BackgroundImmune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, most patients with cancer fail to respond clinically. One potential reason is the accumulation of ...immunosuppressive transforming growth factor β (TGFβ) in the tumor microenvironment (TME). TGFβ drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8+ T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGFβ1, TGFβ2 and TGFβ3, with its expression restricted predominantly to effector Tregs, cancer cells, and platelets.MethodsWe investigated the role of GARP in human patients with cancer by analyzing existing large databases. In addition, we generated and humanized an anti-GARP monoclonal antibody and evaluated its antitumor efficacy and underlying mechanisms of action in murine models of cancer.ResultsWe demonstrate that GARP overexpression in human cancers correlates with a tolerogenic TME and poor clinical response to ICB, suggesting GARP blockade may improve cancer immunotherapy. We report on a unique anti-human GARP antibody (named PIIO-1) that specifically binds the ligand-interacting domain of all latent TGFβ isoforms. PIIO-1 lacks recognition of GARP-TGFβ complex on platelets. Using human LRRC32 (encoding GARP) knock-in mice, we find that PIIO-1 does not cause thrombocytopenia; is preferentially distributed in the TME; and exhibits therapeutic efficacy against GARP+ and GARP- cancers, alone or in combination with anti-PD-1 antibody. Mechanistically, PIIO-1 treatment reduces canonical TGFβ signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8+ T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner.ConclusionGARP contributes to multiple aspects of immune resistance in cancer. Anti-human GARP antibody PIIO-1 is an efficacious and safe strategy to block GARP-mediated LTGFβ activation, enhance CD8+ T cell trafficking and functionality in the tumor, and overcome primary resistance to anti-PD-1 ICB. PIIO-1 therefore warrants clinical development as a novel cancer immunotherapeutic.
Inflammation is viewed as a protective response against insults to the organism. It involves the recruitment of many cell types and the production of various inflammatory mediators in attempts to ...contain and reverse the insult. However, inflammation can lead to irreversible tissue destruction by itself and, therefore, can represent a disease state that causes significant morbidity and mortality. Understanding the molecular mechanisms controlling the inflammatory response is essential to formulate therapeutic strategies for the treatment of inflammatory conditions. In fact, substantial research has unveiled important aspects of the inflammatory machinery, both at the cellular and molecular levels. Recently, sphingolipids (SLs) have emerged as signaling molecules that regulate many cell functions, and ample evidence emphasizes their role in the regulation of inflammatory responses. Here, we review the role of bioactive SL as regulators and mediators of inflammatory responses.
J. Neurochem. (2010) 113, 919-929. The mechanisms by which chronic nicotine self-administration augments hypothalamo-pituitary-adrenal (HPA) responses to stress are only partially understood. ...Nicotine self-administration alters neuropeptide expression in corticotropin-releasing factor (CRF) neurons within paraventricular nucleus (PVN) and increases PVN responsiveness to norepinephrine during mild footshock stress. Glutamate and GABA also modulate CRF neurons, but their roles in enhanced HPA responsiveness to footshock during chronic self-administration are unknown. We show that nicotine self-administration augmented footshock-induced PVN glutamate release, but further decreased GABA release. In these rats, intra-PVN kynurenic acid, a glutamate receptor antagonist, blocked enhanced adrenocorticotropic hormone and corticosterone responses to footshock. In contrast, peri-PVN kynurenic acid, which decreases activity of GABA afferents to PVN, enhanced footshock-induced corticosterone secretion only in control rats self-administering saline. Additionally, in rats self-administering nicotine, footshock-induced elevation of corticosterone was significantly less than in controls after intra-PVN saclofen (GABA-B receptor antagonist). Therefore, the exaggerated reduction in GABA release by footshock during nicotine self-administration disinhibits CRF neurons. This disinhibition combined with enhanced glutamate input provides a new mechanism for HPA sensitization to stress by chronic nicotine self-administration. This mechanism, which does not preserve homeostatic plasticity, supports the concept that smoking functions as a chronic stressor that sensitizes the HPA to stress.
We report on a class of quantum spin Hall insulators (QSHIs) in strained-layer InAs/GaInSb quantum wells, in which the bulk gaps are enhanced up to fivefold as compared to the binary InAs/GaSb QSHI. ...Remarkably, with consequently increasing edge velocity, the edge conductance at zero and applied magnetic fields manifests time reversal symmetry-protected properties consistent with the Z_{2} topological insulator. The InAs/GaInSb bilayers offer a much sought-after platform for future studies and applications of the QSHI.
The severe scattering at metal-oxide-semiconductor (MOS) interfaces, manifesting as carrier mobility declining, is always a puzzle in the field of Si-based field-effect transistors (FETs) towards ...high-performance devices. In this work, an elaborate study on interfacial scattering suppression through process optimization is reported. Dry oxidation is proved to be more efficient in the construction of a damage-free oxide/semiconductor interface. Meanwhile, a thick thermal-SiO2 interlayer (i.e. a long growth time), together with a long-duration post-annealing treatment, is beneficial for interface planarization. Such an interface roughness scattering control, combined with Coulomb and defect scattering restrictions, can be realized with an optimized FET process flow. On this occasion, the as-fabricated Si MOSFETs show a higher gate-controlled drain current, and are with a peak electron mobility of ∼8372 cm2 V−1 s−1 at 1.6 K. Moreover, confined magnetotransport properties of two-dimensional electron gas are further revealed by the integer quantum Hall effects. Notably, our work presents a feasible integration flow to fabricate high-mobility Si MOS devices via scattering suppression, which may promote the evolution of Si-based MOS quantum dots for potential solid-state quantum computing.
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Tannin-immobilized cellulose (CT) hydrogels were successfully fabricated by homogeneous immobilization and crosslinking reaction via a simple method. The structures and properties of hydrogels were ...characterized by SEM and mechanical test. Methlyene Blue (MB) was selected as a cationic dye model, and the adsorption ability of CT hydrogel was evaluated. Tannins immobilized acted as adsorbent sites which combined MB by electrostatic attraction, resulting in the attractive adsorption ability of CT hydrogel. Adsorption kinetics could be better described by the pseudo-second-order model, and the absorption behaviors were in agreement with a Langmuir isotherm. The adsorption-desorption cycle of CT hydrogel was repeated six times without significant loss of adsorption capacity. In this work, both tannin immobilization and hydrogel formation were achieved simultaneously by a facile homogeneous reaction, providing a new pathway to fabricate tannin-immobilized materials for water treatment.
We report an experimental study of proximity induced superconductivity in planar Josephson junction devices made from free-standing InAs nanosheets. The nanosheets are grown by molecular beam ...epitaxy, and the Josephson junction devices are fabricated by directly contacting the nanosheets with superconductor Al electrodes. The fabricated devices are explored by low-temperature carrier transport measurements. The measurements show that the devices exhibit a gate-tunable supercurrent, multiple Andreev reflections, and a good quality superconductor-semiconductor interface. The superconducting characteristics of the Josephson junctions are investigated at different magnetic fields and temperatures and are analyzed based on the Bardeen–Cooper–Schrieffer (BCS) theory. The measurements of the ac Josephson effect are also conducted under microwave radiations with different radiation powers and frequencies, and integer Shapiro steps are observed. Our work demonstrates that InAs nanosheet based hybrid devices are desired systems for investigating the forefront of physics, such as two-dimensional topological superconductivity.
Emerging evidence suggests that microRNAs (miRNAs) play a critical role in the pathogenesis of neuropathic pain. However, the exact role of miRNAs in regulating neuropathic pain remains largely ...unknown. In this study, we aimed to investigate the potential role of miR-93 in a rat model of neuropathic pain induced by chronic constriction sciatic nerve injury (CCI). We found a significant decrease of miR-93 in the spinal cord of CCI rats compared with sham rats. Overexpression of miR-93 significantly alleviated neuropathic pain development and reduced inflammatory cytokine expression, including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in CCI rats. By bioinformatic analysis and dual-luciferase reporter assay, we found that miR-93 directly targeted the 3′-untranslated region (UTR) of signal transducer and activator of transcription 3 (STAT3), an important regulator of inflammation. Overexpression of miR-93 markedly suppressed the expression of STAT3 in vitro and in vivo. Furthermore, overexpression of STAT3 significantly reversed the miR-93 overexpression-induced suppressive effects on neuropathic pain development and neuroinflammation. Taken together, our study suggests that miR-93 inhibits neuropathic pain development of CCI rats possibly through inhibiting STAT3-mediated neuroinflammation. Our findings indicate that miR-93 may serve as a novel therapeutic target for neuropathic pain intervention.
•miR-93 is decreased in CCI rats.•Overexpression of miR-93 alleviates neuropathic pain.•Overexpression of miR-93 attenuates neuroinflammation.•STAT3 is a target gene of miR-93.
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