Hofmeister-Effect-Driven Hybrid Glycerogels for Perfect Wide-Temperature Shape Fixity and Shape Recovery in Soft Robotics Applications.

Shape memory gels have emerged as crucial elements in soft robotics, actuators, and biomedical devices; however, several problems persist, like the trade-off between shape fixity and shape recovery, and the limited temperature range for their application. This article introduces a new class of shape memory hybrid glycerogels (GGs) designed to address these limitations. The well-modulated internal structure of the GGs, facilitated by the Hofmeister salting-out effect, strategically incorporates a higher crystallite content, abundant crosslinking points, and a high elastic modulus. Unlike reported shape memory gels, the GG exhibits a perfect triple-step shape memory behavior in air with 100% shape fixity in a wide programming temperature range (75-135 °C) and simultaneously achieves 100% shape recoverability. The gel recovers its shape at -40 °C under near-infrared light across a wide programming temperature range (25-135 °C), showing unexpected initiation even at subzero temperatures. Inspired by the mechanics of composite structures, a method is proposed to integrate the GG seamlessly with a shape memory alloy, which further expands the temperature range that yields perfect shape memory properties. Finally, two light-controlled fluttering and crawling soft robot prototypes are engineered to illustrate the versatility and potential applications of the composite gel in soft robotics.

Efficacy and safety of BVAC-C in HPV type 16- or 18-positive cervical carcinoma who failed 1st platinum-based chemotherapy: a phase I/IIa study.

Background: BVAC-C, a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV-positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16- or 18-positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy. Patients and methods: Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1-not reported), the median PFS was 5.8 months (95% CI 4.2-10.3), and the median OS was 17.7 months (95% CI 12.0-not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses. Conclusion: BVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response. Clinical trial registration: ClinicalTrials.gov, identifier NCT02866006.

Inhibition of topoisomerase I shapes antitumor immunity through the induction of monocyte-derived dendritic cells.

Understanding the rationale of combining immunotherapy and other anticancer treatment modalities is of great interest because of interpatient variability in single-agent immunotherapy. Here, we demonstrated that topoisomerase I inhibitors, a class of chemotherapeutic drugs, can alter the tumor immune landscape, corroborating their antitumor effects combined with immunotherapy. We observed that topotecan-conditioned TC-1 tumors were occupied by a vast number of monocytic cells that highly express CD11c, CD64, and costimulatory molecules responsible for the favorable changes in the tumor microenvironment. Ly6C+MHC-II+CD11chiCD64hi cells, referred to as topotecan-induced monocyte-derived dendritic cells (moDCs), proliferate and activate antigen-specific CD8+ T cells to levels equivalent to those of conventional DCs. Phenotypic changes in Ly6C+ cells towards moDCs were similarly induced by exposure to topotecan in vitro, which was more profoundly facilitated in the presence of tumor cells. Notably, anti-M-CSFR reversed the acquisition of DC-like properties of topotecan-induced moDCs, leading to the abolition of the antitumor effect of topotecan combined with a cancer vaccine. In short, topoisomerase I inhibitors generate monocyte-derived antigen-presenting cells in tumors, which could be mediated by M-CSF-M-CSFR signaling.

High-Throughput Growth of Wafer-Scale Monolayer Transition Metal Dichalcogenide via Vertical Ostwald Ripening.

For practical device applications, monolayer transition metal dichalcogenide (TMD) films must meet key industry needs for batch processing, including the high-throughput, large-scale production of high-quality, spatially uniform materials, and reliable integration into devices. Here, high-throughput growth, completed in 12 min, of 6-inch wafer-scale monolayer MoS2 and WS2 is reported, which is directly compatible with scalable batch processing and device integration. Specifically, a pulsed metal-organic chemical vapor deposition process is developed, where periodic interruption of the precursor supply drives vertical Ostwald ripening, which prevents secondary nucleation despite high precursor concentrations. The as-grown TMD films show excellent spatial homogeneity and well-stitched grain boundaries, enabling facile transfer to various target substrates without degradation. Using these films, batch fabrication of high-performance field-effect transistor (FET) arrays in wafer-scale is demonstrated, and the FETs show remarkable uniformity. The high-throughput production and wafer-scale automatable transfer will facilitate the integration of TMDs into Si-complementary metal-oxide-semiconductor platforms.

Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses.

For cancer vaccines, the selection of optimal tumor-associated antigens (TAAs) that can maximize the immunogenicity of the vaccine without causing unwanted adverse effects is challenging. In this study, we developed two engineered Human epidermal growth factor receptor 2 (HER2) antigens, K965 and K1117, and compared their immunogenicity to a previously reported truncated HER2 antigen, K684, within a B cell and monocyte-based vaccine (BVAC). We found that BVAC-K965 and BVAC-K1117 induced comparable antigen-specific antibody responses and antigen-specific T cell responses to BVAC-K684. Interestingly, BVAC-K1117 induced more potent antitumor activity than the other vaccines in murine CT26-HER2 tumor models. In addition, BVAC-K1117 showed enhanced antitumor effects against truncated p95HER2-expressing CT26 tumors compared to BVAC-K965 and BVAC-K684 based on the survival analysis by inducing T cell responses against intracellular domain (ICD) epitopes. The increased ICD epitope-specific T cell responses induced by BVAC-K1117 compared to BVAC-K965 and BVAC-K684 were recapitulated in human leukocyte antigen (HLA)-untyped human PBMCs and HLA-A*0201 PBMCs. Furthermore, we also observed synergistic antitumor effects between BVAC-K1117 and anti-PD-L1 antibody treatment against CT26-HER2 tumors. Collectively, our findings demonstrate that inclusion of a sufficient number of ICD epitopes of HER2 in cellular vaccines can improve the antitumor activity of the vaccine and provide a way to optimize the efficacy of anticancer cellular vaccines targeting HER2.

Double-Hydrophobic-Coating through Quenching for Hydrogels with Strong Resistance to Both Drying and Swelling.

In recent years, various hydrogels with a wide range of functionalities have been developed. However, owing to the two major drawbacks of hydrogels-air-drying and water-swelling-hydrogels developed thus far have yet to achieve most of their potential applications. Herein, a bioinspired, facile, and versatile method for fabricating hydrogels with high stability in both air and water is reported. This method includes the creation of a bioinspired homogeneous fusion layer of a hydrophobic polymer and oil in the outermost surface layer of the hydrogel via a double-hydrophobic-coating produced through quenching. As a proof-of-concept, this method is applied to a polyacrylamide hydrogel without compromising its mechanical properties. The coated hydrogel exhibits strong resistance to both drying in air and swelling in multiple aqueous environments. Furthermore, the versatility of this method is demonstrated using different types of hydrogels and oils. Because this method is easy to apply and is not dependent on hydrogel surface chemistry, it can significantly broaden the scope of next-generation hydrogels for real-world applications in both wet and dry environments.

GITR Agonism Triggers Antitumor Immune Responses through IL21-Expressing Follicular Helper T Cells.

Although treatment with the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonistic antibody (DTA-1) has shown antitumor activity in various tumor models, the underlying mechanism is not fully understood. Here, we demonstrate that interleukin (IL)-21-producing follicular helper T (Tfh) cells play a crucial role in DTA-1-induced tumor inhibition. The administration of DTA-1 increased IL21 expression by Tfh cells in an antigen-specific manner, and this activation led to enhanced antitumor cytotoxic T lymphocyte (CTL) activity. Mice treated with an antibody that neutralizes the IL21 receptor exhibited decreased antitumor activity when treated with DTA-1. Tumor growth inhibition by DTA-1 was abrogated in Bcl6 fl/fl Cd4 Cre mice, which are genetically deficient in Tfh cells. IL4 was required for optimal induction of IL21-expressing Tfh cells by GITR costimulation, and c-Maf mediated this pathway. Thus, our findings identify GITR costimulation as an inducer of IL21-expressing Tfh cells and provide a mechanism for the antitumor activity of GITR agonism.

Differentiation of c-Kit+ CD24+ natural killer cells into myeloid cells in a GATA-2-dependent manner.

Myeloid progenitor cells have generally been considered the predominant source of myeloid cells under steady-state conditions. Here we show that NK cells contributed to a myeloid cell lineage pool in naïve and tumor-bearing mice. Using fate tracing of NKp46+ cells, we found that myeloid cells could be derived from NK cells. Notably, among mature CD11b+ CD27+ NK cells, c-Kit+ CD24+ NK cells were capable of differentiating into a range of myeloid lineages in vitro and produced neutrophils and monocytes in vivo. The differentiation was completely inhibited by NK-stimulating cytokines. In addition to the potential for differentiation into myeloid cells, c-Kit+ CD24+ NK cells retained NK cell phenotypes and effector functions. Mechanistically, GATA-2 was necessary for the differentiation of c-Kit+ CD24+ NK cells. Therefore, we discovered that GATA-2-dependent differentiation of c-Kit+ CD24+ NK cells contributes to myeloid cell development and identified a novel pathway for myeloid lineage commitment under physiological conditions.

Monocyte-Derived Dendritic Cells Dictate the Memory Differentiation of CD8+ T Cells During Acute Infection.

Monocyte-derived dendritic cells (moDCs) have been shown to robustly expand during infection; however, their roles in anti-infectious immunity remain unclear. Here, we found that moDCs were dramatically increased in the secondary lymphoid organs during acute LCMV infection in an interferon-γ (IFN-γ)-dependent manner. We also found that priming by moDCs enhanced the differentiation of memory CD8+ T cells compared to differentiation primed by conventional dendritic cells (cDCs) through upregulation of Eomesodermin (Eomes) and T cell factor-1 (TCF-1) expression in CD8+ T cells. Consequently, impaired memory formation of CD8+ T cells in mice that had reduced numbers of moDCs led to defective clearance of pathogens upon rechallenge. Mechanistically, attenuated interleukin-2 (IL-2) signaling in CD8+ T cells primed by moDCs was responsible for the enhanced memory programming of CD8+ T cells. Therefore, our findings unveil a specialization of the antigen-presenting cell subsets in the fate determination of CD8+ T cells during infection and pave the way for the development of a novel therapeutic intervention on infection.

Hard ferromagnetic van-der-Waals metal (Fe,Co)3GeTe2: a new platform for the study of low-dimensional magnetic quantum criticality.

The widely-studied ferromagnetic van-der-Waals (vdW) metal Fe3GeTe2 has great promise for studies of quantum criticality in the 2D limit, but is limited by a relatively high Curie temperature in excess of 200 K. To help render the quantum critical point achievable in such a system within the reach of practically possible tuning methods, we have grown single crystals of a variant of (Fe,Co)3GeTe2 with useful physical properties for both this purpose and the wider study of low-dimensional magnetism and spin transport. (Fe,Co)3GeTe2 is found through x-ray diffraction and electron microscopy to have an equivalent crystal structure to Fe3GeTe2, with a random distribution of the cobalt dopant sites. It exhibits a sharp ferromagnetic transition at a value below 40 K, a stronger anisotropy and a coercive field ten times larger than that of Fe3GeTe2. The transport properties and specific heat show the electronic properties and strong correlations of Fe3GeTe2 to be near-unchanged in this doped material. We demonstrate that (Fe,Co)3GeTe2 can be cleanly exfoliated down to monolayer thickness. This unprecedented hard metallic vdW ferromagnet is a valuable new addition to the limited range of materials available for the study of 2D magnetism.

Conductive Tough Hydrogels with a Staggered Ion-Coordinating Structure for High Self-Recovery Rate.

Conductive hydrogels are attracting increasing attention owing to their great potential for applications in flexible devices. For practical use, these high-water-content materials should not only show good conductivity but also be strong, stretchable, tough, and elastic. Herein, we describe a class of novel conductive tough hydrogels based on strong staggered Fe3+-carboxyl coordinating interactions. They are made from copolymers of acrylamide and N-acryloyl glutamic acid, a bidentate-based comonomer. The design of the staggered structure of Fe3+ and bidentate units is expected to enable energy dissipation and also results in a synergetic effect of two binding sites for fast self-recovery. We demonstrate that the equilibrated hydrogels with a water content of 53 wt % exhibit superior mechanical properties (e.g., highest tensile strength, 12.1 MPa; Young's modulus, 36.1 MPa; work of extension, 42.1 MJ m-3; fracture energy, 10,691 J m-2; compressive strength, 65.1 MPa at 98% strain without a macroscopic fracture) compared to the ion-coordinated hydrogels reported to date, including elasticity at small strain, fast self-recoverability at room temperature (∼25 °C), a high dielectric constant (k = 341-1395 at 100 kHz), and good electrical conductivity (0.0018-0.024 S cm-1). Given their extraordinary overall characteristics, we envision their potential applications in flexible electronic devices.

Roles of NKT cells in cancer immunotherapy.

Cancer immunotherapy has emerged as an effective therapeutic strategy to treat cancer. Among diverse immune populations, invariant natural killer T (iNKT) cells have shown potent antitumor activity by linking innate and adaptive immune systems. Upon activation by lipid antigens on CD1d molecules, iNKT cells rapidly produce various cytokines and trigger antitumor immunity directly or indirectly by activating other antitumor immune cells. Administration of a representative iNKT cell ligand alpha-galactosylceramide (α-GalCer) or α-GalCer-pulsed APCs effectively stimulates iNKT cells and thereby induces antitumor effects. In this review, we will introduce the biology and importance of NKT cells in antitumor immunity. Previous studies have demonstrated that iNKT cells not only activate various immune cells but also reinvigorate exhausted immune cells in the tumor microenvironment. Furthermore, we will summarize the major clinical trials utilizing iNKT-based immunotherapies.

GM-CSF Promotes Antitumor Immunity by Inducing Th9 Cell Responses.

GM-CSF as an adjuvant has been shown to promote antitumor immunity in mice and humans; however, the underlying mechanism of GM-CSF-induced antitumor immunity remains incompletely understood. In this study, we demonstrate that GM-CSF potentiates the efficacy of cancer vaccines through IL9-producing Th (Th9) cells. GM-CSF selectively enhanced Th9 cell differentiation by regulating the COX2-PGE2 pathway while inhibiting the differentiation of induced regulatory T (iTreg) cells in vitro and in vivo GM-CSF-activated monocyte-derived dendritic cells converted tumor-specific naïve Th cells into Th9 cells, and delayed tumor growth by inducing antitumor CTLs in an IL9-dependent manner. Our findings reveal a mechanism for the adjuvanticity of GM-CSF and provide a rationale for the use of GM-CSF in cancer vaccines.

Highly efficient and flexible photodetector based on MoS2-ZnO heterostructures.

Two-dimensional (2D) transition metal dichalcogenides (TMDs) such as molybdenum disulfide (MoS2) and tungsten diselenide (WSe2), have recently attracted attention for their applicability as building blocks for fabricating advanced functional materials. In this study, a high quality hybrid material based on 2D TMD nanosheets and ZnO nanopatches was demonstrated. An organic promoter layer was employed for the large-scale growth of the TMD sheet, and atomic layer deposition (ALD) was utilized for the growth of ZnO nanopatches. Photodetectors based on 2D TMD nanosheets and ZnO nanopatches were successfully fabricated and investigated, which showed a high photoresponsivity of 2.7 A/W. Our novel approach is a promising and effective method for the fabrication of photodetectors with a new structure for application in TMD-based transparent and flexible optoelectronic devices.

Unraveling the Structural and Electronic Properties of Graphene/Ge(110).

The direct growth of graphene on a semiconducting substrate opens a new avenue for future graphene-based applications. Understanding the structural and electronic properties of the graphene on a semiconducting surface is key for realizing such structures; however, these properties are poorly understood thus far. Here, we provide insight into the structural and electronic properties of graphene grown directly on a Ge(110) substrate. Our scanning tunneling microscopy (STM) study reveals that overlaying graphene on Ge(110) promotes the formation of a new Ge surface reconstruction, i.e., a (6 × 2) superstructure, which has been never observed for a bare Ge(110) surface. The electronic properties of the system exhibit the characteristics of both graphene and Ge. The differential conductance (d I/d V) spectrum from a scanning tunneling spectroscopy (STS) study bears a parabolic structure, corresponding to a reduction in the graphene Fermi velocity, exhibiting additional peaks stemming from the p-orbitals of Ge. The density functional theory (DFT) calculations confirm the existence of surface states due to the p-orbitals of Ge.

Hydrogel bowls for cleaning oil spills on water.

We demonstrate a hydrogel bowl capable of selectively and rapidly collecting spilled oil while floating on water. The bowl has macroscopic openings in its sidewall, and its surface is first coated with octadecyltrichlorosilane (OTS) and then with diffusion pump oil, which imparts exceptional hydrophobic, oleophilic, and high oil wettability properties. The use of a hydrogel makes it possible to obtain surface hydrophobicity and oleophilicity, while also being inexpensive, eco-friendly, and easy to fabricate. Using a prototype of the bowl and a small pump system, we demonstrate that oils with a broad range of viscosities (2.7-2000.0 cSt at 20-40 °C) are more rapidly and efficiently collected from the surface of both pure water and seawater than with any other reported technique. The hydrogel bowl can collect oil for more than one month without losing its efficiency and can be stored in oil for reuse. Therefore, such hydrogel bowls represent a new alternative to conventional oil spill remediation techniques.

A diffusion-driven fabrication technique for anisotropic tubular hydrogels.

A bio-inspired, simple, and versatile diffusion-driven method to fabricate complex tubular hydrogels is reported. The controlled diffusion of small ions from a pre-designed core hydrogel through a biopolymer reservoir solution causes the self-gelation of biopolymers with an anisotropic ordered structure on the surface of the core hydrogel. By controlling the concentration, diffusion time, and flow direction of the ions, as well as the size and shape of the core, various types of complex tubular-shaped hydrogels with well-defined 3D architectures were fabricated. The mechanical properties of the designed alginate-based tubular hydrogels were highly tunable and comparable to those of native blood vessels. The method was applied to form a living-cell encapsulated tubular hydrogel, which further strengthens its potential for biomedical applications. The method is suitable for biopolymer-based reaction-diffusion systems and available for further research on the fabrication of functional biomaterials with various biopolymers.

Activation of NKT Cells in an Anti-PD-1-Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells.

PD-1-based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1-resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand α-galactosylceramide (αGC) can enhance the antitumor effect in anti-PD-1-resistant tumors by restoring the effector function of tumor antigen-specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by αGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between αGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1-resistant cancer.Significance: These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. Cancer Res; 78(18); 5315-26. ©2018 AACR.

Characterization of Edge Contact: Atomically Resolved Semiconductor-Metal Lateral Boundary in MoS2.

Despite recent efforts for the development of transition-metal-dichalcogenide-based high-performance thin-film transistors, device performance has not improved much, mainly because of the high contact resistance at the interface between the 2D semiconductor and the metal electrode. Edge contact has been proposed for the fabrication of a high-quality electrical contact; however, the complete electronic properties for the contact resistance have not been elucidated in detail. Using the scanning tunneling microscopy/spectroscopy and scanning transmission electron microscopy techniques, the edge contact, as well as the lateral boundary between the 2D semiconducting layer and the metalized interfacial layer, are investigated, and their electronic properties and the energy band profile across the boundary are shown. The results demonstrate a possible mechanism for the formation of an ohmic contact in homojunctions of the transition-metal dichalcogenides semiconductor-metal layers and suggest a new device scheme utilizing the low-resistance edge contact.

IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours.

During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.