👤 Yuanxuan Xia

FGFR1 is a key member of the fibroblast growth factor receptor family, mediating critical signaling pathways such as RAS-MAPK and PI3K-AKT. which are integral to regulating essential cellular processes, including proliferation, differentiation, and survival. Alterations in FGFR1 can lead to constitutive activation of signaling pathways that drive oncogenesis by promoting uncontrolled cell division, inhibiting apoptosis, and enhancing the metastatic potential of cancer cells. This article reviews the activation mechanisms and signaling pathways of FGFR1 and provides a detailed exposition of the types of FGFR1 aberration. Furthermore, we have compiled a comprehensive overview of current therapies targeting FGFR1 aberration in cancer, aiming to offer new perspectives for future cancer treatments by focusing on drugs that address specific FGFR1 alterations. Show less

Lung cancer, the leading cause of cancer-related incidence and mortality worldwide, is characterised by high invasiveness and poor prognosis. Novel therapeutic targets are required, especially for patients with inoperable metastatic disease requiring systemic therapies to improve patients' welfare. Recently, studies indicated that TMEM176B is a positive regulator in breast and gastric cancers, and it could be a potential target for treatment. In this study, we used single-cell sequencing, proteomics, Co-IP, and in vivo and in vitro experimental models to investigate the role of TMEM176B in lung adenocarcinoma development. Our study indicated that TMEM176B expression was enhanced in lung adenocarcinoma tissues, and it was associated with shorter overall survival (OS). TMEM176B promoted cellular functions, including cell proliferation, invasion, migration and adhesion in vitro and tumour growth in vivo. Moreover, the tube formation ability of endothelial cells was enhanced by treating with the tumour cell-conditioned medium. We have also demonstrated that TMEM176B regulated EMT via the FGFR1/JNK/Vimentin/Snail signalling cascade. Overall, our study suggests TMEM176B could be a potential therapeutic target in lung adenocarcinoma. Show less

Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Here, we report that PTEN deficiency induced Krüppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-α, which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1. Show less

Intrahepatic Cholangiocarcinoma (iCCA) with FGFR alterations is relatively rare, and its identification is important in the era of targeted therapy. We collected a large series of FGFR-altered cases in the Chinese population and characterized their clinicopathological and genetic features. Among the 18 FGFR-altered cases out of 260 iCCAs, 10 were males and 8 were females, ranging in age from 35 to 74 years (mean, 57.3 years; median, 58 years). Pathologically, they include 9 cases of large duct (LD, 50 %) and small duct (SD, 50 %) types each. All of them (100 %, 18/18) showed microsatellite stable (MSS) and low tumor mutation burden (TMB). Genetically, FGFR alterations involved FGFR1 (20 %), FGFR2 (70 %), and FGFR3 (10 %), with FGFR2 rearrangement accounting for the most (11/18). The most frequently altered genes/biological processes were development/proliferation-related pathways (44 %), chromatin organization (20 %), and tumor suppressors (32 %). Our study further revealed the clinicopathological and genetic features of FGFR-altered iCCA and demonstrated that its occurrence may show regional or ethnic variability and is less common in the Chinese population. A significant number of LD-type iCCA cases also have FGFR alterations rather than the SD type. Show less

The cancer-associated fibroblast (CAF)-derived secretome plays critical roles in tumor progression by remodelling tumor microenvironment. Tumorigenesis is accompanied by the transformation of normal fibroblasts (NF) into CAF, leading to significant changes in their secretome. This work aims to identify the differential components of secretome between NFs and CAFs and reveal their functions in gastric cancer (GC). Firstly, our molecular typing studies and immune infiltration analysis showed that CAF infiltration level was increased and showed a significant association with clinical characteristics and poor prognosis of GC patients. Secondly, RNA-seq analysis revealed that a total of 1531 genes showed significant expression changes between NF and CAF. According to the annotation of the Human Protein Atlas (HPA) database, 147 genes encode secreted proteins, including FGF2. Particularly, the cell co-culture and RNA sequencing studies confirmed that exogenous recombinant FGF2 protein treatment promoted GC cell proliferation by enhancing ribosome biogenesis. The rescue assay showed that CAF-secreted FGF2 protein promotes GC cell growth and proliferation in a FGFR1-dependent manner. Our finding provides evidence that targeting blockade of CAF-derived FGF2 protein might be a promising treatment for GC. Show less

Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and permeability limit osteogenic cell ingrowth and vascularization, which is critical for bone regeneration. In the current study, we constructed a novel hierarchically-porous magnesium phosphate bone cement by incorporating extracellular matrix (ECM)-mimicking electrospun silk fibroin (SF) nanofibers. The SF-embedded MPC (SM) exhibited a heterogeneous and hierarchical structure, which effectively facilitated the rapid infiltration of oxygen and nutrients as well as cell ingrowth. Besides, the SF fibers improved the mechanical properties of MPC and neutralized the highly alkaline environment caused by excess magnesium oxide. Bone marrow stem cells (BMSCs) adhered excellently on SM, as illustrated by formation of more pseudopodia. CCK8 assay showed that SM promoted early proliferation of BMSCs. Our study also verified that SM increased the expression of OPN, RUNX2 and BMP2, suggesting enhanced osteogenic differentiation of BMSCs. We screened for osteogenesis-related pathways, including FAK signaing, Wnt signaling and Notch signaling, and found that SM aided in the process of bone regeneration by suppressing the Notch signaling pathway, proved by the downregulation of NICD1, Hes1 and Hey2. In addition, using a bone defect model of rat calvaria, the study revealed that SM exhibited enhanced osteogenesis, bone ingrowth and vascularization compared with MPC alone. No adverse effect was found after implantation of SM Show less

IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis. Show less

Stimulation of myeloid-derived suppressor cell (MDSC) formation represents a potential curative therapeutic approach for graft-versus-host disease (GVHD), which significantly impacts the prognosis of allogeneic hematopoietic stem cell transplantation. However, the lack of an effective strategy for inducing MDSC production in vivo has hindered their clinical application. In our previous study, MDSC expansion was observed in interleukin (IL)-27-treated mice. In this study, we overexpressed exogenous IL-27 in mice using a recombinant adeno-associated virus vector to investigate its therapeutic and exacerbating effects in murine GVHD models. In our study, we demonstrated that exogenous administration of IL-27 significantly suppressed GVHD development in a mouse model. We found that IL-27 treatment indirectly inhibited the proliferation and activation of donor T cells by rapidly expanding recipient and donor myeloid cells, which act as MDSCs after irradiation or under inflammatory conditions, rather than through regulatory T-cell expansion. Additionally, IL-27 stimulated MDSC expansion by enhancing granulocyte-monocyte progenitor generation. Notably, we verified that IL-27 signaling in donor T cells exerted an antagonistic effect on GVHD prevention and treatment. Further investigation revealed that combination therapy involving IL-27 and T-cell depletion exhibited remarkable preventive effects on GVHD in both mouse and xenogeneic GVHD models. Collectively, these findings suggest that IL-27 promotes MDSC generation to reduce the incidence of GVHD, whereas targeted activation of IL-27 signaling in myeloid progenitors or its combination with T-cell depletion represents a potential strategy for GVHD therapy. Show less

Coagulation system is currently known associated with the development of ischemic stroke (IS). Thus, the current study is designed to identify diagnostic value of coagulation genes (CGs) in IS and to explore their role in the immune microenvironment of IS. Aberrant expressed CGs in IS were input into unsupervised consensus clustering to classify IS subtypes. Meanwhile, key CGs involved in IS were further selected by weighted gene co-expression network analysis (WGCNA) and machine learning methods, including random forest (RF), support vector machine (SVM), generalized linear model (GLM) and extreme-gradient boosting (XGB). The diagnostic performance of key CGs were evaluated by receiver operating characteristic (ROC) curves. At last, quantitative PCR (qPCR) was performed to validate the expressions of key CGs in IS. IS patients were classified into two subtypes with different immune microenvironments by aberrant expressed CGs. Further WGCNA, machine learning methods and ROC curves identified ACTN1, F5, TLN1, JMJD1C and WAS as potential diagnostic biomarkers of IS. In addition, their expressions were significantly correlated with macrophages, neutrophils and/or T cells. GSEA also revealed that those biomarkers may regulate IS via immune and inflammation. Moreover, qPCR verified the expressions of ACTN1, F5 and JMJD1C in IS. The current study identified ACTN1, F5 and JMJD1C as novel coagulation-related biomarkers associated with IS immune microenvironment, which enriches our knowledge of coagulation-mediated pathogenesis of IS and sheds light on next-step Show less

Prostate cancer (PCa) is a malignant tumor of the male reproductive system, and its incidence has increased significantly in recent years. This study aimed to further identify candidate biomarkers with prognostic and diagnostic significance by integrating gene expression and DNA methylation data from PCa patients through association analysis. To this end, this paper proposes a sparse partial least squares regression algorithm based on hypergraph regularization (HR-SPLS) by integrating and clustering two kinds of data. Next, module 2, with the most significant weight, was selected for further analysis according to the weight of each module related to DNA methylation and mRNAs. Based on the DNA methylation sites in module 2, this paper uses multiple machine learning methods to construct a PCa diagnosis-related model of 10-DNA methylation sites. The results of Receiver Operating Characteristic (ROC) analysis showed that the DNA methylation-related diagnostic model we constructed could diagnose PCa patients with high accuracy. Subsequently, based on the mRNAs in module 2, we constructed a prognostic model for 7-mRNAs (MYH11, ACTG2, DDR2, CDC42EP3, MARCKSL1, LMOD1, and MYLK) using multivariate Cox regression analysis. The prognostic model could predict the disease free survival of PCa patients with moderate to high accuracy (area under the curve (AUC) =0.761). In addition, Gene Set EnrichmentAnalysis (GSEA) and immune analysis indicated that the prognosis of patients in the risk group might be related to immune cell infiltration. Our findings may provide new methods and insights for identifying disease-related biomarkers by integrating DNA methylation and gene expression data. Show less

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pathology and cognitive dysfunction. Variants of triggering receptor expressed on myeloid cells-2 (TREM2) are known to increase the risk of developing AD. TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis, but the precise mechanism through which it accomplishes this is unknown. Metabolomic analysis of hippocampal tissue from APP/PS1 and APP/PS1-TREM2 knockout (KO) mice found that TREM2 KO was associated with abnormalities in several metabolism pathways, and the effect was particularly pronounced in lipid metabolism and glucose metabolism pathways. Consistently, transcriptomic analysis of these mice determined that most differentially expressed genes were involved in energy metabolism pathways. We screened seven differentially expressed genes in APP/PS1-TREM2 KO mice that may influence AD development by altering energy metabolism. Integrative analysis of the metabolomic and transcriptomic profiles showed that TREM2 may regulate lipid metabolism and sphingolipid metabolism by affecting lipoprotein lipase (LPL) expression, thereby influencing AD progression. Our results prompt further studies of the interactions among TREM2, LPL, glucolipid metabolism, and sphingolipid metabolism in AD to identify new diagnostic and treatment strategies. Show less

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1 Show less

Familial non-medullary thyroid carcinoma (FNMTC) is a type of thyroid cancer characterized by genetic susceptibility, representing approximately 5% of all non-medullary thyroid carcinomas. While some cases of FNMTC are associated with familial multi-organ tumor predisposition syndromes, the majority occur independently. The genetic mechanisms underlying non-syndromic FNMTC remain unclear. Initial studies utilized SNP linkage analysis to identify susceptibility loci, including the 1q21 locus, 2q21 locus, and 4q32 locus, among others. Subsequent research employed more advanced techniques such as Genome-wide Association Study and Whole Exome Sequencing, leading to the discovery of genes such as Show less

Parkinson's disease (PD) is the second most common neurodegenerative disorder whose etiology remains unknown. The immune system has been implicated in hallmarks of PD including aggregation of α-synuclein and death of dopaminergic neurons in the substantia nigra. As a core regulator of immune response and inflammation, liver X receptors (LXRs) have been shown to have protective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. With two isoforms of LXRs (LXRα and LXRβ) expressed in the brain, their roles and distributions in this tissue remain largely unexplored. Here, we used MPTP to mimic symptoms and biomedical changes seen in PD in LXRα Show less

Neurexins, essential synaptic proteins, are linked to neurodevelopmental and neuropsychiatric disorders like autism spectrum disorder (ASD) and schizophrenia. Through this systematic review, we aimed to shed light on the relationship between neurexin dysfunction and its implications in neurodevelopmental and neuropsychiatric manifestations. Both animal and human-induced pluripotent stem cell (hiPSC) models served as our primary investigative platforms. Utilizing the PRISMA 2020 guidelines, our search strategy involved scouring articles from the PubMed and Google Scholar databases covering a span of two decades (2003-2023). Of the initial collection, 27 rigorously evaluated studies formed the essence of our review. Our review suggested the significant ties between neurexin anomalies and neurodevelopmental and neuropsychiatric outcomes, most notably ASD. Rodent-based investigations delineated pronounced ASD-associated behaviors, and hiPSC models derived from ASD-diagnosed patients revealed the disruptions in calcium dynamics and synaptic activities. Additionally, our review underlined the integral role of specific neurexin variants, primarily NRXN1, in the pathology of schizophrenia. It was also evident from our observation that neurexin malfunctions were implicated in a broader array of these disorders, including ADHD, intellectual challenges, and seizure disorders. This review accentuates the cardinal role neurexins play in the pathological process of neurodevelopmental and neuropsychiatric disorders. The findings underscore a critical need for standardized methodologies in developing animal and hiPSC models for future studies, aiming to minimize heterogeneity. Moreover, we highlight the need to expand research into less studied neurexin variants (i.e., NRXN2 and NRXN3), broadening the scope of our understanding in this field. Our observation also projects hiPSC models as potent tools for bridging research gaps, promoting translational research, and fostering the development of patient-specific therapeutic interventions. Show less

Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Show less

Autophagy is a ubiquitous pathological/physiological antioxidant cellular reaction in eukaryotic cells. Vacuolar protein sorting 34 (Vps34 or PIK3C3), which plays a crucial role in autophagy, has received much attention. As the only Class III phosphatidylinositol-3 kinase in mammals, Vps34 participates in vesicular transport, nutrient signaling and autophagy. Dysfunctionality of Vps34 induces carcinogenesis, and abnormal autophagy mediated by dysfunction of Vps34 is closely related to the pathological progression of various human diseases, which makes Vps34 a novel target for tumor immunotherapy. In this review, we summarize the molecular mechanisms underlying macroautophagy, and further discuss the structure-activity relationship of Vps34 inhibitors that have been reported in the past decade as well as their potential roles in anticancer immunotherapy to better understand the antitumor mechanism underlying the effects of these inhibitors. Show less

Platycodon grandiflorum (PG) has been widely applied as a conductant drug by ancient and modern traditional Chinese medicine practitioners during long-term clinical practice. However, determining how to guide other medicines to the targeted lungs in traditional Chinese medicine (TCM) prescription remains unclear. An ethanol soluble fraction (Fr. B) was obtained by macroporous resin and 75 % ethanol precipitate. The components were unambiguously determined as fructooligosaccharides and small molecule weight (M Show less

Thymic epithelial tumors (TETs) are infrequent malignancies that arise from the anterior mediastinum. Therapeutic options for TETs, especially thymic carcinoma (TC), remain relatively constrained. This study aims to investigate the oncogenic hub gene and its underlying mechanisms in TETs, as well as to identify potential therapeutic targets. Weighted gene co-expression network analysis (WGCNA) and differential gene expression (DEG) analysis were utilized to identify significant oncogenes using The Cancer Genome Atlas (TCGA) database. LASSO logistic regression analysis was performed to assess the association between hub genes and clinical parameters. The influence of the hub gene on promoting epithelial-mesenchymal transition (EMT), tumor progression, and regulating cancer stem cell-like properties was assessed both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) was utilized to analyze the alterations in the tumor and its microenvironment following the administration of the hub gene's inhibitor. Multiplex immunohistochemistry (mIHC) was employed to validate the results. The potential mechanism was further elucidated through the utilization of Cleavage Under Targets and Tagmentation (CUT&Tag), RNA-sequencing, chromatin immunoprecipitation (ChIP), CUT&RUN, luciferase reporter assay, co-immunoprecipitation (Co-IP), mass spectrometry (MS) and phosphoproteomic assays. SNAI1 was identified as a hub transcription factor for TETs, and its positive correlation with the invasiveness of the disease was confirmed. Subsequent experiments revealed that the upregulation of SNAI1 augmented the migration, invasion, and EMT of TET cell lines. Furthermore, we observed that the overexpression of SNAI1 sustained cancer stem cell-like properties. ScRNA-seq demonstrated that the use of a SNAI1 inhibitor inhibited the transition of macrophages from M1 to M2 phenotype, a finding further validated by multiplex immunohistochemistry (mIHC). Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) was identified as one of the downstream targets of SNAI1 through CUT&Tag and RNA-sequencing, a finding validated by ChIP-qPCR, CUT&RUN-qPCR, luciferase reporter and immunofluorescence assays. Co-IP, MS and phosphoproteomic assays further confirmed that PIK3R2 directly interacted with phosphorylated EphA2 (p-EphA2), facilitating downstream GSK3β/β-catenin signaling pathway. The tumorigenic role of SNAI1 through the PIK3R2/p-EphA2 axis was preliminarily validated in TETs. A potential therapeutic strategy for TETs may involve the inhibition of SNAI1. Show less

Ovarian cancer represents the most lethal gynecological malignancy with high invasiveness. Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer metastasis. However, the role of ALOX5 in EMT and cancer metastasis in ovarian cancer (OC) remain unclear. In this study, ALOX5 was significantly upregulated in tumorous and metastatic tissue compared with normal tissue. Furthermore, we found that overexpression of ALOX5 promoted cell migration and invasion, while silencing of ALOX5 suppressed migration and invasion in OC cell lines. Mechanistically, we found that enhanced expression of ALOX5 promoted EMT and cancer metastasis through activation of the PI3K/AKT pathway, whereas SNAIl inhibited the transcription of CDH1 in OC cells. Taken together, our results highlight a role for the ALOX5/PI3K/AKT/ SNAI1 axis in OC, which provides novel strategies for the prevention of metastasis in OC. Show less

In mammalian ovaries, the balance between dormancy and activation of primordial follicles determines the female fecundity and endocrine homeostasis. Recently, several functional molecules and pathways have been reported to be involved in the activation of primordial follicles. However, the homeostasis regulatory mechanisms of primordial follicle activation are still scant. Our previous study has proved that a relatively higher concentration of cyclic AMP (cAMP) is required for primordial follicle formation. Here, we identified that cAMP also plays a vital role in the balance between dormancy and activation of primordial follicles. Our results showed that the concentration of cAMP remained stable in neonatal mouse ovaries, which is due to ADCY3, the synthetase of cAMP, and PDE3A, the hydrolytic enzyme of cAMP, were synchronously increased during the activation of primordial follicles in mouse ovaries. Once the concentration of cAMP in neonatal ovaries was either elevated or reduced in vitro, the activation of primordial follicles was either accelerated or decelerated accordingly. In addition, a higher concentration of cAMP in the ovaries of puberty mice improved primordial follicle activation in vivo. Finally, cAMP promoted primordial follicle activation via canonical mTORC1-PI3K signaling cascades and PKA signaling. In conclusion, our findings reveal that the concentration of cAMP acts as a key regulator in balancing the dormancy and activation of primordial follicles in the mouse ovary. Show less

Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having the potential to progress into invasive SCC (iSCC) and metastasize, causing death. This study aimed to investigate the heterogeneity of keratinocytes and how this heterogeneity promoted AK development and progression. We employed single-cell RNA sequencing (scRNA-seq) to examine the heterogeneity of keratinocytes and dermal fibroblast clusters in AKs and adjacent normal skins. Cell clustering, pseudotime trajectory construction, gene ontology enrichment analysis, transcription factor network analysis, and cell-cell communication were used to investigate the heterogeneity of keratinocytes in AK. The cellular identity and function were verified by immunohistochemical and immunofluorescence staining. Using scRNA-seq, we revealed 13 keratinocyte subgroups (clusters 0-12) in AK tissues and characterized 2 AK-specific clusters. Cluster 9 displayed high levels of IL1R2 and WFDC2, and cluster 11 showed high levels of FADS2 and FASN. The percentages of cells in these two clusters significantly increased in AK compared with normal tissues. The existence and spatial localization of AK-specific IL1R2+WFDC2+ cluster were verified by immunohistochemical and immunofluorescence staining. Functional studies indicated that the genes identified in the IL1R2+WFDC2+ cluster were crucial for epithelial cell proliferation, migration, and angiogenesis. Further immunofluorescent staining revealed the interactions between AK-specific keratinocytes and secretory-papillary fibroblasts mainly through ANGPTL4-ITGA5 signalling pathway rarely seen in normal tissues. The findings of this study might help better understand AK pathogenesis. Show less

Colon adenocarcinoma is the most common type of colorectal cancer. The prognosis of advanced colorectal cancer patients who received treatment is still very poor. Therefore, identifying new biomarkers for prognosis prediction has important significance for improving treatment strategies. However, the power of biomarker analyses was limited by the used sample size of individual database. In this study, we combined Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases to expand the number of healthy tissue samples. We screened differentially expressed genes between the GTEx healthy samples and TCGA tumor samples. Subsequently, we applied least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox analysis to identify nine prognosis-related immune genes: Show less

Currently, only the general control of the risk factors is known to prevent lacunar cerebral infarction, but it is unknown which type of medication for controlling the risk factors has a causal relationship with reducing the risk of lacunar infarction. To unlock this medical mystery, drug-target Mendelian randomization analysis was applied to estimate the effect of common antihypertensive agents, hypolipidemic agents, and hypoglycemic agents on lacunar stroke. Lacunar stroke data for the transethnic analysis were derived from meta-analyses comprising 7338 cases and 254,798 controls. We have confirmed that genetic variants mimicking calcium channel blockers were found to most stably prevent lacunar stroke. The genetic variants at or near Show less

ApoC-III inhibits lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. It is unknown whether targeting apoC-III affects hepatic steatosis in patients with hypertriglyceridemia. We studied the effect of volanesorsen, a potent antisense oligonucleotide targeting APOC3 mRNA, on hepatic fat fraction (HFF) assessed by MRI in patients with severe hypertriglyceridemia (SHTG, triglycerides ≥500 mg/dL), familial partial lipodystrophy (FPL, triglycerides ≥200 mg/dL) and familial chylomicronemia syndrome (FCS, triglycerides ≥750 mg/dL). The data were evaluated individually in COMPASS (SHTG), APPROACH (FCS), and BROADEN (FPL) trials. The baseline absolute HFF were elevated in all three trials and ranged from 6.3-18.1%. In COMPASS, compared to placebo, volanesorsen significantly reduced the absolute HFF by -3.02% (95% CI, (-5.60, -0.60), p = 0.009) (placebo-adjusted % change from baseline -24.2%, p = 0.034) from baseline to 6 months. In APPROACH a non-significant absolute -1.0% (95% CI, -2.9, 0.0, p = 0.13) reduction in HFF was noted from baseline to 12 months (placebo-adjusted % change from baseline -37.1%, p = 0.20). In BROADEN volanesorsen significantly reduced the absolute HFF by -8.34% (95% CI, -13.01, -3.67, p = 0.001) from baseline to 12 months (placebo-adjusted % change from baseline -52.7%, p = 0.004). In all 3 trials individually, a strong inverse correlation was present between the baseline HFF and the change in HFF in the volanesorsen groups, but not in the placebo groups. In conclusion, apoC-III inhibition with volanesorsen has favorable effects in HFF in patients with different etiologies of hypertriglyceridemia. Show less

The carbon emission trading policy (CETP) is a market-based environmental instrument to reduce carbon emissions and address climate change. It can further have an impact on companies' green innovation (GI). In this regard, we innovatively propose the internal and external theoretical mechanisms of the impact of CETP on the GI of companies and use the financial data and patent data of Chinese listed companies from a micro perspective to empirically verify them. The findings demonstrate that the CETP has an inducing effect on the GI of companies, which is particularly evident in nonstate-owned companies, large companies, and the cleaning industry. The impact of CETP on companies GI is mainly achieved through internal incentive mechanisms, while the role of external influence mechanisms is not obvious. In terms of internal incentives, cost compliance effects and innovation compensation effects are the main channels for promoting GI. In terms of external effects, the carbon market's efficacy has not contributed to boosting GI for companies; the coordination effect of carbon policy and government intervention on companies' GI is also limited. Our research provides a theoretical basis for effectively encouraging the GI of companies to achieve carbon neutral and carbon peak goals. Show less

PIWI-interacting RNAs (piRNAs) are a class of noncoding RNAs originally reported in the reproductive system of mammals and later found to be aberrantly expressed in tumors. However, the function and mechanism of piRNAs in testicular cancer are not very clear. The expression level and distribution of piR-36249 were detected by RT-qPCR and immunofluorescence staining assay. Testicular cancer cell (NT2) progression was measured by CCK8 assay, colony formation assay and wound healing assay. Cell apoptosis was assessed by flow cytometry and western blot. RNA sequencing and dual-luciferase reporter assay were conducted to identify the potential targets of piR-36249. The relationship between piR-36249 and piR-36249 is significantly downregulated in testicular cancer tissues compared to tumor-adjacent tissues. Functional studies demonstrate that piR-36249 inhibits testicular cancer cell proliferation, migration and activates the cell apoptosis pathway. Mechanically, we identify that piR-36249 binds to the 3'UTR of 2'-5'-oligoadenylate synthetase 2 ( All these data suggest that piR-36249, together with DHX36, functions in inhibiting the malignant phenotype of testicular cancer cells by upregulating OAS2 protein and that piR-36249 may be used as a suppressor factor to regulate the development of testicular cancer. Show less

Despite many advances in treatment over the past few years, the poor 5-year survival rate and high recurrence rate of gastric cancer (GC) remain unsatisfactory. As the most abundant epigenetic modification in the eukaryotic mRNA, N6-methyladenosine (m Show less