Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising ...from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects.
Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe2+/Fe3+ coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo.
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Antibodies targeting PD-1 have been demonstrated durable anti-cancer activity in certain cancer types. However, the anti-PD-1 antibodies are less or not efficacious in many situations, which might be ...attributed to co-expression of multiple inhibitory receptors or presence of immunosuppressive cells in the tumor microenvironment. Most of the anti-PD-1 antibodies used in clinical studies are of IgG4 isotype with the S228P mutation (IgG4
S228P
). The functional impact by the interaction of anti-PD-1 IgG4
S228P
antibody with Fc gamma receptors (FcγRs) is poorly understood. To assess the effects, we generated a pair of anti-PD-1 antibodies: BGB-A317/IgG4
S228P
and BGB-A317/IgG4-variant (abbreviated as BGB-A317), with the same variable regions but two different IgG4 Fc-hinge sequences. There was no significant difference between these two antibodies in binding to PD-1. However, BGB-A317/IgG4
S228P
binds to human FcγRI with high affinity and mediates crosslinking between PD-1 and FcγRI. In contrast, BGB-A317 does neither. Further cell-based assays showed that such crosslinking could reverse the function of an anti-PD-1 antibody from blocking to activating. More importantly, the crosslinking induces FcγRI
+
macrophages to phagocytose PD-1
+
T cells. In a mouse model transplanted with allogeneic human cancer cells and PBMCs, BGB-A317 showed significant tumor growth inhibition, whereas BGB-A317/IgG4
S228P
had no such inhibition. Immunohistochemistry study revealed an inverse correlation between FcγRI
+
murine macrophage infiltration and the density of CD8
+
PD-1
+
human T cells within tumors in the BGB-A317/IgG4
S228P
-treated group. These evidences suggested that FcγRI
+
binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity.
•Parameterized noise simulation was used to simulate the spatial distribution.•Using the Spatial average and statistics sound pressure level as observation indexes.•Determining the degree and scope ...of influence of various urban indexes.•Road area density have the greatest influence on Spatial average sound pressure level.
Urban spatial structure factors can have considerable effects on traffic noise distribution. This study aimed to describe the spatial distribution characteristics of traffic noise and influencing factors in high-density cities. Fifteen indexes were selected from the three aspects of building layout, road organization and land use to analyse the influence of urban spatial structure factors on the noise spatial distribution. This paper selected the central area of Tianjin as the study area. The noise level was generated by the noise simulation software CadnaA, and the numerical statistics were determined by ArcGIS. The correlation between various urban indexes and the spatial distribution of traffic noise were determined with correlation analysis, and multiscale geographically weighted regression (MGWR) analysis was used to determine the degree and scope of influence of various urban indexes on the spatial distribution of traffic noise. The results indicate that there are significant differences in the spatial agglomeration forms of high, medium, and low noise areas among research units, and the spatial agglomeration of low noise areas in each unit is stronger. The building layout indexes, except for the average building height (ABH), are significantly negatively correlated with the noise levels in low noise areas (L70–L90). The road length index (RLI), road area density (RAD), road landscape shape index (RLSI), trunk road length index (TRLI), proportion of traffic land (PT), and degree of land mixing (DLM) are significantly positively correlated with the noise levels of all areas within the unit (L10–L90). Among the three aspects of building layout, road organization, and land use, the architectural landscape shape index (ALSI), RAD, and DLM have the greatest influence on the average spatial sound pressure level (Lavg), with mean regression coefficients of −0.254, 0.520, and 0.174, respectively. The ground space index (GSI), ALSI, proportion of residential land (PR) and PT are the global factors influencing Lavg.
Summary Objective Increased activity of histone deacetylase 2 (HDAC2) has been found in patients with osteoarthritis (OA) and cartilage matrix degradation and has been shown to mediate the repression ...of cartilage-specific gene expression in human chondrocytes. We aimed to determine whether microRNA-92a-3p (miR-92a-3p) regulates cartilage-specific gene expression via targeted HDAC2 in chondrogenesis and degradation. Methods miR-92a-3p expression was assessed in vitro in a human mesenchymal stem cells (hMSCs) model of chondrogenesis and in normal and OA primary human chondrocytes (PHCs), and in normal and OA human cartilage by in situ hybridization. hMSCs and PHCs were transfected with miR-92a-3p or its antisense inhibitor (anti-miR-92a-3p), respectively. PHCs were transfected with miR-92a-3p or anti-miR-92a-3p for 24 h before chromatin immunoprecipitation assay was performed with anti-ac-H3 antibody. Direct interaction between miR-92a-3p and its putative binding site in the 3’ untranslated region (3’-UTR) of HDAC2 mRNA was confirmed by luciferase reporter assay. Results miR-92a-3p expression was elevated in chondrogenic and hypertrophic hMSC, while reduced in OA cartilage compared with normal cartilage. The overexpression of miR-92a-3p suppressed the activity of a reporter construct containing the 3’-UTR and inhibited HDAC2 expression in both hMSCs and PHCs, while treatment with anti-miR-92a-3p enhanced HDAC2 expression. Chromatin immunoprecipitation assays showed that miR-92a-3p enhances H3 acetylation on ACAN, COMP and Col2a1 promoter, and also promotes relative cartilage matrix expression. Conclusion Our results suggest that miR-92a-3p regulates cartilage development and homeostasis, which directly targets HDAC2, indicating histone hyperacetylation plays an important role in increased expression of cartilage matrix.
Building detection is a crucial task in the field of remote sensing, which can facilitate urban construction planning, disaster survey, and emergency landing. However, for large-size remote sensing ...images, the great majority of existing works have ignored the image tilt problem. This problem can result in partitioning buildings into separately oblique parts when the large-size images are partitioned. This is not beneficial to preserve semantic completeness of the building objects. Motivated by the above fact, we first propose a framework for detecting objects in a large-size image, particularly for building detection. The framework mainly consists of two phases. In the first phase, we particularly propose a tilt correction (TC) algorithm, which contains three steps: texture mapping, tilt angle assessment, and image rotation. In the second phase, building detection is performed with object detectors, especially deep-neural-network-based methods. Last but not least, the detection results will be inversely mapped to the original large-size image. Furthermore, a challenging dataset named Aerial Image Building Detection is contributed for the public research. To evaluate the TC method, we also define an evaluation metric to compute the cost of building partition. The experimental results demonstrate the effects of the proposed method for building detection.
Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide and has no effective treatment, yet the molecular basis of hepatocarcinogenesis remains largely unknown. Here we report ...findings from a whole-genome sequencing (WGS) study of 88 matched HCC tumor/normal pairs, 81 of which are Hepatitis B virus (HBV) positive, seeking to identify genetically altered genes and pathways implicated in HBV-associated HCC. We find beta-catenin to be the most frequently mutated oncogene (15.9%) and TP53 the most frequently mutated tumor suppressor (35.2%). The Wnt/beta-catenin and JAK/STAT pathways, altered in 62.5% and 45.5% of cases, respectively, are likely to act as two major oncogenic drivers in HCC. This study also identifies several prevalent and potentially actionable mutations, including activating mutations of Janus kinase 1 (JAK1), in 9.1% of patients and provides a path toward therapeutic intervention of the disease.
Graphene‐based materials still exhibit poor electrocatalytic activities for the hydrogen evolution reaction (HER) although they are considered to be the most promising electrocatalysts. We fabricated ...a graphene‐analogous material displaying exceptional activity towards the HER under acidic conditions with an overpotential (57 mV at 10 mA cm−2) and Tafel slope (44.6 mV dec−1) superior to previously reported graphene‐based materials, and even comparable to the state‐of‐the art Pt/C catalyst. X‐ray absorption near‐edge structure (XANES) and solid‐state NMR studies reveal that the distinct feature of its structure is dual graphitic‐N doping in a six‐membered carbon ring. Density functional theory (DFT) calculations show that the unique doped structure is beneficial for the activation of C−H bonds and to make the carbon atom bonded to two graphitic N atoms an active site for the HER.
That material is dope! Graphene‐analogous particles with dual graphitic‐N doping in a six‐membered carbon ring are successfully prepared. Infrared spectroscopy, synchrotron‐based X‐ray absorption spectroscopy, and solid‐state NMR spectroscopy are applied to study its structure and mechanism in the hydrogen evolution reaction, where a current density of 10 mA cm−2 is achieved at an overpotential of 57 mV.
Paddy soils are susceptible to microplastics (MPs) contamination. As a common soil amendment, biochar (BC) has been extensively applied in paddy fields. The co-occurrence of MPs and BC may cause ...interactive effects on soil biogeochemical processes, which has yet been well studied. In this study, a 41-days of microcosm experiment was conducted using paddy soil added with 0.5–1.5 wt% of low-density polyethylene (LDPE) and 5 wt% of BC individually or jointly. Application of BC, LDPE, or their mixture into soil significantly increased the emission of methane (CH4), but suppressed the emission of carbon dioxide (CO2). LDPE addition lowered soil nitrous oxide (N2O) emissions, while BC exerted an opposite effect. Proteobacteria was the most dominant phylum with a relative abundance range of 35.1–51.0%, followed by Actinobacteria (19.3–30.9%) and Acidobacteria (7.5–23.5%). The abundances of the mcrA gene and pH values were increased in soils added with BC or/and LDPE, which were the possible reasons for the higher CH4 emissions in these treatments. The emission of N2O was positively related to the abundances of norB and narG genes, suggesting denitrification was a major pathway to produce N2O. Results of structural equation modeling demonstrated that addition of BC or/and LDPE MPs could affect greenhouse gas emissions from paddy soil by altering soil chemical properties, microbial community structure, and functional gene abundances.
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•LDPE or/and BC additions increased soil CH4 emissions, but suppressed CO2 fluxes.•Addition of LDPE decreased soil N2O emissions, while BC exerted a promoting effect.•Proteobacteria dominated the soil bacterial communities under different treatments.•The increased pH values and higher mcrA gene abundance promoted soil CH4 emissions.•Denitrification played an important role in regulating soil N2O emissions.
Considering the complexity and diversity of cloud requests in the cloud environment, cloud requests are divided into primary requests (PRs) with high priority and secondary requests (SRs) with low ...priority. We introduce the entry threshold and the entry probability to control the entry of SRs. If the number of busy virtual machines (VMs) is greater than or equal to the entry threshold, the recently arrived SR will enter the system with an entry probability that is inversely proportional to the number of busy VMs. Based on the proposed cloud resource allocation strategy with entry control, a discrete-time queueing model is constructed, and the expressions of performance indicators are derived. Compared with the conventional cloud resource allocation strategy without entry control, the proposed cloud resource allocation strategy with entry control can effectively improve the service experience of PRs. For example, when the arrival rate of PRs is equal to 0.5, under the parameter settings given by experiments, the proposed cloud resource allocation strategy can reduce the blocking rate of PRs by 47% and increase the throughput rate of PRs by 55% at most. Finally, we construct a revenue function to obtain the optimal entry thresholds and maximum revenues under different conditions.
miR-222 is one of the most consistently overexpressed miRNAs in papillary thyroid carcinoma (PTC). Previous studies demonstrated that miR-222 overexpression conferred high-risk features in PTC ...patients, suggesting its value in risk-stratification. However, studies in term of miR-222's utility on stratifying PTCs are lacking.
One hundred patients including 10 with multinodular goiter and 90 with PTC were enrolled. Formalin-fixed paraffin-embedded samples were exploited for miR-222 quantitative reverse transcriptase- polymerase chain reaction (RT-PCR) analysis. Correlations between miR-222 expression and different clinicopathological features, Tumor-node-metastasis (TNM) staging and ATA risk level were analyzed.
miR-222 expression of the PTC group was significantly higher than that of the goiter group (P < .001). Furthermore, miR-222 expression was significantly higher in PTCs with advanced features like larger tumor, capsular invasion, vascular invasion and lymph nodes metastasis. The majority of patients (61%) were in stage I group (similar to ATA low-risk) by TNM staging system. As to the ATA system, the majority (73%) were in intermediate-risk group (similar to TNM stage II and III roughly). Contrary to previous report, here we found that miR-222 expression was correlated with the ATA risk level (P < .001), but not with the TNM staging (P = .122).
In the present study, we demonstrated that miR-222 overexpression was correlated with advanced features like capsular invasion, vascular invasion, larger tumor size and lymph node metastasis in PTCs. Most importantly, miR-222 expression was correlated with ATA risk levels, suggesting its potential value in PTC risk-stratification.
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