RESUMEN
2D field-effect transistors (FETs) fabricated with transition metal dichalcogenide (TMD) materials are a potential replacement for the silicon-based CMOS. However, the lack of advancement in p-type contact is also a key factor hindering TMD-based CMOS applications. The less investigated path towards improving electrical characteristics based on contact geometries with low contact resistance (RC) has also been established. Moreover, finding contact metals to reduce the RC is indeed one of the significant challenges in achieving the above goal. Our research provides the first comparative analysis of the three contact configurations for a WSe2 monolayer with different noble metals (Rh, Ru, and Pd) by employing ab initio density functional theory (DFT) and non-equilibrium Green's function (NEGF) methods. From the perspective of the contact topologies, the RC and minimum subthreshold slope (SSMIN) of all the conventional edge contacts are outperformed by the novel non-van der Waals (vdW) sandwich contacts. These non-vdW sandwich contacts reveal that their RC values are below 50 Ωâµm, attributed to the narrow Schottky barrier widths (SBWs) and low Schottky barrier heights (SBHs). Not only are the RC values dramatically reduced by such novel contacts, but the SSMIN values are lower than 68 mV/dec. The new proposal offers the lowest RC and SSMIN, irrespective of the contact metals. Further considering the metal leads, the WSe2/Rh FETs based on the non-vdW sandwich contacts show a meager RC value of 33 Ωâµm and an exceptional SSMIN of 63 mV/dec. The two calculated results present the smallest-ever values reported in our study, indicating that the non-vdW sandwich contacts with Rh leads can attain the best-case scenario. In contrast, the symmetric convex edge contacts with Pd leads cause the worst-case degradation, yielding an RC value of 213 Ωâµm and an SSMIN value of 95 mV/dec. While all the WSe2/Ru FETs exhibit medium performances, the minimal shift in the transfer curves is interestingly advantageous to the circuit operation. Conclusively, the low-RC performances and the desirable SSMIN values are a combination of the contact geometries and metal leads. This innovation, achieved through noble metal leads in conjunction with the novel contact configurations, paves the way for a TMD-based CMOS with ultra-low RC and rapid switching speeds.
RESUMEN
Realizing n- and p-type transition metal dichalcogenide (TMD)-based field-effect transistors for nanoscale complementary metal oxide semiconductor (CMOS) applications remains challenging owing to undesirable contact resistance. Quantumtransport calculations were performed by replacing single-sided Se atoms of TMD near the interface with As or Br atoms to further improve the contact resistance. Here, partial selenium replacement produced a novel interface with a segment of metamaterial MoSeX (Pt/MoSeX/MoSe2; X = As, Br). Such stable metamaterials exhibit semi-metallicity, and the contact resistance can be thus lowered. Our findings provide insights into the potential of MoSe2-based nano-CMOS logic devices.
RESUMEN
As a type of immunogenic cell death, ferroptosis participates in the creation of immunoactive tumor microenvironments. However, knowledge of spatial location of tumor cells with ferroptosis signature in tumor environments and the role of ferroptotic stress in inducing the expression of immune-related molecules in cancer cells is limited. Here the spatial association of the transcriptomic signatures is demonstrated for ferroptosis and inflammation/immune activation located in the invasive front of head and neck squamous cell carcinoma (HNSCC). The association between ferroptosis signature and inflammation/immune activation is more prominent in HPV-negative HNSCC compared to HPV-positive ones. Ferroptotic stress induces PD-L1 expression through reactive oxygen species (ROS)-elicited NF-κB signaling pathway and calcium influx. Priming murine HNSCC with the ferroptosis inducer sensitizes tumors to anti-PD-L1 antibody treatment. A positive correlation between the ferroptosis signature and the active immune cell profile is shown in the HNSCC samples. This study reveals a subgroup of ferroptotic HNSCC with immune-active signatures and indicates the potential of priming HNSCC with ferroptosis inducers to increase the antitumor efficacy of immune checkpoint inhibitors.
Asunto(s)
Ferroptosis , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Animales , Ratones , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Microambiente TumoralRESUMEN
Reducing the contact resistance is one of the major challenges in developing transistors based on two-dimensional materials. In this study, we perform first-principles quantum-transport calculations by adopting a novel type of partially sulfur-replaced edge contact metal/WSX/WS2 in order to lower the Schottky barrier height and in turn reduce the contact resistance. Here, the sulfur replacements produce a segment of the metamaterial WSX (X = P, As, F, and Cl), using group V or halogen atoms to substitute sulfur atoms on one side of a WS2 monolayer. We further compare the effects of such sulfur replacements on the interface metallization and bonding. Such WSX-buffered contacts exhibit contact resistances as low as 142 and 173 Ω·µm for the p-type Pt/WSP/WS2 and n-type Ti/WSCl/WS2 edge contacts, respectively. Moreover, ab initio molecular dynamics is employed to observe a stable standalone WSX monolayer at room temperature.
RESUMEN
BACKGROUND: Regorafenib and other multikinase inhibitors may enhance antitumor efficacy of anti-program cell death-1 (anti-PD1) therapy in hepatocellular carcinoma (HCC). Its immunomodulatory effects, besides anti-angiogenesis, were not clearly defined. METHODS: In vivo antitumor efficacy was tested in multiple syngeneic liver cancer models. Murine bone marrow-derived macrophages (BMDMs) were tested in vitro for modulation of polarization by regorafenib and activation of cocultured T cells. Markers of M1/M2 polarization were measured by quantitative reverse transcription PCR (RT-PCR), arginase activity, flow cytometry, and ELISA. Knockdown of p38 kinase and downstream Creb1/Klf4 signaling on macrophage polarization were confirmed by using knockdown of the upstream MAPK14 kinase, chemical p38 kinase inhibitor, and chromatin immunoprecipitation. RESULTS: Regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR2 antibody) but produced higher T cell activation and M1 macrophage polarization, increased the ratio of M1/M2 polarized BMDMs and proliferation/activation of cocultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream Creb1/Klf4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells. Synergistic antitumor efficacy between regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment. CONCLUSION: Regorafenib may enhance antitumor immunity through modulation of macrophage polarization, independent of its anti-angiogenic effects. Optimization of regorafenib dosage for rational design of combination therapy regimen may improve the therapeutic index in the clinic.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Macrófagos Asociados a Tumores/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Inhibidores de la Angiogénesis/farmacología , Animales , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/inmunología , Línea Celular Tumoral , Técnicas de Cocultivo , Factor 4 Similar a Kruppel/metabolismo , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/inmunología , Activación de Linfocitos/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/enzimología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Transducción de Señal , Microambiente Tumoral , Macrófagos Asociados a Tumores/enzimología , Macrófagos Asociados a Tumores/inmunologíaRESUMEN
Hypoxia, the reduction of oxygen levels in cells or tissues, elicits a set of genes to adjust physiological and pathological demands during normal development and cancer progression. OCT4, a homeobox transcription factor, is essential for self-renewal of embryonic stem cells, but little is known about the role of OCT4 in non-germ-cell tumorigenesis. Here, we report that hypoxia stimulates a short isoform of OCT4, called OCT4B, via a HIF2α-dependent pathway to induce the epithelial-mesenchymal transition (EMT) and facilitate cancer dissemination. OCT4B overexpression decreased epithelial barrier properties, which led to an increase in cell migration and invasion in lung cancer cells. OCT4B knockdown attenuated HIF2α-induced EMT and inhibited cancer dissemination in cell-line and animal models. We observed that OCT4B bound the SLUG promoter and enhanced its expression, and SLUG silencing inhibited OCT4B-mediated EMT, accompanied with decreased cell migration and invasion. Correlation analysis revealed that OCT4B expression was significantly associated with the SLUG level in lung tumors. These results provide novel insights into OCT4B-mediated oncogenesis in cancer dissemination.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Transición Epitelial-Mesenquimal , Hipoxia/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Células A549 , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Humanos , Hipoxia/genética , Hipoxia/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Factor 3 de Transcripción de Unión a Octámeros/genéticaRESUMEN
Cell differentiation within stem cell lineages can check proliferative potential, but nodal pathways that can limit tumor growth are obscure. Here, we report that lung cancer cell populations generate phenotypic and oncogenic plasticity via a switch between differentiation programs controlled by SOX2 and SOX9, thus altering proliferative and invasive capabilities. In lung cancer cells, SOX2 bound the EPCAM promoter to induce EpCAM-p21Cip1-cyclin A2 signaling, encouraging cell proliferation as well as barrier properties. In contrast, SOX9 bound the SLUG promoter to induce SLUG-mediated cell invasion with a spindle-like phenotype. Pharmacologic inhibition of HDAC elevated a SOX9-positive cell population from SOX2-positive cells, whereas ectopic expression of SOX2 inhibited SOX9 with increased H3K9me2 levels on the SOX9 promoter. In clinical specimens, the expression of SOX2 and SOX9 correlated negatively and positively with lung tumor grade, respectively. Our findings identify SOX2 and SOX9 as nodal epigenetic regulators in determining cancer cell plasticity and metastatic progression. Cancer Res; 76(23); 7036-48. ©2016 AACR.
Asunto(s)
Plasticidad de la Célula/genética , Factor de Transcripción SOX9/genética , Factores de Transcripción SOXB1/genética , Animales , Diferenciación Celular , Epigenómica , Humanos , Ratones , Transducción de SeñalRESUMEN
Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer.
Asunto(s)
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Factores de Transcripción SOXB1/metabolismo , Animales , Apoptosis/fisiología , Autofagia/fisiología , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos , Receptores ErbB/biosíntesis , Receptores ErbB/genética , Receptores ErbB/metabolismo , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Xenoinjertos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ratones , Paclitaxel/farmacología , Factores de Transcripción SOXB1/genética , Transducción de Señal , Análisis de Supervivencia , Proteína bcl-X/metabolismoRESUMEN
We consider the problem of reconstructing an object function f(r) from finitely many linear functional values. In our main application, the function f(r) is a tomographic image, and the data are integrals of f(r) along thin strips. Because the data are limited, resolution can be enhanced through the inclusion of prior knowledge. One way to do that, a generalization of the prior discrete Fourier transform (PDFT) method, was suggested in 1982 [SIAM J. Appl. Math.42,933 (1982)] but was found to be difficult to implement for the tomography problem, and that application was not pursued. Recent advances in approximating the PDFT make it possible to achieve the desired resolution enhancement in an easily implemented procedure.