bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tim‐3 and its role in regulating anti‐tumor immunity
Authors: Das Madhumita , Zhu Chen , Kuchroo Vijay K. 
Published: March 2017

SummaryImmunotherapy is being increasingly recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA‐4 and PD‐1 have achieved durable responses in melanoma, renal cancer, Hodgkin's diseases and lung cancer. However, the success rate of these treatments has been low and a large number of cancers, including colorectal cancer remain largely refractory to CTLA‐4 and PD‐1 blockade. This has provided impetus to identify other co‐inhibitory receptors that could be exploited to enhance response rates of current immunotherapeutic agents and achieve responses to the cancers that are refectory to immunotherapy. Tim‐3 is a co‐inhibitory receptor that is expressed on IFN‐g‐producing T cells, FoxP3+ Treg cells and innate immune cells (macrophages and dendritic cells) where it has been shown to suppress their responses upon interaction with their ligand(s). Tim‐3 has gained prominence as a potential candidate for cancer immunotherapy, where it has been shown that in vivo blockade of Tim‐3 with other check‐point inhibitors enhances anti‐tumor immunity and suppresses tumor growth in several preclinical tumor models. This review discusses the recent findings on Tim‐3, the role it plays in regulating immune responses in different cell types and the rationale for targeting Tim‐3 for effective cancer immunotherapy.
The third group of the B7‐CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7‐H3
Authors: Janakiram Murali , Shah Urvi A. , Liu Weifeng , Zhao Aimin , Schoenberg Mark P. , Zang Xingxing 
Published: March 2017

SummaryThe B7‐CD28 family of ligands and receptors play important roles in T‐cell co‐stimulation and co‐inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7‐H3 [CD276], B7x [B7‐H4/B7S1], and HHLA2 [B7H7/B7‐H5]/TMIGD2 [IGPR‐1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7‐H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection. Various immunotherapeutical approaches are emerging including antagonistic monoclonal antibodies and agonistic fusion proteins to inhibit or potentiate these molecules and pathways in cancers and autoimmune diseases.
TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy
Authors: Akalu Yemsratch T. , Rothlin Carla V. , Ghosh Sourav 
Published: March 2017

SummaryCancer immunotherapy utilizing T‐cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients tend to have non‐T‐cell‐inflamed tumors that lack markers associated with the activation of adaptive anti‐tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the development of improved therapies against cancer. Here, we review the TAM receptor tyrosine kinases—TYRO3, AXL, and MERTK—as an emerging class of innate immune checkpoints that participate in key steps of anti‐tumoral immunity. Namely, TAM‐mediated efferocytosis, negative regulation of dendritic cell activity, and dysregulated production of chemokines collectively favor the escape of malignant cells. Hence, disabling TAM signaling may promote engagement of adaptive immunity and complement T‐cell checkpoint blockade.
Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy
Authors: Kean Leslie S. , Turka Laurence A. , Blazar Bruce R. 
Published: March 2017

SummaryIn the past decade, the power of harnessing T‐cell co‐signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR‐Ts) and second, re‐animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re‐ignite T‐cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T‐cell co‐signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy's Yang, and focus on manipulating T‐cell co‐signaling to induce tolerance rather than activation. In this review, we discuss the major T‐cell signaling pathways that are being investigated for tolerance induction, detailing preclinical studies and the path to the clinic for many of these molecules. These include blockade of co‐stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector vs regulatory T‐cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system.
New checkpoints in cancer immunotherapy
Authors: Ni Ling , Dong Chen 
Published: March 2017

SummaryImmune responses must be fine‐tuned to allow effective clearance of invading pathogens, while maintain tolerance to self‐antigens. T cells are the major effector cells for fighting and killing tumor cells. Immune checkpoints play a pivotal role in T cell activation, and determine the functional outcome of T cell receptor (TCR) signaling. The blockade of immune checkpointsCTLA‐4 andPD‐1 has already been one of the most successful cancer immunotherapies. In this review, we will focus on three novel inhibitory B7 family checkpoint molecules, B7‐H3, B7S1 andVISTA. The aim of this article is to summarize their expressions in tumors as well as their roles in controlling and suppressing T cell immune responses and anti‐tumor immunity. These pathways may be explored in future cancer immunotherapy.
Immunoregulatory functions of VISTA
Authors: Nowak Elizabeth C. , Lines J. Louise , Varn Frederick S. , Deng Jie , Sarde Aurelien , Mabaera Rodwell , Kuta Anna , Le Mercier Isabelle , Cheng Chao , Noelle Randolph J. 
Published: March 2017

SummaryUtilization of negative checkpoint regulators (NCRs) for cancer immunotherapy has garnered significant interest with the completion of clinical trials demonstrating efficacy. While the results of monotherapy treatments are compelling, there is increasing emphasis on combination treatments in an effort to increase response rates to treatment. One of the most recently discovered NCRs is VISTA (V‐domain Ig‐containing Suppressor of T cell Activation). In this review, we describe the functions of this molecule in the context of cancer immunotherapy. We also discuss factors that may influence the use of anti‐VISTA antibody in combination therapy and how genomic analysis may assist in providing indications for treatment.
Viewing Siglecs through the lens of tumor immunology
Authors: Fraschilla Isabella , Pillai Shiv 
Published: March 2017

SummaryMany Siglecs function as inhibitory receptors on innate and adaptive immune cells and may contribute to the attenuation of immune responses to tumors. Siglec 9 on neutrophils and Siglec 7 on NK cells are prominent examples of inhibitory Siglecs that can potentially dampen anti‐tumor immunity. CD169 is a Siglec that may function as an adhesion molecule and a facilitator of the recognition and internalization of sialic acid decorated apoptotic bodies and exosomes derived from tumors. It can potentially contribute to both the attenuation as well as the facilitation of anti‐tumor immunity. Siglecs have been best studied in the tumor context in animal models of cancer. Modulators of Siglec function are likely to be developed and investigated clinically in a cancer context over the next few years.
The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer
Authors: Matlung Hanke L. , Szilagyi Katka , Barclay Neil A. , van den Berg Timo K. 
Published: March 2017

SummaryImmune checkpoint inhibitors, including those targeting CTLA‐4/B7 and the PD‐1/PD‐L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell‐mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the ‘don't‐eat me’ signal CD47, which is a protein broadly expressed on normal cells and often overexpressed on cancer cells, and its counter‐receptor, the myeloid inhibitory immunoreceptor SIRPα. Blocking CD47‐SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. Furthermore, there is growing evidence that targeting of the CD47‐SIRPα axis may also promote antigen‐presenting cell function and thereby stimulate adaptive T cell‐mediated anti‐cancer immunity. The development of CD47‐SIRPα checkpoint inhibitors and the potential side effects that these may have are discussed. Collectively, this identifies the CD47‐SIRPα axis as a promising innate immune checkpoint in cancer, and with data of the first clinical studies with CD47‐SIRPα checkpoint inhibitors expected within the coming years, this is an exciting and rapidly developing field.
The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets
Authors: Allard Bertrand , Longhi Maria Serena , Robson Simon C. , Stagg John 
Published: March 2017

SummaryCancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection‐type processes or blocking suppressive pathways. Extracellular adenosine generated by the ectonucleotidases CD39 and CD73 is a newly recognized “immune checkpoint mediator” that interferes with anti‐tumor immune responses. In this review, we focus on CD39 and CD73 ectoenzymes and encompass aspects of the biochemistry of these molecules as well as detailing the distribution and function on immune cells. Effects of CD39 and CD73 inhibition in preclinical and clinical studies are discussed. Finally, we provide insights into potential clinical application of adenosinergic and other purinergic‐targeting therapies and forecast how these might develop in combination with other anti‐cancer modalities.
Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma
Authors: Lucca Liliana E. , Hafler David A. 
Published: March 2017

SummaryThe introduction of immunotherapy with checkpoint receptor blockade has changed the treatment of advanced cancers, at times inducing prolonged remission. Nevertheless, the success rate of the approach is variable across patients and different tumor types, and treatment is often accompanied by severe immune‐related side effects, suggesting the importance of co‐inhibitory pathway for both prevention of autoimmunity and failure of tumor rejection. A better understanding of how to uncouple anti‐tumor activity from loss of self‐tolerance is necessary to increase the therapeutic efficacy of checkpoint immunotherapy. In this review, we describe basic concepts of T‐cell exhaustion that occur in cancer, highlighting the role of co‐inhibitory receptors in contributing to this process while preventing immunopathology. By providing an overview of the current therapeutic success and immune‐related burden of secondary effects of checkpoint immunotherapy, we illustrate the “double‐edged sword” related to interference with immune‐regulatory pathways. Finally, since achieving tumor rejection while preserving self‐tolerance is particularly important for the central nervous system, we analyze the case for checkpoint immunotherapy in glioblastoma, the most common adult brain tumor.
Potential targeting of B7‐H4 for the treatment of cancer
Authors: Podojil Joseph R. , Miller Stephen D. 
Published: March 2017

SummaryObservations noting the presence of white blood cell infiltrates within tumors date back more than a century, however the cellular and molecular mechanisms regulating tumor immunity continue to be elucidated. The recent successful use of monoclonal antibodies to block immune regulatory pathways to enhance tumor‐specific immune responses for the treatment of cancer has encouraged the identification of additional immune regulatory receptor/ligand pathways. Over the past several years, a growing body of data has identified B7‐H4 (VTCN1/B7x/B7S1) as a potential therapeutic target for the treatment of cancer. The potential clinical significance of B7‐H4 is supported by the high levels of B7‐H4 expression found in numerous tumor tissues and correlation of the level of expression on tumor cells with adverse clinical and pathologic features, including tumor aggressiveness. The biological activity of B7‐H4 has been associated with decreased inflammatory CD4+ T‐cell responses and a correlation between B7‐H4‐expressing tumor‐associated macrophages and FoxP3+ regulatory T cells (Tregs) within the tumor microenvironment. Since B7‐H4 is expressed on tumor cells and tumor‐associated macrophages in various cancer types, therapeutic blockade of B7‐H4 could favorably alter the tumor microenvironment allowing for antigen‐specific clearance tumor cells. The present review highlights the therapeutic potential of targeting B7‐H4.
Wide‐range thermometry based on green up‐conversion luminescence of K3LuF6:Yb3+/Er3+ bulk oxyfluoride glass ceramics
Authors: Cao JiangKun , Hu FangFang , Chen LiPing , Guo Hai , Duan Changkui , Yin Min 
Published: March 2017

AbstractYb3+/Er3+ ions codoped bulk glass ceramics (GC) with embedded monoclinic K3LuF6 nanocrystals are reported for potential temperature‐sensing application by using the fluorescence intensity ratio method. Such GC with good transparency and enhanced up‐conversion were prepared by the simple conversional melt‐quenching method and subsequent annealing process. Optical, structural, and temperature‐sensing up‐conversion properties were characterized systematically. Optical spectroscopy analysis confirms the incorporation of Yb3+/Er3+ into the K3LuF6 crystalline lattice, resulting in enhanced up‐conversion luminescence. Compared to other Er3+‐doped typical systems, Er3+ ions in K3LuF6 GC present large energy gap (870 cm−1) and high relative sensitivity (37.6 × 10−4 K−1 at 625 K), revealing that K3LuF6:Yb3+/Er3+ GC can be excellent candidates for optical thermometers.
Experimental and first‐principles study of Ti–C–O system: Interplay of thermodynamic and structural properties
Authors: Jiang Bo , Xiao Jiusan , Huang Kai , Hou Jungang , Jiao Shuqiang , Zhu Hongmin 
Published: March 2017

AbstractThe thermodynamic properties and vacancy formation mechanism of Ti–C–O system were investigated by means of empirical calorimetry method and first‐principles calculations. The heat of combustion of titanium oxycarbides (TiC1−xOx, 0≤x≤1) solid solution were first measured by burning the materials in oxygen bomb calorimeter through sophisticated design experimental environment. The mixing enthalpy of the reaction (1−x)TiC + xTiO=TiC1−xOx was further calculated based on the measured data. Mixing enthalpy was also calculated via efficient first‐principles method based on the density functional theory. The vacancies in TiC1−xOx were described as two kinds of models that are disordered and segregated vacancies in titanium oxycarbides solid solution. The calculation results with segregation model show good agreement with the calorimetric results. The heat capacity values were further calculated to deduce the mixing and formation Gibbs free energy. The additive law of the heat capacity and entropy means that the structure of titanium oxycarbides tends to be in order, and this result shows a good agreement with the segregated model in TiC1−xOx. These results are explained on the basis of the interplay between thermodynamic and structural properties, which offered the important theoretic foundation for the novel titanium production process.
Electromechanical properties of CaZrO3 modified (K,Na)NbO3‐based lead‐free piezoceramics under uniaxial stress conditions
Authors: Wang Ke , Yao Fang‐Zhou , Koruza Jurij , Cheng Li‐Qian , Schader Florian H. , Zhang Mao‐Hua , Rödel Jürgen , Li Jing‐Feng , Webber Kyle G. 
Published: March 2017

AbstractPiezoelectric actuators are typically preloaded with a modest mechanical compressive stress during actuation to reduce cracking and allow for operation in the dynamic range. In addition, actuators are required to carry out mechanical work during operation, resulting in a nonlinear relationship between stress and actuation voltage. In fact, mechanical loading can significantly impact the electromechanical performance of lead‐free piezoelectrics. Herein, we report the dependence of electromechanical properties of CaZrO3 modified (K,Na)NbO3‐based lead‐free piezoceramics on uniaxial compressive stress, comparing to their lead‐based counterparts. It is demonstrated that increased non‐180° domain switching enhances the strain output at a moderate stress of approximately −50 MPa from room temperature to 150°C. Larger uniaxial stress, however, is found to suppress ferroelectric domain switching, resulting in the continuous strain and polarization decrease.
Microstructure evolution and thermomechanical properties of plasma‐sprayed Yb2SiO5 coating during thermal aging
Authors: Zhong Xin , Niu Yaran , Li Hong , Zeng Yi , Zheng Xuebin , Ding Chuanxian , Sun Jinliang 
Published: March 2017

AbstractRare‐earth monosilicates (RE2SiO5, RE: rare‐earth elements), such as Yb2SiO5, have been developed for potential application as environmental barrier coating (EBC) materials. Yb2SiO5 coating would experience microstructure evolution under high‐temperature environment and accordingly its thermomechanical properties would be altered. In this study, Yb2SiO5 coating was fabricated by atmospheric plasma spray technique. The phase stability and microstructure change before and after thermal aging at 1300°C, 1400°C, and 1500°C were investigated. The changes in mechanical and thermal properties were characterized. The results showed that the as‐sprayed coating was mainly composed of Yb2SiO5 with a small amount of Yb2O3 and amorphous phase. Defects in the coating, including interfaces, pores, and microcracks, were greatly reduced with grain growth after thermal treatment. Thermal aging significantly modified the thermal and mechanical properties of the coating. The average CTE was increased by 13.1%, and the hardness and elastic modulus was increased by 42.4% and 49.4%, respectively, after thermal aging at 1500°C for 50 hour. The thermal conductivity of thermal‐aged coating was much higher than that of the as‐sprayed coating, which was still less than 2 W/(m·K). The influence of coating microstructure on the properties was analyzed and related to the failure mechanism of EBCs.
Cold sintering process of Li1.5Al0.5Ge1.5(PO4)3 solid electrolyte
Authors: Berbano Seth S. , Guo Jing , Guo Hanzheng , Lanagan Michael T. , Randall Clive A. 
Published: March 2017

AbstractThe recently developed technique of cold sintering process (CSP) enables densification of ceramics at low temperatures, i.e., <300°C. CSP employs a transient aqueous solvent to enable liquid phase‐assisted densification through mediating the dissolution‐precipitation process under a uniaxial applied pressure. Using CSP in this study, 80% dense Li1.5Al0.5Ge1.5(PO4)3 (LAGP) electrolytes were obtained at 120°C in 20 minutes. After a 5 minute belt furnace treatment at 650°C, 50°C above the crystallization onset, Li‐ion conductivity was 5.4 × 10−5 S/cm at 25°C. Another route to high ionic conductivities ~10−4 S/cm at 25°C is through a composite LAGP ‐ (PVDF‐HFP) co‐sintered system that was soaked in a liquid electrolyte. After soaking 95, 90, 80, 70, and 60 vol% LAGP in 1 M LiPF6 EC‐DMC (50:50 vol%) at 25°C, Li‐ion conductivities were 1.0 × 10−4 S/cm at 25°C with 5 to 10 wt% liquid electrolyte. This paper focuses on the microstructural development and impedance contributions within solid electrolytes processed by (i) Crystallization of bulk glasses, (ii) CSP of ceramics, and (iii) CSP of ceramic‐polymer composites. CSP may offer a new route to enable multilayer battery technology by avoiding the detrimental effects of high temperature heat treatments.
Crystallization, mechanical, and optical properties of transparent, nanocrystalline gahnite glass‐ceramics
Authors: Molla Atiar R. , Rodrigues Alisson M. , Singh Shiv Prakash , Lancelotti Ricardo Felipe , Zanotto Edgar D. , Rodrigues Ana C.M. , Reza Dousti Mohammad , de Camargo Andrea S.S. , Magon Claudio José , Silva Igor D′Anciães Almeida 
Published: March 2017

AbstractThis paper describes the preparation of a transparent glass‐ceramic from the SiO2‐K2O‐ZnO‐Al2O3‐TiO2 system containing a single crystalline phase, gahnite (ZnAl2O4). TiO2 was used as a nucleating agent for the heat‐induced precipitation of gahnite crystals of 5‐10 nm. The evolution of the ZnAl2O4 spinel structure through the gradual formation of Al‐O bonds was examined by infrared spectroscopy. The dark brown color of the transparent precursor glass and glass‐ceramic was eliminated using CeO2. The increase in transparency of the CeO2‐doped glass and glass‐ceramics was demonstrated by UV‐visible absorption spectroscopy. EPR measurements confirmed the presence of Ce3+ ions, indicating that CeO2 was effective in eliminating the brown color introduced by Ti3+ ions via oxidation to Ti+4. The hardness of the glass‐ceramic was 30% higher than that of the as‐prepared glasses. This work offers key guidelines to produce hard, transparent glass‐ceramics which may be potential candidates for a variety of technological applications, such as armor and display panels.