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Shiv Nadar University

(SoNS) School of Natural Sciences

Purpose: Mutations in receptor tyrosine kinase (RTK) genes can confer resistance to receptor-targeted therapies. A T798M mutation in the HER2 oncogene has been shown to confer resistance to the tyrosine kinase inhibitor (TKI) lapatinib. We studied the mechanisms of HER2-T798M-induced resistance to identify potential strategies to overcome that resistance. Experimental Design: HER2-T798M was stably expressed in BT474 and MCF10A cells. Mutant cells and xenografts were evaluated for effects of the mutation on proliferation, signaling, and tumor growth after treatment with combinations of inhibitors targeting the EGFR/HER2/HER3/PI3K axis. Results: A low3%allelic frequency of the T798M mutant shifted 10-fold the IC50 of lapatinib. In mutantexpressing cells, lapatinib did not block basal phosphorylation of HER2, HER3, AKT, and ERK1/2. In vitro kinase assays showed increased autocatalytic activity of HER2-T798M. HER3 association with PI3K p85 was increased in mutant-expressing cells. BT474-T798M cells were also resistant to the HER2 antibody trastuzumab. These cells were sensitive to the pan-PI3K inhibitors BKM120 and XL147 and the irreversible HER2/EGFR TKI afatinib but not the MEK1/2 inhibitor CI-1040, suggesting continued dependence of the mutant cells on ErbB receptors and downstream PI3K signaling. BT474-T798M cells showed increased expression of the EGFR ligands EGF, TGFa, amphiregulin, and HB-EGF. Addition of the EGFR neutralizing antibody cetuximab or lapatinib restored trastuzumab sensitivity of BT474-T798M cells and xenografts, suggesting that increased EGFR ligand production was causally associated with drug resistance. Conclusions: Simultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene-amplified breast cancer cells harboring T798M mutant alleles. © 2013 American Association for Cancer Research.

World University root node

Life Sciences

Fulltext

Clinical Cancer Research

Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2

Riboflavin tetraacetate-catalyzed aerobic photooxidation of 1-(4-methoxyphenyl)ethanol was investigated as a model reaction under blue visible light in different soft gel materials, aiming to establish their potential as reaction vessels for photochemical transformations. Three strategies involving different degrees of organization of the catalyst within the gel network were explored, and the results compared to those obtained in homogeneous and micellar solutions. In general, physical entrapment of both the catalyst and the substrate under optimized concentrations into several hydrogel matrices (including low-molecular-weight and biopolymer-based gels) allowed the photooxidation with conversions between 55 and 100% within 120 min (TOF ∼ 0.045-0.08 min-1; kobs ∼ 0.011-0.028 min -1), albeit with first-order rates ca. 1-3-fold lower than in solution under comparable non-stirred conditions. Remarkably, the organogel made of a cyclohexane-based bisamide gelator in CH3CN not only prevented the photodegradation of the catalyst but also afforded full conversion in less than 60 min (TOF ∼ 0.167 min-1; kobs ∼ 0.073 min-1) without the need of additional proton transfer mediators (e.g., thiourea) as it occurs in CH3CN solutions. In general, the gelators could be recycled without detriment to their gelation ability and reaction rates. Moreover, kinetics could be fine-tuned according to the characteristics of the gel media. For instance, entangled fibrillar networks with relatively high mechanical strength were usually associated with lower reaction rates, whereas wrinkled laminated morphologies seemed to favor the reaction. In addition, the kinetics results showed in most cases a good correlation with the aeration efficiency of the gel media. © The Royal Society of Chemistry.

Chemistry

Journal of Materials Chemistry A

Organophotocatalysis in nanostructured soft gel materials as tunable reaction vessels: Comparison with homogeneous and micellar solutions

This chapter contains sections titled: Introduction Ta Substitution in TiO2: Doping or Alloying? Diluted Magnetic Semiconductors (DMS) Defect-Mediated Ferromagnetism Magnetic Impurity Analysis in Ti1-xTaxO2 System Defect-Induced Ferromagnetism in Ti1-xTaxO2 Film First-Principles Spin-Polarized GGA + U Calculations Mechanism of Defect-Mediated FM Optimization of Ferromagnetism Outlook for Defect-Mediated Properties of Ti1-xTaxO2 References © 2013 Wiley-VCH Verlag GmbH & Co. KGaA.

Physics

Functional Metal Oxides: New Science and Novel Applications

Effect of ta alloying on the optical, electronic, and magnetic properties of tio2 thin films

In the present study, we have demonstrated the diversity oriented synthesis of nitrogen heterocycles viz. chiral piperidinones, quinolizidinones and diaryl pyrrolidinones from Michael adducts generated via a TiCl4-catalyzed highly stereoselective Michael reaction with nitrostyrenes and an Evans chiral auxiliary. We also reported a Cu-4,4'-(isopropyl)-substituted isopropylidene-bridged 2,2'-bis-1,3'-oxazoline catalyst mediated catalytic asymmetric version of this reaction. In silico analysis is utilized to evaluate the diversity of the set of compounds against shape space (PMI), polar surface area (PSA) calculations and relevant drug like properties (viz. HBA, HBD, PSA, mol. wt., log P and log D). Finally, the molecules were screened against microorganisms to assess their antimicrobial properties. © 2013 The Royal Society of Chemistry.

RSC Advances

A reagent based DOS strategy via Evans chiral auxiliary: Highly stereoselective Michael reaction towards optically active quinolizidinones, piperidinones and pyrrolidinones

An elegant reagent-controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In silico studies were used to estimate the drug-like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemistry - An Asian Journal

Synthesis of privileged scaffolds by using diversity-oriented synthesis

The study of interfacial properties, especially of their change upon lithiation, is a fundamentally significant and challenging topic in designing heterogeneous nanostructured electrodes for lithium ion batteries. This issue becomes more intriguing for Si electrodes, whose ultrahigh capacity is accompanied by large volume expansion and mechanical stress, threatening with delamination of silicon from the metal current collector and failure of the electrode. Instead of inferring interfacial properties from experiments, in this work, we have combined density functional theory (DFT) and ab initio molecular dynamics (AIMD) calculations with time-of-flight secondary ion mass spectrometry (TOF-SIMS) measurements of the lithium depth profile, to study the effect of lithiation on the a-Si/Cu interface. Our results clearly demonstrate Li segregation at the lithiated a-Si/Cu interface (more than 20\% compared to the bulk concentration). The segregation of Li is responsible for a small decrease (up to 16\%) of the adhesion strength and a dramatic reduction (by one order of magnitude) of the sliding resistance of the fully lithiated a-Si/Cu interface. Our results suggest that this almost frictionless sliding stems from the change of the bonding nature at the interface with increasing lithium content, from directional covalent bonding to uniform metallic. These findings are an essential first step toward an in-depth understanding of the role of lithiation on the a-Si/Cu interface, which may contribute in the development of quantitative electrochemical mechanical models and the design of nonfracture-and-always-connected heterogeneous nanostructured Si electrodes. © 2013 American Chemical Society.

Nano Letters

Li segregation induces structure and strength changes at the amorphous Si/Cu interface

In this paper I discuss some consequences and manifestations of a mereology of structured wholes in chemistry, with particular reference to the concept of atoms in molecules. © 2012 Springer Science+Business Media Dordrecht.

Foundations of Chemistry

The atom in a molecule as a mereological construct in chemistry

Primary electron energy (Ep) dependent change in target current was studied on a grounded Au film in the range of 40 to 3500 eV. The current jumped suddenly from a negative to a positive value at ∼650 eV with increasing Ep, while it disappeared in reverse sweep and with increasing substrate temperature. Detailed analysis suggests that Ep dependent surface charging plays a pivotal role in flashover. Prior to critical Ep in the forward sweep, a gradual shift of a double peak-like structure towards high kinetic energy region in the secondary electron spectra also confirms surface charging effect. © 2013 AIP Publishing LLC.

Journal of Applied Physics

Primary electron energy dependent flashover in surface polarity on Au films

The search for oxide-based room-temperature ferromagnetism has been one of the holy grails in condensed matter physics. Room-temperature ferromagnetism observed in Nb-doped SrTiO3 single crystals is reported in this Rapid Communication. The ferromagnetism can be eliminated by air annealing (making the samples predominantly diamagnetic) and can be recovered by subsequent vacuum annealing. The temperature dependence of magnetic moment resembles the temperature dependence of carrier density, indicating that the magnetism is closely related to the free carriers. Our results suggest that the ferromagnetism is induced by oxygen vacancies. In addition, hysteretic magnetoresistance was observed for magnetic field parallel to the current, indicating that the magnetic moments are in the plane of the samples. The x-ray photoemission spectroscopy, the static time-of-flight and the dynamic secondary ion mass spectroscopy and proton induced x-ray emission measurements were performed to examine the magnetic impurities, showing that the observed ferromagnetism is unlikely due to any magnetic contaminant. © 2013 American Physical Society.

Physical Review B - Condensed Matter and Materials Physics

Reversible room-temperature ferromagnetism in Nb-doped SrTiO3 single crystals

The observation of a high-mobility two-dimensional electron gas between two insulating complex oxides, especially LaAlO3 /SrTiO3, has enhanced the potential of oxides for electronics. The occurrence of this conductivity is believed to be driven by polarization discontinuity, leading to an electronic reconstruction. In this scenario, the crystal orientation has an important role and no conductivity would be expected, for example, for the interface between LaAlO3 and (110)-oriented SrTiO3, which should not have a polarization discontinuity. Here we report the observation of unexpected conductivity at the LaAlO3 /SrTiO3 interface prepared on (110)-oriented SrTiO3, with a LaAlO3 -layer thickness-dependent metal-insulator transition. Density functional theory calculation reveals that electronic reconstruction, and thus conductivity, is still possible at this (110) interface by considering the energetically favourable (110) interface structure, that is, buckled TiO 2 /LaO, in which the polarization discontinuity is still present. The conductivity was further found to be strongly anisotropic along the different crystallographic directions with potential for anisotropic superconductivity and magnetism, leading to possible new physics and applications. © 2013 Macmillan Publishers Limited. All rights reserved.