprecedented combination of high proton conductivity and superior mechanical strength are achieved. This intriguing design may pave the way for the bioinspired design of next-generation high-performance solid electrolytes.

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Tunable Photocontrolled Motions Using Stored Strain Energy in Malleable Azobenzene Liquid Crystalline Polymer Actuators

A new strategy for enhancing the photoinduced mechanical force is demonstrated using a reprocessable azobenzene-containing liquid crystalline network (LCN). The basic idea is to store mechanical strain energy in the polymer beforehand so that UV light can then be used to generate a mechanical force not only from the direct light to mechanical energy conversion upon the trans–cis photoisomerization of azobenzene mesogens but also from the light-triggered release of the prestored strain energy. It is shown that the two mechanisms can add up to result in unprecedented photoindued mechanical force. Together with the malleability of the polymer stemming from the use of dynamic covalent bonds for chain crosslinking, large-size polymer photoactuators in the form of wheels or spring-like "motors" can be constructed, and, by adjusting the amount of prestored strain energy in the polymer, a variety of robust, light-driven motions with tunable rolling or moving direction and speed can be achieved. The approach of prestoring a controllable amount of strain energy to obtain a strong and tunable photoinduced mechanical force in azobenzene LCN can be further explored for applications of light-driven polymer actuators.

By prestoring mechanical strain energy in a reprocessable liquid crystal polymer network containing azobenzene mesogens, unprecedented mechanical force can be generated under UV light irradiation, which enables continuous light-driven motions of large polymer actuators in the form of wheels and spring-like "motors," with tunable moving speed and controllable moving direction.

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Reviving Lithium-Metal Anodes for Next-Generation High-Energy Batteries

Lithium-metal batteries (LMBs), as one of the most promising next-generation high-energy-density storage devices, are able to meet the rigid demands of new industries. However, the direct utilization of metallic lithium can induce harsh safety issues, inferior rate and cycle performance, or anode pulverization inside the cells. These drawbacks severely hinder the commercialization of LMBs. Here, an up-to-date review of the behavior of lithium ions upon deposition/dissolution, and the failure mechanisms of lithium-metal anodes is presented. It has been shown that the primary causes consist of the growth of lithium dendrites due to large polarization and a strong electric field at the vicinity of the anode, the hyperactivity of metallic lithium, and hostless infinite volume changes upon cycling. The recent advances in liquid organic electrolyte (LOE) systems through modulating the local current density, anion depletion, lithium flux, the anode–electrolyte interface, or the mechanical strength of the interlayers are highlighted. Concrete strategies including tailoring the anode structures, optimizing the electrolytes, building artificial anode–electrolyte interfaces, and functionalizing the protective interlayers are summarized in detail. Furthermore, the challenges remaining in LOE systems are outlined, and the future perspectives of introducing solid-state electrolytes to radically address safety issues are presented.

Dendrite growth, continuous side reactions, and infinite volume changes inside a lithium-metal anode severely hamper its application in high-energy batteries. Concrete failure mechanisms and effective strategies, including lowering the local current density, reducing anion depletion, smoothing interfaces, reshaping the lithium-ion flux, and mechanically blocking dendrites, are comprehensively reviewed.

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Reliable Piezoelectricity in Bilayer WSe2 for Piezoelectric Nanogenerators

Recently, piezoelectricity has been observed in 2D atomically thin materials, such as hexagonal-boron nitride, graphene, and transition metal dichalcogenides (TMDs). Specifically, exfoliated monolayer MoS₂ exhibits a high piezoelectricity that is comparable to that of traditional piezoelectric materials. However, monolayer TMD materials are not regarded as suitable for actual piezoelectric devices due to their insufficient mechanical durability for sustained operation while Bernal-stacked bilayer TMD materials lose noncentrosymmetry and consequently piezoelectricity. Here, it is shown that WSe₂ bilayers fabricated via turbostratic stacking have reliable piezoelectric properties that cannot be obtained from a mechanically exfoliated WSe₂ bilayer with Bernal stacking. Turbostratic stacking refers to the transfer of each chemical vapor deposition (CVD)-grown WSe₂ monolayer to allow for an increase in degrees of freedom in the bilayer symmetry, leading to noncentrosymmetry in the bilayers. In contrast, CVD-grown WSe₂ bilayers exhibit very weak piezoelectricity because of the energetics and crystallographic orientation. The flexible piezoelectric WSe₂ bilayers exhibit a prominent mechanical durability of up to 0.95% of strain as well as reliable energy harvesting performance, which is adequate to drive a small liquid crystal display without external energy sources, in contrast to monolayer WSe₂ for which the device performance becomes degraded above a strain of 0.63%.

WSe₂ bilayers with turbostratic stacking have reliable piezoelectric properties that cannot be obtained from a WSe₂ monolayer. The flexible piezoelectric WSe₂ bilayers exhibit a prominent mechanical durability of up to 0.95% of strain as well as reliable energy harvesting performance, which is adequate to drive a small liquid crystal display without external energy sources.

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Discovery of Rapid and Reversible Water Insertion in Rare Earth Sulfates: A New Process for Thermochemical Heat Storage

Thermal energy storage based on chemical reactions is a prospective technology for the reduction of fossil-fuel consumption by storing and using waste heat. For widespread application, a critical challenge is to identify appropriate reversible reactions that occur below 250 °C, where abundant low-grade waste heat and solar energy might be available. Here, it is shown that lanthanum sulfate monohydrate La₂(SO₄)₃⋅H₂O undergoes rapid and reversible dehydration/hydration reactions in the temperature range from 50 to 250 °C upon heating/cooling with remarkably small thermal hysteresis (<50 °C), and thus it emerges as a new candidate system for thermal energy storage. Thermogravimetry and X-ray diffraction analyses reveal that the reactions proceed through an unusual mechanism for sulfates: water is removed from, or inserted in La₂(SO₄)₃⋅H₂O with progressive change in hydration number x without phase change. It is also revealed that only a specific structural modification of La₂(SO₄)₃ exhibits this reversible dehydration/hydration behavior.

Water molecules can be inserted in crystalline rare earth sulfates such as La₂(SO₄)₃ without phase change, accompanied by heat release. Since the reaction proceeds rapidly and reversibly upon changing temperature and water vapor pressure in the temperature range 50–250 °C, it will be a promising process for thermal energy storage, especially for low-grade waste heat and solar energy.

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Modulation of Metal and Insulator States in 2D Ferromagnetic VS2 by van der Waals Interaction Engineering

2D transition-metal dichalcogenides (TMDCs) are currently the key to the development of nanoelectronics. However, TMDCs are predominantly nonmagnetic, greatly hindering the advancement of their spintronic applications. Here, an experimental realization of intrinsic magnetic ordering in a pristine TMDC lattice is reported, bringing a new class of ferromagnetic semiconductors among TMDCs. Through van der Waals (vdW) interaction engineering of 2D vanadium disulfide (VS₂), dual regulation of spin properties and bandgap brings about intrinsic ferromagnetism along with a small bandgap, unravelling the decisive role of vdW gaps in determining the electronic states in 2D VS₂. An overall control of the electronic states of VS₂ is also demonstrated: bond-enlarging triggering a metal-to-semiconductor electronic transition and bond-compression inducing metallization in 2D VS₂. The pristine VS₂ lattice thus provides a new platform for precise manipulation of both charge and spin degrees of freedom in 2D TMDCs availing spintronic applications.

Van der Waals interaction engineering in VS₂ brings the first intrinsic ferromagnetic semiconductor in 2D transition-metal dichalcogenides (TMDCs). An experimental realization of intrinsic magnetic ordering in a pristine TMDC lattice is reported. The pristine VS₂ lattice provides a new platform for precise manipulation of both charge and spin degrees of freedom in 2D TMDCs, availing spintronic applications.

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Manganese-Based Layered Double Hydroxide Nanoparticles as a T1-MRI Contrast Agent with Ultrasensitive pH Response and High Relaxivity

Recently, Mn(II)-containing nanoparticles have been explored widely as an attractive alternative to Gd(III)-based T₁-weighted magnetic resonance imaging (MRI) contrast agents (CAs) for cancer diagnosis. However, as far as it is known, no Mn-based MRI CAs have been reported to sensitively respond to a very weakly acidic environment (pH 6.5–7.0, i.e., the pH range in a tumor microenvironment) with satisfactory imaging performance. Here, recently devised pH-ultrasensitive Mn-based layered double hydroxide (Mn-LDH) nanoparticles with superb longitudinal relaxivity (9.48 mm⁻¹ s⁻¹ at pH 5.0 and 6.82 mm⁻¹ s⁻¹ at pH 7.0 vs 1.16 mm⁻¹ s⁻¹ at pH 7.4) are reported, which may result from the unique microstructure of Mn ions in Mn-LDH, as demonstrated by extended X-ray absorption fine structure. Further in vivo imaging reveals that Mn-LDH nanoparticles show clear MR imaging for tumor tissues in mice for 2 d post intravenous injection. Thus, this novel Mn-doped LDH nanomaterial, together with already demonstrated capacity for drug and gene delivery, is a very potential theranostic agent for cancer diagnosis and treatment.

Novel Mn-based layered double hydroxide (Mn-LDH) nanoparticles show excellent magnetic resonance imaging capacity with outstanding pH-ultrasensitivity at pH 7.4–6.5 and superb longitudinal relaxivity. These Mn-LDH nanoparticles are able to clearly image tumor tissue for 2 d in vivo. Together with demonstrated capacity for drug and gene delivery, Mn-LDH nanomaterials are potential theranostic agents for cancer treatment.

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Postsynthetic Doping of MnCl2 Molecules into Preformed CsPbBr3 Perovskite Nanocrystals via a Halide Exchange-Driven Cation Exchange

Unlike widely used postsynthetic halide exchange for CsPbX₃ (X is halide) perovskite nanocrystals (NCs), cation exchange of Pb is of a great challenge due to the rigid nature of the Pb cationic sublattice. Actually, cation exchange has more potential for rendering NCs with peculiar properties. Herein, a novel halide exchange-driven cation exchange (HEDCE) strategy is developed to prepare dually emitting Mn-doped CsPb(Cl/Br)₃ NCs via postsynthetic replacement of partial Pb in preformed perovskite NCs. The basic idea for HEDCE is that the partial cation exchange of Pb by Mn has a large probability to occur as a concomitant result for opening the rigid halide octahedron structure around Pb during halide exchange. Compared to traditional ionic exchange, HEDCE is featured by proceeding of halide exchange and cation exchange at the same time and lattice site. The time and space requirements make only MnCl₂ molecules (rather than mixture of Mn and Cl ions) capable of doping into perovskite NCs. This special molecular doping nature results in a series of unusual phenomenon, including long reaction time, core–shell structured mid states with triple emission bands, and dopant molecules composition-dependent doping process. As-prepared dual-emitting Mn-doped CsPb(Cl/Br)₃ NCs are available for ratiometric temperature sensing.

A novel halide exchange-driven cation exchange strategy is developed to prepare dually emitting Mn-doped CsPb(Cl/Br)₃ nanocrystals (NCs). The key is the simultaneous reactions of halide exchange and cation exchange at the same time and lattice site, which can be satisfied only by direct doping of MnCl₂ molecules into NCs.

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Orientational Coupling Locally Orchestrates a Cell Migration Pattern for Re-Epithelialization

Re-epithelialization by collective migration of epithelial cells over a heterogeneous environment to restore tissue integrity and functions is critical for development and regeneration. Here, it is reported that the spatial organization of adjacent adherent paths within sparsely distributed extracellular matrix (ECM) has a significant impact on the orientational coupling between cell polarization and collective cell migration. This coupling effect determines the migration pattern for human keratinocytes to regain their cohesion, which impacts the occupancy of epithelial bridge and the migration velocity in wound repair. Statistical studies suggest the converging organization of ECM, in which adjacent paths become closer to each other and finally converge to a junctional point, facilitating collective cell migration mostly within variable ECM organization, as the polarization of the advancing cell sheet is remodeled to align along the direction of cell migration. The findings may help to design implantable ECM to optimize efficient skin regeneration.

The spatial organization of adjacent adherent paths within sparsely distributed extracellular matrix (ECM) has a significant impact on the orientational coupling between cell polarization and collective cell migration for wound healing. This coupling effect determines the migration pattern and thus the efficiency for human keratinocytes to regain their cohesion. The findings may help to design an implantable ECM to optimize tissue regeneration.

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Graphitized Carbon Fibers as Multifunctional 3D Current Collectors for High Areal Capacity Li Anodes

The Li metal anode has long been considered as one of the most ideal anodes due to its high energy density. However, safety concerns, low efficiency, and huge volume change are severe hurdles to the practical application of Li metal anodes, especially in the case of high areal capacity. Here it is shown that that graphitized carbon fibers (GCF) electrode can serve as a multifunctional 3D current collector to enhance the Li storage capacity. The GCF electrode can store a huge amount of Li via intercalation and electrodeposition reactions. The as-obtained anode can deliver an areal capacity as high as 8 mA h cm⁻² and exhibits no obvious dendritic formation. In addition, the enlarged surface area and porous framework of the GCF electrode result in lower local current density and mitigate high volume change during cycling. Thus, the Li composite anode displays low voltage hysteresis, high plating/stripping efficiency, and long lifespan. The multifunctional 3D current collector promisingly provides a new strategy for promoting the cycling lifespan of high areal capacity Li anodes.

Graphitized carbon fiber electrode is demonstrated to improve the cycling performance of high-areal-capacity Li anodes due to dual reaction types, reduced current density, and confined volume change. This Li anode can deliver a high areal capacity of 8 mA h cm⁻² without Li dendrites and displays low voltage hysteresis, high plating/stripping efficiency, and long cycling lifespan.

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Hierarchical Co(OH)F Superstructure Built by Low-Dimensional Substructures for Electrocatalytic Water Oxidation

The development of new materials/structures for efficient electrocatalytic water oxidation, which is a key reaction in realizing artificial photosynthesis, is an ongoing challenge. Herein, a Co(OH)F material as a new electrocatalyst for the oxygen evolution reaction (OER) is reported. The as-prepared 3D Co(OH)F microspheres are built by 2D nanoflake building blocks, which are further woven by 1D nanorod foundations. Weaving and building the substructures (1D nanorods and 2D nanoflakes) provides high structural void porosity with sufficient interior space in the resulting 3D material. The hierarchical structure of this Co(OH)F material combines the merits of all material dimensions in heterogeneous catalysis. The anisotropic low-dimensional (1D and 2D) substructures possess the advantages of a high surface-to-volume ratio and fast charge transport. The interconnectivity of the nanorods is also beneficial for charge transport. The high-dimensional (3D) architecture results in sufficient active sites per the projected electrode surface area and is favorable for efficient mass diffusion during catalysis. A low overpotential of 313 mV is required to drive an OER current density of 10 mA cm⁻² on a simple glassy carbon (GC) working electrode in a 1.0 m KOH aqueous solution.

3D Co(OH)F microspheres are synthesized for highly efficient electrocatalytic water oxidation. The microspheres are built by 2D nanoflake building blocks, which are further woven by 1D nanorod foundations. The hierarchical structure of this free-standing Co(OH)F material combines the merits of all material dimensions in heterogeneous catalysis.

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Metasurfaces and Colloidal Suspensions Composed of 3D Chiral Si Nanoresonators

High-refractive-index silicon nanoresonators are promising low-loss alternatives to plasmonic particles in CMOS-compatible nanophotonics applications. However, complex 3D particle morphologies are challenging to realize in practice, thus limiting the range of achievable optical functionalities. Using 3D film structuring and a novel gradient mask transfer technique, the first intrinsically chiral dielectric metasurface is fabricated in the form of a monolayer of twisted silicon nanocrescents that can be easily detached and dissolved into colloidal suspension. The metasurfaces exhibit selective handedness and a circular dichroism as large as 160° µm⁻¹ due to pronounced differences in induced current loops for left-handed and right-handed polarization. The detailed morphology of the detached particles is analyzed using high-resolution transmission electron microscopy. Furthermore, it is shown that the particles can be manipulated in solution using optical tweezers. The fabrication and detachment method can be extended to different nanoparticle geometries and paves the way for a wide range of novel nanophotonic experiments and applications of high-index dielectrics.

3D film structuring and a novel gradient mask transfer technique are combined to fabricate the first intrinsically chiral dielectric metasurface in the form of a monolayer of twisted silicon nanocrescents that can be easily detached and dissolved into colloidal suspension.

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A Game Changer: A Multifunctional Perovskite Exhibiting Giant Ferroelectricity and Narrow Bandgap with Potential Application in a Truly Monolithic Multienergy Harvester or Sensor

An ABO₃-type perovskite solid-solution, (K_0.5Na_0.5)NbO₃ (KNN) doped with 2 mol% Ba(Ni_0.5Nb_0.5)O_3−δ (BNNO) is reported. Such a composition yields a much narrower bandgap (≈1.6 eV) compared to the parental composition—pure KNN—and other widely used piezoelectric and pyroelectric materials (e.g., Pb(Zr,Ti)O₃, BaTiO₃). Meanwhile, it exhibits the same large piezoelectric coefficient as that of KNN (≈100 pC N⁻¹) and a much larger pyroelectric coefficient (≈130 µC m⁻² K⁻¹) compared to the previously reported narrow-bandgap material (KNbO₃)_1−x-BNNO_x. The unique combination of these excellent ferroelectric and optical properties opens the door to the development of multisource energy harvesting or multifunctional sensing devices for the simultaneous and efficient conversion of solar, thermal, and kinetic energies into electricity in a single material. Individual and comprehensive characterizations of the optical, ferroelectric, piezoelectric, pyroelectric, and photovoltaic properties are investigated with single and coexisting energy sources. No degrading interaction between ferroelectric and photovoltaic behaviors is observed. This composition may fundamentally change the working principles of state-of-the-art hybrid energy harvesters and sensors, and thus significantly increases the unit-volume energy conversion efficiency and reliability of energy harvesters in ambient environments.

A multifunctional perovskite composition exhibiting giant ferroelectricity and narrow bandgap is reported. Ceramics and thick-films are fabricated via solid-state reaction and laser machining, respectively. Their balanced piezoelectric, pyroelectric, and photovoltaic properties and the multitask feature pave the way to the development of all-in-one multisource energy harvesting and multifunctional sensing devices based on the simplest solution of materials and structures.

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Synthesis of Ultrathin PdCu Alloy Nanosheets Used as a Highly Efficient Electrocatalyst for Formic Acid Oxidation

Inspired by the unique properties of ultrathin 2D nanomaterials and excellent catalytic activities of noble metal nanostructures for renewable fuel cells, a facile method is reported for the high-yield synthesis of ultrathin 2D PdCu alloy nanosheets under mild conditions. Impressively, the obtained PdCu alloy nanosheet after being treated with ethylenediamine can be used as a highly efficient electrocatalyst for formic acid oxidation. The study implicates that the rational design and controlled synthesis of an ultrathin 2D noble metal alloy may open up new opportunities for enhancing catalytic activities of noble metal nanostructures.

Ultrathin PdCu alloy nanosheets are synthesized via a facile wet-chemistry method. These nanosheets after being treated with ethylenediamine exhibit superior electrocatalytic activity toward formic acid oxidation.

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Confining the Nucleation of Pt to In Situ Form (Pt-Enriched Cage)@CeO2 Core@Shell Nanostructure as Excellent Catalysts for Hydrogenation Reactions

Ultrathin (Pt-enriched cage)@CeO₂ core@shell nanostructures are successfully fabricated via a facile hard-template method. It is found that the usage of Pd@Ag@CeO₂ bi-metallic core@shell nanostructure as the hard template plays an important role in avoiding the independent nucleation of Pt metal during the galvanic replacement process between K₂PtCl₄ and Ag components. This unique core@shell samples show extraordinary activity and selectivity for the cinnamaldehyde hydrogenation reaction. It can achieve over 95% conversion with 87% selectivity of hydrocinnamaldehyde in 5 h under 1 atm H₂ pressure. It is considered that such high catalytic performance could be attributed to the densely CeO₂-coated core@shell hybrid form as well as the ultrathin nature of the Pt-enriched cage.

High-quality CeO₂-encapsulated Pt-enriched cages with ultrathin walls are successfully synthesized via a kinetic-controlled process. The products exhibit enhanced catalytic activity and selectivity for cinnamaldehyde hydrogenation reaction among the different CeO₂-based core@shell samples.

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Structurally and Functionally Optimized Silk-Fibroin–Gelatin Scaffold Using 3D Printing to Repair Cartilage Injury In Vitro and In Vivo

Articular cartilage repair remains a great challenge for clinicians and researchers. Recently, there emerges a promising way to achieve one-step cartilage repair in situ by combining endogenic bone marrow stem cells (BMSCs) with suitable biomaterials using a tissue engineering technique. To meet the increasing demand for cartilage tissue engineering, a structurally and functionally optimized scaffold is designed, by integrating silk fibroin with gelatin in combination with BMSC-specific-affinity peptide using 3D printing (3DP) technology. The combination ratio of silk fibroin and gelatin greatly balances the mechanical properties and degradation rate to match the newly formed cartilage. This dually optimized scaffold has shown superior performance for cartilage repair in a knee joint because it not only retains adequate BMSCs, due to efficient recruiting ability, and acts as a physical barrier for blood clots, but also provides a mechanical protection before neocartilage formation and a suitable 3D microenvironment for BMSC proliferation, differentiation, and extracellular matrix production. It appears to be a promising biomaterial for knee cartilage repair and is worthy of further investigation in large animal studies and preclinical applications. Beyond knee cartilage, this dually optimized scaffold may also serve as an ideal biomaterial for the regeneration of other joint cartilages.

A structurally and functionally optimized scaffold is designed for knee cartilage regeneration by integrating silk fibroin with gelatin in combination with bone-marrow-stem-cell (BMSC)-specific-affinity peptide using 3D printing technology. This dually optimized scaffold can efficiently recruit endogenic BMSCs and provide a suitable microenvironment for neocartilage formation, thus successfully achieving regeneration of cartilage in a knee joint.

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Real-Time Observation of Carbon Nanotube Etching Process Using Polarized Optical Microscope

Controllable synthesis of carbon nanotubes (CNTs) is of great importance in its further application, which attracts broad attention. As growth and etching are the two sides in the process of material crystallography and the control of the competition between them forms the foundation for modern technology of materials design and manufacture, the understanding on etching process of carbon nanotubes is still very unclear because technically it is of great challenge to characterize the dynamics in such small one-dimensional (1D) scale. Here the real-time investigation on the etching process of CNTs is reported, by the hot-wall chemical reactor equipped with a polarized optical microscope. It is discovered that the CNT etching behavior in air is totally of random, including the etching sites, termination sites, and structure dependence. Combining with the dynamic simulation, it is revealed that the random behavior reflects the unique "self-termination" phenomenon. A structure-independent etching propagation barrier of 2.4 eV is also obtained, which indicates that the etching propagation process still follows the conventional Kinetic Wulff construction theory. The results represent the new knowledge on the etching process in carbon nanotube and can contribute to its selective enrichment. Furthermore, the "self-termination" phenomenon may be a universal behavior in 1D process.

A hot-wall chemical reactor equipped with a polarized optical microscope is used to realize in situ real-time observation of the etching process in carbon nanotubes, and a "random etching" behavior is discovered. It is revealed that the random behavior reflects the unique "self-termination" phenomenon. Kinetic mechanism of single-walled carbon nanotube etching process is also discussed.

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Approaching Intra- and Interchain Charge Transport of Conjugated Polymers Facilely by Topochemical Polymerized Single Crystals

Charge transport of small molecules is measured well with scanning tunneling microscopy, conducting atomic force microscopy, break junction, nanopore, and covalently bridging gaps. However, the manipulation and measurement of polymer chains remain a long-standing fundamental issue in conjugated polymers and full of challenge since conjugated polymers are naturally disordered materials. Here, a fundamental breakthrough in generating high-quality conjugated-polymer nanocrystals with extended conjugation and exceptionally high degrees of order using a surface-supported topochemical polymerization method is demonstrated. In the crystal the conjugated-polymer chains are extended along the long axis of the crystal with the side chains perpendicular to the long axis. Devices with conducting channels along the polymer chains show efficient charge transport, nearly two orders of magnitude greater than the interchain charge transport along the π–π stacking direction. This is the first example to clarify intra- and interchain charge transport based on an individual single crystal of conjugated polymers, and demonstrate the importance of intrachain charge transport in plastic electronics.

High-quality conjugated-polymer crystals with extended conjugation and exceptionally high degree of molecular order are obtained through a modified topochemical polymerization method. For the first time, the fundamental studies of intra- and interchain charge transport based on an individual polymer crystal are approached, giving a high carrier mobility up to 50 cm² V⁻¹ s⁻¹ along the backbones, which is two orders of magnitude greater than that in the interchain direction.

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Ultrafast Growth of High-Quality Monolayer WSe2 on Au

The ultrafast growth of high-quality uniform monolayer WSe₂ is reported with a growth rate of ≈26 µm s⁻¹ by chemical vapor deposition on reusable Au substrate, which is ≈2–3 orders of magnitude faster than those of most 2D transition metal dichalcogenides grown on nonmetal substrates. Such ultrafast growth allows for the fabrication of millimeter-size single-crystal WSe₂ domains in ≈30 s and large-area continuous films in ≈60 s. Importantly, the ultrafast grown WSe₂ shows excellent crystal quality and extraordinary electrical performance comparable to those of the mechanically exfoliated samples, with a high mobility up to ≈143 cm² V⁻¹ s⁻¹ and ON/OFF ratio up to 9 × 10⁶ at room temperature. Density functional theory calculations reveal that the ultrafast growth of WSe₂ is due to the small energy barriers and exothermic characteristic for the diffusion and attachment of W and Se on the edges of WSe₂ on Au substrate.

Ultrafast growth of high-quality uniform monolayer WSe₂ is achieved by chemical vapor deposition using Au as a reusable substrate. The growth rate is ≈2–3 orders of magnitude faster than those reported due to the small energy barriers and exothermic characteristic, and the materials show excellent crystal quality and extraordinary electrical properties comparable to those of exfoliated samples.

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A High-Performance Li–O2 Battery with a Strongly Solvating Hexamethylphosphoramide Electrolyte and a LiPON-Protected Lithium Anode

The aprotic Li–O₂ battery has attracted a great deal of interest because theoretically it can store more energy than today's Li-ion batteries. However, current Li–O₂ batteries suffer from passivation/clogging of the cathode by discharged Li₂O₂, high charging voltage for its subsequent oxidation, and accumulation of side reaction products (particularly Li₂CO₃ and LiOH) upon cycling. Here, an advanced Li–O₂ battery with a hexamethylphosphoramide (HMPA) electrolyte is reported that can dissolve Li₂O₂, Li₂CO₃, and LiOH up to 0.35, 0.36, and 1.11 × 10⁻³m, respectively, and a LiPON-protected lithium anode that can be reversibly cycled in the HMPA electrolyte. Compared to the benchmark of ether-based Li–O₂ batteries, improved capacity, rate capability, voltaic efficiency, and cycle life are achieved for the HMPA-based Li–O₂ cells. More importantly, a combination of advanced research techniques provide compelling evidence that operation of the HMPA-based Li–O₂ battery is backed by nearly reversible formation/decomposition of Li₂O₂ with negligible side reactions.

A high-performance Li–O₂ battery is realized by employing a strongly solvating hexamethylphosphoramide (HMPA) electrolyte that can effectively dissolve Li₂O₂ and a LiPON-protected lithium anode that can be reversibly cycled in HMPA electrolyte. A combination of advanced research techniques provide compelling evidence that operation of the HMPA-based Li–O₂ battery is backed by nearly reversible formation/decomposition of Li₂O₂ with negligible side reactions.

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A Supramolecular Artificial Light-Harvesting System with an Ultrahigh Antenna Effect

An efficient artificial light-harvesting system is fabricated from a cyclic polysaccharide, sulfato-β-cyclodextrin (SCD); an aggregation-induced emission molecule, an oligo(phenylenevinylene) derivative (OPV-I); and a fluorescent dye, nile red (NiR), via noncovalent interactions in an aqueous solution. In this system, the OPV-I/SCD supramolecular assembly acts as a donor, and NiR that is loaded into the OPV-I/SCD assembly acts as an acceptor. Significantly, an efficient energy-transfer process occurs between the OPV-I/SCD assembly and the loaded NiR, leading to an extremely high antenna effect.

An efficient artificial light-harvesting system is fabricated based on a supramolecular strategy in aqueous solution. In this system, the supramolecular assembly acts as a donor, and nile red that is loaded into the assembly acts as acceptor. Significantly, an efficient energy-transfer process occurs between the assembly and the loaded nile red, leading to an extremely high antenna effect.

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Piezo-Phototronic Effect on Selective Electron or Hole Transport through Depletion Region of Vis–NIR Broadband Photodiode

Silicon underpins nearly all microelectronics today and will continue to do so for some decades to come. However, for silicon photonics, the indirect band gap of silicon and lack of adjustability severely limit its use in applications such as broadband photodiodes. Here, a high-performance p-Si/n-ZnO broadband photodiode working in a wide wavelength range from visible to near-infrared light with high sensitivity, fast response, and good stability is reported. The absorption of near-infrared wavelength light is significantly enhanced due to the nanostructured/textured top surface. The general performance of the broadband photodiodes can be further improved by the piezo-phototronic effect. The enhancement of responsivity can reach a maximum of 78% to 442 nm illumination, the linearity and saturation limit to 1060 nm light are also significantly increased by applying external strains. The photodiode is illuminated with different wavelength lights to selectively choose the photogenerated charge carriers (either electrons or holes) passing through the depletion region, to investigate the piezo-phototronic effect on electron or hole transport separately for the first time. This is essential for studying the basic principles in order to develop a full understanding about piezotronics and it also enables the development of the better performance of optoelectronics.

A high-performance p-Si/n-ZnO broadband photodiode is fabricated, working in a wide wavelength range from visible to near-infrared light. The photodiode is illuminated with different wavelengths to selectively choose the photogenerated charge carriers (either electrons or holes) passing through the depletion region. This enables the possibility to investigate the piezo-phototronic effect on performance in two cases separately for the first time.

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Giant Ferroelectric Polarization in Ultrathin Ferroelectrics via Boundary-Condition Engineering

Tailoring and enhancing the functional properties of materials at reduced dimension is critical for continuous advancement of modern electronic devices. Here, the discovery of local surface induced giant spontaneous polarization in ultrathin BiFeO₃ ferroelectric films is reported. Using aberration-corrected scanning transmission electron microscopy, it is found that the spontaneous polarization in a 2 nm-thick ultrathin BiFeO₃ film is abnormally increased up to ≈90–100 µC cm⁻² in the out-of-plane direction and a peculiar rumpled nanodomain structure with very large variation in c/a ratios, which is analogous to morphotropic phase boundaries (MPBs), is formed. By a combination of density functional theory and phase-field calculations, it is shown that it is the unique single atomic Bi₂O_3−x layer at the surface that leads to the enhanced polarization and appearance of the MPB-like nanodomain structure. This finding clearly demonstrates a novel route to the enhanced functional properties in the material system with reduced dimension via engineering the surface boundary conditions.

A giant enhancement of ferroelectric polarization in ultrathin 2 nm BiFeO₃ film is reported. With the addition of a Bi₂O_3−x monolayer on the surface of ferroelectric BiFeO₃ thin films, the ferroelectric polarization of the ultrathin BiFeO₃ film is stabilized and dramatically increased up to ≈150 µC cm⁻², demonstrating the possibility of enhancing the performance of ferroelectric materials at the reduced dimension.

http://ift.tt/2qW6aYm

Electric-Field-Controlled Dopant Distribution in Organic Semiconductors

Stable electrical doping of organic semiconductors is fundamental for the functionality of high performance devices. It is known that dopants can be subjected to strong diffusion in certain organic semiconductors. This work studies the impact of operating conditions on thin films of the polymer poly(3-hexylthiophene) (P3HT) and the small molecule Spiro-MeOTAD, doped with two differently sized p-type dopants. The negatively charged dopants can drift upon application of an electric field in thin films of doped P3HT over surprisingly large distances. This drift is not observed in the small molecule Spiro-MeOTAD. Upon the dopants' directional movement in P3HT, a dedoped region forms at the negatively biased electrode, increasing the overall resistance of the thin film. In addition to electrical measurements, optical microscopy, spatially resolved infrared spectroscopy, and scanning Kelvin probe microscopy are used to investigate the drift of dopants. Dopant mobilities of 10⁻⁹ to 10⁻⁸ cm² V⁻¹ s⁻¹ are estimated. This drift over several micrometers is reversible and can be controlled. Furthermore, this study presents a novel memory device to illustrate the applicability of this effect. The results emphasize the importance of dynamic processes under operating conditions that must be considered even for single doped layers.

The electric-field-controlled movement of dopants in organic semiconductors is investigated with electrical measurements, optical microscopy, and spatially resolved infrared spectroscopy. This study evaluates two p-type dopants in a polymer and small molecule host material and utilizes the movement to build a proof-of-concept memristive device by reversibly changing the overall conductivity of thin films.

http://ift.tt/2rFKlJL

Meta-analysis of pre-operative magnetic resonance imaging (MRI) and surgical treatment for breast cancer

Abstract

Background

Although there is no consensus on whether pre-operative MRI in women with breast cancer (BC) benefits surgical treatment, MRI continues to be used pre-operatively in practice. This meta-analysis examines the association between pre-operative MRI and surgical outcomes in BC.

Methods

A systematic review was performed to identify studies reporting quantitative data on pre-operative MRI and surgical outcomes (without restriction by type of surgery received or type of BC) and using a controlled design. Random-effects logistic regression calculated the pooled odds ratio (OR) for each surgical outcome (MRI vs. no-MRI groups), and estimated ORs stratified by study-level age. Subgroup analysis was performed for invasive lobular cancer (ILC).

Results

Nineteen studies met eligibility criteria: 3 RCTs and 16 comparative studies that included newly diagnosed BC of any type except for three studies restricted to ILC. Primary analysis (85,975 subjects) showed that pre-operative MRI was associated with increased odds of receiving mastectomy [OR 1.39 (1.23, 1.57); p < 0.001]; similar findings were shown in analyses stratified by study-level median age. Secondary analyses did not find statistical evidence of an effect of MRI on the rates of re-excision, re-operation, or positive margins; however, MRI was significantly associated with increased odds of receiving contralateral prophylactic mastectomy [OR 1.91 (1.25, 2.91); p = 0.003]. Subgroup analysis for ILC did not find any association between MRI and the odds of receiving mastectomy [OR 1.00 (0.75, 1.33); p = 0.988] or the odds of re-excision [OR 0.65 (0.35, 1.24); p = 0.192].

Conclusions

Pre-operative MRI is associated with increased odds of receiving ipsilateral mastectomy and contralateral prophylactic mastectomy as surgical treatment in newly diagnosed BC patients.

http://ift.tt/2sbs89o

Homogeneous 2D MoTe2 p–n Junctions and CMOS Inverters formed by Atomic-Layer-Deposition-Induced Doping

Recently, α-MoTe₂, a 2D transition-metal dichalcogenide (TMD), has shown outstanding properties, aiming at future electronic devices. Such TMD structures without surface dangling bonds make the 2D α-MoTe₂ a more favorable candidate than conventional 3D Si on the scale of a few nanometers. The bandgap of thin α-MoTe₂ appears close to that of Si and is quite smaller than those of other typical TMD semiconductors. Even though there have been a few attempts to control the charge-carrier polarity of MoTe₂, functional devices such as p–n junction or complementary metal–oxide–semiconductor (CMOS) inverters have not been reported. Here, we demonstrate a 2D CMOS inverter and p–n junction diode in a single α-MoTe₂ nanosheet by a straightforward selective doping technique. In a single α-MoTe₂ flake, an initially p-doped channel is selectively converted to an n-doped region with high electron mobility of 18 cm² V⁻¹ s⁻¹ by atomic-layer-deposition-induced H-doping. The ultrathin CMOS inverter exhibits a high DC voltage gain of 29, an AC gain of 18 at 1 kHz, and a low static power consumption of a few nanowatts. The results show a great potential of α-MoTe₂ for future electronic devices based on 2D semiconducting materials.

Homogeneous 2D MoTe₂ p–n junction and complementary metal–oxide–semiconductor (CMOS) inverters integrated by selective n-type doping are demonstrated, which are obtained by H-diffusion during atomic layer deposition on initial p-type MoTe₂. This 2D α-MoTe₂ CMOS inverters with a p–n junction exhibits promising static and dynamic performances, forecasting future prospects to overcome the limits of 3D Si CMOS.

http://ift.tt/2qS85cf

The Optical Janus Effect: Asymmetric Structural Color Reflection Materials

Structurally colored materials are often used for their resistance to photobleaching and their complex viewing-direction-dependent optical properties. Frequently, absorption has been added to these types of materials in order to improve the color saturation by mitigating the effects of nonspecific scattering that is present in most samples due to imperfect manufacturing procedures. The combination of absorbing elements and structural coloration often yields emergent optical properties. Here, a new hybrid architecture is introduced that leads to an interesting, highly directional optical effect. By localizing absorption in a thin layer within a transparent, structurally colored multilayer material, an optical Janus effect is created, wherein the observed reflected color is different on one side of the sample than on the other. A systematic characterization of the optical properties of these structures as a function of their geometry and composition is performed. The experimental studies are coupled with a theoretical analysis that enables a precise, rational design of various optical Janus structures with highly controlled color, pattern, and fabrication approaches. These asymmetrically colored materials will open applications in art, architecture, semitransparent solar cells, and security features in anticounterfeiting materials.

Viewing-direction-dependent reflected color is rationally designed and patterned to create several different types of asymmetric structural color films using a variety of fabrication methods and materials. The reflection properties of these materials are calculated analytically a priori to enable a diverse array of color combinations and effects to be created.

http://ift.tt/2sbu0iA

Carbon Nanotubes as an Ultrafast Emitter with a Narrow Energy Spread at Optical Frequency

Ultrafast electron pulses, combined with laser-pump and electron-probe technologies, allow ultrafast dynamics to be characterized in materials. However, the pursuit of simultaneous ultimate spatial and temporal resolution of microscopy and spectroscopy is largely subdued by the low monochromaticity of the electron pulses and their poor phase synchronization to the optical excitation pulses. Field-driven photoemission from metal tips provides high light-phase synchronization, but suffers large electron energy spreads (3–100 eV) as driven by a long wavelength laser (>800 nm). Here, ultrafast electron emission from carbon nanotubes (≈1 nm radius) excited by a 410 nm femtosecond laser is realized in the field-driven regime. In addition, the emitted electrons have great monochromaticity with energy spread as low as 0.25 eV. This great performance benefits from the extraordinarily high field enhancement and great stability of carbon nanotubes, superior to metal tips. The new nanotube-based ultrafast electron source opens exciting prospects for extending current characterization to sub-femtosecond temporal resolution as well as sub-nanometer spatial resolution.

Field-driven photoemission sources based on metal tips allow ultrafast characterization with ultimate spatio–temporal resolution, but suffer large energy spreads (>3 eV). Photoemission from carbon nanotubes excited by a 410 nm femtosecond laser is realized in the field-driven regime with a 0.25 eV energy spread, which benefits from the high field enhancement and great stability of the carbon nanotubes.

http://ift.tt/2qShXmp

A Molecular Polycrystalline Ferroelectric with Record-High Phase Transition Temperature

An outstanding advantage of inorganic ceramic ferroelectrics is their usability in the polycrystalline ceramic or thin film forms, which has dominated applications in the ferroelectric, dielectric, and piezoelectric fields. Although the history of ferroelectrics began with the molecular ferroelectric Rochelle salt in 1921, so far there have been very few molecular ferroelectrics, with lightweight, flexible, low-cost, and biocompatible superior properties compared to inorganic ceramic ferroelectrics, that can be applied in the polycrystalline form. Here, a multiaxial molecular ferroelectric, guanidinium perchlorate ([C(NH₂)₃]ClO₄), with a record-high phase transition temperature of 454 K is presented. It is the rectangular polarization–electric field (P–E) hysteresis loops recorded on the powder and thin film samples (with respective large P_r of 5.1 and 8.1 µC cm⁻²) that confirm the ferroelectricity of [C(NH₂)₃]ClO₄ in the polycrystalline states. Intriguingly, after poling, the piezoelectric coefficient (d₃₃) of the powder sample shows a significant increase from 0 to 10 pC N⁻¹, comparable to that of LiNbO₃ single crystal (8 pC N⁻¹). This is the first time that such a phenomenon has been observed in molecular ferroelectrics, indicating the great potential of molecular ferroelectrics being used in the polycrystalline form like inorganic ferroelectrics, as well as being viable alternatives or supplements to conventional ceramic ferroelectrics.

Guanidinium perchlorate is found to show multiaxial ferroelectricity with extremly low coercive field. Its polycrystalline samples show properties similar to those in ceramic ferroelectrics, such as switchable polarization and piezoelectric coefficient for the powder-pressed plates.

http://ift.tt/2sbu3uA

Omega-3 supplementation in patients with sepsis: a systematic review and meta-analysis of randomized trials

Nutritional supplementation of omega-3 fatty acids has been proposed to modulate the balance of pro- and anti-inflammatory mediators in sepsis. If proved to improve clinical outcomes in critically ill patients...

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4β-Hydroxycholesterol level significantly correlates with steady-state serum concentration of the CYP3A4 substrate quetiapine in psychiatric patients

Summary

Aim

4β-Hydroxycholesterol (4βOHC) is sensitive towards induction or inhibition of CYP3A4, but its potential usefulness as a dosing biomarker remains to be demonstrated. The aim of this study was to investigate the correlation between 4βOHC levels and steady-concentrations (Css) of quetiapine, a CYP3A4 substrate with high presystemic metabolism, in psychiatric patients.

Methods

Serum samples from 151 patients treated with quetiapine as immediate release (IR; n=98) or slow release (XR; n=53) tablets were included for analysis of 4βOHC. In all patients, Css of quetiapine had been measured at trough level, i.e. 10-14 and 17-25 hours post-dosing for IR and XR tablets, respectively. Correlations between 4βOHC levels and dose-adjusted Css (C/D ratios) of quetiapine were tested by univariate (Spearman's) and multivariate (multiple linear regression) analyses. Gender, age (≥60 vs. <60 years) and tablet formulation were included as potential covariates in the multivariate analysis.

Results

Correlations between 4βOHC levels and quetiapine C/D ratios were highly significant both for IR- and XR-treated patients (P<0.0001). Estimated Spearman r values –were 0.47 (95% confidence interval -0.62, -0.30) and -0.56 (-0.72, -0.33), respectively. The relationship between 4βOHC level and quetiapine C/D ratio was also significant in the multiple linear regression analysis (P<0.001), including gender (P=0.023) and age (P=0.003) as significant covariates.

Conclusions

The present study shows that 4βOHC level is significantly correlated with steady-state concentration of quetiapine. This supports the potential usefulness of 4βOHC as a phenotype biomarker for individualized dosing of quetiapine and other drugs where systemic exposure is mainly determined by CYP3A4 metabolism.

http://ift.tt/2qRYtyn

Improving Care of Transgender Patients

The recent publication, Is It Okay To Ask: Transgender Patient Perspectives on Sexual Orientation and Gender Identity Collection in Healthcare, is significant in its discussion of circumstances affecting willingness of transgender patients to disclose gender identity and sexual orientation as well as the participants' focus on the need for improved LGBT education for medical staff. The authors also emphasize the importance of safe environments in primary care settings and emergency departments where providers may pose questions regarding intimate issues¹.

This article is protected by copyright. All rights reserved.

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HNF4A expression as a potential diagnostic tool to discriminate primary gastric cancer from breast cancer metastasis in a Brazilian cohort

Among the many challenges in cancer diagnosis is the early distinction between metastatic cancer and a secondary tumor. This difficulty stems from the lack of markers that offer high sensitivity and specificit...

http://ift.tt/2sydBCa

Development and validation of a claims-based measure as an indicator for disease status in patients with multiple sclerosis treated with disease-modifying drugs

Administrative healthcare claims data provide a mechanism for assessing and monitoring multiple sclerosis (MS) disease status across large, clinically representative "real-world" populations. The estimation of...

http://ift.tt/2rYWSek

Association between total-Tau and brain atrophy one year after first-ever stroke

Although the most serious consequence of neuronal ischemia is acute neuronal death, mounting evidence suggests similarities between stroke and neurodegenerative disease. Brain atrophy visualized on structural ...

http://ift.tt/2syj9N2

Patterns of antiepileptic drug prescription in Sweden: A register-based approach

Objectives

To determine drug utilization pathways from the incident healthcare visit due to epilepsy and three years onward.

Material and methods

Anti-epileptic drug utilization was calculated using individual information on inpatient- and outpatient care utilization and drug sales. Throughout, we used national register information pertaining to pharmaceutical sales linked to diagnosis-related healthcare utilization. Information on pharmaceutical sales was collected for the 2007-2013 period.

Results

For the entire studied period, a majority of new patients with epilepsy were initiated on anti-epileptic drug treatment with a monotherapy (98%); most of these patients remained on that first treatment (64%). The three most frequently prescribed drugs accounted for 72% of the initiated AED treatments. Patients with epilepsy (ICD-10: G40/41) were most commonly prescribed carbamazepine, lamotrigine and valproate. The most common second-line monotherapy was levetiracetam. About 12% of new patients with epilepsy who were initiated on AED treatment during the period eventually switched to an add-on therapy. The proportion of patients who were initiated on treatment with carbamazepine or valproate decreased, and the proportion of patients who remained on their initial monotherapy increased between 2007 and 2013.

Conclusions

A limited number of anti-epileptic drugs accounted for the treatment of a majority of new patients with epilepsy (carbamazepine, lamotrigine and valproate accounted for more than 70%). Add-on therapies showed the same pattern, as the most frequently prescribed add-on regimens were the same ones that accounted for most of the monotherapies. There was a tendency towards fewer patients being initiated on AED treatment with either carbamazepine or valproate.

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Rationale and protocol of MetNET-2 trial: Lanreotide Autogel plus metformin in advanced gastrointestinal or lung neuroendocrine tumors

Future Oncology Ahead of Print.


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Salvage Strategies for Management of Testicular Tumors

Abstract

Testicular germ cell tumors (GCTs) comprise 2% of all human male malignancies and are the most common solid tumors in men between ages 15 and 35 years. Risk of contralateral testicular GCT is between 1 and 5%. Partial orchidectomy (PO) was originally described in 1984 by Richie. The evolving indications include metachronous tumors and tumor in solitary testicles. Also, small non-palpable lesions detected only by ultrasonography (USG) in asymptomatic patients is another indication. Salvagability is only chosen for tumors less than 2 cm in size. The key feature of PO is an inguinal approach with early vascular control using a rubber tourniquet before testicular mobilization into the field to avoid systemic tumor seeding. After, mass excision with a margin mandatory frozen section is done to assess adequacy of resection. Intra-op USG may be beneficial in small non-palpable lesions. Post op tumor markers are assessed and patients are taught self-examination of testis. Recent series shows that PO is safe and gives adequate oncological control. Carcinoma in situ (CIS) in the affected testis at PO or after testicular sparing surgery remains a challenge. At most centers, 20 Gy is recommended when adjuvant local radiation treatment is chosen to treat CIS. But this dose may hamper Androgen production. Radical orchiectomy remains the gold standard and should be discussed as part of informed consent. It is mandatory to highlight the risks of local recurrence and CIS, and treatment (observation, radiation, or completion orchiectomy) as well as the need for androgen supplementation and fertility risks before choosing testicular salvage procedures.

http://ift.tt/2sy0QHN

Current Concepts in the Management of Non-Muscle Invasive Bladder Cancer

Abstract

Non-muscle invasive bladder cancer, despite advances in the field of medicine, remains an enigmatic problem with no tangible solution of one-time treatment as it needs an invasive surveillance in the form of cystoscopy. There are issues related to diagnosis, ideal resection technique, BCG treatment, and follow-up. In this article, we review the recent developments in the diagnosis of the disease and describe optimal management strategies.

http://ift.tt/2rZ5mls

Whole-Genome Sequence and Variant Analysis of W303, a Widely-Used Strain of Saccharomyces cerevisiae

The yeast Saccharomyces cerevisiae has emerged as a superior model organism. Selection of distinct laboratory strains of S. cerevisiae with unique phenotypic properties, such as superior mating or sporulation efficiencies, has facilitated advancements in research. W303 is one such laboratory strain that is closely related to the first completely sequenced yeast strain, S288C. In this work, we provide a high-quality, annotated genome sequence for W303 for utilization in comparative analyses and genome-wide studies. Approximately 9,500 variations exist between S288C and W303, affecting the protein sequences of about 700 genes. A listing of the polymorphisms and divergent genes is provided for researchers interested in identifying the genetic basis for phenotypic differences between W303 and S288C. Several divergent functional gene families were identified, including flocculation and sporulation genes, likely representing selection for desirable laboratory phenotypes. Interestingly, remnants of ancestor wine strains were found on several chromosomes. Finally, as a test of the utility of the high-quality reference genome, variant mapping revealed more accurate identification of accumulated mutations in passaged mismatch repair defective strains.

http://ift.tt/2rNxkjk

Whole Genome Sequencing of the Braconid Parasitoid Wasp Fopius arisanus, an Important Biocontrol Agent of Pest Tepritid Fruit Flies

The braconid wasp Fopius arisanus (Sonan) is an important biological control agent of tropical and subtropical pest fruit flies including two important global pests, the Mediterranean fruit fly (Ceratitis capitata), and the oriental fruit fly (Bactrocera dorsalis). The goal of this study was to develop foundational genomic resources for this species to provide tools that can be used to answer questions exploring the multitrophic interactions between the host and parasitoid in this important research system. Here we present the a whole genome assembly of F. arisanus, derived from pooled haploid offspring from a single unmated female. The genome is approximately 154 Mb in size, with a N50 contig and scaffold size of 51,867 bp and 0.98 Mb, respectively. Utilizing existing RNA-Seq data for this species, as well as publicly available peptide sequences from related hymenopterans, a high quality gene annotation set, which includes 10,991 protein coding genes, was generated. Prior to this assembly submission, no RefSeq proteins were present for this species. Parasitic wasps play an important role in a diverse ecosystem as well as a role in biological control of agricultural pests. This whole genome assembly and annotation data represents the first genome-scale assembly for this species or any closely related Opiine, and are publicly available in the National Center for Biotechnology Information Genome and RefSeq databases, providing a much needed genomic resource for this hymenopteran group.

http://ift.tt/2sLRU0M

First Tissue-Agnostic Drug Approval Issued [News in Brief]

Pembrolizumab OK'd for mismatch repair–deficient or microsatellite instability–high solid tumors.

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Emory's Winship Earns Comprehensive Status [News in Brief]

Cancer center receives NCI kudos for its clinical trials program and population-based research initiatives.

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Dramatic Responses Seen with TRK Inhibitor [News in Brief]

Treatment with larotrectinib yielded responses in 76% of patients—pediatric and adult—regardless of tumor type.

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Olaparib Keeps Hereditary Breast Tumors in Check [News in Brief]

For metastatic breast cancer with BRCA mutations, PARP inhibitor beats chemo in phase III trial for the first time.

http://ift.tt/2sy0tNd

Anticancer and Cytotoxic Activities of [Cu(C6H16N2O2)2][Ni(CN)4] and [Cu(C6H16N2O2)Pd(CN)4] Cyanidometallate Compounds on HT29, HeLa, C6 and Vero Cell Lines

Background: In cancer, apoptosis relevant proteins—such as CaM kinase, Bcl-2 or P53, topoisomerase I, cell migration feature and DNA/BSA—macromolecules represent significant targets for current chemotherapeutics. Objective: We recently reported two coordination compounds—[Cu(C6H16N2O2)2][Ni(CN)4] (1) and [Cu(C6H16 N2O2)Pd(CN)4] (2)—together with their IR spectra, magnetic properties, thermal analyses and crystal structures. Herein, we describe the ability of these complexes to induce apoptosis in relevant proteins and stimulate topoisomerase I activity, cell migration velocity and DNA/BSA binding properties. Method: The in vitro antiproliferative effects and cell toxicity of both compounds were investigated through pharmacological measurement techniques, and interactions between both compounds and CT-DNA/BSA were studied with UV-Vis spectroscopy and fluorescence spectroscopy. Results & Conclusion: Studies on cells revealed that 2 (i) demonstrated a high antiproliferative effect, which was higher toward HeLa and C6 cancer cells than toward healthy Vero cells; (ii) impaired the migration of HeLa cells; (iii) altered the P53-Bcl-2 ratio in favor of apoptosis; (iv) strongly bound to DNA/BSA macromolecules; and (v) inhibited human topoisomerase I and KpnI or BamHI restriction endonucleases. In conclusion, this preliminary information demonstrates that 2 may represent a promising antiproliferative agent and a potential candidate for a therapeutic approach against HeLa.

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Improved Immunogenicity Against a Her2/neu-Derived Peptide by Employment of a Pan HLA DR-Binding Epitope and CpG in a BALB/c Mice Model

Background: An efficient strategy to improve the immunogenicity of peptide vaccines is the use of a synthetic peptide containing cytotoxic T-lymphocyte (CTL) epitopes with T-helper (Th) inducing-epitopes. Objective: Our purpose was to determine the use of human epidermal growth factor receptor-2 (Her2/neu)- specific CTL epitopes plus the pan HLA DR-binding epitope (PADRE) and CpG oligodeoxynucleotides (ODNs) to induce antitumor effects in vaccinated mice. Method: Female BALB/c mice were immunized subcutaneously with different vaccines. Three mice per group were euthanized to assess immune responses and the others were transplanted with TUBO cells. Enzyme-linked Immuno Spot assay (ELISpot) and flow cytometry studies were followed by tumor size and survival rate measurements in a TUBO tumor mice model. Results: The results showed that mice vaccinated with the P5 peptide plus PADRE plus CpG produced higher antigen-specific CTL responses than mice vaccinated with the P5 peptide alone. Also, tumors in those mice grew more slowly and the survival rates were greater than mice in the other groups. Conclusion: We conclude that peptide vaccines containing epitopes that stimulate both CD4+ and CD8+ T-cells are effective at inducing anti-tumor immunity.

http://ift.tt/2rvdMzE

Preclinical and Clinical Studies of Chidamide (CS055/HBI-8000), An Orally Available Subtype-selective HDAC Inhibitor for Cancer Therapy

Epigenetic modifications play central roles in cellular differentiation and their deregulations really contribute to tumor development. Histone deacetylase (HDAC) enzymes can exert their functions in the epigenetic regulation of gene expression related to oncogenesis via deacetylating the lysine residues of histones in the chromatin and various non-histone proteins. A majority of HDAC inhibitors (HDACIs) have been in different stages of preclinical and clinical trials with potent anticancer activity recently. Among these agents, chidamide tested as either monotherapeutic agent or in combination regimens for numerous hematological and solid malignancies has shown promising potential as an orally active subtype-selective HDACI. Herein we will highlight the progress of clinical trials of chidamide and rationally analyze those results from both preclinical and clinical studies about chidamide as an epigenetic modulator in cancer therapy.

http://ift.tt/2rvmKgj

Design and Synthesis of 4-substituted Quinazolines as Potent EGFR Inhibitors with Anti-breast Cancer Activity

Background: Cancer is a major health problem to human beings around the world. Many quinazoline derivatives were reported to have potent cytotoxic activity. Aims: Our aim in this work is the discovery of potent epidermal growth factor receptor (EGFR) inhibitors with anti-breast cancer activity containing 4-substituted quinazoline pharmacophore. Method: Novel series of 4-substituted 6,8-dibromo-2-(4-chlorophenyl)-quinazoline derivatives have been designed and synthesized. New derivatives were tested against MCF-7 (human breast carcinoma cell line) and screened for their inhibition activity against epidermal growth factor receptor tyrosine kinase (EGFR-TK). Result: Most of the tested compounds show potent antiproliferative activity and EGFR-TK inhibitory activity. Compounds VIIIc and VIIIb exerted powerful cytotoxic activity (IC50 3.1 and 6.3 μM) with potent inhibitory percent (91.1 and 88.4%) against EGFR-TK. Compounds IX, VIIa, X, VIIb, VIc, V, IV, VIa and VIb showed promising cytotoxic effects with IC50 range (12-79 μM) with good activity against EGFR-TK with the inhibitory percent (85.4-60.8%). On the other hand, compounds VIIc, VIIIa exerted low cytotoxic effects as revealed from their IC50 value (124 and 144 μM) with low activity against EGFR-TK with inhibitory percent 30.6 and 29.1% respectively.

http://ift.tt/2qZZ7ZC

The Immunomodulatory Potential of Selected Bioactive Plant-Based Compounds in Breast Cancer: A Review

Breast cancer has continued to cause high cancer death rates among women worldwide. The use of plants' natural products in breast cancer treatment has received more attention in recent years due to their potentially wider safety margin and the potential to complement conventional chemotherapeutic drugs. Plantbased products have demonstrated anticancer potential through different biological pathways including modulation of the immune system. Immunomodulatory properties of medicinal plants have been shown to mitigate breast cancer cell growth. Different immune cell types participate in this process especially cytotoxic T cells and natural killer cells, and cytokines including chemokines and tumor necrosis factor-α. Medicinal plants such as Glycyrrhiza glabra, Uncaria tomentosa, Camellia sinensis, Panax ginseng, Prunus armenaica (apricot), Allium sativum, Arctium lappa and Curcuma longa were reported to hold strong potential in breast cancer treatment in various parts of the world. Interestingly, research findings have shown that these plants possess bioactive immunomodulators as their main constituents producing the anticancer effects. These immunomodulatory compounds include ajoene, arctigenin, β-carotene, curcumin, epigallocatechin-3-gallate, ginsan, glabridin and quinic acid. In this review, we discussed the ability of these eight immunomodulators in regulating the immune system potentially applicable in breast cancer treatment via anti-inflammatory (curcumin, arctigenin, glabridin and ajoene) and lymphocytes activation (β-carotene, epigallocatechin-3-gallate, quinic acid and ginsan) properties, as well as future research direction in their use for breast cancer treatment.

http://ift.tt/2qZKpBW

Development on PEG-modified Poly (Amino Acid) Copolymeric Micelles for Delivery of Anticancer Drug

Background: Polymeric micelles can provide a valid way for cancer treatment with several benefits including high water-solubility of lipophilic drugs, low unwanted effects of cytotoxic drugs by way of reduced systemic exposure and prolonged retention time in the circulatory system. Objective: Recently, there is an increasing interest in preparing poly (ethylene glycol)-poly (amino acid) copolymeric micelles as drug delivery carriers due to their multifunctional property, easy decoration and biosafety. The copolymer contains several functional groups, which show stronger interactions with drugs or can be transferred to develop different types of the copolymers showing pH-, reduction-, thermo-sensitive, targeted or double-function properties. In addition, conjugation of drugs with these copolymers also becomes a novel modification method with the aim of higher drug loading capacity and stability. Copolymeric micelles show exciting advantages on improving a drug's water-solubility, release behavior, in vitro activity, targeted delivery pharmacokinetic property and biodistribution. In this review, we will introduce the recent development of poly(ethylene glycol)-modified poly (amino acid) copolymeric micelles as anticancer drug delivery systems containing different stimuli (such as thermo-, pH-, reduction- or special enzyme- condition) functional groups and targeting ligands to improve cellular uptake or biostablility of drug-loaded micelles. Conclusion: Poly (ethylene glycol)-poly (amino acid) copolymeric micelles provide an opportunity to realize anticancer drug delivery with environment-responsive and/or targeting property.

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Meet Our Editorial Board Member

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Natural Scaffolds for Regenerative Medicine: Direct Determination of Detergents Entrapped in Decellularized Heart Valves

The increasing urgency for replacement of pathological heart valves is a major stimulus for research on alternatives to glutaraldehyde-treated grafts. New xenogeneic acellular heart valve substitutes that can be repopulated by host cells are currently under investigation. Anionic surfactants, including bile acids, have been widely used to eliminate the resident cell components chiefly responsible for the immunogenicity of the tissue, even if detergent toxicity might present limitations to the survival and/or functional expression of the repopulating cells. To date, the determination of residual detergent has been carried out almost exclusively on the washings following cell removal procedures. Here, a novel HPLC-based procedure is proposed for the direct quantification of detergent (cholate, deoxycholate, and taurodeoxycholate) residues entrapped in the scaffold of decellularized porcine aortic and pulmonary valves. The method was demonstrated to be sensitive, reproducible, and extendable to different types of detergent. This assessment also revealed that cell-depleted heart valve scaffolds prepared according to procedures currently considered for clinical use might contain significant amount of surfactant.

http://ift.tt/2rv31xq

2-(ω-Carboxyethyl)pyrrole Antibody as a New Inhibitor of Tumor Angiogenesis and Growth

Background: Angiogenesis is a fundamental process in the progression, invasion, and metastasis of tumors. Therapeutic drugs such as bevacizumab and ranibuzumab have thus been developed to inhibit vascular endothelial growth factor (VEFG)-promoted angiogenesis. While these anti-angiogenic drugs have been commonly used in the treatment of cancer, patients often develop significant resistance that limits the efficacy of anti-VEGF therapies to a short period of time. This is in part due to the fact that an independent pathway of angiogenesis exists, which is mediated by 2-(ω-carboxyethyl)pyrrole (CEP) in a TLR2 receptor-dependent manner that can compensate for inhibition of the VEGF-mediated pathway. Aims: In this work, we evaluated a CEP antibody as a new tumor growth inhibitor that blocks CEP-induced angiogenesis. Method: We first evaluated the effectiveness of a CEP antibody as a monotherapy to impede tumor growth in two human tumor xenograft models. We then determined the synergistic effects of bevacizumab and CEP antibody in a combination therapy, which demonstrated that blocking of the CEP-mediated pathway significantly enhanced the anti-angiogenic efficacy of bevacizumab in tumor growth inhibition indicating that CEP antibody is a promising chemotherapeutic drug. To facilitate potential translational studies of CEP-antibody, we also conducted longitudinal imaging studies and identified that FMISO-PET is a non-invasive imaging tool that can be used to quantitatively monitor the anti-angiogenic effects of CEP-antibody in the clinical setting. Results: That treatment with CEP antibody induces hypoxia in tumor tissue WHICH was indicated by 43% higher uptake of [18F]FMISO in CEP antibody-treated tumor xenografs than in the control PBS-treated littermates.

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Dehydroleucodine Induces a TP73-dependent Transcriptional Regulation of Multiple Cell Death Target Genes in Human Glioblastoma Cells

Background: Dehydroleucodine, a natural sesquiterpene lactone from Artemisia douglassiana Besser (Argentine) and Gynoxys verrucosa (Ecuador). Objective: To define the molecular mechanisms underlying the effect of dehydroleucodine on the human glioblastoma cells. Method: Various techniques (cDNA expression array, real-time quantitative PCR, chromatin immunprecipitation, luciferase reporter assay, use of phosphospecific antibodies, immunoprecipitation, immunoblotting, apoptosis and autophagy assays) were employed to define and validate multiple molecular gene targets affected in human glioblastoma cells upon dehydroleucodine exposure. Results: Dehydroleucodine exposure upregulated the total and phosphorylated (p-Y99) levels of TP73 in U87- MG glioblastoma cells. We found that TP73 silencing led to a partial rescue of U87-MG cells from the cell death induced by dehydroleucodine. Upon the dehydroleucodine exposure numerous gene targets were upregulated and downregulated through a TP73-dependent transcriptional mechanism. Some of these gene targets are known to be involved in cell cycle arrest, apoptosis, autophagy and necroptosis. Dehydroleucodine induced the TP73 binding to the specific genes promoters (CDKN1A, BAX, TP53AIP1, CYLD, RIPK1, and APG5L). Moreover, the exposure of U87-MG cells to dehydroleucodine upregulated the protein levels of CDKN1A, BAX, TP53AIP1, CYLD, RIPK1, APG5L, and downregulated the CASP8 level. The formation of RIPK1 protein complexes and phosphorylation of MLKL were induced by dehydroleucodine supporting the notion of multiple cell death mechanisms implicated in the tumor cell response to dehydroleucodine. Conclusion: This multifaceted study led to a conclusion that dehydroleucodine induces the phosphorylation of tumor protein TP73 and in turn activates numerous TP73-target genes regulating apoptosis, autophagy and necroptosis in human glioblastoma cells..

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Curcumin Targets Circulating Cancer Stem Cells by Inhibiting Self-Renewal Efficacy in Non-Small Cell Lung Carcinoma

Background: The ultimate goal of the study was to find a role of curcumin in targeting lung cancer stem cells by reducing their self-renewal efficiency causing DNA damage. Materials and Methods: Circulating lung cancer stem cells were isolated by sphere formation assay and further analysed by flow-cytometry and qRT-PCR for the presence of stem cell and stem cell transcription markers. The IC50 values of gemcitabine and curcumin were analysed by MTT assay, while curcumin induced DNA damage was scrutinized by single cell gel electrophoresis assay. Results and Conclusion: Our results demonstrated that curcumin significantly affect the self-renewal ability of circulating lung cancer stem cells. The no. of spheres formed in the presence of curcumin was shown to be significantly decreased. Additionally, our results depicted that 4.52±0.72 % and 95.47±0.72 % (p

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Synthesis and Anti-cancer Activity of 3-substituted Benzoyl-4-substituted Phenyl-1H-pyrrole Derivatives

Background: Cancer is considered a major public health problem worldwide. Objective: The aim of this paper is to design and synthesis of novel anticancer agents with potent anticancer activity and minimum side effects. Method: A series of pyrrole derivatives were synthesized, their anti-cancer activity against nine cancer cell lines and two non-cancer cell lines were evaluated by MTT assay, and their cell cycle progression were determined by flow cytometry analysis. Results: The study of the structure-activity relationships revealed that the introduction of the electron-donation groups at the 4th position of the pyrrole ring increased the anti-cancer activity. Among the synthesized compounds, specially the compounds bearing 3,4-dimethoxy phenyl at the 4th position of the pyrrole ring showed potent anti-cancer activity, cpd 19 was the most potent against MGC 80-3, HCT-116 and CHO cell lines (IC50s = 1.0－1.7 μM), cpd 21 was the most potent against HepG2, DU145 and CT-26 cell lines (IC50s = 0.5－0.9 μM), and cpd 15 was the most potent against A549 (IC50 = 3.6 μM). Moreover, these potent compounds showed weak cytotoxicity against HUVEC and NIH/3T3. Thus, the cpds 15, 19 and 21 show potential anti-cancer for further investigation. Furthermore, the flow cytometry analysis revealed that cpd 21 arrested the CT-26 cells at S phase, and induced the cell apoptosis. Conclusion: Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.

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ATRA Entrapped in DSPC Liposome Enhances Anti-metastasis Effect on Lung and Liver During B16F10 Cell Line Metastasis in C57BL6 Mice

Background: The high mortality rate of lung cancer is highly associated with faster metastasis spread. All Trans Retinoic Acid (ATRA), being the first choice drug for leukemia therapy is now under intense study for its therapeutic efficiency in other solid cancers. Objectives: This study was aimed to investigate the anti-metastasis activity of free ATRA and liposome entrapped ATRA (5:4:1) in the experimental C57BL/6 mice model developed by the injection of B16F10 cell line into the tail vein. Method: The ATRA drug was given via i.p for 21 days. The visual lung and liver metastatic tumor nodules were noted. Various biochemical markers of cancer metastasis in the serum as well as tissues were also analyzed after sacrifice. Results: Tumor nodules have significantly decreased in ATRA treatment groups (32.83 ± 1.83 for free ATRA, 23 ± 2.36 for DSPC Lipo-ATRA) when compared with metastasis control (63.16 ± 2.9) in the lungs. Among the treatment groups, the DSPC lipo-ATRA treated group showed a significant tumor growth inhibition (63.6%) than that of in the free ATRA treated groups (48%). Similar anti-metastatic effect was observed in liver also. Furthermore lipo-ATRA has shown a significant change in the levels of biochemical cancer markers analyzed in this study. Conclusion: Our results concluded that the liposome encapsulated ATRA has an enhanced anti-metastasis potency than the free ATRA during B16F10 metastatic cell line implantation.

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Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy. Cancer Res; 77(12); 1–4. ©2017 AACR.

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TLR-3/9 Agonists Synergize with Anti-ErbB2 mAb—Letter

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Level of cystatin C in functional thyroid disorders and its relation to GFR

Abstract

Thyroid hormones affect the development and physiology of the kidneys. Hypothyroidism and hyperthyroidism affect glomerular filtration rate (GFR), tubular function, renal blood flow, and structure of the kidney. Cystatin C is a non-glycosylated neuroendocrine protein. It is freely filtered at the glomerulus and completely reabsorbed and catabolized by cells of tubules. Cystatin C levels, affected by the thyroid state, is being increased in hyperthyroidism and decreased in hypothyroidism. The current study was conducted on 66 patients of thyroid disorder and 21 healthy control subjects. Total T3, total T4, and TSH were measured by cobas e 411. Human Cystatin C was measured using ELISA kit based on sandwich enzyme-linked immunosorbent assay. Cystatin C was significantly increased in both total hyperthyroid and clinical hyperthyroid groups as compared to control (p < 0.001). eGFR_{Cys C} and eGFR_{Cr-Cys C} were significantly decreased in hyperthyroid and clinical hyperthyroid (p < 0.001). Cystatin C was significantly reduced in hypothyroid group and subgroups comparing to control group (p < 0.001, p < 0.001, and p = 0.004, respectively). As regard to eGFR_{Cys C}, it was significantly an overestimate clearance in hypothyroid group and subgroups when compared to normal subjects (p < 0.001, p < 0.001, and p = 0.002, respectively). Thyroid dysfunction affects cystatin C level as well as cystatin-based eGFR so it is not suitable in thyroid dysfunction specially in clinical dysfunction.

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Human Subjects Protection and Cancer Surveillance Research: Revised Regulations, Expanded Opportunities

On January 19, 2017, the United States federal government issued revisions to the Common Rule under which scientists who receive federal funding conduct research involving human subjects. The revised Common Rule expressly addresses public health surveillance in relation to scientific research and the protection of human subjects, and its impacts are anticipated to contribute to the efficiency of activities, including cancer registration and surveillance, and research that uses cancer registry data. Cancer Res; 77(12); 1–4. ©2017 AACR.

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FOXM1 in Cancer: Interactions and Vulnerabilities

FOXM1 is a transcription factor of the Forkhead family that is required for cell proliferation of normal cells. However, FOXM1 is repeatedly overexpressed in a variety of human cancers, and it has been implicated in all major hallmarks of cancer delineated by Hanahan and Weinberg. It has been postulated that the oncogenic potential of FOXM1 is determined by its capacity to transactivate target genes that are implicated in different phases of cancer development. However, FOXM1 may also play an oncogenic role by interacting with other proteins, such as β-catenin or SMAD3 to induce oncogenic WNT and TGFβ signaling pathways, respectively. In this review, I will discuss the protein–protein interactions of FOXM1 that are critical for cancer development and may represent novel targets for anticancer drugs. Cancer Res; 77(12); 1–5. ©2017 AACR.

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Initial treatment of cancer patients with fluconazole susceptible dose-dependent Candida glabrata fungemia: Better outcome with an echinocandin or polyene compared to an azole? [PublishAheadOfPrint]

28-day crude mortality in 68 cancer patients with fluconazole susceptible dose-dependent Candida glabrata fungemia started on treatment (within 48 hours after blood culture collection) with an echinocandin or liposomal amphotericin-B was better (30%), compared to those treated with azole monotherapy (52%, p=0.07). After adjusting for confounders, azole monotherapy was associated with worse 28-day survival (hazard ratio 3.8, p=0.003).

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Micafungin plasma levels are not affected by continuous renal replacement therapy - experience in critically ill patients [PublishAheadOfPrint]

Background: Critically ill patients often experience acute kidney injury and the need for renal replacement therapy in the course of their treatment on an ICU. These patients are at an increased risk for candidiasis. Although there have been several reports of micafungin disposition during renal replacement therapy, there are up to this date no data describing the elimination of micafungin during high dose continuous venovenous haemodiafiltration with modified AN69 membranes. The aim of this prospective open label pharmacokinetic study was to assess whether Micafungin plasma levels are affected by continuous haemodiafiltration in critical ill patients using the commonly employed AN69 membrane.

Methods: a total of 10 critically ill patients with micafungin treatment due to suspected or proven candidaemia were included in this trial.

Results: Pre-filter/post-filter micafungin clearance was measured to be 46.0 ml/min (±21.7 ml/min, n=75 individual timepoints), while haemofilter clearance calculated by sieving coefficient was 0.0038 ml/min (±0.002 ml/min, n=75 individual timepoints). Total body clearance was measured to be 14.0 ml/min (±7.0, n=12). The population AUC_0-24h was calculated as 158.5 mg.h/L (±79.5 mg.h/L, n=13).

Conclusion: In spite of high protein binding, no dose modification is necessary in patients receiving continuous venovenous haemodiafiltration with AN69 membranes. A dose elevation may however be justified in certain cases.

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In vitro Antibiofilm Activity of Eucarobustol E against Candida albicans [PublishAheadOfPrint]

Formyl-phloroglucinol meroterpenoids (FPMs) are an important type of natural products with various bioactivities. Our antifungal susceptibility assay showed that one of the Eucalyptus robusta derived FPMs-Eucarobustol E (EE) exerted strong inhibitory effect against Candida albicans biofilms at a concentration of 16 μg/ml. EE was found to block the yeast-to-hypha transition and reduce the cellular surface hydrophobicity of the biofilm cells. RNA sequencing and real time reverse-transcription PCR analysis showed that exposure to 16 μg/ml of EE resulted in marked reduction of expressions of genes involved in hyphal growth (EFG1, CPH1, TEC1, EED1, UME6, and HGC1) and cell surface proteins (ALS3, HWP1, and SAP5). Interestingly, in response to EE, genes involved in ergosterol biosynthesis were down-regulated while farnesol encoding gene (DPP3) was up-regulated, which were in agreement with the quantification of ergosterol and farnesol. Combining with the obvious elevation of negative regulator genes (TUP1, NRG1), we speculated that EE's inhibitions on carbon flow to ergosterol triggered the negative regulation mechanisms of hyphal growth, and eventually led to biofilm inhibition.

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Multi-mechanistic monoclonal antibodies targeting S. aureus {alpha}-toxin and clumping factor A: Activity and efficacy comparisons of a mAb combination and an engineered bispecific antibody approach [PublishAheadOfPrint]

Secreted α-toxin (AT) and surface-localized clumping factor A (ClfA) are key virulence determinants in S. aureus bloodstream infections. We previously demonstrated that prophylaxis with a multi-mechanistic monoclonal antibody (mAb) combination against AT (MEDI4893*) and ClfA (11H10) provided greater strain coverage and improved efficacy in a S. aureus lethal bacteremia model. Subsequently, 11H10 was found to exhibit reduced affinity and impaired inhibition of fibrinogen binding to ClfA002 expressed by members of a predominant hospital associated MRSA clone, ST5. Consequently, we identified another anti-ClfA mAb (SAR114) from human tonsillar B-cells with >100-fold increased affinity for three prominent ClfA variants, including ClfA002, and potent inhibition of bacterial agglutination by 112 diverse clinical isolates. We next constructed bispecific (BiS) Abs comprised of 11H10 or SAR114 as IgG scaffold and grafted anti-AT (MEDI4893*) scFv to the amino or carboxy-terminus of the anti-ClfA heavy chains. Although the BiSAbs exhibited in vitro potencies similar to the parental mAbs, only 11H10-BiSAb, but not SAR114-BiSAb showed protective activity in murine infection models comparable to the respective mAb combination. In vivo activity with SAR114-BiSAb was observed in infection models with S. aureus lacking ClfA. Our data suggest that high affinity binding to ClfA sequesters the SAR114-BiSAb to the bacterial surface, thereby reducing both AT neutralization and protection in vivo. These results indicate that a mAb combination targeting ClfA and AT is more promising for future development than the corresponding BiSAb.

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Genomic Analysis of Multidrug-Resistant Escherichia coli from North Carolina Community Hospitals: Ongoing Circulation of CTX-M-Producing ST131-H30Rx and ST131-H30R1 Strains [PublishAheadOfPrint]

Escherichia coli sequence type 131 (ST131) predominates globally among multidrug-resistant (MDR) E. coli. We used whole-genome sequencing (WGS) to investigate 63 MDR E. coli isolates from 7 North Carolina community hospitals (2010-2015). Of these, 39 (62%) represented ST131, including 37 (95%) from the ST131-H30R subclone: 10 (27%) from its H30R1 subset, and 27 (69%) from its H30Rx subset. ST131 core genomes differed by a median of 15 single-nucleotide variants (SNVs) overall (range, 0-490), vs. only 7 within H30R1 (range, 3-12 SNVs) and 11 within H30Rx (range, 0-21). The four isolates with identical core genomes all were H30Rx. Epidemiological and clinical characteristics did not vary significantly by strain type, but many patients with MDR E. coli or H30Rx infection were critically ill and had poor outcomes. H30Rx isolates characteristically exhibited fluoroquinolone resistance and CTX-M-15 production, had a high prevalence of trimethoprim-sulfamethoxazole resistance (89%), sul1 (89%), and dfrA17 (85%), were enriched for specific virulence traits, and all qualified as extraintestinal pathogenic E. coli. The high overall prevalence of CTX-M-15 appeared possibly attributable to its association with the ST131-H30Rx subclone and IncF[F2:A1:B-] plasmids. Some phylogenetically clustered non-ST131 MDR E. coli isolates also had distinctive serotypes/fimH types, fluoroquinolone mutations, CTX-M variants, and IncF types. Thus, WGS analysis of our community hospital-source MDR E. coli isolates suggested ongoing circulation and differentiation of E. coli ST131 subclones, with clonal segregation of CTX-M variants, other resistance genes, Inc-type plasmids, and virulence genes.

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Identification of novel efflux proteins Rv0191, Rv3756c, Rv3008 and Rv1667c involved in pyrazinamide resistance in Mycobacterium tuberculosis [PublishAheadOfPrint]

Pyrazinamide (PZA) is a critical drug used for the treatment of tuberculosis (TB). PZA is a prodrug that requires conversion to the active component pyrazinoic acid (POA) by pyrazinamidase (PZase) encoded by the pncA gene. Although resistance to PZA is mostly caused by pncA mutations and less commonly by rpsA, panD, and clpC1, clinical strains without these mutations are known to exist. While efflux of POA was demonstrated in Mycobacterium tuberculosis previously, the efflux proteins involved have not been identified. Here we performed POA binding studies with M. tuberculosis proteome microarray and identified four efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c that bind POA. Overexpression of the four efflux pump genes in M. tuberculosis caused low level resistance to PZA and POA but not other drugs. Furthermore, addition of efflux pump inhibitors such as reserpine, piperine and verapamil caused increased susceptibility to PZA in M. tuberculosis strains overexpressing the efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c. Our studies indicate that these four efflux proteins may be responsible for PZA/POA efflux and cause PZA resistance in M. tuberculosis. Future studies are needed to assess their roles in PZA resistance in clinical strains.

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Rapid identification of different Escherichia coli ST131 clades [PublishAheadOfPrint]

Escherichia coli sequence type 131 (ST131) is a pandemic clonal lineage that is responsible for the global increase in fluoroquinolone-resistance and extended-spectrum β-lactamase (ESBL)-producers. The ST131 clade C, especially subclades C2 and C1-M27, are associated with ESBLs. We developed a multiplex conventional PCR assay with the ability to detect all ST131 clades (A, B, and C) as well as C subclades (C1-M27, C1-nM27 [C1-non-M27], and C2). To validate the assay, we used 80 ST131 global isolates that had been fully sequenced. We then used the assay to define the prevalence of each clade in 2 Japanese collections consisting of 460 ESBL-producing E. coli ST131 (2001-12) and 329 E. coli from extra-intestinal sites [ExPEC] (2014). The assay correctly identified the different clades in all 80 global isolates: clades A (n=12), B (n=12), and C, including subclades C1-M27 (n=16), C1-nM27 (n=20), C2 (n=17) and other C (n=3). The assay also detected all 565 ST131 isolates in both collections without any false positives. Isolates from clades A (n=54), B (n=23), and C (n=483) corresponded to the O serotypes and the fimH types of O16-H41, O25b-H22, and O25b-H30, respectively. Of the 483 clade C isolates, C1-M27 was the most common subclade (36%), followed by C1-nM27 (32%) and C2 (15%). The C1-M27 subclade with bla_CTX-M-27 became especially prominent after 2009. Our novel multiplex PCR assay revealed the predominance of the C1-M27 subclade in recent Japanese ESBL-producing E. coli and is a promising tool for epidemiological studies of ST131.

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