129 research outputs found
Afatinib efficacy against squamous cell carcinoma of the head and neck cell lines in vitro and in vivo.
Epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in squamous cell carcinoma of the head and neck (SCCHN). In addition to EGFR, other ErbB family members are expressed and activated in SCCHN. Afatinib is an ErbB family blocker that has been approved for treating patients with EGFR-mutated nonsmall cell lung cancer. We sought to determine the efficacy of afatinib in preclinical models and compare this to other EGFR-targeted agents. Afatinib efficacy was characterized in a panel of ten SCCHN cell lines and found to be most effective against cell lines amplified for EGFR. Afatinib had lower IC(50) values than did gefitinib against the same panel. Two EGFR-amplified cell lines that are resistant to gefitinib are sensitive to afatinib. Cetuximab was not found to have a synergistic effect with afatinib either in vitro or in vivo. Both afatinib and cetuximab were effective in tumor xenograft model. Afatinib is an effective agent in SCCHN especially in models with EGFR amplification
Probing the dynamics of quasicrystal growth using synchrotron live imaging
The dynamics of quasicrystal growth remains an unsolved problem in condensed
matter. By means of synchrotron live imaging, facetted growth proceeding by the
tangential motion of ledges at the solid-melt interface is clearly evidenced
all along the solidification of icosahedral AlPdMn quasicrystals. The effect of
interface kinetics is significant so that nucleation and free growth of new
facetted grains occur in the melt when the solidification rate is increased.
The evolution of these grains is explained in details, which reveals the
crucial role of aluminum rejection, both in the poisoning of grain growth and
driving fluid flow
Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival
Breast cancer is a heterogeneous disease with known expression-defined tumor subtypes. DNA copy number studies have suggested that tumors within gene expression subtypes share similar DNA Copy number aberrations (CNA) and that CNA can be used to further sub-divide expression classes. To gain further insights into the etiologies of the intrinsic subtypes, we classified tumors according to gene expression subtype and next identified subtype-associated CNA using a novel method called SWITCHdna, using a training set of 180 tumors and a validation set of 359 tumors. Fisher’s exact tests, Chi-square approximations, and Wilcoxon rank-sum tests were performed to evaluate differences in CNA by subtype. To assess the functional significance of loss of a specific chromosomal region, individual genes were knocked down by shRNA and drug sensitivity, and DNA repair foci assays performed. Most tumor subtypes exhibited specific CNA. The Basal-like subtype was the most distinct with common losses of the regions containing RB1, BRCA1, INPP4B, and the greatest overall genomic instability. One Basal-like subtype-associated CNA was loss of 5q11–35, which contains at least three genes important for BRCA1-dependent DNA repair (RAD17, RAD50, and RAP80); these genes were predominantly lost as a pair, or all three simultaneously. Loss of two or three of these genes was associated with significantly increased genomic instability and poor patient survival. RNAi knockdown of RAD17, or RAD17/RAD50, in immortalized human mammary epithelial cell lines caused increased sensitivity to a PARP inhibitor and carboplatin, and inhibited BRCA1 foci formation in response to DNA damage. These data suggest a possible genetic cause for genomic instability in Basal-like breast cancers and a biological rationale for the use of DNA repair inhibitor related therapeutics in this breast cancer subtype.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-011-1846-y) contains supplementary material, which is available to authorized users
Resonant magnetic exciton mode in the heavy-fermion antiferromagnet CeB6
Resonant magnetic excitations are widely recognized as hallmarks of
unconventional superconductivity in copper oxides, iron pnictides, and
heavy-fermion compounds. Numerous model calculations have related these modes
to the microscopic properties of the pair wave function, but the mechanisms
underlying their formation are still debated. Here we report the discovery of a
similar resonant mode in the non-superconducting, antiferromagnetically ordered
heavy-fermion metal CeB6. Unlike conventional magnons, the mode is
non-dispersive, and its intensity is sharply concentrated around a wave vector
separate from those characterizing the antiferromagnetic order. The magnetic
intensity distribution rather suggests that the mode is associated with a
coexisting order parameter of the unusual antiferro-quadrupolar phase of CeB6,
which has long remained "hidden" to the neutron-scattering probes. The mode
energy increases continuously below the onset temperature for
antiferromagnetism, in parallel to the opening of a nearly isotropic spin gap
throughout the Brillouin zone. These attributes bear strong similarity to those
of the resonant modes observed in unconventional superconductors below their
critical temperatures. This unexpected commonality between the two disparate
ground states indicates the dominance of itinerant spin dynamics in the ordered
low-temperature phases of CeB6 and throws new light on the interplay between
antiferromagnetism, superconductivity, and "hidden" order parameters in
correlated-electron materials
BRCA1: A Novel Prognostic Factor in Resected Non-Small-Cell Lung Cancer
BACKGROUND: Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). METHODOLOGY AND PRINCIPAL FINDINGS: We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). CONCLUSIONS: Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated
Surface structure of Al-Pd-Mn quasicrystals: Existence of supersaturated bulk vacancy concentrations
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