Immune checkpoint blockade (ICB) therapy shows excellent efficacy against malignancies; however, insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (TME) are ...considered as the two major stumbling blocks to a broad ICB response. Here, a combinational therapeutic strategy is reported, wherein TME‐reactive oxygen species/pH dual‐responsive signal transducers and activators of transcription 3 inhibitor nanoprodrugs MPNPs are combined with oncolytic herpes simplex virus 1 virotherapy to synergistically ignite pyroptosis for enhancing immunotherapy. MPNPs exhibit a certain level of tumor accumulation, reduce tumor cell stemness, and enhance antitumor immune responses. Furthermore, the simultaneous application of oncolytic viruses (OVs) confers MPNPs with higher tumor penetration capacity and remarkable gasdermin‐E‐mediated pyroptosis, thereby reshaping the TME and transforming “cold” tumors into “hot” ones. This “fire of immunity” strategy successfully activates robust T‐cell‐dependent antitumor responses, potentiating ICB effects against local recurrence and pulmonary metastasis in preclinical “cold” murine triple‐negative breast cancer and syngeneic oral cancer models. Collectively, this work may pave a new way and offer an unprecedented opportunity for the combination of OVs with nanomedicine for cancer immunotherapy.
Combination therapy with oHSV + MPNPs boosts the effects of immune checkpoint therapy by inducing gasdermin‐E‐based tumor pyroptosis, reversing the immunosuppressive microenvironment, and inducing effective immune memory, thus potentiating anti‐PD‐1 effects against local recurrence and pulmonary metastasis and consequently elongating the survival period. The nanoprodrugs + oncolytic viruses strategy represents a promising way to overcome immune checkpoint blockade resistance.
Uniaxial compression experiments were performed for brittle sandstone samples containing a single fissure by a rock mechanics servo-controlled testing system. Based on the experimental results of ...axial stress-axial strain curves, the influence of single fissure geometry on the strength and deformation behavior of sandstone samples is analyzed in detail. Compared with the intact sandstone sample, the sandstone samples containing a single fissure show the localization deformation failure. The uniaxial compressive strength, Young’s modulus and peak axial strain of sandstone samples with pre-existing single fissure are all lower than that of intact sandstone sample, which is closely related to the fissure length and fissure angle. The crack coalescence was observed and characterized from tips of pre-existing single fissure in brittle sandstone sample. Nine different crack types are identified based on their geometry and crack propagation mechanism (tensile, shear, lateral crack, far-field crack and surface spalling) for single fissure, which can be used to analyze the failure mode and cracking process of sandstone sample containing a single fissure under uniaxial compression. To confirm the subsequence of crack coalescence in sandstone sample, the photographic monitoring and acoustic emission (AE) technique were adopted for uniaxial compression test. The real-time crack coalescence process of sandstone containing a single fissure was recorded during the whole loading. In the end, the influence of the crack coalescence on the strength and deformation failure behavior of brittle sandstone sample containing a single fissure is analyzed under uniaxial compression. The present research is helpful to understand the failure behavior and fracture mechanism of engineering rock mass (such as slope instability and underground rock burst).
Long-term experiments were performed on red sandstones after different thermal treatments (25, 300, 700 and 1000 °C) under multi-step loading and unloading cycles and a confining pressure of 25 MPa. ...Furthermore, to quantitatively analyse the temperature influence on the deformation behaviours of the specimens, the concept of the temperature–strain rate was proposed to describe the relationship between strain and temperature, and the experimental results were corrected to identical temperatures (i.e., 20 °C), to overcome the influence of periodic fluctuations in ambient temperature. The results show that the axial mean temperature–strain rate first increased as temperature increased from 25 to 300 °C and then decreased with increasing temperature, whereas the lateral mean temperature–strain rate decreased with increasing temperature. The total strain was divided into the instantaneous elastic strain, the instantaneous plastic strain, the visco-elastic strain and the visco-plastic strain. The total axial strain increased with increasing deviatoric stress, and the irrecoverable strain increased with increasing loading and unloading history. Furthermore, the total axial strain increased with increasing temperature; specifically, at 1000 °C, it was approximately two times that at 700 °C and three times those at 25 and 300 °C. The instantaneous elastic strain and the instantaneous plastic strain increased approximately linearly with increasing deviatoric stress, whereas the creep strain varied with deviatoric stress in complicated ways at different temperatures. However, under identical deviatoric stress, the instantaneous elastic strain and the instantaneous plastic strain increased slightly as temperature increased from 25 to 700 °C and then increased substantially as temperature reached 1000 °C, whereas the variations in the creep strain, the visco-elastic strain and the visco-plastic strain were dependent on temperature and stress level. Finally, the permeability first decreased slightly as temperature increased from 25 to 300 °C and then increased with increasing temperature.
Frequency combs have applications that extend from the ultra-violet into the mid-infrared bands. Microcombs, a miniature and often semiconductor-chip-based device, can potentially access most of ...these applications, but are currently more limited in spectral reach. Here, we demonstrate mode-locked silica microcombs with emission near the edge of the visible spectrum. By using both geometrical and mode-hybridization dispersion control, devices are engineered for soliton generation while also maintaining optical Q factors as high as 80 million. Electronics-bandwidth-compatible (20 GHz) soliton mode locking is achieved with low pumping powers (parametric oscillation threshold powers as low as 5.4 mW). These are the shortest wavelength soliton microcombs demonstrated to date and could be used in miniature optical clocks. The results should also extend to visible and potentially ultra-violet bands.
Abstract
Frustrated magnets hold the promise of material realizations of exotic phases of quantum matter, but direct comparisons of unbiased model calculations with experimental measurements remain ...very challenging. Here we design and implement a protocol of employing many-body computation methodologies for accurate model calculations—of both equilibrium and dynamical properties—for a frustrated rare-earth magnet TmMgGaO
4
(TMGO), which explains the corresponding experimental findings. Our results confirm TMGO is an ideal realization of triangular-lattice Ising model with an intrinsic transverse field. The magnetic order of TMGO is predicted to melt through two successive Kosterlitz–Thouless (KT) phase transitions, with a floating KT phase in between. The dynamical spectra calculated suggest remnant images of a vanishing magnetic stripe order that represent vortex–antivortex pairs, resembling rotons in a superfluid helium film. TMGO therefore constitutes a rare quantum magnet for realizing KT physics, and we further propose experimental detection of its intriguing properties.
Compact, low-noise microwave sources are required throughout a wide range of application areas including frequency metrology, wireless-communications and airborne radar systems. And the photonic ...generation of microwaves using soliton microcombs offers a path towards integrated, low noise microwave signal sources. In these devices, a so called quiet-point of operation has been shown to reduce microwave frequency noise. Such operation decouples pump frequency noise from the soliton's motion by balancing the Raman self-frequency shift with dispersive-wave recoil. Here, we explore the limit of this noise suppression approach and reveal a fundamental noise mechanism associated with fluctuations of the dispersive wave frequency. At the same time, pump noise reduction by as much as 36 dB is demonstrated. This fundamental noise mechanism is expected to impact microwave noise (and pulse timing jitter) whenever solitons radiate into dispersive waves belonging to different spatial mode families.
Abstract
Background
The relationship between triglyceride-glucose index (TyG index) and the prevalence and prognosis of cardiovascular disease has been confirmed by former studies. However, it ...remains uncertain whether TyG index has a prognostic impact in patients with type 2 diabetes mellitus (T2DM) and non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).
Methods
The study retrospectively enrolled 798 patients (mean age: 60.9 ± 8.3 years; 68.3% men) with T2DM and NSTE-ACS who underwent PCI at Beijing Anzhen Hospital from January to December 2015. TyG index was calculated as previously reported: ln fasting TGs (mg/dL) * FBG (mg/dL)/2. The primary endpoint was a composite of adverse events as follows: all-cause death, non-fatal myocardial infarction (MI) and ischemia-driven revascularization.
Results
TyG index was significantly higher in patients with a primary endpoint event compared with those without. Multivariate Cox proportional hazards analysis showed that 1-unit increase of TyG index was independently associated with higher risk of primary endpoint, independent of other risk factors hazard ratio (HR) 3.208 per 1-unit increase, 95% confidence interval (CI) 2.400–4.289, P < 0.001. The addition of TyG index to a baseline risk model had an incremental effect on the predictive value for adverse prognosis AUC: baseline risk model, 0.800 vs. baseline risk model + TyG index, 0.856, P for comparison < 0.001; category-free net reclassification improvement (NRI) 0.346, P < 0.001; integrated discrimination improvement (IDI) 0.087, P < 0.001.
Conclusions
Increased TyG index is a significant predictor of adverse prognosis in patients with T2DM and NSTE-ACS undergoing PCI. Further studies need to be performed to determine whether interventions for TyG index have a positive impact on improving clinical prognosis.
The modification of protein and nanoparticle therapeutics with polyethylene glycol (PEG), a flexible, uncharged, and highly hydrophilic polymer, is a widely adopted approach to reduce RES clearance, ...extend circulation time, and improve drug efficacy. Nevertheless, an emerging body of literature, generated by numerous research groups, demonstrates that the immune system can produce antibodies that specifically bind PEG, which can lead to the ‘accelerated blood clearance’ of PEGylated therapeutics. In animals, anti‐PEG immunity is typically robust but short‐lived and consists of a predominantly anti‐PEG IgM response. Rodent studies suggest that the induction of anti‐PEG antibodies (α‐PEG Abs) primarily occurs through a type 2 T‐cell independent mechanism. Although anti‐PEG immunity is less well‐studied in humans, the presence of α‐PEG Abs has been correlated with reduced efficacy of PEGylated therapeutics in clinical trials. The prevalence of anti‐PEG IgG and reports of memory immune responses, as well as the existence of α‐PEG Abs in healthy untreated individuals, suggests that the mechanism(s) and features of human anti‐PEG immune responses may differ from those of animal models. Many questions, including the incidence rate of pre‐existing α‐PEG Abs and immunological mechanism(s) of α‐PEG Ab formation in humans, must be answered in order to fully address the potential complications of anti‐PEG immunity. WIREs Nanomed Nanobiotechnol 2015, 7:655–677. doi: 10.1002/wnan.1339
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Aqueous Zn batteries that provide a synergistic integration of absolute safety and high energy density have been considered as highly promising energy‐storage systems for powering electronics. ...Despite the rapid progress made in developing high‐performance cathodes and electrolytes, the underestimated but non‐negligible dendrites of Zn anode have been observed to shorten battery lifespan. Herein, this dendrite issue in Zn anodes, with regard to fundamentals, protection strategies, characterization techniques, and theoretical simulations, is systematically discussed. An overall comparison between the Zn dendrite and its Li and Al counterparts, to highlight their differences in both origin and topology, is given. Subsequently, in‐depth clarifications of the specific influence factors of Zn dendrites, including the accumulation effect and the cathode loading mass (a distinct factor for laboratory studies and practical applications) are presented. Recent advances in Zn dendrite protection are then comprehensively summarized and categorized to generate an overview of respective superiorities and limitations of various strategies. Accordingly, theoretical computations and advanced characterization approaches are introduced as mechanism guidelines and measurement criteria for dendrite suppression, respectively. The concluding section emphasizes future challenges in addressing the Zn dendrite issue and potential approaches to further promoting the lifespan of Zn batteries.
Zinc‐based batteries demonstrate both intrinsic safety and high energy density compared with other metal batteries. Nevertheless, zinc‐dendrite issues such as special morphology and nucleation require unique protections, which develop rapidly and need further improvement. The remaining challenges are discussed and the future directions, i.e., dynamic contact, atomic‐level ionic flow mediation, dendrite protection under high depth of discharge, etc., are proposed.
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