Vascular architecture characters and risk factors analysis of unstable moyamoya disease.

Background: In some MMD patients, the digital subtraction angiography (DSA) examination found, occlusion in the ipsilateral internal carotid artery or middle cerebral artery, accompanied by the formation of numerous moyamoya vessels. Conversely, the contralateral internal carotid artery or middle cerebral artery shows signs of stenosis without the presence of moyamoya vessels. Notably, cerebral perfusion studies reveal a similar or even more severe reduction in perfusion on the occluded side compared to the stenotic side. Importantly, clinical symptoms in these patients are typically attributed to ischemia caused by the stenotic side. This condition is referred to as unstable moyamoya disease (uMMD). Objective: This clinical research focuses on evaluating risk factors related to MMD and developing strategies to minimize postoperative complications. The study aims to analyze vascular characteristics and identify potential risk factors in patients with uMMD. Methods: The authors reviewed consecutive cases with complete clinical and radiological documentation of patients who underwent surgery between January 2018 and June 2023. Univariate analysis and multivariate logistic regression analysis were employed to understand the risk factors and prognosis of postoperative complications in uMMD. Results: Postoperative complications were retrospectively analyzed in 1481 patients (aged 14 to 65). Among them, 1,429 patients were assigned to the conventional treatment group, while 52 were in the unstable moyamoya disease group. The uMMD treatment group showed a significantly higher incidence of early postoperative complications such as RIND, cerebral infarction, and cerebral hemorrhage (p < 0.05). Univariate and multivariate logistic regression analyses were conducted on the postoperative complications of 52 uMMD patients. Initial symptoms of stenosis ≤50% (univariate: p = 0.008, multivariate: p = 0.015; OR [95% CI] =23.149 [1.853-289.217]) and choosing occluded side surgery (univariate: p = 0.043, multivariate: p = 0.018; OR [95% CI] =0.059 [0.006-0.617]) were identified as significant risk factors for postoperative neurological complications. Conclusion: Compared to the conventional treatment group, uMMD has higher complication rates, with vascular stenosis degree and surgical side selection identified as significant risk factors. A comprehensive understanding of preoperative clinical symptoms and vascular characteristics in moyamoya disease patients, coupled with the formulation of rational surgical plans, contributes positively to decreasing postoperative mortality and disability rates in uMMD.

Toosendanin Induces Lung Squamous Cell Carcinoma Cell Apoptosis and Inhibits Tumor Progression via the BNIP3/AMPK Signaling Pathway.

Lung squamous cell carcinoma (LUSC) is the second most common type of non-small cell lung cancer. Toosendanin can target critical cancer cell survival and proliferation. However, the function of toosendanin in LUSC is limited. Cancer cell proliferative capacity is detected using cell morphology, colony formation, and flow cytometry. The invasiveness of the cells is detected by a Transwell assay, western blotting, and RT-qPCR. Nude mice are injected with H226 (1×106) and received an intraperitoneal injection of toosendanin every 2 days for 21 days. RNA sequence transcriptome analysis is performed on toosendanin-treated cells to identify target genes and signaling pathways. With increasing concentrations of toosendanin, the rate of cell proliferation decreases and apoptotic cells increases. The number of migrated cells significantly reduces and epithelial-mesenchymal transition is reversed. Injection of toosendanin in nude mice leads to a reduction in tumor volume, weight, and the number of metastatic tumors. Furthermore, KEGG shows that genes related to the AMPK pathway are highly enriched. BNIP3 is the most differentially expressed gene, and its expression along with phosphorylated-AMPK significantly increases in toosendanin-treated cells. Toosendanin exerts anticancer effects, induces apoptosis in LUSC cells, and inhibits tumor progression via the BNIP3/AMPK signaling pathway.

Bmi1 facilitates the progression of cholangiocarcinoma by inhibiting Foxn2 expression dependent on a histone H2A ubiquitination manner.

Cholangiocarcinoma (CCA), an exceptionally aggressive malignancy originating from the epithelium of the bile duct, poses a formidable challenge in cancer research and clinical management. Currently, attention is focused on exploring the oncogenic role and prognostic implications associated with Bmi1 in the context of CCA. In our study, we assessed the correlation of Bmi1 and Foxn2 expression across all types of CCA and evaluated their prognostic significance. Our results demonstrated that Bmi1 exhibits significantly upregulated expression in CCA tissues, while Foxn2 expression shows an inverse pattern. Simultaneously, the high expression of Bmi1, coupled with the low expression of Foxn2, indicates an unfavorable prognosis. Through in vitro and in vivo experiments, we confirmed the crucial role of Foxn2 in the proliferation, metastasis, and epithelial-mesenchymal transition (EMT) of CCA. Mechanistically, Bmi1 promotes the ubiquitination of histone H2A (H2AUb), leading to chromatin opening attenuation and a decrease in Foxn2 expression, ultimately driving CCA progression. Additionally, we described the potential value of Bmi1 and H2AUb inhibitors in treating CCA through in vitro experiments and orthotopic models. This study is of significant importance in deepening our understanding of the interaction between Bmi1 and Foxn2 in CCA and has the potential to advance the development of precision therapies for CCA.

Coarse-grained modeling and dynamics tracking of nanoparticles diffusion in human gut mucus.

The gastrointestinal (GI) tract's mucus layer serves as a critical barrier and a mediator in drug nanoparticle delivery. The mucus layer's diverse molecular structures and spatial complexity complicates the mechanistic study of the diffusion dynamics of particulate materials. In response, we developed a bi-component coarse-grained mucus model, specifically tailored for the colorectal cancer environment, that contained the two most abundant glycoproteins in GI mucus: Muc2 and Muc5AC. This model demonstrated the effects of molecular composition and concentration on mucus pore size, a key determinant in the permeability of nanoparticles. Using this computational model, we investigated the diffusion rate of polyethylene glycol (PEG) coated nanoparticles, a widely used muco-penetrating nanoparticle. We validated our model with experimentally characterized mucus pore sizes and the diffusional coefficients of PEG-coated nanoparticles in the mucus collected from cultured human colorectal goblet cells. Machine learning fingerprints were then employed to provide a mechanistic understanding of nanoparticle diffusional behavior. We found that larger nanoparticles tended to be trapped in mucus over longer durations but exhibited more ballistic diffusion over shorter time spans. Through these discoveries, our model provides a promising platform to study pharmacokinetics in the GI mucus layer.

Multimodal data integration for predicting progression risk in castration-resistant prostate cancer using deep learning: a multicenter retrospective study.

Purpose: Patients with advanced prostate cancer (PCa) often develop castration-resistant PCa (CRPC) with poor prognosis. Prognostic information obtained from multiparametric magnetic resonance imaging (mpMRI) and histopathology specimens can be effectively utilized through artificial intelligence (AI) techniques. The objective of this study is to construct an AI-based CRPC progress prediction model by integrating multimodal data. Methods and materials: Data from 399 patients diagnosed with PCa at three medical centers between January 2018 and January 2021 were collected retrospectively. We delineated regions of interest (ROIs) from 3 MRI sequences viz, T2WI, DWI, and ADC and utilized a cropping tool to extract the largest section of each ROI. We selected representative pathological hematoxylin and eosin (H&E) slides for deep-learning model training. A joint combined model nomogram was constructed. ROC curves and calibration curves were plotted to assess the predictive performance and goodness of fit of the model. We generated decision curve analysis (DCA) curves and Kaplan-Meier (KM) survival curves to evaluate the clinical net benefit of the model and its association with progression-free survival (PFS). Results: The AUC of the machine learning (ML) model was 0.755. The best deep learning (DL) model for radiomics and pathomics was the ResNet-50 model, with an AUC of 0.768 and 0.752, respectively. The nomogram graph showed that DL model contributed the most, and the AUC for the combined model was 0.86. The calibration curves and DCA indicate that the combined model had a good calibration ability and net clinical benefit. The KM curve indicated that the model integrating multimodal data can guide patient prognosis and management strategies. Conclusion: The integration of multimodal data effectively improves the prediction of risk for the progression of PCa to CRPC.

SOX-1 antibodies positive Lambert-Eaton myasthenic syndrome with occult small cell lung cancer: A case report.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare paraneoplastic neurological syndrome of the neuromuscular transmission. The symptoms often progress slowly and can be misdiagnosed in early stage. Seropositive SOX-1 antibodies are support for the diagnosis of LEMS and have high specificity for small cell lung cancer (SCLC). In this paper, we report a case of a 56-year-old man with smoking history who was admitted to hospital with progressive muscle weakness of the proximal legs. LEMS was diagnosed by repetitive nerve stimulation (RNS) testing and seropositive SOX-1 antibodies. Primary screening with chest computed tomography (CT) and integrated PET/CT did not reveal any tumor. After continuous follow-up, SCLC was found by chest CT and confirmed with pathological examination 10 months after the diagnosis of LEMS. Long-term follow-up and screening for occult SCLC in LEMS patients with positive SOX-1 antibodies are very important.

Function of mast cell and bile-cholangiocarcinoma interplay in cholangiocarcinoma microenvironment.

OBJECTIVE: The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites. DESIGN: Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9. RESULTS: Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gαq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferation by activating HRH1-Gαq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gαs signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and SLC22A3 deletion resulted in HA accumulation. CONCLUSION: Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.

Allosteric inhibitor of SHP2 enhances macrophage endocytosis and bacteria elimination by increasing caveolae activation and protects against bacterial sepsis.

The uncontrolled bacterial infection-induced cytokine storm and sequential immunosuppression are commonly observed in septic patients, which indicates that the activation of phagocytic cells and the efficient and timely elimination of bacteria are crucial for combating bacterial infections. However, the role of dysregulated immune cells and their disrupted function in sepsis remains unclear. Here, we found that macrophages exhibited the impaired endocytosis capabilities in sepsis by Single-cell RNA sequencing and bulk RNA sequencing. Caveolae protein Caveolin-1 (Cav-1) of macrophages was inactivated by SHP2 rapidly during Escherichia coli (E.coli) infection. Allosteric inhibitor of SHP2 effectively maintains Cav-1 phosphorylation to enhance macrophage to endocytose and eliminate bacteria. Additionally, TLR4 endocytosis of macrophage was also enhanced upon E.coli infection by SHP099, inducing an increased and rapidly resolved inflammatory response. In vivo, pretreatment or posttreatment with inhibitor of SHP2 significantly reduced the bacterial burden in organs and mortality of mice subjected E.coli infection or CLP-induced sepsis. The cotreatment of inhibitor of SHP2 with an antibiotic conferred complete protection against mortality in mice. Our findings suggest that Cav-1-mediated endocytosis and bacterial elimination may play a critical role in the pathogenesis of sepsis, highlighting inhibitor of SHP2 as a potential therapeutic agent for sepsis.

Exosomal noncoding RNAs as noninvasive biomarkers in bladder cancer: a diagnostic meta-analysis.

BACKGROUND: In view of discordance consisting in different reports, a meta-analysis was conducted to comprehensively evaluate the diagnostic efficacy of exosomal noncoding RNAs (ncRNAs) in blood and urine in the detection of bladder cancer. METHODS: Eligible studies were acquired by systematic retrieval through PubMed, Cochrane Library, and Embase. The pooled diagnostic efficacy was appraised by reckoning the area under the summary receiver operating characteristic (SROC) curve. The latent sources of heterogeneity were probed by subgroup analyses and meta-regression. STATA 12.0, Meta-DiSc 1.4, and RevMan 5.3 were applied to carry out all statistical analyses and plots. RESULTS: A total of 46 studies from 15 articles comprising 2622 controls and 3015 bladder cancer patients were included in our meta-analysis. Exosomal ncRNAs in blood and urine represented relatively satisfactory diagnostic efficacy in detecting bladder cancer, with a pooled sensitivity of 0.75, a specificity of 0.79, and an area under the SROC curve (AUC) of 0.84. Exosomal microRNAs (miRNAs) exhibited better diagnostic value with a pooled AUC of 0.91 than that of exosomal long noncoding RNAs (lncRNAs). To some extent, the heterogeneity among studies was induced by exosomal ncRNA types (miRNA or lncRNA), exosomal ncRNA profiling (single- or multiple-ncRNA), sample size, specimen types, and ethnicity. CONCLUSION: Exosomal ncRNAs in blood and urine may play a vital role in diagnosing bladder cancer as prospective noninvasive biomarkers; nonetheless, their clinical performance needs to be confirmed by further massive proactive researches.

Bile exosomal miR-182/183-5p increases cholangiocarcinoma stemness and progression by targeting HPGD and increasing PGE2 generation.

BACKGROUND AIMS: Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary ducts. Current CCA diagnostic and prognostic assessments cannot satisfy the clinical requirement. Bile detection is rarely performed, and herein, we aim to estimate the clinical significance of bile liquid biopsy by assessing bile exosomal concentrations and components. APPROACH RESULTS: Exosomes in bile and sera from CCA, pancreatic cancer, and common bile duct stone were identified and quantified by transmission electronmicroscopy, nanoparticle tracking analysis, and nanoFCM. Exosomal components were assessed by liquid chromatography with tandem mass spectrometry and microRNA sequencing (miRNA-seq). Bile exosomal concentration in different diseases had no significant difference, but miR-182-5p and miR-183-5p were ectopically upregulated in CCA bile exosomes. High miR-182/183-5p in both CCA tissues and bile indicates a poor prognosis. Bile exosomal miR-182/183-5p is secreted by CCA cells and can be absorbed by biliary epithelium or CCA cells. With xenografts in humanized mice, we showed that bile exosomal miR-182/183-5p promotes CCA proliferation, invasion, and epithelial-mesenchymal transition (EMT) by targeting hydroxyprostaglandin dehydrogenase in CCA cells and mast cells (MCs), and increasing prostaglandin E2 generation, which stimulates PTGER1 and increases CCA stemness. In single-cell mRNA-seq, hydroxyprostaglandin dehydrogenase is predominantly expressed in MCs. miR-182/183-5p prompts MC to release VEGF-A release from MC by increasing VEGF-A expression, which facilitates angiogenesis. CONCLUSIONS: CCA cells secret exosomal miR-182/183-5p into bile, which targets hydroxyprostaglandin dehydrogenase in CCA cells and MCs and increases prostaglandin E2 and VEGF-A release. Prostaglandin E2 promotes stemness by activating PTGER1. Our results reveal a type of CCA self-driven progression dependent on bile exosomal miR-182/183-5p and MCs, which is a new interplay pattern of CCA and bile.

Eriocalyxin B alleviated ischemic cerebral injury by limiting microglia-mediated excessive neuroinflammation in mice.

Excessive neuroinflammation mediated by microglia has a detrimental effect on the progression of ischemic stroke. Eriocalyxin B (EriB) was found with a neuroprotective effect in mice with Parkinson's disease via the suppression of microglial overactivation. This study aimed to investigate the roles of EriB in permanent middle cerebral artery occlusion (pMCAO) mice. The pMCAO was induced in the internal carotid artery of the mice by the intraluminal filament method, and EriB (10 mg/kg) was administered immediately after surgery by intraperitoneal injection. The behavior score, 2,3,5-triphenyltetrazole chloride staining, Nissl staining, TUNEL, immunohistochemistry, immunofluorescence, PCR, ELISA, and immunoblotting revealed that EriB administration reduced brain infarct and neuron death and ameliorated neuroinflammation and microglia overactivation in pMCAO mice, manifested by alterations of TUNEL-positive cell numbers, ionized calcium binding adaptor molecule 1 (Iba-1)-positive cell numbers, and expression of tumor necrosis factor-α, interleukin 6, IL-1ß, inducible nitric oxide synthase, and arginase 1. In addition, EriB suppressed ischemia-induced activation of nuclear factor kappa B (NF-κB) signaling in the brain penumbra, suggesting the involvement of NF-κB in EriB function. In conclusion, EriB exerted anti-inflammatory effects in ischemia stroke by regulating the NF-κB signaling pathway, and this may provide insights into the neuroprotective effect of EriB in the treatment of ischemic stroke.

Study on the mechanism of acid treatment La0.8Sr0.2Mn0.8Cu0.2O3 to improve the catalytic activity of formaldehyde at low temperature.

To address the issue of surface enrichment of A-site ions in perovskite and the resulting suppression of catalytic activity, the La0.8Sr0.2Mn0.8Cu0.2O3 was modified by treatment with dilute nitric acid (2 mol/L) and dilute acetic acid (2 mol/L). The results show that the effect of dilute nitric acid treatment on the morphology and catalytic activity of the catalyst is more significant. The specific surface area of the catalyst after dilute nitric acid treatment (268.78 m2/g) is seven times higher than before treatment (37.55 m2/g). The low-temperature catalytic oxidation activity of HCHO of the catalyst after dilute nitric acid treatment is significantly improved, achieving a 50% HCHO oxidation efficiency at 80 °C, while the original sample requires 127 °C to achieve a 50% HCHO conversion. The excellent catalytic activity of the catalyst after dilute nitric acid treatment is related to its large specific surface area, high surface-active site density, and abundant Mn4+ ions. Stability and water resistance experiments show that the catalyst after dilute nitric acid treatment has excellent reaction stability and good water resistance ability. The mechanism of the formaldehyde oxidation reaction is that formaldehyde is first oxidized to a dioxymethylene (DOM) intermediate and DOM dehydrogenation reaction is responsible for the formation of formate species (HCOO-).

PTPN9 dephosphorylates FGFR2 pY656/657 through interaction with ACAP1 and ameliorates pemigatinib effect in cholangiocarcinoma.

ABSTRACT AND AIM: Cholangiocarcinoma (CCA) is a highly aggressive and lethal cancer that originates from the biliary epithelium. Systemic treatment options for CCA are currently limited, and the first targeted drug of CCA, pemigatinib, emerged in 2020 for CCA treatment by inhibiting FGFR2 phosphorylation. However, the regulatory mechanism of FGFR2 phosphorylation is not fully elucidated. APPROACH AND RESULTS: Here we screened the FGFR2-interacting proteins and showed that protein tyrosine phosphatase (PTP) N9 interacts with FGFR2 and negatively regulates FGFR2 pY656/657 . Using phosphatase activity assays and modeling the FGFR2-PTPN9 complex structure, we identified FGFR2 pY656/657 as a substrate of PTPN9, and found that sec. 14p domain of PTPN9 interacts with FGFR2 through ACAP1 mediation. Coexpression of PTPN9 and ACAP1 indicates a favorable prognosis for CCA. In addition, we identified key amino acids and motifs involved in the sec. 14p-APCP1-FGFR2 interaction, including the "YRETRRKE" motif of sec. 14p, Y471 of PTPN9, as well as the PH and Arf-GAP domain of ACAP1. Moreover, we discovered that the FGFR2 I654V substitution can decrease PTPN9-FGFR2 interaction and thereby reduce the effectiveness of pemigatinib treatment. Using a series of in vitro and in vivo experiments including patient-derived xenografts (PDX), we showed that PTPN9 synergistically enhances pemigatinib effectiveness and suppresses CCA proliferation, migration, and invasion by inhibiting FGFR2 pY656/657 . CONCLUSIONS: Our study identifies PTPN9 as a negative regulator of FGFR2 phosphorylation and a synergistic factor for pemigatinib treatment. The molecular mechanism, oncogenic function, and clinical significance of the PTPN9-ACAP1-FGFR2 complex are revealed, providing more evidence for CCA precision treatment.

Case Report: A novel EPAS1 mutation in a case of paraganglioma complicated with polycythemia and atrial septal defect.

Background: Paraganglioma is a rare neuroendocrine tumor and is highly associated with hereditary susceptibility genes, often occurring as part of a genetic syndrome. The genetic heterogeneity of paraganglioma poses challenges in diagnosis, counseling, and clinical management. Case summary: We present the case of a 60-year-old woman with hypertension, atrial septal defect, and polycythemia, who experienced paroxysmal palpitations, sweating, headache, abdominal pain, nausea, and vomiting. Her blood pressure was severely unstable. Blood laboratory tests revealed elevated catecholamine levels, contrast-enhanced CT of her whole abdomen showed a round retroperitoneal mass with soft tissue density, and somatostatin receptor imaging (68Ga PET-CT) indicated a retroperitoneal mass with abnormally increased expression of somatostatin receptor. It is interesting to note that whole exome sequencing (WES) analyses on both blood and tumor samples revealed a novel EPAS1 mutation, specifically the c.2501A > G; p.Tyr834Cys variant, which has never been reported. The patient was diagnosed with paraganglioma and underwent successful Da Vinci robot-assisted laparoscopic resection of the retroperitoneal tumor. During a 3-month follow-up period, her blood pressure stabilized, and her symptoms significantly improved. Conclusion: This case reveals that the EPSA1 mutation may be the primary driver of paraganglioma complicated by atrial septal defect and polycythemia. Additionally, the utilization of Da Vinci robot-assisted laparoscopic surgery contributed to a favorable prognosis for the patient.

Multiparametric MRI radiomics in prostate cancer for predicting Ki-67 expression and Gleason score: a multicenter retrospective study.

PURPOSE: Prostate cancer (PCa) with high Ki-67 expression and high Gleason Scores (GS) tends to have aggressive clinicopathological characteristics and a dismal prognosis. In order to predict the Ki-67 expression status and the GS in PCa, we sought to construct and verify MRI-based radiomics signatures. METHODS AND MATERIALS: We collected T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) images from 170 PCa patients at three institutions and extracted 321 original radiomic features from each image modality. We used support vector machine (SVM) and least absolute shrinkage and selection operator (LASSO) logistic regression to select the most informative radiomic features and built predictive models using up sampling and feature selection techniques. Using receiver operating characteristic (ROC) analysis, the discriminating power of this feature was determined. Subsequent decision curve analysis (DCA) assessed the clinical utility of the radiomic features. The Kaplan-Meier (KM) test revealed that the radiomics-predicted Ki-67 expression status and GS were prognostic factors for PCa survival. RESULT: The hypothesized radiomics signature, which included 15 and 9 selected radiomics features, respectively, was significantly correlated with pathological Ki-67 and GS outcomes in both the training and validation datasets. Areas under the curve (AUC) for the developed model were 0.813 (95% CI 0.681,0.930) and 0.793 (95% CI 0.621, 0.929) for the training and validation datasets, respectively, demonstrating discrimination and calibration performance. The model's clinical usefulness was verified using DCA. In both the training and validation sets, high Ki-67 expression and high GS predicted by radiomics using SVM models were substantially linked with poor overall survival (OS). CONCLUSIONS: Both Ki-67 expression status and high GS correlate with PCa patient survival outcomes; therefore, the ability of the SVM classifier-based model to estimate Ki-67 expression status and the Lasso classifier-based model to assess high GS may enhance clinical decision-making.

SMAD4 regulates the progression of cholangiocarcinoma by modulating the expression of STING1.

SMAD4 is a tumour suppressor and an important regulator of tumour immune scape which is downregulated in cholangiocarcinoma (CCA). STING1 is a vital sensing factor of abnormal DNA; however, the correlation between SMAD4 and STING1 and the role of the SMAD4-STING1 interaction in the progression of CCA have not yet been evaluated. Public database was analysed to reveal the expression of SMAD4 and STING1. A cohort comprising 50 iCCA, 113 pCCA and 119 dCCA patients was assembled for the study. Immunohistochemistry was employed to evaluate the expression levels of STING1 and SMAD4. In vitro transwell and CCK8 assays, along with luciferase reporter assay, were conducted to analyse the potential regulatory mechanisms of SMAD4 on the expression of STING1. Expression of SMAD4 and STING1 were downregulated in CCA tumours and STING1 expression correlated with SMAD4 expression. The overexpression of SMAD4 was found to suppress the migration, invasion and proliferation capabilities of CCA cells; whereas, the knockdown of SMAD4 enhanced these abilities. Furthermore, it was observed that SMAD4 translocated into the nucleus following TGF-ß1 stimulation. Knockdown of SMAD4 resulted in the inhibition of STING1 transcriptional activity, whereas the overexpression of SMAD4 promoted the transcriptional activity of STING1. Clinically, low STING1 and SMAD4 expression indicated poor prognosis in CCA, and simultaneously low expression of STING1 and SMAD4 predicts poorer patient survival. SMAD4 regulates the expression of STING1 through its transcription regulating function. Dual low expression of STING1 and SMAD4 had more power in predicting patient survival. These results indicate that SMAD4-silenced CCA may downregulate its STING1 expression to adapt to the immune system.

Purification and functional characterization of novel human skeletal stem cell lineages.

Human skeletal stem cells (hSSCs) hold tremendous therapeutic potential for developing new clinical strategies to effectively combat congenital and age-related musculoskeletal disorders. Unfortunately, refined methodologies for the proper isolation of bona fide hSSCs and the development of functional assays that accurately recapitulate their physiology within the skeleton have been lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs), commonly used to describe the source of precursors for osteoblasts, chondrocytes, adipocytes and stroma, have held great promise as the basis of various approaches for cell therapy. However, the reproducibility and clinical efficacy of these attempts have been obscured by the heterogeneous nature of BMSCs due to their isolation by plastic adherence techniques. To address these limitations, our group has refined the purity of individual progenitor populations that are encompassed by BMSCs by identifying defined populations of bona fide hSSCs and their downstream progenitors that strictly give rise to skeletally restricted cell lineages. Here, we describe an advanced flow cytometric approach that utilizes an extensive panel of eight cell surface markers to define hSSCs; bone, cartilage and stromal progenitors; and more differentiated unipotent subtypes, including an osteogenic subset and three chondroprogenitors. We provide detailed instructions for the FACS-based isolation of hSSCs from various tissue sources, in vitro and in vivo skeletogenic functional assays, human xenograft mouse models and single-cell RNA sequencing analysis. This application of hSSC isolation can be performed by any researcher with basic skills in biology and flow cytometry within 1-2 days. The downstream functional assays can be performed within a range of 1-2 months.

Prediction of acrylamide content in potato chips using near-infrared spectroscopy.

Acrylamide (ACR), a neurotoxin with carcinogenic properties that can affect fertility, is commonly found in fried and baked foods such as potato chips. This study was carried out to predict the ACR content in fried and baked potato chips using near-infrared (NIR) spectroscopy. Effective wavenumbers were identified using competitive adaptive reweighted sampling (CARS) and the successive projections algorithm (SPA). Six wavenumbers (12799 cm-1, 12007 cm-1, 10944 cm-1, 10943 cm-1, 5801 cm-1, and 4332 cm-1) were selected using the ratio (λi/λj) and difference (λi-λj) of any two wavenumbers from the CARS and SPA results. First, partial least squares (PLS) models were established based on full spectral wavebands (12799-4000 cm-1), and the prediction models were subsequently redeveloped based on effective wavenumbers to predict ACR content. Results showed that the full and selected wavenumbers-based PLS models obtained the coefficient of determination (R2) of 0.7707 and 0.6670, respectively, and the root mean square errors of prediction (RMSEP) of 53.0442 µg/kg and 64.3810 µg/kg, respectively, in the prediction sets. The results of this work demonstrate the suitability of NIR spectroscopy as a non-destructive method for predicting ACR content in potato chips.

Safety and efficacy of aspirin after combined cerebral revascularization for ischemic moyamoya disease: A prospective study.

Objective: To analyze the safety and efficacy of regular aspirin use after combined cerebral revascularization in patients with ischemic moyamoya disease. Methods: From December 2020 to October 2021, a total of 326 patients diagnosed with ischemic moyamoya disease by global cerebral angiography and undergoing first-time combined cerebral revascularization at the Moyamoya Disease Diagnosis and Treatment Research Center of our hospital were selected. Combined cerebral revascularization: superficial temporal artery-middle cerebral artery (STA-MCA) +encephalo-duro-myo-synangiosis (EDMS).Patients were screened by 2 senior physicians according to established inclusion/exclusion criteria. Patients were divided into aspirin and non-aspirin groups based on whether they received regular oral aspirin after surgery. A total of 133 patients were enrolled in the aspirin group. A total of 71 patients (204 cases) were enrolled in the non-aspirin group. Related data were collected before and 1 year after surgery and statistically analyzed to assess the prognosis of both groups. Results: In the two groups, the mRS Score was significantly different after one year (P = 0.023). TIA occurred in 26 patients (19.5%) in the aspirin group and 27 patients (38.0%) in the non-aspirin group within one year after surgery, and the difference between the two groups was statistically significant (P = 0.004). There was no significant difference in cerebral perfusion stage, the improvement rate of cerebral perfusion, Matsushima grading, bypass patency, and other complications within one year after the operation (P > 0.05). Conclusions: In patients with ischemic moyamoya disease who underwent combined cerebral revascularization, postoperative administration of aspirin can reduce the incidence of TIA without increasing the risk of bleeding, but it can not significantly improve the cerebral perfusion of the operation side, Matsushima grading, and bypass patency.

Advances in molecular and cell therapy for immunotherapy of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a highly malignant tumor of the hepatobiliary system that has failed to respond to many traditional therapies to a certain extent, including surgery, chemotherapy and radiotherapy. In recent years, the new therapeutic schemes based on immunology have fundamentally changed the systemic treatment of various malignant tumors to a certain extent. In view of the immunogenicity of CCA, during the occurrence and development of CCA, some immunosuppressive substances are released from cells and immunosuppressive microenvironment is formed to promote the escape immune response of its own cells, thus enhancing the malignancy of the tumor and reducing the sensitivity of the tumor to drugs. Some immunotherapy regimens for cholangiocarcinoma have produced good clinical effects. Immunotherapy has more precise characteristics and less adverse reactions compared with traditional treatment approaches. However, due to the unique immune characteristics of CCA, some patients with CCA may not benefit in the long term or not benefit at all after current immunotherapy. At present, the immunotherapy of CCA that have been clinically studied mainly include molecular therapy and cell therapy. In this article, we generalized and summarized the current status of immunotherapy strategies including molecular therapy and cell therapy in CCA in clinical studies, and we outlined our understanding of how to enhance the clinical application of these immunotherapy strategies.