Avapritinib efficacy in primary hepatic neuroendocrine carcinoma with elevated PDGFRA expression: Insights from a PDX model study.

BACKGROUND & AIMS: Primary Hepatic Neuroendocrine Carcinoma (PHNEC) is a rare and aggressive tumor with high recurrence rates. Surgical resection remains the only therapeutic strategy. The effectiveness of tyrosine kinase inhibitors (TKIs) for PHNEC remains unclear due to limited research. METHODS: We employed immunohistochemical staining to diagnose PHNEC and assess the expression of eight tyrosine kinase receptors in tumor tissues, including VEGFRs, PDGFRA, EGFR, FGFRs et al. A patient-derived xenograft (PDX) model was established using PHNEC tumor tissues to test the efficacy of TKIs. PDX mice bearing tumors were treated with Avapritinib, an FDA-approved PDGFRA-targeting drug, at a daily oral dose of 10 mg/kg for 2 weeks. RESULTS: Pathological analysis confirmed the diagnosis of PHNEC with positive expression of Neural cell adhesion molecule (NCAM/CD56), Synaptophysin (Syn), and Somatostatin receptor 2 (SSTR-2), and negative expression of Hep (Hepatocyte Paraffin 1), a biomarker for Hepatocellular carcinoma. Notably, PDGFRA was significantly overexpressed in PHNEC tumor tissues compared to other tyrosine kinases. Avapritinib treatment significantly reduced tumor growth in PDX mice by 73.9 % (p = 0.008). Additionally, Avapritinib treatment led to a marked decrease in PDGFRA and Ki-67 expression, suggesting that it inhibits tumor cell proliferation by suppressing PDGFRA. CONCLUSION: Our findings suggest that PDGFRA is a potential therapeutic target for PHNEC, and its inhibition with Avapritinib may offer clinical benefits to patients with this rare malignancy.

The association of blood urea nitrogen-to-creatinine ratio and in-hospital mortality in acute ischemic stroke patients with atrial fibrillation: data from the MIMIC-IV database.

Objective: This research aimed to investigate the association between the blood urea nitrogen-to-creatinine (BUN/Cr) ratio and the rate of in-hospital mortality in patients with acute ischemic stroke (AIS) and atrial fibrillation (AF), who are also receiving care in intensive care unit (ICU). Methods: A retrospective study was conducted using the MIMIC-IV database. We collected data on BUN/Cr levels at admission for patients with AIS and concurrent AF. To assess the association between BUN/Cr and in-hospital mortality rate, statistical analysis was conducted employing multivariable logistic regression models and restricted cubic spline models. These models were utilized to investigate the potential relationship and provide insights into the impact of BUN/Cr on the likelihood of in-hospital mortality. Interaction and subgroup analyses were performed to evaluate the consistency of the correlation. Results: There were a total of 856 patients (age ≥ 18 years) with a median age of 78.0 years, of which 466 (54.4%) were female. Out of 856 patients, 182 (21.26%) died in the hospital. Upon controlling for confounding factors, the multivariable logistic regression analysis elucidated that patients falling within the third trisection (Q3 > 22.41 mg/dL) exhibited a noticeably increased susceptibility to in-hospital mortality when contrasted with their counterparts positioned in the second trisection (Q2: 17.2-22.41 mg/dL) (OR = 2.02, 95% CI: 1.26-3.26, p = 0.004). A non-linear J-shaped relationship was observed between BUN/Cr at ICU admission and in-hospital mortality rate (p = 0.027), with a turning point at 19.63 mg/dL. In the threshold analysis, there was a 4% rise in in-hospital mortality for each 1 mg/dL increase in BUN/Cr (OR: 1.04, 95% CI: 1.01-1.06, p = 0.012). Conclusion: In patients with AIS complicated by AF, BUN/Cr at admission shows a J-shaped correlation with in-hospital mortality rate. When BUN/Cr exceeds 19.63 mg/dL, the in-hospital mortality rate increases.

Stevioside protects against acute kidney injury by inhibiting gasdermin D pathway.

Recent studies indicate a significant upregulation of gasdermin D (GSDMD) in acute kidney injury (AKI), a severe medical condition characterized by high morbidity and mortality globally. In this study, we identified and validated the therapeutic effects of small molecule inhibitors targeting the GSDMD pathway for AKI treatment. Using a drug screening assay, we evaluated thousands of small molecules from DrugBank against Lipopolysaccharide (LPS) and Nigericin-stimulated immortalized bone marrow-derived macrophages (iBMDMs) to discern GSDMD pathway activators. We simulated AKI in primary renal tubular epithelial cells using hydrogen peroxide (H2O2) exposure. Furthermore, AKI in mouse models was induced via cisplatin and ischemia/reperfusion. Our findings highlight stevioside as a potent GSDMD activator exhibiting minimal toxicity. Experimental results, both in vitro and in vivo, demonstrate stevioside's significant potential in alleviating renal tubular epithelial cell injury and AKI histological damage. After stevioside treatment, a notable decrease in cleaved GSDMD-N terminal levels was observed coupled with diminished inflammatory factor release. This observation was consistent in both cisplatin- and ischemia/reperfusion-induced AKI mouse models. Collectively, our research suggests that stevioside could be a promising candidate for modulating GSDMD signaling in AKI treatment.

The role of radiotherapy in the treatment of sinonasal undifferentiated carcinoma: A population-based analysis.

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive disease with ambiguous management and poor prognosis. This study aimed to evaluate the role of radiation therapy (RT) and explore the optimal treatment sequence. METHODS: Retrospective analysis of survival trends of 410 SNUC patients between 1973 and 2015. RESULTS: The 5-year cancer-specific survival (CSS) rate (45.1%) and overall survival (OS) rates (38.1%) were reported in the 84-month median follow-up. Radiotherapy was a prognosticator for improving CSS (hazard ratio [HR] = 0.425, 95% confidence interval [CI]: 0.299-0.603, p = 0.000) and OS (HR = 0.415, 95% CI: 0.303-0.570, p = 0.000), either with surgery (p = 0.000) or without surgery (p = 0.000). However, in a combined therapy of surgery and RT, preoperative and postoperative RT (5-year OS rates were 47.1% and 45.6%, respectively, p = 0.486) were not significantly different. CONCLUSIONS: Radiotherapy plays a key role in improving SNUC survival rates. No significant difference in survival rates was observed in preoperative and postoperative RT treatment.

Neutrophil-Mediated Nanozyme Delivery System for Acute Kidney Injury Therapy.

Reactive oxygen species (ROS) scavenging of nanozymes toward acute kidney injury (AKI) is a current promising strategy, however, the glomerular filtration barrier (GFB) limits their application for treating kidney related diseases. Here, a neutrophil-mediated delivery system able to hijack neutrophil to transport nanozyme-loaded cRGD-liposomes to inflamed kidney for AKI treatment by cRGD targeting integrin αvß1 is reported. The neutrophil-mediated nanozyme delivery system demonstrated great antioxidant and anti-apoptosis ability in HK-2 and NRK-52E cell lines. Moreover, in ischemia-reperfusion (I/R) induced AKI mice, a single dose of LM@cRGD-LPs 12 h post-ischemia significantly reduces renal function indicators, alleviates renal pathological changes, and inhibits apoptosis of renal tubular cells and the expression of renal tubular injured marker, thus remarkably reducing the damage of AKI. Mechanistically, the treatment of LM@cRGD-LPs markedly inhibits the process of Nrf2 to the nucleus and reduces the expression of the downstream HO-1, achieves a 99.51% increase in renal tissue Nrf2 levels, and an 86.31% decrease in HO-1 levels after LM@cRGD-LPs treatment. In short, the strategy of neutrophil-mediated nanozyme delivery system hold great promise as a potential therapy for AKI or other inflammatory diseases.

No increase of soil wind erosion with the establishment of center pivot irrigation system in Mu-Us sandy land.

Center Pivot Irrigation system (CPIs) is widely used in newly exploited arable land in sandy lands. These sandy lands are currently stable because of climate change and ecological restoration efforts since the beginning of the 21st century in northern China. The exploitation of these fixed sandy lands to arable land with CPIs may affect the soil wind erosion, yet it remains unknown. The temporal changes of CPIs and its effect on wind erosion module were analyzed and modeled from 2000 to 2020 in Mu-Us sandy land using satellite images and Revised Wind Erosion Equation (RWEQ). The establishment of CPIs started from 2010, boomed in 2015 and peaked in 2020. They were mainly transformed from woodland, grassland, and barren land near rivers in east and southeast, and from cropland in inter-dunes in west and southwest of Mu-Us sandy land. The temporal and spatial pattern of CPIs well aligns with the land consolidation and requisition-compensation balance policies. In most of the Mu-Us sandy land, the annual erosion module is <25 t ha-1 a-1. Despite great variation, the annual, Winter and Spring erosion module of the Mu-Us sandy land or in Otog Qian and Yuyang, the CPIs concentrated counties, all decreased during 2000-2019. Although, wind erosion module in CPIs was lower than the surrounding area, it increased in 2019 given the same climate conditions as in 2010. Our results suggest 1) the establishment of CPIs in Mu-Us sandy land greatly depends on the local policy and natural endowment, and 2) although the set-up of CPIs showed no impact on the wind erosion with CPIs accounting for <1 % of Mu-Us sandy land, post-harvest of CPIs should be carefully concerned to prevent soil wind erosion.

Van der Waals Magnetic Electrode Transfer for Two-Dimensional Spintronic Devices.

Two-dimensional (2D) materials are promising candidates for spintronic applications. Maintaining their atomically smooth interfaces during integration of ferromagnetic (FM) electrodes is crucial since conventional metal deposition tends to induce defects at the interfaces. Meanwhile, the difficulties in picking up FM metals with strong adhesion and in achieving conductance match between FM electrodes and spin transport channels make it challenging to fabricate high-quality 2D spintronic devices using metal transfer techniques. Here, we report a solvent-free magnetic electrode transfer technique that employs a graphene layer to assist in the transfer of FM metals. It also serves as part of the FM electrode after transfer for optimizing spin injection, which enables the realization of spin valves with excellent performance based on various 2D materials. In addition to two-terminal devices, we demonstrate that the technique is applicable for four-terminal spin valves with nonlocal geometry. Our results provide a promising future of realizing 2D spintronic applications using the developed magnetic electrode transfer technique.

Genome-Wide Analysis of MYB Gene Family in Chrysanthemum ×morifolium Provides Insights into Flower Color Regulation.

MYBs constitute the second largest transcription factor (TF) superfamily in flowering plants with substantial structural and functional diversity, which have been brought into focus because they affect flower colors by regulating anthocyanin biosynthesis. Up to now, the genomic data of several Chrysanthemum species have been released, which provides us with abundant genomic resources for revealing the evolution of the MYB gene family in Chrysanthemum species. In the present study, comparative analyses of the MYB gene family in six representative species, including C. lavandulifolium, C. seticuspe, C. ×morifolium, Helianthus annuus, Lactuca sativa, and Arabidopsis thaliana, were performed. A total of 1104 MYBs, which were classified into four subfamilies and 35 lineages, were identified in the three Chrysanthemum species (C. lavandulifolium, C. seticuspe, and C. ×morifolium). We found that whole-genome duplication and tandem duplication are the main duplication mechanisms that drove the occurrence of duplicates in CmMYBs (particularly in the R2R3-MYB subfamily) during the evolution of the cultivated chrysanthemums. Sequence structure and selective pressure analyses of the MYB gene family revealed that some of R2R3-MYBs were subjected to positive selection, which are mostly located on the distal telomere segments of the chromosomes and contain motifs 7 and 8. In addition, the gene expression analysis of CmMYBs in different organs and at various capitulum developmental stages of C. ×morifolium indicated that CmMYBS2, CmMYB96, and CmMYB109 might be the negative regulators for anthocyanin biosynthesis. Our results provide the phylogenetic context for research on the genetic and functional evolution of the MYB gene family in Chrysanthemum species and deepen our understanding of the regulatory mechanism of MYB TFs on the flower color of C. ×morifolium.

Single-cell transcriptional profiling in osteosarcoma and the effect of neoadjuvant chemotherapy on the tumor microenvironment.

Osteosarcoma (OS), a malignant tumor, originates from the bone marrow. Currently, treatment for OS remains limited, making it urgent to understand the immune response in the tumor microenvironment of patients with OS. A comprehensive bioinformatics analysis was performed, including cell clustering subgroups, differential expression genes screening, proposed temporal order, and genomic variant analysis on single-cell RNA-sequencing data, from ten pre-chemotherapy patients and eleven post-chemotherapy patients. Subsequently, we analyzed the differentiation trajectories of osteoblasts, osteoclasts, fibroblasts, myeloid cells, and tumor-infiltrating lymphocytes (TILs) in detail to compare the changes in cell proportions and differential genes pre- and post-chemotherapy. The nine cell types were identified, including fibroblasts, myeloid cells, osteoblasts, TILs, osteoclasts, proliferative osteoblasts, pericytes, endothelial cells, and B cells. Post-chemotherapy treatment, the proportions of myeloid cells and TILs in OS were declined, while the number of osteoblasts was elevated. Besides, a decrease was observed in CD74, FTL, FTH1, MT1X and MT2A, and an increase in PTN, COL3A1, COL1A1, IGFBP7 and FN1. Meanwhile, EMT, DNA repair, G2M checkpoint, and E2F targets were highly enriched post-chemotherapy. Furthermore, there was a down-regulation in the proportions of CD14 monocytes, Tregs, NK cells and CD1C-/CD141-DCs, while an up-regulation was observed in the proportions of SELENOP macrophages, IL7R macrophages, COL1A1 macrophages, CD1C DCs, CD4+ T cells and CD8+ T cells. Overall, these findings revealed changes in the tumor microenvironment of OS post-chemotherapy treatment, providing a new direction for investigating OS treatment.

A PSMA PET/CT-based risk model for prediction of concordance between targeted biopsy and combined biopsy in detecting prostate cancer.

PURPOSE: This study is to investigate the diagnostic value of 68Ga-PSMA-11 in improving the concordance between mpMRI-TB and combined biopsy (CB) in detecting PCa. METHODS: 115 consecutive men with 68Ga-PSMA-11 PET/CT prior to prostate biopsy were included for analysis. PSMA intensity, quantified as maximum standard uptake value (SUVmax), minimum apparent diffusion coefficient (ADCmin) and other clinical characteristics were evaluated relative to biopsy concordance using univariate and multivariate logistic regression analyses. A prediction model was developed based on the identified parameters, and a dynamic online diagnostic nomogram was constructed, with its discrimination evaluated through the area under the ROC curve (AUC) and consistency assessed using calibration plots. To assess its clinical applicability, a decision curve analysis (DCA) was performed, while internal validation was conducted using bootstrapping methods. RESULTS: Concordance between mpMRI-TB and CB occurred in 76.5% (88/115) of the patients. Multivariate logistic regression analyses performed that SUVmax (OR= 0.952; 95% CI 0.917-0.988; P= 0.010) and ADCmin (OR= 1.006; 95% CI 1.003-1.010; P= 0.001) were independent risk factors for biopsy concordance. The developed model showed a sensitivity, specificity, accuracy and AUC of 0.67, 0.78, 0.81 and 0.78 in the full sample. The calibration curve demonstrated that the nomogram's predicted outcomes closely resembled the ideal curve, indicating consistency between predicted and actual outcomes. Furthermore, the decision curve analysis (DCA) highlighted the clinical net benefit achievable across various risk thresholds. These findings were reinforced by internal validation. CONCLUSIONS: The developed prediction model based on SUVmax and ADCmin showed practical value in guiding the optimization of prostate biopsy pattern. Lower SUVmax and Higher ADCmin values are associated with greater confidence in implementing mono-TB and safely avoiding SB, effectively balancing benefits and risks.

Integration of Whole-Genome Resequencing and Transcriptome Sequencing Reveals Candidate Genes in High Glossiness of Eggshell.

Eggshell gloss is an important characteristic for the manifestation of eggshell appearance. However, no study has yet identified potential candidate genes for eggshell gloss between high-gloss (HG) and low-gloss (LG) chickens. The aim of this study was to perform a preliminary investigation into the formation mechanism of eggshell gloss and to identify potential genes. The eggshell gloss of 300-day-old Rhode Island Red hens was measured from three aspects. Uterine tissues of the selected HG and LG (n = 5) hens were collected for RNA-seq. Blood samples were also collected for whole-genome resequencing (WGRS). RNA-seq analysis showed that 150 differentially expressed genes (DEGs) were identified in the uterine tissues of HG and LG hens. These DEGs were mainly enriched in the calcium signaling pathway and the neuroactive ligand-receptor interaction pathway. Importantly, these two pathways were also significantly enriched in the WGRS analysis results. Further joint analysis of WGRS and RNA-seq data revealed that 5-hydroxytryptamine receptor 1F (HTR1F), zinc finger protein 536 (ZNF536), NEDD8 ubiquitin-like modifier (NEDD8), nerve growth factor (NGF) and calmodulin 1 (CALM1) are potential candidate genes for eggshell gloss. In summary, our research provides a reference for the study of eggshell gloss and lays a foundation for improving egg glossiness in layer breeding.

miR-29b-3p targetedly regulates VEGF to inhibit tumor progression and cisplatin resistance through Nrf2/HO-1 signaling pathway in non-small cell lung cancer.

BACKGROUNDS: Non-small cell lung carcinoma (NSCLC) is a common type of lung cancer. Prior investigations have elucidated the pivotal role of miR-29b-3p in restraining tumor growth and metastasis. Nonetheless, it remains to be determined whether miR-29b-3p can effectively suppress NSCLC progression and enhance the sensitivity of NSCLC cells to cisplatin. This investigation sought to determine the mechanism by which miR-29b-3p inhibited the advancement of NSCLC and mitigated resistance to cisplatin. METHODS: We initially assessed miR-29b-3p and VEGF levels in NSCLC tissues and cell lines. Next, miR-29b-3p expression was elevated in NSCLC cell lines H1975 and A549 by overexpression plasmid transfection. Following this, a sequence of molecular biology experiments was conducted to evaluate the impact of miR-29b-3p on the biological behaviors of NSCLC cells and their resistance to cisplatin. Additionally, we predicted VEGF was a target gene of miR-29b-3p by bioinformatics analysis. We next employed western blot to evaluate the protein expression of Nrf2 and HO-1 in NSCLC cells. Finally, we elucidated the effects of VEGF and Nrf2/HO-1pathway on NSCLC progression and cisplatin resistance by in vitro assays. RESULTS: In comparison to paracancerous tissues and human normal lung epithelial cells, the expression of miR-29b-3p was notably reduced and VEGF expression was clearly elevated in NSCLC tissues and cells. Moreover, miR-29b-3p upregulated obviously suppressed the biological activities of NSCLC cells and increased their sensitivity to cisplatin. Furthermore, in NSCLC cells, miR-29b-3p bound to VEGF and negatively regulate its transcription. Additionally, miR-29b-3p overexpression also inhibited the Nrf2/HO-1 signaling pathway. Finally, the overexpression of VEGF and the activation of the Nrf2/HO-1 pathway reversed miR-29b-3p-mediated inhibitory effect on biological behaviors of NSCLC cells and increased the cisplatin resistance. CONCLUSION: Our findings indicate that miR-29b-3p impedes NSCLC cells' biological behaviors and augments their sensitivity to cisplatin by targeting VEGF to modulate the Nfr2/HO-1 signaling pathway.

A comparative study of mono-exponential and advanced diffusion-weighted imaging in differentiating stage IA endometrial carcinoma from benign endometrial lesions.

PURPOSE: The purpose of the current investigation is to compare the efficacy of different diffusion models and diffusion kurtosis imaging (DKI) in differentiating stage IA endometrial carcinoma (IAEC) from benign endometrial lesions (BELs). METHODS: Patients with IAEC, endometrial hyperplasia (EH), or a thickened endometrium confirmed between May 2016 and August 2022 were retrospectively enrolled. All of the patients underwent a preoperative pelvic magnetic resonance imaging (MRI) examination. The apparent diffusion coefficient (ADC) from the mono-exponential model, pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) from the bi-exponential model, distributed diffusion coefficient (DDC), water molecular diffusion heterogeneity index from the stretched-exponential model, diffusion coefficient (Dk) and diffusion kurtosis (K) from the DKI model were calculated. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic efficiency. RESULTS: A total of 90 patients with IAEC and 91 patients with BELs were enrolled. The values of ADC, D, DDC and Dk were significantly lower and D* and K were significantly higher in cases of IAEC (p < 0.05). Multivariate analysis showed that K was the only predictor. The area under the ROC curve of K was 0.864, significantly higher compared with the ADC (0.601), D (0.811), D* (0.638), DDC (0.743) and Dk (0.675). The sensitivity, specificity and accuracy of K were 78.89%, 85.71% and 80.66%, respectively. CONCLUSION: Advanced diffusion-weighted imaging models have good performance for differentiating IAEC from EH and endometrial thickening. Among all of the diffusion parameters, K showed the best performance and was the only independent predictor. Diffusion kurtosis imaging was defined as the most valuable model in the current context.

Calcium gluconate-based flame retardant towards simultaneously high-efficiency fire safety and mechanical enhancement for epoxy resin.

Flame retardants containing biomass receive growing interest in environmental friendliness and sustainability but usually face the low flame-retardant efficiency and deterioration on mechanical property of matrix. Herein, a calcium gluconate-based flame retardant (CG@APP) was chemically prepared using calcium gluconate (CG) and ammonium polyphosphate (APP) via ion exchange reaction, and enabled the excellent fire safety and mechanical enhancement for epoxy resin (EP). The resulted EP composites containing 6 wt% CG@APP (EP/CG@APP6) exhibited V-0 ratings in UL-94 test. Furthermore, with respect to EP/APP6, the peak of heat release rate (pHRR) and peak of smoke production rate (pSPR) of EP/CG@APP6 decreased by 70.5 % and 50.0 %, respectively. The well synergistic flame-retardant mechanism of CG@APP between gaseous and solid phases was revealed to generate denser and more continuous charring residuals, which could do well work on insulation for heat transfer and fuel diffusion. In addition, the shell rich in hydroxyl group and Ca2+ on the surface of CG@APP well enhanced the interface compatibility through the hydrogen bond and coordinated bond, thus the tensile strength, flexural strength and impact strength of EP/CG@APP6 increased by 18.2 %, 4.5 % and 9.1 % compared with pure EP, respectively. This work provided a simple and sustainable way to construct excellent fire-safety composites.

Suppression of B-Cell Activation by Human Cord Blood-Derived Stem Cells (CB-SCs) through the Galectin-9-Dependent Mechanism.

We developed the Stem Cell Educator therapy among multiple clinical trials based on the immune modulations of multipotent cord blood-derived stem cells (CB-SCs) on different compartments of immune cells, such as T cells and monocytes/macrophages, in type 1 diabetes and other autoimmune diseases. However, the effects of CB-SCs on the B cells remained unclear. To better understand the molecular mechanisms underlying the immune education of CB-SCs, we explored the modulations of CB-SCs on human B cells. CB-SCs were isolated from human cord blood units and confirmed by flow cytometry with different markers for their purity. B cells were purified by using anti-CD19 immunomagnetic beads from human peripheral blood mononuclear cells (PBMCs). Next, the activated B cells were treated in the presence or absence of coculture with CB-SCs for 7 days before undergoing flow cytometry analysis of phenotypic changes with different markers. Reverse transcription-polymerase chain reaction (RT-PCR) was utilized to evaluate the levels of galectin expressions on CB-SCs with or without treatment of activated B cells in order to find the key galectin that was contributing to the B-cell modulation. Flow cytometry demonstrated that the proliferation of activated B cells was markedly suppressed in the presence of CB-SCs, leading to the downregulation of immunoglobulin production from the activated B cells. Phenotypic analysis revealed that treatment with CB-SCs increased the percentage of IgD+CD27- naïve B cells, but decreased the percentage of IgD-CD27+ switched B cells. The transwell assay showed that the immune suppression of CB-SCs on B cells was dependent on the galectin-9 molecule, as confirmed by the blocking experiment with the anti-galectin-9 monoclonal antibody. Mechanistic studies demonstrated that both calcium levels of cytoplasm and mitochondria were downregulated after the treatment with CB-SCs, causing the decline in mitochondrial membrane potential in the activated B cells. Western blot exhibited that the levels of phosphorylated Akt and Erk1/2 signaling proteins in the activated B cells were also markedly reduced in the presence of CB-SCs. CB-SCs displayed multiple immune modulations on B cells through the galectin-9-mediated mechanism and calcium flux/Akt/Erk1/2 signaling pathways. The data advance our current understanding of the molecular mechanisms underlying the Stem Cell Educator therapy to treat autoimmune diseases in clinics.

RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stabilization.

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcription initiation and is essential for maintaining gene silencing at heterochromatic loci. Inhibition of CDK9 increases sensitivity to immunotherapy, but the underlying mechanism remains unclear. We now report that RNF20 stabilizes LSD1 via K29-mediated ubiquitination, which is dependent on CDK9-mediated phosphorylation. This CDK9- and RNF20-dependent LSD1 stabilization is necessary for the demethylation of histone H3K4, then subsequent repression of endogenous retrovirus, and an interferon response, leading to epigenetic immunosuppression. Moreover, we found that loss of RNF20 sensitizes cancer cells to the immune checkpoint inhibitor anti-PD-1 in vivo and that this effect can be rescued by the expression of ectopic LSD1. Our findings are supported by the observation that RNF20 levels correlate with LSD1 levels in human breast cancer specimens. This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.

Microglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice.

Anxiety-associated symptoms following acute stress usually become extinct gradually within a period of time. However, the mechanisms underlying how individuals cope with stress to achieve the extinction of anxiety are not clear. Here we show that acute restraint stress causes an increase in the activity of GABAergic neurons in the CeA (GABACeA) in male mice, resulting in anxiety-like behaviors within 12 hours; meanwhile, elevated GABACeA neuronal CX3CL1 secretion via MST4 (mammalian sterile-20-like kinase 4)-NF-κB-CX3CL1 signaling consequently activates microglia in the CeA. Activated microglia in turn inhibit GABACeA neuronal activity via the engulfment of their dendritic spines, ultimately leading to the extinction of anxiety-like behaviors induced by restraint stress. These findings reveal a dynamic molecular and cellular mechanism in which microglia drive a negative feedback to inhibit GABACeA neuronal activity, thus facilitating maintenance of brain homeostasis in response to acute stress.

The residual cancer burden index as a valid prognostic indicator in breast cancer after neoadjuvant chemotherapy.

PURPOSE: The residual cancer burden index (RCB) was proposed as a response evaluation criterion in breast cancer patients treated with Neoadjuvant Chemotherapy (NAC). This study evaluated the relevance of RCB with replase-free survival (RFS). METHODS: The clinical data of 254 breast cancer patients who received NAC between 2016 and 2020 were retrospectively collected. The relationship between clinicopathologic factors and RFS was evaluated using Cox proportional hazards regression models. RFS estimates were determined by Kaplan-Meier(K-M) analysis and compared using the log-rank test. Multivariate logistic regression analysis was used to evaluate the risk factors associated with RCB. Receiver operating characteristic (ROC) curves showed the potential of the RCB and MP grading systems as biomarkers for RFS. RESULTS: At a median follow-up of 52 months, 59 patients(23.23%) developed relapse. Multivariate Cox regression showed that older age (P = 0.022), high Pathologic T stage after NAC (P = 0.023) and a high RCB score(P = 0.003) were risk factors for relapse. The outcomes of the multivariate logistic analysis indicated that RCB 0 (pathologic complete response [pCR]) was associated with HER2-positive patients (P = 0.002) and triple-negative breast cancer (TNBC) patients (P = 0.013). In addition, the RCB and MP scoring systems served as prognostic markers for patients who received NAC, and their area under curves (AUCs) were 0.691 and 0.342, respectively. CONCLUSION: These data suggest that RCB can be equally applied to predict RFS in Chinese patients with NAC. The application of RCB may help guide the selection of treatment strategies.

A Fusion Strategy for Vehicle Positioning at Intersections Utilizing UWB and Onboard Sensors.

For vehicle positioning applications in Intelligent Transportation Systems (ITS), lane-level or even more precise localization is desired in some typical urban scenarios. With the rapid development of wireless positioning technologies, ultrawide bandwidth (UWB) has stood out and become a prominent approach for high-precision positioning. However, in traffic scenarios, the UWB-based positioning method may deteriorate because of not-line-of-sight (NLOS) propagation, multipath effect and other external interference. To overcome these problems, in this paper, a fusion strategy utilizing UWB and onboard sensors is developed to achieve reliable and precise vehicle positioning. It is a two-step approach, which includes the preprocessing of UWB raw measurements and the global estimation of vehicle position. Firstly, an ARIMA-GARCH model to address the NLOS problem of UWB at vehicular traffic scenarios is developed, and then the NLOS of UWB can be detected and corrected efficiently. Further, an adaptive IMM algorithm is developed to realize global fusion. Compared with traditional IMM, the proposed AIMM is capable of adjusting the model probabilities to make them better matching for current driving conditions, then positioning accuracy can be improved. Finally, the method is validated through experiments. Field test results verify the effectiveness and feasibility of the proposed strategy.