Grainyhead-like 2 (GRHL2) knockout abolishes oral cancer development through reciprocal regulation of the MAP kinase and TGF-β signaling pathways

Grainyhead-Like 2 (GRHL2) is an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Prior studies suggested inverse regulation between GRHL2 and TGF-β in epithelial plasticity and potential carcinogenesis. Here, we report the role of GRHL2 in oral carcinogenesis in vivo using a novel Grhl2 knockout (KO) mouse model and the underlying mechanism involving its functional interaction with TGF-β signaling. We developed epithelial-specific Grhl2 conditional KO mice by crossing Grhl2 floxed mice with those expressing CreER driven by the K14 promoter. After induction of Grhl2 KO, we confirmed the loss of GRHL2 and its target proteins, while Grhl2 KO strongly induced TGF-β signaling molecules. When exposed to 4-nitroquinoline 1-oxide (4-NQO), a strong chemical carcinogen, Grhl2 wild-type (WT) mice developed rampant oral tongue tumors, while Grhl2 KO mice completely abolished tumor development. In cultured oral squamous cell carcinoma (OSCC) cell lines, TGF-β signaling was notably induced by GRHL2 knockdown while being suppressed by GRHL2 overexpression. GRHL2 knockdown or KO in vitro and in vivo, respectively, led to loss of active p-Erk1/2 and p-JNK MAP kinase levels; moreover, ectopic overexpression of GRHL2 strongly induced the MAP kinase activation. Furthermore, the suppressive effect of GRHL2 on TGF-β signaling was diminished in cells exposed to Erk and JNK inhibitors. These data indicate that GRHL2 activates the Erk and JNK MAP kinases, which in turn suppresses the TGF -β signaling. This novel signaling represents an alternative pathway by which GRHL2 regulates carcinogenesis, and is distinct from the direct transcriptional regulation by GRHL2 binding at its target gene promoters, e.g., E-cadherin, hTERT, p63, and miR-200 family genes. Taken together, the current study provides the first genetic evidence to support the role of GRHL2 in carcinogenesis and the underlying novel mechanism that involves the functional interaction between GRHL2 and TGF-β signaling through the MAPK pathways

Geometrical barriers and lower critical field in MgB2 single crystals

International audienceThe first penetration field sHpd has been deduced from local magnetization and specific heat measurements in magnesium diboride single crystals. For Ha ic, the geometrical barriers (GB) play a dominant role in the irreversibility mechanism. In thin samples, neglecting the GB in this direction would then lead to a large overestimation of Hc1 deduced from Hp through the standard elliptical formula. The lower critical field is found to be isotropic at low temperature (0.11±0.01 T)

Human papillomavirus 16 E6 induces FoxM1B in oral keratinocytes through GRHL2

High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPVoral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development

2008-2009 President\u27s Report

The Linfield College President\u27s Annual Report is a collection of information about the year in review, including academics, student life and athletics, enrollment, finances, philanthropy, and leadership

Could a Shigella vaccine impact long-term health outcomes?: Summary report of an expert meeting to inform a Shigella vaccine public health value proposition, March 24 and 29, 2021.

Shigellosis is a leading cause of diarrhea and dysentery in young children from low to middle-income countries and adults experiencing traveler's diarrhea worldwide. In addition to acute illness, infection by Shigella bacteria is associated with stunted growth among children, which has been linked to detrimental long-term health, developmental, and economic outcomes. On March 24 and 29, 2021, PATH convened an expert panel to discuss the potential impact of Shigella vaccines on these long-term outcomes. Based on current empirical evidence, this discussion focused on whether Shigella vaccines could potentially alleviate the long-term burden associated with Shigella infections. Also, the experts provided recommendations about how to best model the burden, health and vaccine impact, and economic consequences of Shigella infections. This international multidisciplinary panel included 13 scientists, physicians, and economists from multiple relevant specialties. According to the panel, while the relationship between Shigella infections and childhood growth deficits is complex, this relationship likely exists. Vaccine probe studies are the crucial next step to determine whether vaccination could ameliorate Shigella infection-related long-term impacts. Infants should be vaccinated during their first year of life to maximize their protection from severe acute health outcomes and ideally reduce stunting risk and subsequent negative long-term developmental and health impacts. With vaccine schedule crowding, targeted or combination vaccination approaches would likely increase vaccine uptake in high-burden areas. Shigella impact and economic assessment models should include a wider range of linear growth outcomes. Also, these models should produce a spectrum of results-ones addressing immediate benefits for usual health care decision-makers and others that include broader health impacts, providing a more comprehensive picture of vaccination benefits. While many of the underlying mechanisms of this relationship need better characterization, the remaining gaps can be best addressed by collecting data post-vaccine introduction or through large trials

Intelligent tracking control of a DC motor driver using self-organizing TSK type fuzzy neural networks

[[abstract]]In this paper, a self-organizing Takagi–Sugeno–Kang (TSK) type fuzzy neural network (STFNN) is proposed. The self-organizing approach demonstrates the property of automatically generating and pruning the fuzzy rules of STFNN without the preliminary knowledge. The learning algorithms not only extract the fuzzy rule of STFNN but also adjust the parameters of STFNN. Then, an adaptive self-organizing TSK-type fuzzy network controller (ASTFNC) system which is composed of a neural controller and a robust compensator is proposed. The neural controller uses an STFNN to approximate an ideal controller, and the robust compensator is designed to eliminate the approximation error in the Lyapunov stability sense without occurring chattering phenomena. Moreover, a proportional-integral (PI) type parameter tuning mechanism is derived to speed up the convergence rates of the tracking error. Finally, the proposed ASTFNC system is applied to a DC motor driver on a field-programmable gate array chip for low-cost and high-performance industrial applications. The experimental results verify the system stabilization and favorable tracking performance, and no chattering phenomena can be achieved by the proposed ASTFNC scheme.[[notice]]補正完畢[[incitationindex]]SCI[[booktype]]紙本[[booktype]]電子

Measurement of the D+ and Ds+ decays into K+K-K+

We present the first clear observation of the doubly Cabibbo suppressed decay D+ --> K-K+K+ and the first observation of the singly Cabibbo suppressed decay Ds+ --> K-K+K+. These signals have been obtained by analyzing the high statistics sample of photoproduced charm particles of the FOCUS(E831) experiment at Fermilab. We measure the following relative branching ratios: Gamma(D+ --> K-K+K+)/Gamma(D+ --> K-pi+pi+) = (9.49 +/- 2.17(statistical) +/- 0.22(systematic))x10^-4 and Gamma(Ds+ --> K-K+K+)/Gamma(Ds+ --> K-K+pi+) = (8.95 +/- 2.12(statistical) +2.24(syst.) -2.31(syst.))x10^-3.Comment: 10 pages, 8 figure

New Measurements of the D+ to K* mu nu Form Factor Ratios

Using a large sample of D+ to K- pi+ mu+ nu decays collected by the FOCUS photoproduction experiment at Fermilab, we present new measurements of two semileptonic form factor ratios: rv and r2. We find rv = 1.504 \pm 0.057 \pm 0.039 and r2 = 0.875 \pm 0.049 \pm 0.064. Our form factor results include the effects of the s-wave interference discussed in a previous paper.Comment: 12 pages, 5 figure

Charm System Tests of CPT and Lorentz Invariance with FOCUS

We have performed a search for CPT violation in neutral charm meson oscillations. While flavor mixing in the charm sector is predicted to be small by the Standard Model, it is still possible to investigate CPT violation through a study of the proper time dependence of a CPT asymmetry in right-sign decay rates for $D^0\to K^-\pi^+$ and \d0b\to K^+\pi^-. This asymmetry is related to the CPT violating complex parameter $\xi$ and the mixing parameters $x$ and $y$: $A_{CPT}\propto{\rm Re} \xi y-{\rm Im} \xi x$ . Our 95% confidence level limit is $-0.0068<{\rm Re} \xi y-{\rm Im} \xi x<0.0234$. Within the framework of the Standard Model Extension incorporating general CPT violation, we also find 95% confidence level limits for the expressions involving coefficients of Lorentz violation of $(-2.8<N(x,y,\delta)(\Delta a_0 + 0.6 \Delta a_Z)<4.8)\times 10^{-16}$ GeV, $(-7.0<N(x,y,\delta)\Delta a_X<3.8)\times 10^{-16}$ GeV, and $(-7.0<N(x,y,\delta)\Delta a_Y<3.8)\times 10^{-16}$ GeV, where $N(x,y,\delta)$ is the factor which incorporates mixing parameters $x$, $y$ and the doubly Cabibbo suppressed to Cabibbo favored relative strong phase $\delta$.Comment: 12 pages 5 figure