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Jiahan Qiu,1,2 Jiaxun Chen,2 Gaopi Deng,1,* Shuo Yuan1,* 1Department of Gynaecology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuo Yuan, Department of Gynaecology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Jichang Road 16#, District Baiyun, Guangzhou, 510405, People’s Republic of China, Tel +86-13632466654, Email twinklingyuan@gzucm.edu.cnBackground: In this study, we conducted an integrated study of the diagnostic value of MiR-223 in ectopic pregnancy (EP).Methods: We used GSE44731 downloaded from GEO and GEO2R to identify differentially expressed miRNA. The hub genes corresponding to the differential miRNA were then identified by using the Xiantao academic tool, GO (Gene Ontology), and KEGG (Kyoto Encyclopedia of Genes and Genomes). Afterward, we used the miEAA database to perform gene set enrichment analysis (GSEA) of differential miRNA, and used Xiantao academic tools again to conduct the ceRNA network based on the target genes. Protein–protein interaction (PPI) network construction and lncRNA of hub miRNA target genes were then predicted by the starbase database. For validation, the villus tissue from intrauterine pregnancy and tubal pregnancy was collected and assayed by qPCR.Results: In total 19 differentially expressed miRNAs were screened out, of which MiR-223 had a relatively clear diagnostic significance. Hub genes were enriched and analyzed by GO, KEGG, and GSEA, and the results showed that regulation of NF-κB and other signaling pathways are primarily enriched in ectopic pregnancy. We also obtained 215 key genes from PPI analysis. Our ceRNA analysis indicated that LRRC75A-AS1 and PITPNA-AS1 were associated with MiR-223, and the expression of MiR-223 in qPCR was significantly high in tubal pregnancy group.Conclusion: We found that MiR-223 can be used in the diagnosis of EP. Our findings provide valuable information and direction for future research into novel targets for EP diagnosis.Keywords: MiRNA-223, tubal pregnancy, disease marker, biomarker, GEO

List of primers used in real-time PCR experiments

Purpose:KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis.Experimental Design: A total of 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacologic methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations.Results: Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557–558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557–558 deletion (KIT Δ557–558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT Δ557–558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT Δ557–558–mediated cell migration. Moreover, KIT Δ557–558–induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT Δ557–558 was prevented. In addition, KIT exon 11 codons 557–558 deletion enhanced CXCL12-mediated GIST cell migration and invasion.Conclusions:KIT exon 11 557–558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs. Clin Cancer Res; 22(14); 3477–87. ©2016 AACR.

KIT and PDGFRα mutation types in primary GISTs with respect to liver metastasis

List of antibodies

Primers used for ChIP experiments

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly neurodevelopmental disorders with a complex symptomatology in children, and frequently suffer from deficits in executive functions and motor abilities. Although medication-based treatments usually have a positive effect, possible side effects may result in a need for an adjunctive intervention. Present studies show positive effect of physical exercise on cognitive function. Therefore, the purpose of the current study is thoroughly examine the effects of physical exercise in children with ADHD. Preliminary evidence shows both acute and chronic physical exercise are beneficial to ADHD symptoms, executive function, and motor abilities. Benefits of acute exercise may gradually accumulate over time. Such benefits reflect the positive correlation between cognition and physical activity, and these benefits will also lead to changes in executive function after long-term training. Aerobic could induce to increase the neurotransmitter ie. serotonin, dopamine, brain-derived neurotrophic factor (BDNF) and brain blood flow. Perceptual motor and meditation could lead to neuroplasticity in nerve cells and synaptic connections; furthermore, strengthening the sensory-motor base contributes to the improvement of attention. An exercise program for children with ADHD include to moderate to high intensity interval training and cognitive tasks are suitable. The preliminary state of the evidence supports physical exercise as an adjunctive treatment for ADHD at this time.

The purpose of this study was to investigate whether modeling within separate body mass index (BMI) stratifications improves the accuracy of maximal oxygen uptake (VO

In this paper, we will consider a class of continuous-time stochastic control systems with both unknown nonlinear structure and unknown disturbances, and investigate the capability of the classical proportional-integral-derivative(PID) controller in tracking time-varying reference signals. First, under some suitable conditions on system nonlinear functions, reference signals, and unknown disturbances, we will show that PID controllers can be designed to globally stabilize such systems and ensure the boundedness of the tracking error. Analytic design formulae for PID gain matrices are also provided, which only involve some prior knowledge of the partial derivatives of system structural nonlinear functions. Besides, it will be shown that the steady-state tracking error hinges on three critical factors: i) the change rate of reference signals and external disturbances; ii) the intensity of random noises; iii) the selection of PID gains, and can be made arbitrarily small by choosing PID gains suitably large. Finally, by introducing a desired transient process which is shaped from the reference signal, we will present a new PID tuning rule, which can guarantee both nice steady-state and superior transient control performances.

Adversarial poisoning attacks pose huge threats to various machine learning applications. Especially, the recent accumulative poisoning attacks show that it is possible to achieve irreparable harm on models via a sequence of imperceptible attacks followed by a trigger batch. Due to the limited data-level discrepancy in real-time data streaming, current defensive methods are indiscriminate in handling the poison and clean samples. In this paper, we dive into the perspective of model dynamics and propose a novel information measure, namely, Memorization Discrepancy, to explore the defense via the model-level information. By implicitly transferring the changes in the data manipulation to that in the model outputs, Memorization Discrepancy can discover the imperceptible poison samples based on their distinct dynamics from the clean samples. We thoroughly explore its properties and propose Discrepancy-aware Sample Correction (DSC) to defend against accumulative poisoning attacks. Extensive experiments comprehensively characterized Memorization Discrepancy and verified its effectiveness. The code is publicly available at: https://github.com/tmlr-group/Memorization-Discrepancy., Comment: accepted by ICML 2023

Adverse conditions typically suffer from stochastic hybrid weather degradations (e.g., rainy and hazy night), while existing image restoration algorithms envisage that weather degradations occur independently, thus may fail to handle real-world complicated scenarios. Besides, supervised training is not feasible due to the lack of a comprehensive paired dataset to characterize hybrid conditions. To this end, we have advanced the aforementioned limitations with two tactics: framework and data. First, we present a novel unified framework, dubbed RAHC, to Restore Arbitrary Hybrid adverse weather Conditions in one go. Specifically, our RAHC leverages a multi-head aggregation architecture to learn multiple degradation representation subspaces and then constrains the network to flexibly handle multiple hybrid adverse weather in a unified paradigm through a discrimination mechanism in the output space. Furthermore, we devise a reconstruction vectors aided scheme to provide auxiliary visual content cues for reconstruction, thus can comfortably cope with hybrid scenarios with insufficient remaining image constituents. Second, we construct a new dataset, termed HAC, for learning and benchmarking arbitrary Hybrid Adverse Conditions restoration. HAC contains 31 scenarios composed of an arbitrary combination of five common weather, with a total of ~316K adverse-weather/clean pairs. Extensive experiments yield superior results and establish new state-of-the-art results on both HAC and conventional datasets., Comment: In submission

Patients with bipolar disorder (BD) exhibit individual variability in the treatment outcome, and genetic background could contribute to BD itself and the treatment outcome. Leptin levels significantly change in BD patients treated with valproate (VPA), but whether

In order to meet the growing demand of new services and facilitate the application of communication technology in vertical industries, mobile communication networks will gradually evolve with more intelligence, finally resulting in endogenous intelligence in the 6G era. However, most of the current research focuses on artificial intelligence(AI) based transmission and network optimization methods and rarely discusses how to support AI efficiently in the perspective of network architecture design. To fill this gap, this paper introduces the advances in wireless network architectures with endogenous intelligence proposed by both industry and academia and then discusses two use cases as well as related challenges.

Manipulation of the valley degree of freedom provides a new path for quantum information technology, but the real intrinsic large valley-polarization materials are rarely reported up to date. Here, we perform first-principles calculations to predict a class of 2H-phase single layer (SL) materials LuX 2 (X = Cl, Br, I) to be ideal candidates. SL-LuX 2 are ferrovalley materials with a giant valley-polarization of 55 meV–148 meV as a result of its large spin–orbital coupling (SOC) and intrinsic ferromagnetism (FM). The magnetic transition temperatures of SL-LuI2 and SL-LuCl2 are estimated to be 89 K–124 K, with a sizable magnetic anisotropy at out-of-plane direction. Remarkably, the anomalous valley Hall effect (AVHE) can be controlled in SL-LuX 2 when an external electric field is applied. Moreover, the intrinsic valley-polarization of SL-LuI2 is highly robust for biaxial strain. These findings provide a promising ferrovalley material system for the experimentation of valleytronics and subsequent applications.

Tessaratoma papillosa (Drury) first invaded Taiwan in 2009. Every year, T. papillosa causes severe damage to the longan crops. Novel applications for edge intelligence are applied in this study to establish an intelligent pest recognition system to manage this pest problem. We used a detecting drone to photograph the pest and employed a Tiny-YOLOv3 neural network model built on an embedded system NVIDIA Jetson TX2 to recognize T. papillosa in the orchard to determine the position of the pests in real-time. The pests’ positions are then used to plan the optimal pesticide spraying route for the agricultural drone. Apart from planning the optimized spraying of pesticide for the spraying drone, the TX2 embedded platform also transmits the position and generation of pests to the cloud to record and analyze the growth of longan with a computer or mobile device. This study enables farmers to understand the pest distribution and take appropriate precautions in real-time. The agricultural drone sprays pesticides only where needed, which reduces pesticide use, decreases damage to the environment, and increases crop yield.

Background: Whether intermittent chest compressions have an effect on the quality of CPR is worthy of discussion. The purpose of this study was to investigate differences in the chest compression quality of emergency medical technicians (EMTs) performing cardiopulmonary resuscitation (CPR) with different rest intervals. Methods: Seventy male firefighters with EMT licenses participated in this study. Participants completed body composition measurements and three CPR quality tests, as follows: (1) CPR-uninterrupted for 10 minutes; (2) after 2 days of rest, CPR 10s-intermittent (CPR-10s), for 2 minutes each time and 5 cycles; (3) after another 2 days of rest, CPR 20s-intermittent (CPR-20s), for 2 minutes each time and 5 cycles. Results: Body composition results showed that body mass (BM), body mass index (BMI), upper limb muscle mass (ULMM), core muscle mass (CMM), and upper limb-core muscle mass (UL+CMM) were positively correlated with chest compression depth (CCD) (p < 0.05). Analysis of the three different modes of CPR quality analysis indicated significant differences in the chest compression fraction (CCF, F = 6.801, p = 0.001), chest compression rebound rate (CCRR, F = 3.919, p = 0.021), and ratings of perceived exertion (RPE, F = 23.815, p < 0.001). Among the different performance cycles of CPR-10s, significant differences were found in CCF, CCD, CCR (chest compression rate), and RPE (p < 0.05). On the other hand, among the different performance cycles of CPR-20s, significant differences were found in CCD, CCR, and RPE (p < 0.05). Moreover, the CCF, CCD, and RPE scores of the two tests reached significant differences in specific phases (p < 0.05). Conclusions: This study confirmed that the upper limb muscle mass or the weight of the upper body of EMTs is positively correlated with the quality of CPR. In addition, intermittent chest compressions with safe interruption intervals can reduce fatigue caused by long-term chest compressions and maintain better chest compression quality.

The stabilization of isotropic pitch (IP)-derived pitch fibers (PFs) and mesophase pitch (MP)-derived PFsin air was performed at different heating rates and with different final stabilization temperatures. The stabilized fibers (SFs) and carbon fibers (CFs) were characterized by elemental analysis, FT-IR, TG-MS and SEM to investigate the influence of the degree of oxidation of the SFs on the microstructures and mechanical properties of the CFs. Results showed that a slow heating rate during stabilization was beneficial to the oxidative cross-linking of PFs, and the corresponding CFs had a higher carbonization yield and tensile strength at the lower heating rate. When both IPF and MPF were stabilized at 270 oC, the two resulting CFs all reached their optimal performance. In addition, the FTIR peak intensity ratio of the C=O band at about 1700 cm–1 to the C=C band at 1600 cm–1 of the SFs had a good relationship to the carbonization yield and tensile strength of the CFs, and thiscan beusedto optimize the degree of oxidation of the SFs. Moreover, insufficiently stabilized fibers released a great deal of H2 and CH4, causing some porosity in the resulting CFs with a low tensile strength, especially forthe insufficiently stabilized IPCF. While over-stabilized fibers released a large amount of CO and CO2, causing cracked textures in the corresponding CFs, especially inthe over-stabilizedMPCF. Therefore, this research into the stabilization and carbonization behaviors of pitch fibers has great significance for improving the mechanical properties of pitch-based CFs.

It is a challenge to obtain sufficient eggs during in vitro fertilization (IVF) in women with impending ovarian failure (IOF)/diminished ovarian reserve (DOR). Although studies have suggested that more than one wave of follicle growth exists, the efficacy of controlled ovulation stimulation (COS) in both follicular and luteal phases of the same ovarian cycle (DuoStim) is not established in women with IOF/DOR. We investigated the efficacy of DuoStim using the intraovarian injection of recombinant human follicle-stimulating hormone (rhFSH) during oocyte retrieval in women with DOR. For luteal-phase stimulation, intraovarian (Group A, N = 28) or superficial subcutaneous (Group B, N = 18) injection of 300 IU rhFSH immediately after oocyte retrieval was administered as the first dose, and intermittent superficial subcutaneous addition of gonadotropins was employed accordingly for further COS in both groups. In Group A, significantly lower Gn doses, a shorter duration of COS, a greater number of antral follicle counts, and an increased number of retrieved mature and total oocytes were noted. Compared with the clinical outcomes of luteal-phase COS, the average daily doses of rhFSH used in Group A were significantly lower. In summary, the novel approach using intraovarian rhFSH injection provides an efficient treatment regimen in women with IOF/DOR.

It is a challenge to obtain enough oocytes during in vitro fertilization (IVF) in women who have a poor ovarian response (POR) in achieving conception. We have adopted the characteristics of the first uterine pass effect, which we pioneered in employing the vaginal administration of gonadotropins in women receiving IVF treatments. In our previous study employing vaginal administration, faster absorption and slower elimination of gonadotropins were demonstrated, and, female subjects presented proper ovarian follicle growth and pregnancy rates. In this study, during 2016–2020, 300 to 675 IU of gonadotropins were administered vaginally every three days in 266 POR women for their controlled ovarian hyperstimulation (COH). The injections were performed with needles angled at 15–30° towards the middle-upper portions of the bilateral vaginal wall, with an injection depth of 1–2 mm. For the COH results, these women, on average, received 3.0 ± 0.9 vaginal injections and a total dose of 1318.4 ± 634.4 IU gonadotropins, resulting in 2.2 ± 1.9 mature oocytes and 1.0 ± 1.2 good embryos. Among these embryos, 0.9 ± 1.0 were transferred to reach a clinical pregnancy rate of 18.1% and a live birth rate of 16.7%. In conclusion, the intermittent vaginal administration of gonadotropins proved to be effective in POR women for their IVF treatments.

SummaryPD-1/PD-L1-blockade immunotherapies have limited efficacy in the treatment of muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Here, we show thatKLRC1(NKG2A) expression associates with improved survival and responsiveness to PD-L1 blockade immunotherapy inCD8Ahighbladder tumors. The loss of antigen presentation is a common mechanism for tumor escape in bladder cancer. NKG2A+CD8 T cells are able to circumvent HLA-ABC loss through TCR-independent cytotoxicity, which is partly mediated by DNAM-1. In bladder tumors, NKG2A is acquired on a subset of PD-1+CD8 T cells, alongside stronger tissue-residency memory features, TCR-independent cytotoxicity and evidence of recent proliferation. HLA-E is low but variably expressed on bladder tumors. When expressed, NKG2A+CD8 T cell anti-tumor responses to HLA-ABC-deficient tumors are inhibited and partly restored upon NKG2A blockade. Overall, our study identifies an alternative path for CD8 T cell exhaustion, that is mediated by NKG2A upregulation and TCR-independent cytotoxicity.

In this study, artificial intelligence and image recognition technologies are combined with environmental sensors and the Internet of Things (IoT) for pest identification. Real-time agricultural meteorology and pest identification systems on mobile applications are evaluated based on intelligent pest identification and environmental IoT data. We combined the current mature AIoT technology and deep learning and applied it to smart agriculture. We used deep learning YOLOv3 for image recognition to obtain the location of Tessaratoma papillosa and analyze the environmental information from weather stations through Long Short-Term Memory (LSTM) to predict the occurrence of pests. The experimental results showed that the pest identification accuracy reached 90%. Precise positioning can effectively reduce the amount of pesticides used and reduce pesticide damage to the soil. The current research provides the location of the pest and the extent of the pests to farmers can accurately use pesticide application at a precise time and place and thus reduce the agricultural workforce required for timely pest control, thus achieving the goal of smart agriculture. The proposed system notifies farmers of the presence of different pests before they start multiplying in large numbers. It improves overall agricultural economic value by providing appropriate pest control methods that decrease crop losses and reduce the environmental damage caused by the excessive usage of pesticides.

Non-muscle invasive bladder cancer, a disease with the oldest immunotherapeutic standard of care, has seen recent improvements in treatment via the application of checkpoint blocking antibodies. Unfortunately, response rates to programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) blocking antibodies remain low despite stratification by biomarkers. Sharing common biology with T cells but lacking true antigen-specificity and responding earlier to tumorigenic threats, natural killer (NK) cells present an ideal target for combination immunotherapies. NK-targeted immunotherapies under clinical investigation, including anti-NKG2A antibodies, interleukin agonists, and engineered viral vectors, hold promise in altering the immunotherapeutic landscape in bladder cancer and will be the focus of this review.

Cardiovascular diseases, also known as circulatory diseases, are diseases of the heart and blood vessels, and its etiology is hyperlipidemia, thick blood, atherosclerosis, and hypertension. Due to its high prevalence, disability, and mortality, it seriously threatens human health. According to reports, the incidence of cardiovascular disease is still on the rise. Rhodiola rosea is a kind of traditional Chinese medicine, which has the effects of antimyocardial ischemia-reperfusion injury, lowering blood fat, antithrombosis, and antiarrhythmia. Rhodiola rosea has various chemical components, and different chemical elements have the same pharmacological effects and medicinal values for various cardiovascular diseases. This article reviews the research on the pharmacological effects of Rhodiola rosea on cardiovascular diseases and provides references for the clinical treatment of cardiovascular diseases.

We propose a new consistency test for the $Λ$CDM cosmology using baryonic acoustic oscillations (BAO) and redshift space distortion (RSD) measurements from galaxy redshift surveys. Specifically, we determine the peak position of $fσ_8(z)$ in redshift $z$ offered by a RSD measurement, and compare it to the one predicted by the BAO observables assuming a flat $Λ$CDM cosmology. We demonstrate this new test using the simulated data for the DESI galaxy survey, and argue that this test complements those using the background observables alone, and is less subject to systematics in the RSD analysis, compared to traditional methods using values of $fσ_8(z)$ directly., 9 pages, 6 figures; accepted to Research in Astronomy and Astrophysics (RAA)

The maximal oxygen uptake (VO2max) prediction models established by step tests are often used for evaluating cardiorespiratory fitness (CRF). However, it is unclear which type of stepping frequency sequence is more suitable for the public to assess the CRF. Therefore, the main purpose of this study was to test the effectiveness of two 3-min incremental step-in-place (3MISP) tests (i.e., 3MISP30s and 3MISP60s) with the same total number of steps but different step-frequency sequences in predicting VO2max. In this cross-sectional study, a total of 200 healthy adults in Taiwan completed 3MISP30s and 3MISP60s tests, as well as cardiopulmonary exercise testing. The 3MISP30s and 3MISP60s models were established through multiple stepwise regression analysis by gender, age, percent body fat, and 3MISP-heart rate. The statistical analysis included Pearson’s correlations, the standard errors of estimate, the predicted residual error sum of squares, and the Bland–Altman plot to compare the measured VO2max values and those estimated. The results of the study showed that the exercise intensity of the 3MISP30s test was higher than that of the 3MISP60s test (% heart rate reserve (HRR) during 3MISP30s vs. %HRR during 3MISP60s = 81.00% vs. 76.81%, p < 0.001). Both the 3MISP30s model and the 3MISP60s model explained 64.4% of VO2max, and the standard errors of the estimates were 4.2043 and 4.2090 mL·kg−1·min−1, respectively. The cross-validation results also indicated that the measured VO2max values and those predicted by the 3MISP30s and 3MISP60s models were highly correlated (3MISP30s model: r = 0.804, 3MISP60s model: r = 0.807, both p < 0.001). There was no significant difference between the measured VO2max values and those predicted by the 3MISP30s and 3MISP60s models in the testing group (p > 0.05). The results of the study showed that when the 3MISP60s test was used, the exercise intensity was significantly reduced, but the predictive effectiveness of VO2max did not change. We concluded that the 3MISP60s test was physiologically less stressful than the 3MISP30s test, and it could be a better choice for CRF evaluation.

The quantum anomalous Hall effect (QAHE) has special quantum properties that are ideal for possible future spintronic devices. However, the experimental realization is rather challenging due to its low Curie temperature and small non-trivial bandgap in two-dimensional (2D) materials. In this paper, we demonstrate through first-principles calculations that monolayer Co2Te material is a promising 2D candidate to realize QAHE in practice. Excitingly, through Monte Carlo simulations, it is found that the Curie temperature of single-layer Co2Te can reach 573 K. The band crossing at the Fermi level in monolayer Co2Te is opened when spin–orbit coupling is considered, which leads to QAHE with a sizable bandgap of E g = 96 meV, characterized by the non-zero Chern number (C = 1) and a chiral edge state. Therefore, our findings not only enrich the study of quantum anomalous Hall effect, but also broaden the horizons of the spintronics and topological nanoelectronics applications.

Based on the ReaxFF reactive potential, the interaction of O2 molecules with three types of surfaces (100, 110, 111) of ferritic Fe–Cr alloy has been studied by classical molecular dynamics at constant O2 concentrations and temperatures.

BackgroundBladder cancer is characterized by a poor prognosis, with muscle-invasive cases harboring a 34–76% 10-year recurrence-free survival rate.1 Neoadjuvant PD-1/PD-L1 blockade strategies have recently been approved by the US Food and Drug Administration for bladder cancer treatment, yet only achieving a complete response rate of 31–37%, thereby suggesting additional mechanisms of resistance.2 HLA-E is a known inhibitor of NKG2A+ CD8 T cells and NK cell responses. A monoclonal antibody binding to the NKG2A receptor has been developed and proven to restore CD8 T cell and NK cell responses in head and neck cancer, with ongoing clinical trials across multiple tumor indications.3 4 We evaluated the potential role of the HLA-E/NKG2A inhibitory pathway in modulating T cell immunity in bladder cancer.MethodsCyTOF was performed on CD8+ T cells from fresh bladder tumors (n=6), as well as on expanded CD8+ T cells from bladder-draining lymph nodes (n=11) and tumors (n=8). Flow cytometry (n=25) and single-cell RNA-sequencing (scRNAseq) (n=13) were performed on cells from fresh bladder tumors.ResultsMechanisms of tumor escape from CD8+ T cell recognition include impairment of antigen presentation. Accordingly, we found a significant reduction of HLA class I expression on tumors. However, expression of DNAM-1-activating ligands (e.g. CD112,CD155) on bladder tumors was retained, indicating a possible role for TCR-independent activation pathways traditionally ascribed to natural killer (NK) cells. Using mass cytometry and scRNAseq, we observed that acquisition of NKG2A on tumor-derived PD-1+ CD8+ T cells promotes tissue-resident memory features alongside diminished CD28 expression and significantly weaker sensitivity to CD3/CD28-signaling. However, NKG2A+ CD8 T cells possess a proliferative advantage with enhanced expression of DNAM-1 and cytolytic machinery.Strikingly, we found that NKG2A+PD-1+ CD8 T cells are strongly activated in response to HLA class I-deficient tumors compared to their NKG2A- PD-1+ CD8 T cell counterparts. TCR-independent NK-like function by NKG2A+ CD8 T cell is partly mediated by the DNAM-1 pathway and inhibited by HLA-E. NKG2A+ CD8 T cell functions are restored upon NKG2A blockade, where efficiency positively correlates with HLA-E expression on bladder tumors.ConclusionsCollectively, our data indicate that NKG2A+ CD8 T cells display a strong capacity for TCR-independent activation that enables them to circumvent bladder tumor evasion mechanisms. NKG2A+ CD8 T cells lack expression of CD28 suggesting a lower susceptibility to PD-1-mediated inhibiton. Our data suggest a need for thorough reappraisal of current protocols that assess CD8 T cell exhaustion and for strategies to restore their antitumor functions.ReferencesSanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, Lotan Y. Bladder cancer. Nat Rev Dis Primers 2017 April 13;3:17022. doi: 10.1038/nrdp.2017.22. PMID: 28406148. Rouanne M, Bajorin DF, Hannan R, Galsky MD, Williams SB, Necchi A, Sharma P, Powles T. Rationale and outcomes for neoadjuvant immunotherapy in urothelial carcinoma of the bladder. Eur Urol Oncol 2020 December;3(6):728–738. doi: 10.1016/j.euo.2020.06.009. Epub 2020 Nov 8. PMID: 33177001. André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, Bléry M, Bonnafous C, Gauthier L, Morel A, Rossi B, Remark R, Breso V, Bonnet E, Habif G, Guia S, Lalanne AI, Hoffmann C, Lantz O, Fayette J, Boyer-Chammard A, Zerbib R, Dodion P, Ghadially H, Jure-Kunkel M, Morel Y, Herbst R, Narni-Mancinelli E, Cohen RB, Vivier E. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK Cells. Cell 2018 December 13;175(7):1731–1743.e13. doi: 10.1016/j.cell.2018.10.014. Epub 2018 Nov 29. PMID: 30503213; PMCID: PMC6292840. van Hall T, André P, Horowitz A, Ruan DF, Borst L, Zerbib R, Narni-Mancinelli E, van der Burg SH, Vivier E. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J Immunother Cancer 2019 October 17;7(1):263. doi: 10.1186/s40425-019-0761-3. PMID: 31623687; PMCID: PMC6798508.

Stabilization is the most complicated and time-consuming step in the manufacture of carbon fibers (CFs), which is important to prepare CFs with high performance. Accelerated stabilization was successfully demonstrated under effective plasma irradiation-assisted modification (PIM) of mesophase pitch fibers (PFs). The results showed that the PIM treatment could obviously introduce more oxygen-containing groups into PFs, which was remarkably efficient in shortening the stabilization time of PFs with a faster stabilization heating rate, as well as in preparing the corresponding CFs with higher performance. The obtained graphitized fiber (GF-5) from the PF-5 under PIM treatment of 5 min presented a higher tensile strength of 2.21 GPa, a higher tensile modulus of 502 GPa, and a higher thermal conductivity of 920 W/m·K compared to other GFs. Therefore, the accelerated stabilization of PFs by PIM treatment is an efficient strategy for developing low-cost pitch-based CFs with high performance.

Recombinant human thrombomodulin (rhTM), an angiogenesis factor, has been demonstrated to stimulate cell proliferation, keratinocyte migration and wound healing. The objective of this study was to develop nanostructured lipid carrier (NLC) formulations encapsulating rhTM for promoting chronic wound healing. RhTM-loaded NLCs were prepared and characterized. Encapsulation efficiency was more than 92%. The rate of rhTM release from different NLC formulations was influenced by their lipid compositions and was sustained for more than 72 h. Studies on diabetic mouse wound model suggested that rhTM-NLC 1.2 µg accelerated wound healing and was similar to recombinant human epidermal growth factor-NLC (rhEGF-NLC) 20 µg. By incorporating 0.085% carbopol (a highly crosslinked polyacrylic acid polymer) into rhTM NLC, the NLC-gel presented similar particle characteristics, and demonstrated physical stability, sustained release property and stability within 12 weeks. Both rhTM NLC and rhTM NLC-gel improved wound healing of diabetic mice and cell migration of human epidermal keratinocyte cell line (HaCaT) significantly. In comparison with rhTM solution, plasma concentrations of rhTM post applications of NLC and NLC-gel formulations were lower and more sustained in 24 h. The developed rhTM NLC and rhTM NLC-gel formulations are easy to prepare, stable and convenient to apply to the wound with reduced systemic exposure, which may warrant potential delivery systems for the care of chronic wound patients.

INTRODUCTION AND OBJECTIVE:Tumor infiltrating B cells in bladder cancer (BCa) have been associated with cancer invasion, but little is understood regarding their role in the tumor microenvironment....

INTRODUCTION AND OBJECTIVE:Several prognostic models have been described for clear cell renal cell carcinoma (ccRCC). Some techniques used to evaluate molecular biomarkers are cost-prohibitive, the...

Glioblastoma multiforme (GBM) is a grade IV, highly malignant brain tumor. Because of the heterogeneity of GBM, a multitarget drug is a rational strategy for GBM treatment. Histone deacetylase inhibitors (HDACis) regulate the expression of numerous genes involved in cell death, apoptosis, and tumorigenesis. We found that the HDAC4/HDAC5 inhibitor LMK235 at 0.5 µM significantly reduced the cell viability and colony formation of patient-derived, temozolomide-resistant GBM P#5 TMZ-R, U-87 MG, and T98G cells. Moreover, LMK235 also significantly increased TUBA acetylation, which is an indicator of HDAC inhibition. Interestingly, LMK235 induced MAP1LC3 robust readout and puncta accumulation but did not enhance PARP1 cleavage or the proportion of annexin V-positive cells, suggesting that LMK235-induced cell death occurred via autophagy activation. Further RNA-seq analysis after LMK235 treatment showed that 597 different expression genes compared to control. After bioinformatic analysis by KEGG and STRING, we focused on 34 genes and validated their mRNA expression by qPCR. Further validation showed that 2 µM LMK235 significantly reduced the mRNA and protein expression of SCNN1A. Cell viability of SCNN1A-silenced cells were reduced, but cells were rescued while treated with an autophagy inhibitor bafilomycin A1. Conclusively, SCNN1A plays a role in LMK235-induced autophagy and cell death in GBM cells.

AIMS Glioblastoma (GBM) is a highly malignant brain tumor. After treatment with the first-line drug temozolomide, only 50% of patients are responsive. Recent literature shows that the difficulty in treating GBM is mainly due to the heterogeneity of its four major cellular states, which are characterized by differences in EGFR, PDGFRA, CDK4, and NF1. Therefore, development of a multitarget drug is a potential strategy for treating heterogeneous GBM. MAIN METHODS In this study, the antitumor ability of a potent heat shock protein 90 inhibitor, NVP-AUY922 (AUY922), was evaluated in GBM cell lines (U-87 MG and T98G cells) and patient-derived GBM cell lines [P#5 and P#5 temozolomide-resistant (TMZ-R) cells]. KEY FINDINGS We found that AUY922 significantly reduced cell viability and colony formation in four GBM cell lines. AUY922 also significantly induced apoptosis by increasing PARP1 cleavage and the number of annexin V-positive cells. The autophagy indicators as MAP1LC3B cleavage and MAP1LC3B puncta were increased after AUY922 treatment. AUY922-induced cell death could be partially reversed by pharmacological inhibition of either apoptotic inhibitor or autophagy inhibitor. Moreover, AUY922 reduced the mRNA and protein expressions of EGFR, PDGFRA, CDK4, and NF1, which contribute to the four cellular state subtypes in GBM cells. In addition, the downstream signaling proteins of these four proteins, AKT/p-AKT, MAPK/p-MAPK, and BRAF, were downregulated after AUY922 treatment. SIGNIFICANCE Taken together, AUY922 led to GBM cell death via apoptosis and autophagy, and reduced the mRNA and protein expression of EGFR, PDGFRA, CDK4, and NF1in heterogeneous GBM cells.

Mesozoic granitoid rocks in the eastern Qinling terrane along the southern margin of the North China Craton are significant for understanding geodynamics processes related to lithospheric delaminat...

The geochemical compositions and zircon U-Pb ages of the Muhuguan and Mangling plutons of the North Qinling Terrane (NQT), China, provide insights into the basement rocks involved in magma genesis and the Mesozoic tectonic evolution of the NQT. Monzogranites from the two plutons are characterized by high SiO2 contents (69.3–77.0 wt%), low Mg numbers (0.21–0.38), enriched light rare-earth elements, Th, U, and Pb, depleted high-field-strength elements, and negative Eu anomalies. The source of the Mangling monzogranite is interpreted to have been deeper than that of the Muhuguan monzogranite, on the basis of its higher Sr/Y, (Dy/Yb)N, and (La/Yb)N ratios and lower SiO2 content. Sr-Nd isotopic compositions indicate similar but heterogeneous magma sources for the two granites: 87Sr/86Sri = 0.7070–0.7103 and eNd(t) = −7.0 to −15.0 for the Muhuguan granite, and 87Sr/86Sri = 0.7054–0.7083 and eNd(t) = −7.9 to −16.0 for the Mangling granite. The zircon U-Pb age results fall into two groups: (1) syn-magmatic zircons (153 to 140 Ma); and (2) inherited zircons that define five age clusters, namely Neoarchean-Paleoproterozoic (2633–2103 Ma), Paleoproterozoic to Mesoproterozoic (1988–1377 Ma), Neoproterozoic (975–605 Ma), Paleozoic (535–382 Ma), and Late Paleozoic – Early Mesozoic (329–187 Ma). These data are consistent with a derivation of the granites by mixing between melted underplated juvenile crust within the NQT and melts from basement rocks similar to those of the Xiong'er Group within the southern margin of the North China Craton (S-NCC). The involvement of S-NCC material is also supported by the unradiogenic whole-rock Pb isotopic composition of the Muhuguan and Mangling granites, which is similar to that of the S-NCC basement rocks. These results suggest that the widespread Late Jurassic to Early Cretaceous granitoid intrusions within the NQT were generated in an extensional geological setting associated with mantle upwelling. Melts were derived from underthrust S-NCC basement material and juvenile Neoproterozoic basaltic rocks.

A search for bioactive natural products as anticancer lead compounds resulted in the isolation of one previously undescribed and three known clerodane diterpenoids (1–4) from Casearia kurzii. The structures of these compounds were established by analysis of their NMR, MS, and electronic circular dichroism data. The cytotoxic activities of four compounds against three human cancer cell lines were evaluated. Compound 2 was found to be the most active with an IC50 value of 4.1 μM against HeLa cells, and was selected to investigate the possible cytotoxic mechanism.