Predicting occult lymph node metastasis in solid-predominantly invasive lung adenocarcinoma across multiple centers using radiomics-deep learning fusion model.

BACKGROUND: In solid-predominantly invasive lung adenocarcinoma (SPILAC), occult lymph node metastasis (OLNM) is pivotal for determining treatment strategies. This study seeks to develop and validate a fusion model combining radiomics and deep learning to predict OLNM preoperatively in SPILAC patients across multiple centers. METHODS: In this study, 1325 cT1a-bN0M0 SPILAC patients from six hospitals were retrospectively analyzed and divided into pathological nodal positive (pN+) and negative (pN-) groups. Three predictive models for OLNM were developed: a radiomics model employing decision trees and support vector machines; a deep learning model using ResNet-18, ResNet-34, ResNet-50, DenseNet-121, and Swin Transformer, initialized randomly or pre-trained on large-scale medical data; and a fusion model integrating both approaches using addition and concatenation techniques. The model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: All patients were assigned to four groups: training set (n = 470), internal validation set (n = 202), and independent test set 1 (n = 227) and 2 (n = 426). Among the 1325 patients, 478 (36%) had OLNM (pN+). The fusion model, combining radiomics with pre-trained ResNet-18 features via concatenation, outperformed others with an average AUC (aAUC) of 0.754 across validation and test sets, compared to aAUCs of 0.715 for the radiomics model and 0.676 for the deep learning model. CONCLUSION: The radiomics-deep learning fusion model showed promising ability to generalize in predicting OLNM from CT scans, potentially aiding personalized treatment for SPILAC patients across multiple centers.

CircATP13A1 (hsa_circ_0000919) promotes cell proliferation and metastasis and inhibits cell apoptosis in pancreatic ductal adenocarcinoma via the miR-186/miR-326/HMGA2 axis: implications for novel therapeutic targets.

Pancreatic ductal adenocarcinoma (PDAC) is a notoriously aggressive malignancy with a survival rate of merely 9%. The prognosis in patients with PDAC is relatively poor, particularly in patients with advanced distant metastases. However, the mechanisms of PDAC progression remain elusive. Circular RNAs (circRNAs) have been implicated in the development of various malignancies, including PDAC. Therefore, this study aimed to investigate how a novel circRNA, circATP13A1, regulates PDAC progression. We used the GEO database to determine circATP13A1 expression levels in cancer and adjacent cells and employed the limma package of R software to identify differentially expressed circRNAs. We detected the expression of circATP13A1, miR-186, and miR-326 using qRT-PCR and investigated the effect of circATP13A1 on cell proliferation, migration, invasion, and apoptosis in vitro using the Cell Counting Kit-8 (CCK-8), the transwell migration assay, and the flow cytometry assay. We then performed RNA pull-down assay, RNA immunoprecipitation (RIP), and Western blot to verify the interaction between circATP13A1, miR-186, miR-326, and HMGA2. Moreover, we used a naked mice model to determine how circATP13A1 affects tumor growth and progression in vivo. Loss and gain of function analyses revealed that circATP13A1 upregulation promotes cell proliferation, migration, invasion and tumor growth both in vitro and in vivo, which results in PDAC progression and poor prognosis in patients. CircATP13A1 knockdown significantly impaired cell proliferation and migration of PDAC cell lines. Additionally, circATP13A1 knockdown significantly increased the expression of miR-186 and miR-326, while reducing the expression of HMGA2 (P < 0.05), indicating that miR-186 and miR-326 are downstream targets of circATP13A1. Rescue experiments support the interactions between circATP13A1, miR-186, miR-326, and HMGA2. In conclusion, we demonstrated that circATP13A1 sponges the miR-186/miR-326/HMGA2/axis, acting as an oncogene to promote PDAC development.

Relay Catalysis for Highly Selective Conversion of Methanol to Ethylene in Syngas.

The precise C-C coupling is a challenging goal in C1 chemistry. The conversion of methanol, a cheap and easily available C1 feedstock, into value-added and largely demanded olefins has been playing a game-changing role in the production of olefins. The current methanol-to-olefin (MTO) process, however, suffers from limited selectivity to a specific olefin. Here, we present a relay-catalysis route for the high-selective conversion of methanol to ethylene in syngas (H2/CO) typically used for methanol synthesis. A bifunctional catalyst composed of selectively dealuminated H-MOR zeolite and ZnO-TiO2, which implemented methanol carbonylation with CO to acetic acid and selective acetic acid hydrogenation to ethylene in tandem, offered ethylene selectivity of 85% at complete methanol conversion at 583 K. The selective removal of Brønsted acid sites in the 12-membered ring channel of H-MOR favors the selectivity of acetic acid in CH3OH carbonylation. The high capabilities of ZnO-TiO2 in the adsorption of acetic acid and the activation of H2 play key roles in selective hydrogenation of acetic acid to ethylene. Our work provides a promising relay-catalysis strategy for precise C-C coupling of C1 to C2 molecules.

Umbelliprenin induces autophagy and apoptosis while inhibits cancer cell stemness in pancreatic cancer cells.

BACKGROUND: Umbelliprenin is a sesquiterpene coumarin isolated from Artemisia absinthium L. and shows antitumor effects in various cancers by inducing apoptosis. However, the antitumor effect of umbelliprenin in human pancreatic cancer has not been clarified. METHODS: The antitumor effects were determined by MTT and AnnexinV/PI double staining assay in vitro and xenograft mice in vivo. Autophagy was determined via immunofluorescence analysis. Apoptotic or autophagic related proteins were measured by immunoblotting. The pancreatic cancer cell stemness were determined by mammosphere formation and ALDEFLUOR assay. RESULTS: It revealed that umbelliprenin inhibited pancreatic cancer cell proliferation in vitro and pancreatic cancer tumor growth in vivo. Moreover, umbelliprenin induced pancreatic cancer cell BxPC3 apoptosis and autophagy as evidenced by upregulated apoptosis and autophagy- related protein expression (p < 0.01). Blocking autophagy by 3-MA or Atg7 knockout enhanced umbelliprenin-induced apoptosis (p < 0.05). Umbelliprenin also reduced pancreatic cancer cell stemness by reducing Oct4, Nanog, and Sox2 mRNA levels (p < 0.01). Mechanistically, umbelliprenin greatly inhibited Akt/mTOR and Notch1 signal pathway. CONCLUSION: Umbelliprenin may be a novel therapeutic approach for pancreatic cancer treatment.

HPV16 E6/E7 -based mRNA vaccine is therapeutic in mice bearing aggressive HPV-positive lesions.

HPV (Human papillomavirus) affects 600,000 people worldwide each year. Almost all cervical cancers are associated with a past HPV infection. In particular, the positivity to the high-risk type HPV16 is detected in most of the invasive cervical cancers. FDA has approved prophylactic vaccines that protect against new HPV16 infections, but do not induce immunity in those patients with established infections or neoplasms. To date, no therapeutic vaccine targeting HPV16-associated lesions has been authorized. We have developed an mRNA-based vaccine against the HPV16 late oncoproteins E6 and E7, which are abundantly and exclusively expressed in high-grade squamous intraepithelial lesions (HSILs), a stage of the cervical disease that precedes the progression to carcinoma. Our in vitro and in vivo studies demonstrated that the translated mRNA is functional and elicits an antigen-specific adaptive immune response. Upon immunization with the vaccine, mice with HPV16+ lesions exhibited tumor growth inhibition, extension of lifespan, and development of a protective immune memory. In light of these results and the remarkable clinical success of mRNA vaccines against SARS-CoV2, we believe that our mRNA-based therapeutic vaccine has the potential to offer a non-invasive treatment alternative to the current standard of care for HPV16+ HSILs.

The role of main pancreatic duct stent in the enucleation of benign/borderline pancreatic head tumors: a cohort study.

PURPOSE: This study aimed to reveal the role of preoperative main pancreatic duct (MPD) stent placement in reducing the intraoperative main pancreatic duct injury rate and the incidence of postoperative pancreatic leakage following pancreatic tumor enucleation. METHODS: A retrospective cohort analysis was performed for all patients with benign/borderline pancreatic head tumors who were treated with enucleation. The patients were divided into two groups (standard vs. stent) depending on whether they underwent main pancreatic duct stent placement prior to surgery. RESULTS: Thirty-three patients were finally included in the analytical cohort. Compared with the standard group, patients in the stent group had a shorter distance between tumors and main pancreatic duct (p=0.01) and presented with larger tumors (p<0.01). The rates of POPF (grade B&C) were 39.1% (9/23) and 20% (2/10) in the standard and stent groups, respectively (p<0.01). Major postoperative complications occurred more frequently in the standard group than in the stent group (14 versus 2; p<0.01). No significant differences in mortality, in-hospital stay or medical cost were observed between the two groups (p>0.05). CONCLUSIONS: MPD stent placement prior to surgery may facilitate pancreatic tumor enucleation, minimize MPD injury and decrease the occurrence of postoperative fistula.

Meta-analysis of iron metabolism markers levels of Parkinson's disease patients determined by fluid and MRI measurements.

BACKGROUND: Parkinson' s disease (PD) is a progressive neurodegenerative disease featured neuropathologically by the loss of dopaminergic neurons of the substantia nigra (SN). Iron overload in the SN is mainly relative to the pathology and pathogenesis of PD. Postmortem samples of PD has indicated the increased levels of brain iron. However, there is no consensus on iron content through iron-sensitive magnetic resonance imaging (MRI) techniques and the alteration of iron and iron related metabolism markers levels in blood and cerebrospinal fluids (CSF) are still unclear based on the current studies. In this study, we performed a meta-analysis to explore the iron concentration and iron metabolism markers levels through iron-sensitive MRI quantification and body fluid. METHODS: A comprehensive literature search was performed in PubMed, EMBASE and Cochrane Library databases for relevant published studies that analyzed iron load in the SN of PD patients using quantitative susceptibility mapping (QSM) or susceptibility weighting imaging (SWI), and iron metabolism markers, iron, ferritin, transferrin, total iron-binding capacity（TIBC）in CSF sample or serum/plasma sample (from Jan 2010 to Sep 2022 to filter these inaccurate researches attributed to unadvanced equipment, inaccurate analytical methods). Standardized mean differences (SMD) or mean differences (MD) and 95% confidence intervals (CI) with random or fixed effect model was used to estimate the results. RESULTS: Forty-two articles fulfilled the inclusion criteria including 19 for QSM, 6 for SWI, and 17 for serum/plasma/CSF sample including 2874 PD patients and 2821 healthy controls (HCs). Our meta-analysis results founded a notable difference for QSM values increase (19.67, 95% CI=18.69-20.64) and for SWI measurements (-1.99, 95% CI= -3.52 to -0.46) in the SN in PD patients. However, the serum/plasma/CSF iron levels and serum/plasma ferritin, transferrin, total iron-binding capacity (TIBC) did not differ significantly between PD patients and HCs. CONCLUSIONS: Our meta-analysis showed the consistent increase in the SN in PD patients using QSM and SWI techniques of iron-sensitive MRI measures while no significant differences were observed in other iron metabolism markers levels.

Formulation and evaluation of a two-stage targeted liposome coated with hyaluronic acid for improving lung cancer chemotherapy and overcoming multidrug resistance.

Multidrug resistance (MDR) has emerged as a prominent challenge contributing to the ineffectiveness of chemotherapy in treating non-small cell lung cancer (NSCLC) patients. Currently, mitochondria of cancer cells are identified as a promising target for overcoming MDR due to their crucial role in intrinsic apoptosis pathway and energy supply centers. Here, a two-stage targeted liposome (HA/TT LP/PTX) was successfully developed via a two-step process: PTX-loaded cationic liposome (TT LP/PTX) were formulated by lipid film hydration & ultrasound technique, followed by further coating with natural anionic polysaccharide hyaluronic acid (HA). TT, an amphipathic polymer conjugate of triphenylphosphine (TPP)-tocopheryl polyethylene glycol succinate (TPGS), was used to modify the liposomes for mitochondrial targeting. The average particle size, zeta potential and encapsulation efficiency (EE%) of HA/TT LP/PTX were found to be 153 nm, -30.3 mV and 92.1% based on the optimal prescription of HA/TT LP/PTX. Compared to cationic liposome, HA-coated liposomes showed improved stability and safety, including biological stability in serum, cytocompatibility, and lower hemolysis percentage. In drug-resistant A549/T cells, HA was shown to improve the cellular uptake of PTX through CD44 receptor-mediated endocytosis and subsequent degradation by hyaluronidase (HAase) in endosomes. Following this, the exposure of TT polymer facilitated the accumulation of PTX within the mitochondria. As a result, the function of mitochondria in A549/T cells was disturbed, leading to an increased ROS level, decreased ATP level, dissipated MMP, and increased G2/M phase arrest. This resulted in a higher apoptotic rate and stronger anticancer efficacy.

Novel rapid coordination of ascorbic acid 2-phosphate and iron(III) as chromogenic substrate system based on Fe2O3 nanoparticle and application in immunoassay for the colorimetric detection of carcinoembryonic antigen.

This work for the first time reports on a simple and rapid colorimetric immunoassay with rapid coordination of ascorbic acid 2-phosphate (AAP) and iron (III) for determination of carcinoembryonic antigen (CEA, used as a model) by using Fe2O3 nanoparticle based-chromogenic substrate system. The signal was produced rapidly (1 min) from the coordination of AAP and iron (III) with color development of colorless to brown. TD-DFT calculation methods were employed to simulate the UV-Vis spectra of AAP-Fe2+ and AAP-Fe3+ complexes. Moreover, Fe2O3 nanoparticle could be dissolved with the aid of acid, thereby releasing free iron (III). Herein, a sandwich-type immunoassay was established based on Fe2O3 nanoparticle as labels. As target CEA concentration increased, the number of Fe2O3 labelled-antibodies (bound specifically) increased, resulting in loading more Fe2O3 nanoparticle on platform. The absorbance increased as the number of free iron (III), derived from Fe2O3 nanoparticle, increased. So, the absorbance of reaction solution is positively correlated with antigen concentration. Under optimal conditions, the current results showed good performance for CEA detection in the range 0.02-10.0 ng/mL with a detection limit of 11 pg/mL. Moreover, the repeatability, stability, and selectivity of the colorimetric immunoassay were also acceptable.

hENT1's role in adjuvant intra-arterial gemcitabine-based chemotherapy for resectable pancreatic cancer patients.

BACKGROUND: We aimed to verify the role of hENT1 as a prognostic predictor for patients with resectable pancreatic ductal adenocarcinoma (PDAC) who underwent radical resection followed by intra-arterial infusion of gemcitabine-based regimen. METHODS: We collected surgical samples from 102 patients with resectable PDAC who received radical resection followed by intra-arterial infusion of gemcitabine-based regimen. The hENT1 expression with the help of immunohistochemistry was conducted using formalin-fixed and paraffin embedded tissues. The Kaplan-Meier analyses and Cox regression were used to evaluate the mortality hazard associated with the discrepancy between strong and weak of hENT1 expression. Patients' clinical and pathological characteristics were compared between the two groups, then the role of hENT1 as a prognostic predictor was further explored. RESULTS: A total of 102 patients were included to assess the hENT1 expression. 50 patients were classified into high hENT1 expression group, the other 52 patients were attributed into low hENT1 expression group. High hENT1 expression was related to a significantly improved overall survival (OS) (p = 0.014) and disease-free survival (DFS) (p = 0.004). Both univariate (p = 0.001) and multivariate analyses (p < 0.001) indicated that high hENT1 expression was related to a decreased mortality. CONCLUSIONS: High expression of hENT1 is positive prognostic factor for adjuvant intra-arterial gemcitabine-based chemotherapy in resectable PDAC.

Exosomal proteomics identifies RAB13 as a potential regulator of metastasis for HCC.

BACKGROUND: Exosomal proteins from cancer cells are becoming new biomarkers for cancer monitoring and efficacy evaluation. However, their biological function and molecular mechanism underlying tumor metastasis are largely unknown. METHODS: Bioinformatic methods such as bulk gene expression analysis, single-cell RNA sequencing data analysis, and gene set enrichment analysis were employed to identify metastasis-associated proteins. The in vitro and in vivo experiments were used to investigate the function of RAB13 in HCC metastasis. RESULTS: We identified RAB13 as one of the critical regulators of metastasis in HCC-derived exosomes for the first time. In vitro, the invasiveness of HCC cell lines could be attenuated by RAB13 silence. In vivo, tumor size and proportion of high-grade lung metastatic nodule could be reduced in the mice with orthotopic transplantation of tumors and intravenously injected with exosomes derived from MHCC97H cell with RAB13 silence (si-RAB13-Exo), as compared with those without RAB13 silence (si-NC-Exo). Moreover, in si-RAB13-Exo group, circulating tumor cell counts were decreased at the third, fourth, and fifth weeks after orthotopic transplantation of tumors, and MMP2 (matrix metalloproteinase 2)/TIMP2 (tissue inhibitor of metalloproteinases 2) ratio was also significantly decreased. In addition, RAB13 expression was also associated with VEGF levels, microvessel density, and tube formation of vascular endothelial cells by both in vitro and in vivo models, indicating that RAB13 was associated with angiogenesis in HCC. CONCLUSIONS: We have demonstrated exosomal RAB13 as a potential regulator of metastasis for HCC by in silico, in vitro, and in vivo methods, which greatly improve our understanding of the functional impact of exosomal proteins on HCC metastasis.

A clinically feasible circulating tumor cell sorting system for monitoring the progression of advanced hepatocellular carcinoma.

BACKGROUND: Hematogenous metastasis is essential for the progression of advanced hepatocellular carcinoma (HCC) and can occur even after patients receive multidisciplinary therapies, including immunotherapy and hepatectomy; circulating tumor cells (CTCs) are one of the dominant components of the metastatic cascade. However, the CTC capture efficiency for HCC is low due to the low sensitivity of the detection method. In this study, epithelial cell adhesion molecule (EpCAM)/vimentin/Glypican-3 (GPC3) antibody-modified lipid magnetic spheres (LMS) were used to capture tumor cells with epithelial phenotype, mesenchymal phenotype and GPC3 phenotype, respectively, in order to capture more CTCs with a more comprehensive phenotype for monitoring tumor metastasis. RESULTS: The novel CTC detection system of Ep-LMS/Vi-LMS/GPC3-LMS was characterized by low toxicity, strong specificity (96.94%), high sensitivity (98.12%) and high capture efficiency (98.64%) in vitro. A sudden increase in CTC counts accompanied by the occurrence of lung metastasis was found in vivo, which was further validated by a clinical study. During follow-up, the rapid increase in CTCs predicted tumor progression in HCC patients. Additionally, genetic testing results showed common genetic alterations in primary tumors, CTCs and metastatic tissues. The proportion of patients predicted to benefit from immunotherapy with the CTC detection method was higher than that for the tissue detection method (76.47% vs. 41.18%, P = 0.037), guiding the application of clinical individualized therapy. CONCLUSIONS: The Ep-LMS/Vi-LMS/GPC3-LMS sequential CTC capture system is convenient and feasible for the clinical prediction of HCC progression. CTCs captured by this system could be used as a suitable alternative to HCC tissue detection in guiding immunotherapy, supporting the clinical application of CTC liquid biopsy.

Quinoa husk peptides reduce melanin content via Akt signaling and apoptosis pathways.

To improve the treatment of pigmentation disorders, looking for natural and safe inhibitors of melanin synthesis has become an area of research interest. The quinoa husk peptides reportedly elicit various biological activities (e.g., anti-cancer, antioxidant, anti-hypertensive, and so forth), but its effects on melanin inhibition remain unknown. In the current study, we purified quinoa husk peptides with 30 and 80% ethanol using a macroporous adsorption resin (DA201-C). Component screening revealed that the 80%-ethanol fraction (i.e., QHP fraction) contained numerous short peptides (84.41%) and hydrophobic amino acids (45.60%), while eliciting a superior tyrosinase [TYR]-inhibition rate, 2,2-diphenyl-1-picryhydrazil-scavenging rate, reducing activity, and chelating capacity compared to the 30% fraction and was thus applied in subsequent analyses. Differentially expressed genes in the QHP fraction were primarily enriched in the Akt-signaling pathways based on transcriptomics. Thus, we assessed the expression of related proteins and genes in A375 cells and rat skin cells following treatment with QHP.

A comparative study of gastric histopathology sub-size image classification: From linear regression to visual transformer.

Introduction: Gastric cancer is the fifth most common cancer in the world. At the same time, it is also the fourth most deadly cancer. Early detection of cancer exists as a guide for the treatment of gastric cancer. Nowadays, computer technology has advanced rapidly to assist physicians in the diagnosis of pathological pictures of gastric cancer. Ensemble learning is a way to improve the accuracy of algorithms, and finding multiple learning models with complementarity types is the basis of ensemble learning. Therefore, this paper compares the performance of multiple algorithms in anticipation of applying ensemble learning to a practical gastric cancer classification problem. Methods: The complementarity of sub-size pathology image classifiers when machine performance is insufficient is explored in this experimental platform. We choose seven classical machine learning classifiers and four deep learning classifiers for classification experiments on the GasHisSDB database. Among them, classical machine learning algorithms extract five different image virtual features to match multiple classifier algorithms. For deep learning, we choose three convolutional neural network classifiers. In addition, we also choose a novel Transformer-based classifier. Results: The experimental platform, in which a large number of classical machine learning and deep learning methods are performed, demonstrates that there are differences in the performance of different classifiers on GasHisSDB. Classical machine learning models exist for classifiers that classify Abnormal categories very well, while classifiers that excel in classifying Normal categories also exist. Deep learning models also exist with multiple models that can be complementarity. Discussion: Suitable classifiers are selected for ensemble learning, when machine performance is insufficient. This experimental platform demonstrates that multiple classifiers are indeed complementarity and can improve the efficiency of ensemble learning. This can better assist doctors in diagnosis, improve the detection of gastric cancer, and increase the cure rate.

Antiviral effects of the petroleum ether extract of Tournefortia sibirica L. against enterovirus 71 infection in vitro and in vivo.

Enterovirus 71 (EV71) is the major cause of severe hand, foot, and mouth disease (HFMD). Compared to other HFMD pathogens, like coxsackievirus A16 (CVA16), EV71 can invade the central nervous system and cause permanent damage. At present, there are no available antivirals against EV71 for clinical treatment. Herein, multiple Chinese botanical drugs were collected, and 47 types of botanical extracts were extracted using aqueous solutions and organic solvents. Based on the cytopathic effect inhibition assay, petroleum ether extract of Tournefortia sibirica L. (PE-TS) demonstrated 97.25% and 94.75% inhibition rates for EV71 infection (at 250 µg/ml) and CVA16 infection (at 125 µg/ml), respectively, with low cytotoxicity. Preliminary mechanistic studies showed that PE-TS inhibits replication of EV71 genomic RNA and synthesis of the EV71 protein. The released extracellular EV71 progeny virus titer decreased by 3.75 lg under PE-TS treatment. Furthermore, using a newborn mouse model, PE-TS treatment protected 70% and 66.7% of mice from lethal dose EV71 intracranial challenge via administration of intraperitoneal injection at 0.4 mg/g and direct lavage at 0.8 mg/g, respectively. The chemical constituents of the PE-TS were analyzed by Gas Chromatography-Mass Spectrometer (GC-MS), and a total of 60 compounds were identified. Compound-target network analysis and molecular docking implied potential bioactive compounds and their protein targets against EV71 associated pathology. The present study identified antiviral effects of PE-TS against EV71/CVA16 infection in vitro and EV71 infection in vivo, providing a potential antiviral botanical drug extract candidate for HFMD drug development.

Cordycepin Inhibits the Growth of Hepatocellular Carcinoma by Regulating the Pathway of Aerobic Glycolysis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China, with a high incidence and mortality rate. Glucose metabolism reprogramming is a major characteristic of tumor cells. Increasing evidence indicates that aerobic glycolysis is associated with tumor growth and insensitivity to chemotherapy. Cordycepin inhibits the growth of HCC cells, but the mechanism is yet to be elucidated. Herein, in vitro and in vivo methods were utilized to investigate the cordycepin-inhibited growth of HCC by regulating the metabolic pathway of aerobic glycolysis. In vitro analyses using colony formation and flow cytometry revealed that cordycepin inhibits HCC cells' proliferation and promotes apoptosis. In addition, cordycepin reduced the production of lactic acid and pyruvate, reduced the uptake of glucose, and decreased the extracellular acidification in HCC cells. Specifically, cordycepin inhibited the expression of HK2, LDHA, and PKM2 in aerobic glycolysis via the AMPK-Akt pathway. Taken together, these findings revealed that cordycepin reduces the tumor energy supply and decreases lactic acid production, thereby inhibiting the growth of HCC cells by regulating the metabolic pathway of aerobic glycolysis. These findings might provide novel insights into the mechanisms underlying cordycepin-mediated inhibition of tumor growth as well as a new treatment for HCC.

Exosomal MicroRNA signature acts as an efficient biomarker for non-invasive diagnosis of gallbladder carcinoma.

Through a three-step study that relies on biomarker discovery, training, and validation, we identified a set of five exosomal microRNAs (miRNAs) that can be used to evaluate the risk of gallbladder carcinoma (GBC), including miR-552-3p, miR-581, miR-4433a-3p, miR-496, and miR-203b-3p. When validated in 102 GBC patients and 112 chronic cholecystitis patients from multiple medical centers, the AUC of this combinatorial biomarker was 0.905, with a sensitivity of 81.37% and a specificity of 86.61%. The performance of this biomarker is superior to that of the standard biomarkers CA199 and CEA and is suited for GBC early diagnosis. The multi-clinicopathological features and prognosis of GBC patients were significantly associated with this biomarker. After building a miRNA-target gene regulation network, cell functions and signaling pathways regulated by these five miRNAs were examined. This biomarker signature can be used in the development of a noninvasive tool for GBC diagnosis, screening and prognosis prediction.

Differences in cognition, short-chain fatty acids and related metabolites in pregnant versus non-pregnant women: a cross-sectional study.

BACKGROUND: Pregnancy induces cognitive reorganization which can lead to mental disorders. The aim of this study is to determine differences in cognitive scores, short-chain fatty acids (SCFAs) and related metabolites between pregnant and non-pregnant participants. METHODS: This cross-sectional study included 67 full-term pregnant women and 31 non-pregnant women. We compared scores of mental state and cognitive assessment tests, as well as serum concentrations of SCFAs, hormones, inflammatory factors, and neurotransmitters between these groups. RESULTS: Scores for information processing speed, immediate visual memory, motor response speed and accuracy, execution ability and verbal use ability in the pregnant group were lower than those in the non-pregnant group (p < 0.05 for all tests). Total serum SCFAs in the pregnant group were significantly lower than those in the non-pregnant group (P = 0.031). Among them, acetate and propionate were significantly decreased (P = 0.013 and 0.037, respectively) whereas butyrate was significantly increased (P = 0.035). Serum peptide YY, glucagon-like peptide-1, γ-aminobutyric acid, and dopamine showed no differences between the two groups. However, cortisol, adrenocorticotropic hormone, and acetylcholine were significantly increased in the pregnant group as compared with the non-pregnant group (P = 0.039, 0.016, and 0.012, respectively). Tumor necrosis factor-α was increased and interleukin-10 significantly decreased in the pregnant group (P = 0.045 and 0.019, respectively). CONCLUSION: According to our study findings, cognitive reorganization in the third trimester of pregnancy showed that both the passive storage capacity of working memory and the executive function of online information processing were decreased to varying degrees. At the same time, the changes in total SCFAs, the proportions of SCFAs and related metabolites were also detected. These changes in the internal environment may be increasing the risk of perinatal mental illness.

Integrative Analysis Identifies Cell-Type-Specific Genes Within Tumor Microenvironment as Prognostic Indicators in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, but effective early detection and prognostication methods are lacking. Methods: The Cox regression model was built to stratify the HCC patients. The single-cell RNA sequencing data analysis and gene set enrichment analysis were employed to investigate the biological function of identified markers. PLCB1 gain- or loss-of-function experiments were performed, and obtained HCC samples were analyzed using quantitative real-time PCR and immunohistochemistry assay to validate the biological function of identified markers. Results: In this study, we developed a model using optimized markers for HCC recurrence prediction. Specifically, we screened out 8 genes through a series of data analyses, and built a multivariable Cox model based on their expression. The risk stratifications using the Eight-Gene Cox (EGC) model were closely associated with the recurrence-free survivals (RFS) in both training and three validation cohorts. We further demonstrated that this risk stratification could serve as an independent predictor in predicting HCC recurrence, and that the EGC model could outperform other models. Moreover, we also investigated the cell-type-specific expression patterns of the eight recurrence-related genes in tumor microenvironment using single-cell RNA sequencing data, and interpreted their functional roles from correlation and gene set enrichment analyses, in vitro and in vivo experiments. Particularly, PLCB1 and SLC22A7 were predominantly expressed in malignant cells, and they were predicted to promote angiogenesis and to help maintain normal metabolism in liver, respectively. In contrast, both FASLG and IL2RB were specifically expressed in T cells, and were highly correlated with T cell marker genes, suggesting that these two genes might assist in maintaining normal function of T cell-mediated immune response in tumor tissues. Conclusion: In conclusion, the EGC model and eight identified marker genes could not only facilitate the accurate prediction of HCC recurrence, but also improve our understanding of the mechanisms behind HCC recurrence.

Macrophage SCAP Contributes to Metaflammation and Lean NAFLD by Activating STING-NF-κB Signaling Pathway.

BACKGROUND & AIMS: Sterol regulatory element binding protein cleavage-activating protein (SCAP) is a cholesterol sensor that confers a broad range of functional effects in metabolic diseases. Lean nonalcoholic fatty liver disease (NAFLD) is characterized by a decrease in subcutaneous fat and ectopic fat deposition in the liver. SCAP may mediate the development of lean NAFLD, but the mechanism of action remains unclear. METHODS: C57BL/6J wild-type and macrophage SCAP-specific knockout mice (SCAPΔMϕ) were subjected to Paigen diet (PD) feeding induced lean NAFLD. Inflammation and lipid metabolism of adipose and liver were evaluated. The STING-NF-κB signaling pathway was examined in vivo and in vitro to explore the underlying mechanism of macrophage SCAP on metaflammation. RESULTS: The data showed heterogeneity of lipid metabolic processes in liver and epididymal white adipose tissue due to inflammation mediated by macrophage infiltration. Meanwhile, we found that the macrophage SCAP was abnormally increased in the adipose and liver tissues of PD-fed mice. Intriguingly, the SCAPΔMϕ mice attenuated PD-induced metaflammation and ectopic lipid deposition by reducing hepatic stimulator of interferon gene (STING)-nuclear factor kappa B (NF-κB) pathway activation. In-depth molecular analysis revealed that SCAP specifically recruits the STING and tank-binding kinase 1 onto the Golgi to activate the NF-κB in macrophages, thereby promoting the release of inflammatory factors. This process ultimately led to an increased lipolysis in adipocytes and lipid uptake and synthesis in hepatocytes. CONCLUSIONS: Our findings suggest that SCAP acts as a novel regulator of the macrophage inflammatory response and the pathogenesis of lean NAFLD by activating the STING-NF-κB signaling pathway. Inhibition of macrophage SCAP may represent a new therapeutic strategy for the treatment of lean NAFLD.