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Cell-fate control gene therapy (CFCGT)-based strategies can augment existing gene therapy and cell transplantation approaches by providing a safety element in the event of deleterious outcomes. Previously, we described a novel enzyme/prodrug combination for CFCGT. Here, we present results employing novel lentiviral constructs harboring sequences for truncated surface molecules (CD19 or low-affinity nerve growth factor receptor) directly fused to that CFCGT cDNA (TmpkF105Y). This confers an enforced one-to-one correlation between cell marking and eradication functions. In-vitro analysis demonstrated the full functionality of the fusion product. Next, low-dose 3′-azido-3′-deoxythymidine (AZT) administration to non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice injected with transduced clonal K562 cells suppressed tumor growth; furthermore, one integrated vector on average was sufficient to mediate cytotoxicity. Further, in a murine xenogeneic leukemia-lymphoma model we also demonstrated in-vivo control over transduced Raji cells. Finally, in a proof-of-principle study to examine the utility of this cassette in combination with a therapeutic cDNA, we integrated this novel CFCGT fusion construct into a lentivector designed for treatment of Fabry disease. Transduction with this vector restored enzyme activity in Fabry cells and retained AZT sensitivity. In addition, human Fabry patient CD34+ cells showed high transduction efficiencies and retained normal colony-generating capacity when compared with the non-transduced controls. These collective results demonstrated that this novel and broadly applicable fusion system may enhance general safety in gene- and cell-based therapies. [ABSTRACT FROM AUTHOR]

Activity and specificity of chemotherapeutic agents against solid tumors can be augmented via the targeted or localized delivery of 'suicide' genes. Selective activation of specific prodrugs in cells expressing the 'suicide' gene drives their elimination by apoptosis, while also enabling the killing of adjacent bystander cells. Strong bystander effects can compensate for poor 'suicide' gene delivery, and depend on the prodrugs used and mechanisms for the acquisition of activated drug by the bystander population, such as the presence of gap junctional intercellular communications. Although a number of 'suicide' gene therapies for cancer have been developed and characterized, such as herpes simplex virus-derived thymidine kinase (HSV-tk)-based activation of ganciclovir, their limited success highlights the need for the development of more robust approaches. Limiting activation kinetics and evolution of chemoresistance are major obstacles. Here we describe 'suicide' gene therapy of cancer based on the lentivirus-mediated delivery of a thymidine-active human deoxycytidine kinase variant. This enzyme possesses substrate plasticity that enables it to activate a multitude of prodrugs, some with distinct mechanisms of action. We evaluated the magnitude and mechanisms of bystander effects induced by different prodrugs, and show that when used in combination, they can synergistically enhance the bystander effect while avoiding off-target toxicity. [ABSTRACT FROM AUTHOR]

Recent investigations have demonstrated that adenoviral and lentiviral vectors encoding HER-2 can be utilized in cancer immunotherapy. However, it is not known whether both viral systems elicit a similar immune response. Here, we compare the immune response in mice induced by dendritic cells (DCs) infected with either recombinant adenovirus or lentivirus encoding rat HER-2 (rHER-2). Both vaccine types yielded similar control of tumor growth, but we found clear differences in their immune responses 10 days after DC immunization. Adenovirus rHER-2-transduced DCs elicited locally and systemically high frequencies of CD4+ and CD8+ T cells, while lentivirus rHER-2-transduced DCs predominantly led to CD4+ T-cell infiltration at the tumor site. Splenocytes from mice immunized with lentivirus rHER-2-transduced DCs secreted higher levels of interferon (IFN)-γ, mainly by CD4+ T cells, following stimulation by RM-1-mHER-2 tumors. In contrast, the adenovirus vaccinated group exhibited CD4+ and CD8+ T cells that both contributed to IFN-γ production. Besides an established cellular immune response, the rHER-2/DC vaccine elicited a significant humoral response that was highest in the adenovirus group. DC subsets and regulatory T cells in the spleen were also differentially modulated in the two vaccine systems. Finally, adoptive transfer of splenocytes from both groups of immunized mice strongly inhibited in vivo tumor growth. Our results suggest that not only the target antigen but also the virus system may determine the nature and magnitude of antitumor immunity by DC vaccination. [ABSTRACT FROM AUTHOR]

Signal transducers and activators of transcription 5 (Stat5) is known to engage in regulating the differentiation and effector function of various subsets of T helper cells. However, how Stat5 regulates the antitumor activity of tumor-infiltrating CD4+ T cells is largely unknown. Here, we showed that mice with specific deletion of Stat5 in CD4+ T cells were less susceptible to developing subcutaneous and lung metastatic B16 melanoma with CD4+ tumor-infiltrating lymphocytes (TILs) remolding. Especially, we confirmed that Stat5-deficient CD4+ naïve T cells were prone to polarization of two subtypes of Th17 cells: IFN-γ+ and IFN-γ− Th17 cells, which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared with wild type Th17 cells. Our study therefore revealed a novel function of Stat5 in regulating tumor-specific Th17 cell differentiation and function in melanoma. This study also provided a new possibility for targeting Stat5 and other Th17-associated pathways to develop novel immunotherapies for melanoma patients. [ABSTRACT FROM AUTHOR]

Two-dimensional (2D) materials like graphene, phosphorene, germanene, silicene, and transition metal dichalcogenides have attracted intense research attention because of their rich physics and potential for integration into next-generation electronic devices. These materials offer superior electrostatic control to their bulk counterparts, which makes them fascinating for device fabrication. After graphene and MoS2, the most intensively explored 2D material is black phosphorus (BP). During the past half-decade, BP has notably achieved excellent performance when included in transistors. This review paper aims to throw some light on BP properties and their performance in a field effect transistor device. The state-of-the-art BP transistors are reviewed, and a balanced view of both the benefits and drawbacks is provided. [ABSTRACT FROM AUTHOR]

This paper analyzes the reliability issues of the Heterostacked-TFET (HS-TFET) in detail. The investigation of the device reliability is carried out by examining the effect of interface trap charges (ITCs) and the temperature affectability of the HS-TFET on various analog parameters and RF FOMs. The analysis is performed at different interface trap charge densities and polarities. The presence of interface traps at the stackedsource/channel junction and the oxide/silicon interface alters the performance of the device significantly. A positive trap charge density of 3 × 1013 cm−2 degrades the current switching ratio tremendously from an order of 1010–104. The off-state current of the device deteriorates excessively at high temperatures. However, the results establish that the HS-TFET is insusceptible to the acceptor interface trap charge as compared to the donor interface trap charge for temperature variation. A high-k gate dielectric of Aluminum oxide (Al2O3) is considered and compared with Hafnium oxide (HfO2) and it is found that Al2O3 gate oxide has a better immunity to the ITC variation. [ABSTRACT FROM AUTHOR]

In this paper, a charge plasma-based phosphorene double-gate tunnel FET (CP-BPDGTFET) is investigated. A hybrid simulation technique involving both atomistic and technology computer-aided design (TCAD) has been used to simulate the device characteristics. First, the density functional theory has been used to simulate phosphorene electrical characteristics (monolayer to few-layer, including armchair and zigzag directions). The parameters such as band gap and effective mass obtained using an atomistic simulator tool are exported into Sentaurus TCAD to simulate the device characteristics. The drain current characteristics are calibrated for conventional double gate phosphorene tunnel FET with non-equilibrium Green's function results. The DC characteristics of the proposed device are studied. The device performance is analysed by varying the device parameters such as gate length (Lg), spacer length (Ls), and gate workfunction (ϕm). Based on the study, an optimised device is designed, and its characteristics are obtained. The optimised device offers an on-current value of 405 µA/µm, SS = 79 mV/dec, Ion/Ioff = 1.13 × 106 for 30 nm gate length. It establishes that CP-BPDGTFET is a suitable candidate for energy-efficient circuit applications. [ABSTRACT FROM AUTHOR]

We investigate the physical properties of compressed gray phosphorus through density functional plus dynamical mean-field theory, showing self-doping and s -wave electronic structure reconstruction. At commensurate electron density, the 3 p spectrum is shown to be almost unaffected by electronic correlations, however upon self-doping largely the normal and superconducting states. These findings provide a microscopic understanding of pressure-induced hole carrier superconductivity on the normal state coherence of s -wave superconductors with well-defined Bogoliubov quasiparticles at low temperatures. Upon internal thermalization, the s -wave superconducting state loses its phase coherence. [ABSTRACT FROM AUTHOR]

This paper reports unique InGaAs-based ion-sensitive field-effect transistor (ISFET) sensor devices having a sensing gate in addition to the traditional floating gate with different kinds of barrier materials such as no barrier, single barrier (InP) and double barrier (InP and InAlAs), at sub-100 nm technology node. The impact of barrier layers coupled with the modified gate architecture on the sensing performance of the proposed devices has been investigated and compared thoroughly in terms of different performance metrics, e.g., threshold voltage sensitivity, ON-current sensitivity, and ON/OFF-current sensitivity. Interestingly, it has been found that the sensor device with a single barrier exhibits the highest threshold voltage sensitivity of ~ 67 mV/pH and largest ION/IOFF ratio sensitivity of 25/pH, compared to the other devices. Furthermore, it is worth mentioning that the threshold voltage sensitivity of the single-barrier sensor device crosses the conventional Nernst limit of 59 mV/pH at room temperature, by 14%. Critically analyzing the results, it is found that the sensor device with a single barrier has evolved as the most promising device for pH-sensing application, not only from the standpoint of high sensitivity parameters, but also from the fabrication point of view. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) inhibitors are emerging as promising anticancer drugs. Because aberrant activity and expression of HDACs have been implicated in various cancer types, a wide range of HDAC inhibitors are being investigated as anticancer agents. Furthermore, due to the demonstrable anticancer activity in both in vitro and in vivo studies, numerous HDAC inhibitors have undergone a rapid phase of clinical development in various cancer types, either as a monotherapy or in combination with other anticancer agents. Although preclinical trials show that HDAC inhibitors have a variety of biological effects across multiple pathways, including regulation of gene expression, inducing apoptosis and cell cycle arrest, inhibiting angiogenesis, and regulation of DNA damage and repair, the mechanism by which the clinical activity is mediated remains unclear. Understanding the mechanisms of anticancer activity of HDAC inhibitors is essential not only for rational drug design for targeted therapies, but for the design of optimized clinical protocols. This paper describes the links between HDACs and cancer, and the underlying mechanisms of action of HDAC inhibitors against hematological malignancies and solid tumors. Further, this review presents the clinical outcomes of vorinostat, romidepsin, and belinostat, which are approved by the United States Food and Drug Administration for the treatment of lymphomas. [ABSTRACT FROM AUTHOR]

Diamond, because of its unique physical, chemical, and electrical properties and the feasibility of growing it in thin-film form, is an ideal choice as a material for the fabrication of reliable, long endurance, microelectromechanical/nanoelectromechanical systems (MEMS/NEMS). However, various practical challenges, including wafer-scale thickness uniformity, CMOS compatibility, surface micromachining, and, more importantly, controlling the internal stress of the diamond films, make this material more challenging for MEMS engineers. Recent advances in the growth of diamond films using chemical vapor deposition have changed this landscape since most technical hurdles have been overcome, enabling a new era of diamond-based MEMS and NEMS development. This article discusses a few examples of MEMS and NEMS devices that have been fabricated using mono-, nano-, and ultrananocrystalline diamond films as well as their performance. [ABSTRACT FROM PUBLISHER]

The miniaturization and integration of frequency-agile microwave circuits-relevant to electronically tunable filters, antennas, resonators and phase shifters-with microelectronics offers tantalizing device possibilities, yet requires thin films whose dielectric constant at gigahertz frequencies can be tuned by applying a quasi-static electric field. Appropriate systems such as BaxSr1−xTiO3 have a paraelectric-ferroelectric transition just below ambient temperature, providing high tunability. Unfortunately, such films suffer significant losses arising from defects. Recognizing that progress is stymied by dielectric loss, we start with a system with exceptionally low loss-Srn+1TinO3n+1 phases-in which (SrO)2 crystallographic shear planes provide an alternative to the formation of point defects for accommodating non-stoichiometry. Here we report the experimental realization of a highly tunable ground state arising from the emergence of a local ferroelectric instability in biaxially strained Srn+1TinO3n+1 phases with n ≥ 3 at frequencies up to 125 GHz. In contrast to traditional methods of modifying ferroelectrics-doping or strain-in this unique system an increase in the separation between the (SrO)2 planes, which can be achieved by changing n, bolsters the local ferroelectric instability. This new control parameter, n, can be exploited to achieve a figure of merit at room temperature that rivals all known tunable microwave dielectrics. [ABSTRACT FROM AUTHOR]

Structural transformation from a linear chain structure to crosslinked chain structure, occuring during the thermal stabilization stage of carbon fiber manufacture, was followed through the use of infrared spectroscopy, differential scanning calorimetry (DSC), elemental analysis and gel-fraction measurements. The results obtained from the analysis of IR spectroscopy showed the gradual and continuous loss of intensity of the nitrile (C≡N) vibration at 2242 cm closely associated with the cyclization reactions whereas the intensity loss of the methylene (CH) groups vibration around 2920-2939 cm has been attributed to the loss of hydrogen atoms as part of the dehydrogenation reactions. The dehydrogenation index, evaluated using the absorbance ratio of A/A, also indicated the gradual loss of hydrogens in agreement with decreasing hydrogen content with progressing stabilization process. IR spectroscopy also showed the emergence of new absorption bands attributed to the formation of crosslinked ladder-like structure in the 1590-1600 cm region. The amount of newly formed crosslinked structure was characterized using DSC conversion index, IR conversion index and gel-fraction measurements. The results are compared and discussed in detail. [ABSTRACT FROM AUTHOR]

In the present paper, a variety of fiber reinforcements, for instance, stabilized OXI-PAN fibers, quasi-carbon fibers, commercial carbon fibers, and their woven fabric forms, have been utilized to fabricate pseudo-unidirectional (pseudo-UD) and 2-directional (2D) phenolic matrix composites using a compression molding method. Prior to fabricating quasi-carbon fiber/phenolic (QC/P) composites, stabilized OXI-PAN fibers and fabrics were heat-treated under low temperature carbonization processes to prepare quasi-carbon fibers and fabrics. The thermal conductivity and thermal expansion/contraction behavior of QC/P composites have been investigated and compared with those of carbon fiber/phenolic (C/P) and stabilized fiber/phenolic composites. Also, the chemical compositions of the fibers used have been characterized. The results suggest that use of proper quasi-carbonization process may control effectively not only the chemical compositions of resulting quasi-carbon fibers but also the thermal conductivity and thermal expansion behavior of quasi-carbon fibers/phenolic composites in the intermediate range between stabilized PAN fiber- and carbon fiber-reinforced phenolic composites. [ABSTRACT FROM AUTHOR]