Legumain in cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, having become a global public health problem, so the pathophysiological mechanisms and therapeutic strategies of CVDs need further study. Legumain is a powerful enzyme that is widely distributed in mammals and plays an important role in a variety of biological processes. Recent research suggests that legumain is associated with the occurrence and progression of CVDs. In this review, we provide a comprehensive overview of legumain in the pathogenesis of CVDs. The role of legumain in CVDs, such as carotid atherosclerosis, pulmonary hypertension, coronary artery disease, peripheral arterial disease, aortic aneurysms and dissection, is discussed. The potential applications of legumain as a biomarker of these diseases are also explored. By understanding the role of legumain in the pathogenesis of CVDs, we aim to support new therapeutic strategies to prevent or treat these diseases.

Cistanche phenylethanoid glycosides induce apoptosis and pyroptosis in T-cell lymphoma.

Cistanche deserticola, known for its extensive history in Traditional Chinese Medicine (TCM), is valued for its therapeutic properties. Recent studies have identified its anticancer capabilities, yet the mechanisms underlying these properties remain to be fully elucidated. In this study, we determined that a mixture of four cistanche-derived phenylethanoid glycosides (CPhGs), echinacoside, acteoside, 2-acetylacteoside, and cistanoside A, which are among the main bioactive compounds in C. deserticola, eliminated T-cell lymphoma (TCL) cells by inducing apoptosis and pyroptosis in vitro and attenuated tumor growth in vivo in a xenograft mouse model. At the molecular level, these CPhGs elevated P53 by inhibiting the SIRT2-MDM2/P300 and PI3K/AKT carcinogenic axes and activating PTEN-Bax tumor-suppressing signaling. Moreover, CPhGs activated noncanonical and alternative pathways to trigger pyroptosis. Interestingly, CPhGs did not activate canonical NLRP3-caspase-1 pyroptotic signaling pathway; instead, CPhGs suppressed the inflammasome factor NLRP3 and the maturation of IL-1ß. Treatment with a caspase-1/4 inhibitor and silencing of Gasdermin D (GSDMD) or Gasdermin E (GSDME) partially rescued CPhG-induced cell death. Conversely, forced expression of NLRP3 restored cell proliferation. In summary, our results indicate that CPhGs modulate multiple signaling pathways to achieve their anticancer properties and perform dual roles in pyroptosis and NLRP3-driven proliferation. This study offers experimental support for the potential application of CPhGs in the treatment of TCL.

C5aR plus MEK inhibition durably targets the tumor milieu and reveals tumor cell phagocytosis.

Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of NF1 and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages. We defined pharmacokinetic and immunomodulatory properties of a C5aR1/2 antagonist and tested if peptide antagonists augment the effects of MEK inhibition. MEK inhibition recruited C5AR1 to the macrophage surface; short-term inhibition of C5aR elevated macrophage apoptosis and Schwann cell death, without affecting MEK-induced tumor shrinkage. PNF macrophages lacking C5aR1 increased the engulfment of dying Schwann cells, allowing their visualization. Halting combination therapy resulted in altered T-cell distribution, elevated Iba1+ and CD169+ immunoreactivity, and profoundly altered cytokine expression, but not sustained trumor shrinkage. Thus, C5aRA inhibition independently induces macrophage cell death and causes sustained and durable effects on the PNF microenvironment.

Gastric Ganglioneuroblastoma in an Elderly man: A Case Report and Literature Review.

Background. Ganglioneuroblastoma is a borderline tumor of sympathetic origin that is considered a childhood disease, with the majority of patients occurring in children less than five years old and few patients occurring in adults. There are no treatment guidelines for adult ganglioneuroblastoma. Here, we report a rare patient of adult gastric ganglioneuroblastoma that was completely resected by a laparoscopic approach. Case presentation. A 73-year-old man presented with dull pain in the upper abdomen along with abdominal distension for one month. Gastroscopy examination revealed chronic gastritis and submucosal tumors of the gastric antrum. Endoscopic ultrasonography showed a hypoechoic mass in the gastric antrum arising from the muscularis propria. An abdominal computed tomography scan revealed an irregular soft tissue mass in the gastric antrum with heterogeneous enhancement in the arterial phase. The mass was completely resected by laparoscopic surgery. Postoperative histopathology revealed that the mass contained differentiated neuroblasts, mature ganglion cells and ganglioneuroma components. The pathological diagnosis was ganglioneuroblastoma intermixed, and the patient was determined to be in stage I. The patient received no adjuvant chemotherapy or radiotherapy. At his two-year follow-up, the patient was doing well and showed no signs of recurrence. Conclusion. Despite the rarity of gastric ganglioneuroblastoma as a primary site of origin, it should be considered in the differential diagnosis of gastric masses in adults. Radical surgery is sufficient for the treatment of ganglioneuroblastoma intermixed, and long-term follow-up should be performed.

Ethylene and jasmonate signaling converge on gibberellin catabolism during thigmomorphogenesis in Arabidopsis.

Touch induces marked morphological changes in plants, including reduced rosette diameters and delayed flowering, a process called thigmomorphogenesis. Previous studies have revealed that thigmomorphogenesis in Arabidopsis (Arabidopsis thaliana) results from touch-induced accumulation of jasmonic acid (JA) and GIBBERELLIN 2-OXIDASE7 (GA2ox7) transcripts, which encode a gibberellin (GA) catabolism enzyme, leading to reduced levels of active GAs. However, the mechanisms underlying thigmomorphogenesis remain uncharacterized. Here, we showed that touch induces ethylene (ET) production in Arabidopsis. After touch treatment, ET biosynthesis and signaling mutants exhibited even greater thigmomorphogenic changes and more decreased GA4 contents than did wild-type (WT) plants. Biochemical analysis indicated that the transcription factor ETHYLENE INSENSITIVE3 (EIN3) of the ET pathway binds to the promoter of GA2ox8 (encoding another GA 2-oxidase performing the same GA modification as GA2ox7) and represses GA2ox8 transcription. Moreover, MYC2, the master regulator of JA signaling, directly promoted GA2ox7 expression by binding the G-box motif on GA2ox7 promoter. Further genetic analysis suggested that the ET and JA pathways independently control the expression of GA2ox8 and GA2ox7, respectively. This study reveals that the ET pathway is a novel repressor of touch-induced thigmomorphogenesis and highlights that the ET and JA pathways converge on GA catabolism but play opposite roles to fine-tune GA4 content during thigmomorphogenesis.

Proteomics analysis of carotid body tumor revealed potential mechanisms and molecular differences among Shamblin classifications.

Carotid body tumors (CBTs) are a rare type of paraganglioma, and surgical resection is the only effective treatment. Because of the proximity of CBTs to the carotid artery, jugular vein, and cranial nerve, surgery is extremely difficult, with high risks of hemorrhage and neurovascular injury. The Shamblin classification is used for CBT clinical evaluation; however, molecular mechanisms underlying classification differences remain unclear. This study aimed to investigate pathogenic mechanisms and molecular differences between CBT types. In Shamblin I, II, and III tumors, differentially expressed proteins (DEPs) were identified using direct data-independent acquisition (DIA). DEPs were validated using immunohistochemistry. Proteomics profiling of three Shamblin subtypes differed significantly. Bioinformatics analysis showed that adrenomedullin signaling, protein kinase A signaling, vascular endothelial growth factor (VEGF) signaling, ephrin receptor signaling, gap junction signaling, interleukin (IL)-1 signaling, actin cytoskeleton signaling, endothelin-1 signaling, angiopoietin signaling, peroxisome proliferator-activated receptor (PPAR) signaling, bone morphogenetic protein (BMP) signaling, hypoxia-inducible factor 1-alpha (HIF-1α) signaling, and IL-6 signaling pathways were significantly enriched. Furthermore, 60 DEPs changed significantly with tumor progression. Immunohistochemistry validated several important DEPs, including aldehyde oxidase 1 (AOX1), mediator complex subunit 22 (MED22), carnitine palmitoyltransferase 1A (CPT1A), and heat shock transcription factor 1 (HSF1). To our knowledge, this is the first application of proteomics quantification in CBT. Our results will deepen the understanding of CBT-related pathogenesis and aid in identifying therapeutic targets for CBT treatment.

Laparoscopic resection for gastric schwannoma larger than 30 mm with long-term outcomes.

BACKGROUND AND AIMS: Laparoscopic resection has been reported as effective and safe for gastric schwannoma (GS) in the form of case reports. However, study on laparoscopic surgery in patients with GS larger than 30 mm has been rarely reported. To this end, the present study aimed to evaluate the safety and efficacy of laparoscopic resection for the treatment of GS larger than 30 mm and its long-term outcomes. METHODS: This is a retrospective case series study of patients with GS larger than 30 mm who underwent laparoscopic resection at our hospital between January 2014 and December 2020. Clinical pathology, surgical and follow-up data were collected and analyzed. RESULTS: A total of 10 patients with a mean age of 51.6 years were included. Seven tumors were located in gastric body, 2 in antrum and 1 in fundus. Laparoscopic gastric wedge resection was performed in 7 patients, while laparoscopic gastric local resection was performed in 3 patients. All patients achieved complete resection. The mean operation time was 112.6 ± 34.3 min, and the mean postoperative hospital stay was 13.8 ± 5.1 days. Postoperative gastroplegia occurred in 2 patients and was treated with conservative therapy. No recurrence, metastasis or residue was found during the follow-up of mean 45.1 months. CONCLUSIONS: Laparoscopic resection is a safe and effective method for treating GS larger than 30 mm with favorable long-term follow-up outcomes. Laparoscopic resection may be considered as the first-line treatment for GS larger than 30 mm.

Prognostic value of pretreatment Controlling Nutritional Status score in esophageal cancer: a meta-analysis.

Background and purpose: The association between the pretreatment Controlling Nutritional Status (CONUT) score and the prognosis of esophageal cancer patients remains unclear. The aim of this meta-analysis was to further elucidate the prognostic role of the pretreatment CONUT score in esophageal cancer based on current evidence. Methods: The PubMed, Embase, Web of Science and CNKI databases were searched up to 27 September 2022. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS)/cancer-specific survival (CSS), and the hazard ratio (HR) and 95% confidence interval (CI) were pooled for analysis. Results: A total of 11 retrospective studies involving 3,783 participants were included. The pooled results demonstrated that a higher pretreatment CONUT score was significantly related to poor OS (HR = 1.82, 95% CI: 1.31-2.54, p < 0.001), and subgroup analysis stratified by pathological type showed similar results. In addition, the pretreatment CONUT score was associated with poor PFS (HR = 1.19, 95% CI: 1.10-1.28, p < 0.001) and CSS (HR = 2.67, 95% CI: 1.77-4.02, p < 0.001). Conclusion: The pretreatment CONUT score was predictive of worse prognosis in esophageal cancer, and patients with a higher CONUT score showed worse survival.

Exogenous spraying of IAA improved the efficiency of microspore embryogenesis in Wucai (Brassica campestris L.) by affecting the balance of endogenous hormones, energy metabolism, and cell wall degradation.

BACKGROUND: Microspore embryogenesis is an extraordinarily complicated process, comprehensively regulated by a composite network of physiological and molecular factors, among which hormone is one of the most crucial factors. Auxin is required for stress-induced microspore reprogramming, however, the mechanism of its regulation of microspore embryogenesis is still unclear. RESULTS: In this study, we found exogenously spraying 100 mg·L- 1 IAA on the buds of Wucai significantly increased the rate of microspore embryogenesis, and moreover accelerated the process of embryogenesis. Physiological and biochemical tests showed that the contents of amino acids, soluble total sugar, soluble protein, and starch were significantly increased after IAA treatment. Furthermore, exogenously spraying 100 mg·L- 1 IAA significantly enhanced IAA, GA4, and GA9 content, increased catalase (CAT) and malondialdehyde (MDA) activity, and reduced abscisic acid (ABA), MDA and soluble protopectin content, H2O2 and O2·- production rate in the bud with the largest population of late-uninucleate-stage microspores. Transcriptome sequencing was performed on buds respectively treated with 100 mg·L- 1 IAA and fresh water. A total of 2004 DEGs were identified, of which 79 were involved in micropores development, embryonic development and cell wall formation and modification, most of which were upregulated. KEGG and GO analysis revealed that 9.52% of DEGs were enriched in plant hormone synthesis and signal transduction pathways, pentose and glucuronic acid exchange pathways, and oxidative phosphorylation pathways. CONCLUSIONS: These findings indicated that exogenous IAA altered the contents of endogenous hormone content, total soluble sugar, amino acid, starch, soluble protein, MDA and protopectin, the activities of CAT and peroxidase (POD), and the production rate of H2O2 and O2·-. Combined with transcriptome analysis, it was found that most genes related to gibberellin (GA) and Auxin (IAA) synthesis and signal transduction, pectin methylase (PME) and polygalacturonase (PGs) genes and genes related to ATP synthesis and electron transport chain were upregulated, and genes related to ABA synthesis and signal transduction were downregulated. These results indicated that exogenous IAA treatment could change the balance of endogenous hormones, accelerate cell wall degradation, promote ATP synthesis and nutrient accumulation, inhibit ROS accumulation, which ultimately promote microspore embryogenesis.

Plant growth promoting endophyte promotes cadmium accumulation in Solanum nigrum L. by regulating plant homeostasis.

The homeostasis regulating mechanism of endophyte enhancing cadmium (Cd) extraction by hyperaccumulator is poorly understood. Here, an endophyte strain E3 that belonged to Pseudomonas was screened from Cd hyperaccumulator Solanum nigrum L., which significantly improved the Cd phytoextraction efficiency of S. nigrum by 40.26%. The content and translocation factor of nutrient elements indicated that endophyte might regulate Cd accumulation by affecting the uptake and transport of magnesium and iron in S. nigrum. Gene transcriptional expression profile further revealed that SnMGT, SnIRT1, and SnIRT2, etc., were the key genes involved in the regulation of S. nigrum elements uptake by endophyte. However, changes in elemental homeostasis did not negatively affect plant growth. Endophyte inoculation promoted plant growth by fortifying photosynthesis as well as recruiting specific bacteria in S. nigrum endosphere, e.g., Pseudonocardiaceae, Halomonas. Notably, PICRUSt2 analysis and biochemical characterization jointly suggested that endophyte regulated starch degradation in S. nigrum leaves to maintain photosynthetic balance. Our results demonstrated that microecological characteristics of hyperaccumulator could be reshaped by endophyte, also the homeostasis regulation in endophyte enhanced hyperaccumulator Cd phytoextraction was significant.

The association between statin use and prognosis in esophageal cancer patients: A meta-analysis.

BACKGROUND: The impact of statin use on the survival of esophageal cancer patients remains unclear now. The aim of this study was to identify the relationship between statin use and the long-term survival of esophageal cancer patients. METHODS: The PubMed, EMBASE, and Web of Science databases were searched up to August 20, 2022, for relevant studies. The endpoints included overall survival (OS), cancer-specific survival (CSS), recurrence-free survival, and hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were pooled to assess the association between statin use and the prognosis of esophageal cancer patients. Subgroup analysis based on the pathological type (adenocarcinoma vs squamous cell carcinoma), dose of statin use and tumor stage (tumor-node-metastasis I-III vs IV) was further performed. All statistical analyses were conducted using STATA 12.0 software. RESULTS: A total of 7 retrospective studies involving 25,711 participants were included in this meta-analysis. The pooled results indicated that statin use was significantly associated with improved OS (HR = 0.80, 95% CI: 0.74-0.87, P < .001), CSS (HR = 0.77, 95% CI: 0.74-0.89, P < .001), and recurrence-free survival (HR = 0.38, 95% CI: 0.16-0.87, P = .022). Furthermore, subgroup analysis stratified by the pathological type, dose of statin use and tumor stage for OS and CSS showed similar results and indicated the protective role of statin use in the prognosis of esophageal cancer patients. CONCLUSION: Statin use is significantly associated with improved long-term survival of esophageal cancer patients and might serve as a promising prognostic indicator in esophageal cancer. However, more prospective high-quality studies are still needed to verify our findings.

Runx1/3-driven adaptive endoplasmic reticulum stress pathways contribute to neurofibromagenesis.

Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.

Combining SOS1 and MEK Inhibitors in a Murine Model of Plexiform Neurofibroma Results in Tumor Shrinkage.

Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 fl/fl mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibromas are rich in ionized calcium binding adaptor molecule 1 (Iba1)+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEK inhibitor plus SOS1 inhibition in this preclinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas. SIGNIFICANCE STATEMENT: Interfering with the RAS-mitogen-activated protein kinase (RAS-MAPK) cascade upstream of mitogen activated protein kinase kinase (MEK), together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas.

Identification of the BcLEA Gene Family and Functional Analysis of the BcLEA73 Gene in Wucai (Brassica campestris L.).

Late embryogenesis abundant (LEA) proteins are important developmental proteins in the response of plants to abiotic stress. In our previous study, BcLEA73 was differentially expressed under low-temperature stress. Herein, we combined bioinformatics analysis, subcellular localization, expression assays, and stress experiments (including salt, drought, and osmotic stress) to identify and analyze the BcLEA gene family. Gene cloning and functional analysis of BcLEA73 were performed in tobacco and Arabidopsis. Based on the sequence homology and the available conservative motif, 82 BrLEA gene family members were identified and were divided into eight subfamilies in the genome-wide database of Chinese cabbage. The analysis showed that the BrLEA73 gene was located on chromosome A09 and belonged to the LEA_6 subfamily. Quantitative real-time PCR analysis indicated that the BcLEA genes were differentially expressed to varying degrees in the roots, stems, leaves, and petioles of Wucai. The overexpressed BcLEA73 transgenic plants exhibited no significant differences in root length and seed germination rates compared to the wild-type (WT) plants under control conditions. Under salt and osmotic stress treatment, the root length and seed germination rates of the BcLEA73-OE strain were significantly greater than those of WT plants. Under salt stress, the total antioxidant capacity (T-AOC) of the BcLEA73-OE lines increased significantly, and the relative conductivity, (REL), hydrogen peroxide (H2O2) content, and superoxide anion (O2-) production rate decreased significantly. Under drought treatment, the survival rate of the BcLEA73-OE lines was significantly higher than that of WT plants. These results showed that the BcLEA73 gene of Wucai functions in enhancing the tolerance of plants to salt, drought, and osmotic stress. This study provides a theoretical basis to explore the relevant functions of the BcLEA gene family members of Wucai.

Single-cell transcriptomic analyses provide insights into the cellular origins and drivers of brain metastasis from lung adenocarcinoma.

BACKGROUND: Brain metastasis (BM) is the most common intracranial malignancy causing significant mortality, and lung cancer is the most common origin of BM. However, the cellular origins and drivers of BM from lung adenocarcinoma (LUAD) have yet to be defined. METHODS: The cellular constitutions were characterized by single-cell transcriptomic profiles of 11 LUAD primary tumor (PT) and 10 BM samples (GSE131907). Copy number variation (CNV) and clonality analysis were applied to illustrate the cellular origins of BM tumors. Brain metastasis-associated epithelial cells (BMAECs) were identified by pseudotime trajectory analysis. By using machine-learning algorithms, we developed the BM-index representing the relative abundance of BMAECs in the bulk RNA-seq data indicating a high risk of BM. Therapeutic drugs targeting BMAECs were predicted based on the drug sensitivity data of cancer cell lines. RESULTS: Differences in macrophages and T cells between PTs and BMs were investigated by single-cell RNA (scRNA) and immunohistochemistry and immunofluorescence data. CNV analysis demonstrated BM was derived from subclones of PT with a gain of chromosome 7. We then identified BMAECs and their biomarker, S100A9. Immunofluorescence indicated strong correlations of BMAECs with metastasis and prognosis evaluated by the paired PT and BM samples from Peking Union Medical College Hospital. We further evaluated the clinical significance of the BM-index and identified 7 drugs that potentially target BMAECs. CONCLUSIONS: This study clarified possible cellular origins and drivers of metastatic LUAD at the single-cell level and laid a foundation for early detection of LUAD patients with a high risk of BM.

A critical role of RUNX1 in governing megakaryocyte-primed hematopoietic stem cell differentiation.

As a transcription factor in the RUNT domain core-binding factor family, RUNX1 is crucial in multiple stages of hematopoiesis, and its mutation can cause familial platelet disorder with a predisposition to acute myeloid leukemia. Previous work has established that RUNX1 is involved in the maturation of megakaryocytes (MKs) and the production of platelets. Recent studies have shown that there exists a subpopulation of hematopoietic stem cells (HSCs) with relatively high expression of von Willebrand factor and CD41 at the apex of the HSC hierarchy, termed MK-HSCs, which can give rise to MKs without going through the traditional differentiation trajectory from HSC via MPP (multipotent progenitors) and MEP (megakaryocyte-erythroid progenitor). Here, by using Runx1F/FMx1-Cre mouse model, we discovered that the MK-HSC to MK direct differentiation can occur within 1 cell division, and RUNX1 is an important regulator in the process. Runx1 knockout results in a drastic decrease in platelet counts and a severe defect in the differentiation from MK-HSCs to MKs. Single cell RNA sequencing (RNAseq) analysis shows that MK-HSCs have a distinct gene expression signature compared with non-MK-HSCs, and Runx1 deletion alters the platelet and MK-related gene expression in MK-HSCs. Furthermore, bulk RNAseq and Cut&Run analyses show that RUNX1 binds to multiple essential MK or platelet developmental genes, such as Spi1, Selp, and Itga2b and regulates their expressions in MK-HSCs. Thus, by modulating the expression of MK-related genes, RUNX1 governs the direct differentiation from MK-HSCs to MKs and platelets.

[miR-181c promotes the migration and angiogenesis of human A549 cells via targeting inhibition of reversion-inducing cysteine-rich protein with Kazal motifs (RECK)].

Objective To investigate the impact of miR-181c on migration and angiogenesis of lung cancer cells. Methods The Oncomine platform, UALCAN was used to analyze the differential expression of miR-181c and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in lung cancer obtained from the Cancer Genome Atlas (TCGA) database. The targeting relationship between miR-181c on RECK gene was predicted using Targetscan software. miR-181c mimic, inhibitor and negative control were introduced into A549 cells respectively. After transfection, the real-time quantitative PCR was used to detect the relative expressions of miR-181c and RECK mRNA, and Western blot analysis was used to detect the expression levels of RECK, matrix metalloproteinase 2 (MMP2) and MMP9 proteins. TranswellTM assay was performed to analyze the cell migration ability. The secretion of vascular endothelial growth factor (VEGF)-A in the cell culture supernatant was analyzed by using ELISA. Human umbilical vein endothelial cells (HUVECs) were treated with the culture supernatant, then in vitro tubule formation assay was carried out to evaluate the angiogenesis ability. The targeting correlation between miR-181c and RECK was validated by double luciferase reporter gene assay. Results UALCAN analysis displayed that the expression of miR-181c was significantly higher and RECK expression was significantly lower in lung cancer tissues compared to that in normal tissues. Targetscan prediction showed that there was a miR-181c binding site in the 3'-untranslated region (3' UTR) of RECK gene. miR-181c could downregulate the expression of RECK, increase the expressions of MMP2 and MMP9, and promote the A549 cell migration. ELISA and tubule formation assay showed that miR-181c could induce the secretion of VEGF-A in A549 cells and enhance the ability of HUVECs differentiae into tubules. The double luciferase reporter gene assay confirmed that RECK was the direct regulation target of miR-181c. Conclusion miR-181c promotes the migration and angiogenesis of human A549 cells by directly targeting RECK.

Assessment of Thigh MRI Radiomics and Clinical Characteristics for Assisting in Discrimination of Juvenile Dermatomyositis.

Magnetic resonance imaging (MRI) is an important non-invasive examination in the early diagnosis of juvenile dermatomyositis (JDM). We aimed to evaluate the feasibility of radiomics to establish a quantitative analysis of MRI images. Radiomics and machine learning were used to retrospectively analyze MRI T2 fat suppression sequences and relevant clinical data. The model associated with radiomics features was established using a cohort of patients who underwent thigh MRI at the children's hospital from June 2014 to September 2021. In total, 75 patients with JDM and 75 control children were included in the training cohort (n = 102) and validation cohort (n = 48). The independent factors including lower muscle strength (OR, 0.75; 95% CI, 0.59-0.90), higher creatine kinase (CK) level (OR, 1.65; 95% CI, 1.20-2.38), and higher radiomics score (OR, 2.30; 95% CI, 1.63-3.62) were associated with a clinical diagnosis of JDM. The combined model achieved good discrimination performance compared the radiomics score model under linear discriminant analyses in the training cohort (AUC, 0.949; 95% CI, 0.912-0.986 vs. AUC, 0.912; 95% CI, 0.858-0.967; p = 0.02) and in the validation cohort (AUC, 0.945; 95% CI, 0.878-1 vs. AUC, 0.905; 95% CI, 0.812-0.998; p = 0.03). The combined model showed the diagnostic value was not weaker than the biopsy (AUC, 0.950; 95% CI, 0.919-0.981, n = 150 vs. AUC, 0.952; 95% CI, 0.889-1, n = 72; p = 0.95) and electromyogram (EMG) (AUC, 0.950; 95% CI, 0.919-0.981 vs. AUC, 0.900; 95% CI, 0.852-0.948; p = 0.10) among all the patients. The combination of radiomics features extracted from the MRI and non-invasive clinical characteristics obtained a pronounced discriminative performance to assist in discriminating JDM.

[Effects of Leptin and Leptin-associated Signaling Pathways on the Occurrence and Progression of Abdominal Aortic Aneurysms].

Abdominal aortic aneurysm(AAA) is a chronic dilated artery disease induced by atherosclerosis,infection,trauma and other related causes.The available studies about AAA mainly focus on the inflammatory response,senility,and microenvironmental changes,while the research on the metabolic changes such as glucose metabolism and lipid metabolism remains to be conducted.As a critical regulatory factor in endocrine,glucose,and lipid metabolisms,leptin is associated with a variety of signaling pathways such as adenosine monophosphate-activated protein kinase,Janus kinase/signal transducer and activator of transcription,and cytokine-cytokine receptor,as demonstrated by the KEGG pathway enrichment analysis.Moreover,these signaling pathways are generally involved in regulating the occurrence of AAA.In addition,leptin affects the occurrence of a variety of diseases such as obesity,diabetes,and hyperlipidemia,which contribute to the formation of AAA.Diabetes might be a protective factor for the formation of AAA,while the relationship of hyperlipidemia and obesity with the formation of AAA remains unclear.Therefore,leptin might play an essential role in the formation of AAA.Further studies about the effect of leptin on AAA may provide the potential research direction and facilitate the discovery of therapeutic targets.

Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment.

To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop neurofibromas, benign tumors driven by NF1 loss in Schwann cells (SCs). By comparing normal nerve cells to plexiform neurofibroma (PN) cells using single-cell and bulk RNA sequencing, we identified changes in 5 SC populations, including a de novo SC progenitor-like (SCP-like) population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and Cd74, with sustained expression of the injury response gene Postn and showed dramatic expansion of immune and stromal cell populations; in corresponding human PNs, the immune and stromal cells comprised 90% of cells. Comparisons between injury-related and tumor monocytes/macrophages support early monocyte recruitment and aberrant macrophage differentiation. Cross-species analysis verified each SC population and unique conserved patterns of predicted cell-cell communication in each SC population. This analysis identified PROS1-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NF-κB as deregulated in NF1 SC populations, including SCP-like cells predicted to influence other types of SCs, stromal cells, and/or immune cells in mouse and human. These findings highlight remarkable changes in multiple types of SCs and identify therapeutic targets for PN.