Conditional deletion of Zeb1 in Csf1r+ cells reduces inflammatory response of the cornea to alkali burn.

ZEB1 is an essential factor in embryonic development. In adults, it is often highly expressed in malignant tumors with low expression in normal tissues. The major biological function of ZEB1 in developing embryos and progressing cancers is to transdifferentiate cells from an epithelial to mesenchymal phenotype; but what roles ZEB1 plays in normal adult tissues are largely unknown. We previously reported that the reduction of Zeb1 in monoallelic global knockout (Zeb1+/-) mice reduced corneal inflammation-associated neovascularization following alkali burn. To uncover the cellular mechanism underlying the Zeb1 regulation of corneal inflammation, we functionally deleted Zeb1 alleles in Csf1r+ myeloid cells using a conditional knockout (cKO) strategy and found that Zeb1 cKO reduced leukocytes in the cornea after alkali burn. The reduction of immune cells was due to their increased apoptotic rate and linked to a Zeb1-downregulated apoptotic pathway. We conclude that Zeb1 facilitates corneal inflammatory response by maintaining Csf1r+ cell viability.

Schiff base functionalized dialdehyde starch for enhanced removal of Cu (II): Preparation, performances, DFT calculations.

Dialdehyde starch modified by 2-hydrazinopyridine (HYD-DAS) based on the reaction of dialdehyde starch (DAS) and 2-hydrazinopyridine was synthesized and characterized by FT-IR spectra, element analysis and SEM. HYD-DAS can efficiently adsorb Cu (II) ion to demonstrate visual color changes from yellow to dark brown in aqueous solutions. The influence on HYD-DAS to Cu (II) adsorption including pH value of solution, isotherm, kinetics, thermodynamics and possible mechanism had also been examined. Batch experiments indicate that HYD-DAS's to Cu (II) adsorption reaches equilibrium within 250 min, and its adsorption capacity and rate are 195.75 mg/g and 98.63 %, respectively. Moreover, HYD-DAS to Cu (II) adsorption remains robust and underscoring after five cycles to exhibit good selectivity and reusability. Kinetics studies suggest the absorption process follows a quasi-second-order with isotherms aligning to the Langmuir monolayer model, and thermodynamics reveals that it is a spontaneous endothermic nature of adsorption. Based on the analyses of XPS and DFT calculations, a possible mechanism for HYD-DAS to Cu (II) adsorption is that Cu (II) combined with nitrogen atoms from Schiff base and hydrazine pyridine ring in HYD-DAS.

Hypoxia-inducible factor 1α inhibits heat stress-induced pig intestinal epithelial cell apoptosis through eif2α/ATF4/CHOP signaling.

Unstoppable global warming and increased frequency of extreme heat leads to human and animals easier to suffer from heat stress (HS), with gastrointestinal abnormalities as one of the initial clinical symptoms. HS induces intestinal mucosal damage owing to intestinal hypoxia and hyperthermia. Hypoxia-inducible factor 1α (HIF-1α) activates numerous genes to mediate cell hypoxic responses; however, its role in HS-treated intestinal mucosa is unknown. This work aimed to explore HIF-1α function and regulatory mechanisms in HS-treated pig intestines. We assigned 10 pigs to control and moderate HS groups. Physical signs, stress, and antioxidant levels were detected, and the intestines were harvested after 72 h of HS treatment to study histological changes and HIF-1α, heat shock protein 90 (HSP90), and prolyl-4-hydroxylase 2 (PHD-2) expression. In addition, porcine intestinal columnar epithelial cells (IPEC-J2) underwent HS treatment (42 °C, 5 % O2) to further explore the functions and regulatory mechanism of HIF-1α. The results of histological examination revealed HS caused intestinal villi damage and increased apoptotic epithelial cell; the expression of HIF-1α and HSP90 increased while PHD-2 showed and opposite trend. Transcriptome sequencing analysis revealed that HS activated HIF-1 signaling. To further explore the role of HIF-1α on HS induced IPEC-J2 apoptosis, the HIF-1α was interfered and overexpression respectively, and the result confirmed that HIF-1α could inhibited cell apoptosis under HS. Furthermore, HS-induced apoptosis depends on eukaryotic initiation factor 2 alpha (eif2α)/activating transcription factor 4 (ATF4)/CCAAT-enhancer-binding protein homologous protein (CHOP) pathway, and HIF-1α can inhibit this pathway to alleviate IPEC-J2 cell apoptosis. In conclusion, this study suggests that HS can promote intestinal epithelial cell apoptosis and cause pig intestinal mucosal barrier damage; the HIF-1α can alleviate cell apoptosis by inhibiting eif2α/ATF4/CHOP signaling. These results indicate that HIF-1α plays a protective role in HS, and offers a potential target for HS prevention and mitigation.

Comparison of Radiofrequency Ablation and Craniotomy Microvascular Decompression for Treatment of Hemifacial Spasm.

BACKGROUND: Hemifacial spasm (HFS) is distinguished by sudden and involuntary spasms of the facial muscles, predominantly on one side of the face. Microvascular decompression (MVD) is an efficacious surgical technique for treating HFS; however, MVD may occasionally lead to noteworthy postoperative complications. Previously, we reported the successful utilization of an innovative awake computed tomography-guided percutaneous puncture of the stylomastoid foramen for administering radiofrequency ablation (RFA) therapy in the treatment of HFS. STUDY DESIGN: Prospective clinical research study. SETTING: Department of Anesthesiology and Pain Medical Center, Ningbo, China. OBJECTIVES: The aim of this study was to compare and contrast the clinical outcomes and adverse reactions associated with attempts to use RFA and MVD to manage primary HFS. METHODS: Three hundred patients received either RFA or MVD treatment (Group R and Group M). We tracked and recorded each patient's cure rate, remission rate, intraoperative and postoperative complications, short-term and long-term therapeutic outcomes, hospitalization duration, hospitalization expenses, and operation time. RESULTS: One hundred and fifty-eight patients were placed in the R group, and 142 patients were sorted into the M group. In the R group, 87.34% of patients showed improvement, 9.49% experienced relief, and 3.16% experienced treatment failure. Similarly, in the M group, 85.92% of patients showed improvement, 10.56% experienced relief, and 3.52% experienced treatment failure. The difference in therapeutic efficacy between the 2 groups was not significant. However, the M group had significantly lower recurrence rates at 3 months, 6 months, and one year post-operation than the R group did. Notably, the M group also experienced a higher rate of postoperative complications. Among the complications reported in the M group were 25 cases of dizziness or headache (17.6%) following the operation, 22 cases of hearing damage, including one case of complete hearing loss on the side involved, and 28 cases of peripheral nerve injury with abnormal skin sensation. Postoperative facial paralysis occurred in 15 patients, including 10 cases of moderate to severe facial paralysis that were relieved to grade II after one year. In comparison, the R group had 40 cases of grade II and 53 cases of grade III, and no cases of more severe facial paralysis were found. There were also 13 cases of peripheral nerve injury, such as local skin numbness and tenderness. Importantly, there were no cases of facial hematoma, intracranial hemorrhage, infection, or any other complications in either group, and no fatalities occurred during the study period. LIMITATIONS: The limitations of this study are the exclusion of transient postoperative complications, the lack of in-person follow-up with patients, and the potential underestimation of certain complications. CONCLUSION: The short-term outcome was found to be comparable between the 2 treatment modalities. Notably, RFA demonstrates both safety and efficacy as a method for managing primary HFS; however, the procedure may lead to mild facial paralysis. In situations during which surgery is contraindicated, especially among elderly or high-risk surgical patients, percutaneous facial nerve RFA at the stylomastoid foramen may be considered as an alternative therapeutic approach.

Echo-Level SAR Imaging Simulation of Wakes Excited by a Submerged Body.

The paper introduces a numerical simulation method for Synthetic Aperture Radar (SAR) imaging of submerged body wakes by integrating hydrodynamics, electromagnetic scattering, and SAR imaging simulation. This work is helpful for better understanding SAR images of submerged body wakes. Among these, the hydrodynamic model consists of two sets of ocean dynamics closely related to SAR imaging, namely the wake of the submerged body and wind waves. For the wake, we simulated it using computational fluid dynamics (CFD) numerical methods. Furthermore, we compared and computed the electromagnetic scattering characteristics of wakes under various navigation parameters and sea surface conditions. Following that, based on the operational principles and imaging theory of synthetic aperture radar (SAR), we established the SAR raw echo signal of the wake. Employing a Range-Doppler (RD) algorithm, we generated simulated SAR images of the wake. The results indicate that utilizing Computational Fluid Dynamics (CFD) numerical methods enables the simulation of wake characteristics generated by the motion of a submerged body with different velocities. The backscattering features of wakes are closely associated with the relative orientation between the wake and the radar line of sight. Under specific wind speeds, the wake gets masked within the sea surface background, resulting in less discernible characteristics of the wake in SAR images. This suggests that at lower speeds of submerged body or under specific wind conditions, the detectability of the wake in SAR images significantly diminishes.

Short chain fatty acids inhibit corneal inflammatory responses to TLR ligands via the ocular G-protein coupled receptor 43.

PURPOSE: Short chain fatty acids (SCFAs) produced by gut microbiota are known to play primary roles in gut homeostasis by immunomodulation partially through G-protein coupled receptors (GPR) 43. Using mouse models of TLR ligand induced keratitis, we investigated whether SCFAs and GPR43 play any regulatory roles in the pathogenesis of inflammatory responses in the eye. METHODS: Both human and mouse eyes were labeled with a specific antibody for GPR43 and imaged by a laser scanning confocal microscope. Corneal cups from naïve C57BL/6J (B6) and GPR43 knockout (KO) mice were stimulated with TLR ligands in the presence or absence of sodium butyrate overnight and then processed for RT-PCR assay for expression of GPR43 and cytokines. Keratitis was induced by Poly I:C in wild type (WT) B6, GPR43KO and chimeric mice and the disease severity was evaluated by the corneal fluorescein staining test, and infiltrating cell staining and calculating in corneal whole mount. RESULTS: GPR43 is expressed in both human and mouse eyes and the expression is bidirectionally regulated by TLR ligands and butyrate. Butyrate significantly inhibited inflammation caused by several TLR ligands such as Poly I:C, Flagellin, and CpG-ODN (TLR-3, 5 and 9 agonists, respectively) in WT, but not GPR43KO, mice. Butyrate inhibition of TLR-induced keratitis is mediated by the GPR43 expressed in tissue but not hematopoietic, cells. CONCLUSIONS: This is the first report to demonstrate of the protective effect of SCFAs on microbial keratitis, and the dynamic expression and anti-inflammatory function of GPR43 in the eye. SCFAs can modulate inflammation and immunity in the eye through GPR43.

Attenuation of pro-tumorigenic senescent secretory phenotype by StN, a novel derivative of stevioside, potentiates its inhibitory activity on hepatocellular carcinoma.

Ent-13-Hydroxy-15-kaurene-19-acid N-Methylpiperazine Ethyl Ester (StN) is a novel derivative of the natural diterpene stevioside isolated from Stevia rebaudiana (Bertoni). In this study, we examined the effects of StN against hepatocellular carcinoma (HCC) in vitro and in vivo as well as its anticancer mechanisms by inhibiting proliferation and regulating the senescence-associated secretory phenotype (SASP). We showed that StN significantly inhibited HCC cell proliferation by inducing cellular senescence, as observed by increased senescence-associated ß-galactosidase activity and cell cycle arrest. Mechanistically, StN impaired lysosomal stability and triggered the release of cathepsin B from the lysosomes into the nucleus where it promoted DNA damage. Cathepsin B-mediated DNA damage contributed to cellular senescence triggered by StN. Meanwhile, StN transcriptionally suppressed multiple pro-inflammatory SASP components, including IL-6, IL-1α, IL-1ß, and IL-8, resulting in the reduction of pro-tumorigenic impact of SASP. Further study revealed that StN inactivated NF-κB and PI3K/Akt signaling, which significantly accounted for its inhibition on the SASP factors. In HCC xenograft mice, administration of StN significantly suppressed tumor growth, while no significant toxicity was detected. This study demonstrates a novel mechanism that suppressing the SASP by StN in senescent cells potentiates its anticancer efficacy, thus defining a potential compound for cancer treatment.

Analysis of Onboard Verification Flight Test for the Salinity Satellite Scatterometer.

The upcoming Salinity Satellite, scheduled for launch in 2024, will feature the world's first phased array radar scatterometer. To validate its capability in measuring ocean surface backscatter coefficients, this paper conducts an in-depth analysis of the onboard verification flight test for the Salinity Satellite scatterometer. This paper provides a detailed introduction to the system design of the Salinity Satellite scatterometer, which utilizes phased array radar technology and digital beamforming techniques to achieve accurate measurements of sea surface scattering characteristics. The paper elaborates on the derivation of backscatter coefficients, system calibration, and phase amplitude correction for the phased array scatterometer. Furthermore, it describes the process of the onboard calibration flight test. By analyzing internal noise signals, onboard calibration signals, and external noise signals, the stability and reliability of the scatterometer system are validated. The experiment covers both land and ocean observations, with a particular focus on complex sea surface conditions in nearshore areas. Through the precise analysis of backscatter coefficients, the paper successfully distinguishes the different backscatter coefficient characteristics between ocean and land. The research results effectively demonstrate the feasibility of the Salinity Satellite scatterometer for measuring backscatter coefficients in a phased array configuration, as well as its outstanding performance in complex marine environments.

Mouse Corneal Epithelial and Stromal Cell Isolation and Culture.

Corneal epithelium and stroma are the major cellular structures for ocular protection and vision accuracy; they play important roles in corneal wound healing and inflammation under pathological conditions. Unlike human, murine corneal and stromal fibroblast cells are difficult to isolate for cell culture. In our laboratory, we successfully used an ex vivo culture procedure and an enzymatic procedure to isolate, purify, and culture mouse corneal epithelial and stromal fibroblast cells. Key features • Primary cell culture models of a disease are critical for cellular and molecular mechanism studies. • Corneal tissues with the limbus contain stem cells to generate both epithelial and stromal cells. • An ex vivo corneal culture provides a constant generation of primary corneal cells for multiple passages. • The isolated cells are validated by the corneal epithelial cell markers Krt12 and Cdh1 and the stromal fibroblast marker Vim.

Revalidation of the ATTRACTION-4 study in a real-world setting: a multicenter, retrospective propensity score matching study in China.

Background: Immune-checkpoint inhibitors (ICIs) combined with chemotherapy have been successfully used in clinical trials to treat advanced gastric cancer. However, the efficacy and safety of first-line immunotherapy combined with chemotherapy in Chinese patients are unknown. Methods: This multicenter retrospective study included patients with human epidermal growth factor receptor-2 (HER-2) negative advanced gastric cancer treated with first-line chemotherapy or chemotherapy with an ICI between January 2019 and December 2022. Propensity score matching was used to compare progression-free survival (PFS), overall survival, objective response rates, and adverse reactions between cohorts. Results: After propensity score matching, 138 patients, who had balanced baseline characteristics, were included in the chemotherapy and combination treatment groups. The median follow-up duration was 16.90 months, and the median PFS was 8.53 months (95% confidence interval [CI] 7.77-9.28) in the combination treatment group and 5.97 months (95% CI 4.56-7.37) in the chemotherapy group. The median survival duration was 17.05 months (95% CI 14.18-19.92) in the combination treatment group and 16.46 months (95% CI 12.99-19.93) in the chemotherapy group. The PFS subgroup analysis revealed that age ≥65 years, women, Eastern Cooperative Oncology Group performance status of 1, non-signet ring cell carcinoma, esophagogastric junction, liver metastasis, peritoneal metastasis, no massive ascites, only one metastatic organ, and combined platinum-based chemotherapy correlated with treatment benefit. The incidences of adverse events above grade 3 were comparable between groups. Conclusions: Our study confirmed the ATTRACTION-4 trial results. Compared with chemotherapy, first-line ICIs combined with chemotherapy prolonged PFS but did not improve overall survival in patients with HER-2-negative advanced gastric cancer.

Identification of molecular pattern and prognostic risk model based on ligand-receptor pairs in liver cancer.

Introduction: The tumor microenvironment of hepatocellular carcinoma is composed of multiple cells, and the interactive communication between cells drives tumor progression and characterizes the tumor. Communication between cells is mainly achieved through signal transduction between receptor ligands, and the rise of single-cell technology has made it possible to analyze the communication network between cells. Methods: We applied a train of bioinformatic techniques and in vitro experiments. We analyzed the composition of the microenvironment of liver cancer by combining single-cell sequencing data and transcriptome sequencing data from liver cancer to construct molecular typing and risk models for LRs. Then, we analyzed association of it with prognosis, mutation, KEGG, tumor microenvironment (TME), immune infiltration, tumor mutational burden (TMB) and drug sensitivity in liver cancer. qPCR and was used to identify SLC1A5 expression in LIHC cell lines and CCK8, transwell and cell colony formation were performed to validate the function of SLC1A5. Meanwhile, we also performed polarization of macrophages. Results: In this experiment, we found that liver cancer tissues are rich in immune and mesenchymal cells, and there is extensive signaling between individual cells, so we constructed molecular typing and risk models for LRs. Combining clinical data revealed significant differences in clinical characteristics, prognosis and mutated genes between the molecular typing of receptor-ligand pairs, as well as in sensitivity to drugs; similarly, there were significant prognostic differences between the risk models. There were also notable differences in activated signaling pathways, infiltrating immune cells and immune subtypes. Subsequently, we used siRNA to knock down SLC1A5 in hepatocellular carcinoma cells and found that cell proliferation, migration and invasion were diminished. Conclusions: In conclusion, our LRs model may become a marker to guide clinical treatment and prognosis.

Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa.

Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.

Development and validation of a contrast-enhanced CT-based radiomics nomogram for preoperative diagnosis in neuroendocrine carcinoma of digestive system.

Objectives: To develop and validate a contrast-enhanced CT-based radiomics nomogram for the diagnosis of neuroendocrine carcinoma of the digestive system. Methods: The clinical data and contrast-enhanced CT images of 60 patients with pathologically confirmed neuroendocrine carcinoma of the digestive system and 60 patients with non-neuroendocrine carcinoma of the digestive system were retrospectively collected from August 2015 to December 2021 at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and randomly divided into a training cohort (n=84) and a validation cohort (n=36). Clinical characteristics were analyzed by logistic regression and a clinical diagnosis model was developed. Radiomics signature were established by extracting radiomic features from contrast-enhanced CT images. Based on the radiomic signature and clinical characteristics, radiomic nomogram was developed. ROC curves and Delong's test were used to evaluate the diagnostic efficacy of the three models, calibration curves and application decision curves were used to analyze the accuracy and clinical application value of nomogram. Results: Logistic regression results showed that TNM stage (stage IV) (OR 6.8, 95% CI 1.320-43.164, p=0. 028) was an independent factor affecting the diagnosis for NECs of the digestive system, and a clinical model was constructed based on TNM stage (stage IV). The AUCs of the clinical model, radiomics signature, and radiomics nomogram for the diagnosis of NECs of the digestive system in the training, validation cohorts and pooled patients were 0.643, 0.893, 0.913; 0.722, 0.867, 0.932 and 0.667, 0.887, 0.917 respectively. The AUCs of radiomics signature and radiomics nomogram were higher than clinical model, with statistically significant difference (Z=4.46, 6.85, both p < 0.001); the AUC difference between radiomics signature and radiomics nomogram was not statistically significant (Z=1.63, p = 0.104). The results of the calibration curve showed favorable agreement between the predicted values of the nomogram and the pathological results, and the decision curve analysis indicated that the nomogram had favorable application in clinical practice. Conclusions: The nomogram constructed based on contrast-enhanced CT radiomics and clinical characteristics was able to effectively diagnose neuroendocrine carcinoma of the digestive system.

Current Progress on Predictive Biomarkers for Response to Immune Checkpoint Inhibitors in Gastric Cancer: How to Maximize the Immunotherapeutic Benefit?

Gastric cancer is the fifth most prevalent cancer and the fourth leading cause of cancer death globally. Delayed diagnosis and pronounced histological and molecular variations increase the complexity and challenge of treatment. Pharmacotherapy, which for a long time was systemic chemotherapy based on 5-fluorouracil, is the mainstay of management for advanced gastric cancer. Trastuzumab and programmed cell death 1 (PD-1) inhibitors have altered the therapeutic landscape, contributing to noticeably prolonged survivorship in patients with metastatic gastric cancer. However, research has revealed that immunotherapy is only beneficial to some individuals. Biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and tumor mutational load (TMB), have been shown to correlate with immune efficacy in numerous studies and are increasingly employed for the selection of patients most likely to respond to immunotherapy. Gut microorganisms, genetic mutations like POLE/POLD1 and NOTCH4, tumor lymphoid infiltrating cells (TILs), and other novel biomarkers have the potential to develop into new predictors. Prospective immunotherapy for gastric cancer should be guided by a biomarker-driven precision management paradigm, and multidimensional or dynamic marker testing could be the way to go.

Zeb1 facilitates corneal epithelial wound healing by maintaining corneal epithelial cell viability and mobility.

The cornea is the outmost ocular tissue and plays an important role in protecting the eye from environmental insults. Corneal epithelial wounding provokes pain and fear and contributes to the most ocular trauma emergency assessments worldwide. ZEB1 is an essential transcription factor in development; but its roles in adult tissues are not clear. We identify Zeb1 is an intrinsic factor that facilitates corneal epithelial wound healing. In this study, we demonstrate that monoallelic deletion of Zeb1 significantly expedites corneal cell death and inhibits corneal epithelial EMT-related cell migration upon an epithelial debridement. We provide evidence that Zeb1-regulation of corneal epithelial wound healing is through the repression of genes required for Tnfa-induced epithelial cell death and the induction of genes beneficial for epithelial cell migration. We suggest utilizing TNF-α antagonists would reduce TNF/TNFR1-induced cell death in the corneal epithelium and inflammation in the corneal stroma to help corneal wound healing.

Ventral tegmental area astrocytes modulate cocaine reward by tonically releasing GABA.

Addictive drugs increase ventral tegmental area (VTA) dopamine (DA) neuron activity through distinct cellular mechanisms, one of which involves disinhibition of DA neurons by inhibiting local GABA neurons. How drugs regulate VTA GABA neuron activity and drive addictive behaviors remains poorly understood. Here, we show that astrocytes control VTA GABA neuron activity in cocaine reward via tonic inhibition in mice. Repeated cocaine exposure potentiates astrocytic tonic GABA release through volume-regulated anion channels (VRACs) and augments tonic inhibition of VTA GABA neurons, thus downregulating their activities and disinhibiting nucleus accumbens (NAc) projecting DA neurons. Attenuation of tonic inhibition by either deleting Swell1 (Lrrc8a), the obligatory subunit of VRACs, in VTA astrocytes or disrupting δ subunit of GABAA receptors in VTA GABA neurons reduces cocaine-evoked changes in neuron activity, locomotion, and reward behaviors in mice. Together, our findings reveal the critical role of astrocytes in regulating the VTA local circuit and cocaine reward.

CJ2: A Novel Potent Platinum(IV) Prodrug Enhances Chemo-Immunotherapy by Facilitating PD-L1 Degradation in the Cytoplasm and Cytomembrane.

Platinum drugs as primary chemotherapy drugs have been applied to various cancer patients. However, their therapeutic applicability is limited due to the adverse effects and immunosuppression. To minimize the side effects and boost the immune response, we designed and synthesized platinum(IV) prodrugs that introduced BRD4 inhibitor JQ-1. Among them, CJ2 had the most potent therapeutic activity and less toxicity. With the introduction of ligand JQ-1, CJ2-reduced PD-L1 protein was found in the cytoplasm and cytomembrane for the first time. By interfering with the PD-L1 synthesis, CJ2 could arouse the immune system and promote CD8+ T cell infiltration. Meanwhile, CJ2 could accelerate PD-L1 degradation in the cytoplasm to block DNA damage repair. In vivo, CJ2 markedly suppressed tumor growth by reversing the immunosuppression microenvironment and enhancing DNA damage. These findings provide an effective approach to improve the selectivity and activity of the platinum drugs with elevated immune response.

FKA-A NPs enhances PTX-A NPs efficacy to suppress ovarian cancer via regulating Skp2/YAP pathway.

Recurrence and distant metastasis after paclitaxel (PTX)-based chemotherapy in ovarian cancer (OC) patients remains a clinical obstacle. Flavokawain A (FKA) is a novel chalcone from kava plant that can induce G2/M arrest and inhibit invasion and metastasis in different tumor cells. In this study, we examined the effects and the molecular mechanism of sodium aescinate (Aes)-stabilized nanoparticles FKA-A NPs in enhancing the efficacy of PTX-A NPs in vitro and in vivo. We showed that FKA-A NPs combined with PTX-A NPs notably inhibited the proliferation and migration and reduced the expression of EMT-related markers in OCs. YAP nuclear translocation and its downstream signaling pathway were remarkably activated after PTX-A NPs treatment in OCs. FKA-A NPs obviously inhibited YAP nuclear translocation and reduced the transcriptional activity of YAP target genes. Simultaneously, FKA-A NPs dose and time dependently inhibited Skp2 expression in A2780 and Skov3 cells. In contrast, overexpression of Skp2 significantly attenuated the inhibition of FKA-A NPs on YAP nuclear translocation. In OC homograft mice, treatment with FKA-A NPs and PTX-A NPs significantly suppressed the growth of homograft tumor compared with PTX-A NPs but did not decrease mice's body weight. In summary, we demonstrate that FKA-A NPs enhance the efficacy of PTX-A NPs against OCs in vitro and in vivo via reducing Skp2 expression, thus suppressing YAP nuclear translocation and activity of its target genes.

Future perspective of stem cell-derived exosomes: Cell-free therapeutic strategies for retinal degeneration.

With continued expansion of the aged population, the number of patients with retinal degeneration, which is a leading cause of vision loss worldwide, is growing. Stem cell therapies offer hope for regeneration and repair of damaged retinal tissue. Recent reports have highlighted stem cell-derived paracrine mediators, such as exosomes, which appear to exert a therapeutic benefit similar to their cell of origin and do not carry the risk of cell transplantation. One speculated role is that exosomes likely mediate intercellular communication and material exchange. This review depicts the molecular mechanisms underlying exosome-based therapy, especially in retina degeneration diseases. In the future, the use of stem cell-derived exosomes could be considered a novel and cell-free therapeutic strategy in regenerative medicine.

Research on Ultra-Wideband NLFM Waveform Synthesis and Grating Lobe Suppression.

Ultra-wideband (UWB) nonlinear frequency modulation (NLFM) waveforms have the advantages of low sidelobes and high resolution. By extending the frequency domain wideband synthesis method to the NLFM waveform, the synthetic bandwidth will be limited, and the grating lobe will grow as the number of subpulses increases at a fixed synthetic bandwidth. Aiming for the highly periodic grating lobes caused by equally spaced splicing and small subpulse time-bandwidth products (TxBW), a multisubpulse UWB NLFM waveform synthesis method is proposed in this paper. Random frequency hopping and spectral correction are utilized to disperse the energy of periodic grating lobes and optimize the matched filter of the subpulse, thereby reducing notches and Fresnel ripples in the synthesized spectrum. The results of the hardware-in-the-loop simulation experiment show that the peak sidelobe ratio (PSLR) and the integral sidelobe ratio (ISLR) of the NLFM synthetic wideband waveform (SWW) obtained by 50 subpulses with a bandwidth of 36 MHz are improved by 4.8 dBs and 4.5 dBs, respectively, when compared to the frequency domain wideband synthesis method, and that the grating lobe is suppressed by an average of 10.6 dBs. It also performs well in terms of point target resolution, and it has potential for 2D radar super-resolution imaging.