[Intraspinal Metastasis of Thymic Carcinoma:Report of One Case].

Intraspinal metastasis from malignant carcinomas in other body parts is rarely reported.Intraspinal metastases are often epidural,with primary tumors mostly from the lung and prostate.The extramedullary subdural metastasis of thymic carcinoma is particularly rare and prone to misdiagnosis due to overlapping imaging features with primary intraspinal tumors.This article reports one case of intraspinal metastasis of thymic carcinoma,with the main diagnostic clues including a history of thymic carcinoma,fast growth rate,and irregular shape.

Effect of volatile versus propofol anaesthesia on major complications and mortality after cardiac surgery: a multicentre randomised trial.

BACKGROUND: The comparative effectiveness of volatile anaesthesia and total intravenous anaesthesia (TIVA) in terms of patient outcomes after cardiac surgery remains a topic of debate. METHODS: Multicentre randomised trial in 16 tertiary hospitals in China. Adult patients undergoing elective cardiac surgery were randomised in a 1:1 ratio to receive volatile anaesthesia (sevoflurane or desflurane) or propofol-based TIVA. The primary outcome was a composite of predefined major complications during hospitalisation and mortality 30 days after surgery. RESULTS: Of the 3123 randomised patients, 3083 (98.7%; mean age 55 yr; 1419 [46.0%] women) were included in the modified intention-to-treat analysis. The composite primary outcome was met by a similar number of patients in both groups (volatile group: 517 of 1531 (33.8%) patients vs TIVA group: 515 of 1552 (33.2%) patients; relative risk 1.02 [0.92-1.12]; P=0.76; adjusted odds ratio 1.05 [0.90-1.22]; P=0.57). Secondary outcomes including 6-month and 1-yr mortality, duration of mechanical ventilation, length of ICU and hospital stay, and healthcare costs, were also similar for the two groups. CONCLUSIONS: Among adults undergoing cardiac surgery, we found no difference in the clinical effectiveness of volatile anaesthesia and propofol-based TIVA. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IOR-17013578).

IFN-α/ß/IFN-γ/IL-15 pathways identify GBP1-expressing tumors with an immune-responsive phenotype.

Immunotherapy is widely used in cancer treatment; however, only a subset of patients responds well to it. Significant efforts have been made to identify patients who will benefit from immunotherapy. Successful anti-tumor immunity depends on an intact cancer-immunity cycle, especially long-lasting CD8+ T-cell responses. Interferon (IFN)-α/ß/IFN-γ/interleukin (IL)-15 pathways have been reported to be involved in the development of CD8+ T cells. And these pathways may predict responses to immunotherapy. Herein, we aimed to analyze multiple public databases to investigate whether IFN-α/ß/IFN-γ/IL-15 pathways could be used to predict the response to immunotherapy. Results showed that IFN-α/ß/IFN-γ/IL-15 pathways could efficiently predict immunotherapy response, and guanylate-binding protein 1 (GBP1) could represent the IFN-α/ß/IFN-γ/IL-15 pathways. In public and private cohorts, we further demonstrated that GBP1 could efficiently predict the response to immunotherapy. Functionally, GBP1 was mainly expressed in macrophages and strongly correlated with chemokines involved in T-cell migration. Therefore, our study comprehensively investigated the potential role of GBP1 in immunotherapy, which could serve as a novel biomarker for immunotherapy and a target for drug development.

NK cell transfer overcomes resistance to PD-(L)1 therapy in aged mice.

BACKGROUND: Cancer is the leading cause of death among older adults. Although the integration of immunotherapy has revolutionized the therapeutic landscape of cancer, the complex interactions between age and immunotherapy efficacy remain incompletely defined. Here, we aimed to elucidate the relationship between aging and immunotherapy resistance. METHODS: Flow cytometry was performed to evaluate the infiltration of immune cells in the tumor microenvironment (TME). In vivo T cell proliferation, cytotoxicity and migration assays were performed to evaluate the antitumor capacity of tumor antigen-specific CD8+ T cells in mice. Real-time quantitative PCR (qPCR) was used to investigate the expression of IFN-γ-associated gene and natural killer (NK)-associated chemokine. Adoptive NK cell transfer was adopted to evaluate the effects of NK cells from young mice in overcoming the immunotherapy resistance of aged mice. RESULTS: We found that elderly patients with advanced non-small cell lung cancer (aNSCLC) aged ≥ 75 years exhibited poorer progression-free survival (PFS), overall survival (OS) and a lower clinical response rate after immunotherapy. Mechanistically, we showed that the infiltration of NK cells was significantly reduced in aged mice compared to younger mice. Furthermore, the aged NK cells could also suppress the activation of tumor antigen-specific CD8+ T cells by inhibiting the recruitment and activation of CD103+ dendritic cells (DCs). Adoptive transfer of NK cells from young mice to aged mice promoted TME remodeling, and reversed immunotherapy resistance. CONCLUSION: Our findings revealed the decreased sensitivity of elderly patients to immunotherapy, as well as in aged mice. This may be attributed to the reduction of NK cells in aged mice, which inhibits CD103+ DCs recruitment and its CD86 expression and ultimately leads to immunotherapy resistance.

Biological characteristics and clinical treatment of pulmonary sarcomatoid carcinoma: a narrative review.

Background and Objective: Pulmonary sarcomatoid carcinoma (PSC) is a subset of non-small cell lung cancer (NSCLC) with highly malignant, aggressive, and heterogeneous features. Patients with this disease account for approximately 0.1-0.4% of lung cancer cases. The absence of comprehensive summaries on the basic biology and clinical treatments for PSC means there is limited systematic awareness and understanding of this rare disease. This paper provides an overview of the biological characteristics of PSC and systematically summarizes various treatment strategies available for patients with this disease. Methods: For this narrative review, we have searched literature related to the basic biology and clinical treatment approaches of PSC by searching the PubMed database for articles published from July 16, 1990 to August 29, 2023. The following keywords were used: "pulmonary sarcomatoid carcinoma", "genetic mutations", "immune microenvironment", "hypoxia", "angiogenesis", "overall survival", "surgery", "radiotherapy", "chemotherapy", and "immune checkpoint inhibitors". Key Content and Findings: Classical PSC comprises epithelial and sarcomatoid components, with most studies suggesting a common origin. PSC exhibits a higher tumor mutational burden (TMB) and mutation frequency than other types of NSCLC. The tumor microenvironment (TME) of PSC is characterized by hypoxia, hypermetabolism, elevated programmed cell death protein 1/programmed cell death-ligand 1 expression, and high immune cell infiltration. Treatment strategies for advanced PSC are mainly based on traditional NSCLC treatments, but PSC exhibits resistance to chemotherapy and radiotherapy. The advancement of genome sequencing has introduced targeted therapies as an option for mutation-positive PSC cases. Moreover, due to the characteristics of the immune microenvironment of PSC, many patients positively respond to immunotherapy, demonstrating its potential for the management of PSC. Conclusions: Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.

Quantitative MR imaging biomarkers for distinguishing inflammatory pancreatic mass and pancreatic cancer-a systematic review and meta-analysis.

OBJECTIVES: To evaluate the diagnostic performance of quantitative magnetic resonance (MR) imaging biomarkers in distinguishing between inflammatory pancreatic masses (IPM) and pancreatic cancer (PC). METHODS: A literature search was conducted using PubMed, Embase, the Cochrane Library, and Web of Science through August 2023. Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was used to evaluate the risk of bias and applicability of the studies. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were calculated using the DerSimonian-Laird method. Univariate meta-regression analysis was used to identify the potential factors of heterogeneity. RESULTS: Twenty-four studies were included in this meta-analysis. The two main types of IPM, mass-forming pancreatitis (MFP) and autoimmune pancreatitis (AIP), differ in their apparent diffusion coefficient (ADC) values. Compared with PC, the ADC value was higher in MFP but lower in AIP. The pooled sensitivity/specificity of ADC were 0.80/0.85 for distinguishing MFP from PC and 0.82/0.84 for distinguishing AIP from PC. The pooled sensitivity/specificity for the maximal diameter of the upstream main pancreatic duct (dMPD) was 0.86/0.74, with a cutoff of dMPD ≤ 4 mm, and 0.97/0.52, with a cutoff of dMPD ≤ 5 mm. The pooled sensitivity/specificity for perfusion fraction (f) was 0.82/0.68, and 0.82/0.77 for mass stiffness values. CONCLUSIONS: Quantitative MR imaging biomarkers are useful in distinguishing between IPM and PC. ADC values differ between MFP and AIP, and they should be separated for consideration in future studies. CLINICAL RELEVANCE STATEMENT: Quantitative MR parameters could serve as non-invasive imaging biomarkers for differentiating malignant pancreatic neoplasms from inflammatory masses of the pancreas, and hence help to avoid unnecessary surgery. KEY POINTS: • Several quantitative MR imaging biomarkers performed well in differential diagnosis between inflammatory pancreatic mass and pancreatic cancer. • The ADC value could discern pancreatic cancer from mass-forming pancreatitis or autoimmune pancreatitis, if the two inflammatory mass types are not combined. • The diameter of main pancreatic duct had the highest specificity for differentiating autoimmune pancreatitis from pancreatic cancer.

Cold EMR vs. Hot EMR for the removal of sessile serrated polyps larger than 10 mm: a systematic review and meta-analysis.

BACKGROUND: Endoscopic mucosal resection (EMR) appears to be a promising technique for the removal of sessile serrated polyps (SSPs) ≥ 10 mm. To assess the effectiveness and safety of EMR for removing SSPs ≥ 10 mm, we conducted this systematic review and meta-analysis. METHODS: We conducted a thorough search of Embase, PubMed, Cochrane, and Web of Science databases for relevant studies reporting on EMR of SSPs ≥ 10 mm, up until December 2023. Our primary endpoints of interest were rates of technical success, residual SSPs, and adverse events (AE). RESULTS: Our search identified 426 articles, of which 14 studies with 2262 SSPs were included for analysis. The rates of technical success, AEs, and residual SSPs were 100%, 2.0%, and 3.1%, respectively. Subgroup analysis showed that the technical success rates were the same for polyps 10-19 and 20 mm, and en-bloc and piecemeal resection. Residual SSPs rates were similar in en-bloc and piecemeal resection, but much lower in cold EMR (1.0% vs. 4.2%, P = 0.034). AEs rates were reduced in cold EMR compared to hot EMR (0% vs. 2.9%, P = 0.168), in polyps 10-19 mm compared to 20 mm (0% vs. 4.1%, P = 0.255), and in piecemeal resection compared to en-bloc (0% vs. 0.7%, P = 0.169). CONCLUSIONS: EMR is an effective and safe technique for removing SSPs ≥ 10 mm. The therapeutic effect of cold EMR is superior to that of hot EMR, with a lower incidence of adverse effects. PROSPERO REGISTRATION NUMBER: CRD42023388959.

Machine learning unveils immune-related signature in multicenter glioma studies.

In glioma molecular subtyping, existing biomarkers are limited, prompting the development of new ones. We present a multicenter study-derived consensus immune-related and prognostic gene signature (CIPS) using an optimal risk score model and 101 algorithms. CIPS, an independent risk factor, showed stable and powerful predictive performance for overall and progression-free survival, surpassing traditional clinical variables. The risk score correlated significantly with the immune microenvironment, indicating potential sensitivity to immunotherapy. High-risk groups exhibited distinct chemotherapy drug sensitivity. Seven signature genes, including IGFBP2 and TNFRSF12A, were validated by qRT-PCR, with higher expression in tumors and prognostic relevance. TNFRSF12A, upregulated in GBM, demonstrated inhibitory effects on glioma cell proliferation, migration, and invasion. CIPS emerges as a robust tool for enhancing individual glioma patient outcomes, while IGFBP2 and TNFRSF12A pose as promising tumor markers and therapeutic targets.

Application of magnetic resonance imaging radiomics in endometrial cancer: a systematic review and meta-analysis.

PURPOSE: We aimed to systematically assess the methodological quality and clinical potential application of published magnetic resonance imaging (MRI)-based radiomics studies about endometrial cancer (EC). METHODS: Studies of EC radiomics analyses published between 1 January 2000 and 19 March 2023 were extracted, and their methodological quality was evaluated using the radiomics quality score (RQS) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Pairwise correlation analyses and separate meta-analyses of studies exploring differential diagnoses and risk prediction were also performed. RESULTS: Forty-five studies involving 3 aims were included. The mean RQS was 13.77 (range: 9-22.5); publication bias was observed in the areas of 'index test' and 'flow and timing'. A high RQS was significantly associated with therapy selection-aimed studies, low QUADAS-2 risk, recent publication year, and high-performance metrics. Raw data from 6 differential diagnosis and 34 risk prediction models were subjected to meta-analysis, revealing diagnostic odds ratios of 23.81 (95% confidence interval [CI] 8.48-66.83) and 18.23 (95% CI 13.68-24.29), respectively. CONCLUSION: The methodological quality of radiomics studies involving patients with EC is unsatisfactory. However, MRI-based radiomics analyses showed promising utility in terms of differential diagnosis and risk prediction.

Network pharmacology and in vivo evidence of the pharmacological mechanism of geniposide in the treatment of atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is a fundamental pathological state in various cardiovascular diseases. Geniposide, which is the main active component of Gardenia jasminides, is effective against AS. However, the underlying molecular mechanisms remain unclear. Here, we sought to elucidate them. METHODS: The targets of AS and geniposide were collected from online public databases. The potential mechanism of Geniposide in treating AS was predicted by constructing a protein-protein interaction (PPI) network and conducting Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses. Hub proteins and core pathways were verified by molecular docking and in vivo experiments. Moreover, the effect of geniposide on AS was assessed by measuring the atherosclerotic plaque area in the thoracic aorta of mice. ApoE-/- mice were used to establish AS models and randomly divided into different groups. Two different doses of geniposide were administered to the mice. Hematoxylin and eosin (HE) staining was performed to evaluate the effects of geniposide on AS. Oil Red O and Sirius Red staining were used to evaluate plaque stability. The protein expression of key markers involved in the signalling pathways was examined using western blotting and immunofluorescence. RESULTS: A total of 239 active targets, 3418 AS-related disease targets, and 129 overlapping targets were identified. Hub genes were detected, and molecular docking revealed that geniposide strongly interacted with hub proteins (AKT1, VEGFA, CTNNB1, MMP9, and EGFR). Moreover, 109 signalling pathways, including the Rap1 signalling pathway, were identified using enrichment analysis. The results of in vivo experiments demonstrated that geniposide reduced body weight and blood lipid levels, alleviated the formation of atherosclerotic plaques, enhanced plaque stability, and inhibited inflammation, at least partially, by activating the Rap1/PI3K/Akt signalling pathway in ApoE-/- mice. CONCLUSION: Geniposide can alleviate AS and enhance the stability of atherosclerotic plaques by regulating the Rap1/PI3K/Akt signalling pathway.

SIRT6 Protects Against Lipopolysaccharide-Induced Inflammation in Human Pulmonary Lung Microvascular Endothelial Cells.

Inflammatory response in the pulmonary endothelium drives the pathogenesis of acute lung injury and sepsis. Sirtuin 6 (SIRT6), a member of class III NAD+-dependent deacetylases belonging to the sirtuin family, regulates senescence, metabolism, and inflammation and extends lifespan in mice and model organisms. However, the role of SIRT6 in pulmonary endothelial inflammation is unknown. Thus, we hypothesized that SIRT6 suppresses inflammatory response in human lung microvascular cells (HLMEC) and ensues monocyte adhesion to endothelial cells. Primary HLMECs were treated with control or SIRT6 adenovirus or SIRT6 agonist, with or without lipopolysaccharide (LPS) treatment. We observed that treatment with LPS did not affect the protein expression of SIRT6 in HLMECs. However, adenovirus-mediated SIRT6 overexpression attenuated LPS-induced VCAM1 gene and protein expression, followed by decreased monocyte adhesion to endothelial cells. Similarly, activation of SIRT6 by a recently reported SIRT6 activator UBCS039, but not the regioisomer negative control compound UBCS060, ameliorated LPS-induced VCAM1 mRNA and protein expression as well as monocyte adhesion. Moreover, luciferase assay revealed that SIRT6 adenovirus decreased the activity of NF-κB, the master regulator of vascular inflammation. Taken together, these results indicate that molecular and pharmacological activation of SIRT6 protects against lung microvascular inflammation via suppressing NF-κB activation, implicating the therapeutic potential of the SIRT6 activators for lung disorders associated with microvascular inflammation.

Synthesis and degradation of the cyclic dinucleotide messenger c-di-AMP in the hyperthermophilic archaeon Pyrococcus yayanosii.

Cyclic di-adenosine monophosphate (c-di-AMP) is a newly identified prokaryotic cyclic dinucleotide second messenger well elucidated in bacteria, while less studied in archaea. Here, we describe the enzymes involved in c-di-AMP metabolism in the hyperthermophilic archaeon Pyrococcus yayanosii. Our results demonstrate that c-di-AMP is synthesized from two molecules of ATP by diadenylate cyclase (DAC) and degraded into pApA and then to AMP by a DHH family phosphodiesterase (PDE). DAC can be activated by a wider variety of ions, using two conserved residues, D188 and E244, to coordinate divalent metal ions, which is different from bacterial CdaA and DisA. PDE possesses a broad substrate spectrum like bacterial DHH family PDEs but shows a stricter base selection between A and G in cyclic dinucleotides hydrolysis. PDE shows differences in substrate binding patches from bacterial counterparts. C-di-AMP was confirmed to exist in Thermococcus kodakarensis cells, and the deletion of the dac or pde gene supports that the synthesis and degradation of c-di-AMP are catalyzed by DAC and PDE, respectively. Our results provide a further understanding of the metabolism of c-di-AMP in archaea.

[CT-Based Weighted Radiomic Score Predicts Tumor Response to Immunotherapy in Non-Small Cell Lung Cancer].

Objective To develop a CT-based weighted radiomic model that predicts tumor response to programmed death-1(PD-1)/PD-ligand 1(PD-L1)immunotherapy in patients with non-small cell lung cancer.Methods The patients with non-small cell lung cancer treated by PD-1/PD-L1 immune checkpoint inhibitors in the Peking Union Medical College Hospital from June 2015 to February 2022 were retrospectively studied and classified as responders(partial or complete response)and non-responders(stable or progressive disease).Original radiomic features were extracted from multiple intrapulmonary lesions in the contrast-enhanced CT scans of the arterial phase,and then weighted and summed by an attention-based multiple instances learning algorithm.Logistic regression was employed to build a weighted radiomic scoring model and the radiomic score was then calculated.The area under the receiver operating characteristic curve(AUC)was used to compare the weighted radiomic scoring model,PD-L1 model,clinical model,weighted radiomic scoring + PD-L1 model,and comprehensive prediction model.Results A total of 237 patients were included in the study and randomized into a training set(n=165)and a test set(n=72),with the mean ages of(64±9)and(62±8)years,respectively.The AUC of the weighted radiomic scoring model reached 0.85 and 0.80 in the training set and test set,respectively,which was higher than that of the PD-L1-1 model(Z=37.30,P<0.001 and Z=5.69,P=0.017),PD-L1-50 model(Z=38.36,P<0.001 and Z=17.99,P<0.001),and clinical model(Z=11.40,P<0.001 and Z=5.76,P=0.016).The AUC of the weighted scoring model was not different from that of the weighted radiomic scoring + PD-L1 model and the comprehensive prediction model(both P>0.05).Conclusion The weighted radiomic scores based on pre-treatment enhanced CT images can predict tumor responses to immunotherapy in patients with non-small cell lung cancer.

Heterogeneity of the tumor immune microenvironment and clinical interventions.

The tumor immune microenvironment (TIME) is broadly composed of various immune cells, and its heterogeneity is characterized by both immune cells and stromal cells. During the course of tumor formation and progression and anti-tumor treatment, the composition of the TIME becomes heterogeneous. Such immunological heterogeneity is not only present between populations but also exists on temporal and spatial scales. Owing to the existence of TIME, clinical outcomes can differ when a similar treatment strategy is provided to patients. Therefore, a comprehensive assessment of TIME heterogeneity is essential for developing precise and effective therapies. Facilitated by advanced technologies, it is possible to understand the complexity and diversity of the TIME and its influence on therapy responses. In this review, we discuss the potential reasons for TIME heterogeneity and the current approaches used to explore it. We also summarize clinical intervention strategies based on associated mechanisms or targets to control immunological heterogeneity.

A systematic review and meta-analysis of CT and MRI radiomics in ovarian cancer: methodological issues and clinical utility.

OBJECTIVES: We aimed to present the state of the art of CT- and MRI-based radiomics in the context of ovarian cancer (OC), with a focus on the methodological quality of these studies and the clinical utility of these proposed radiomics models. METHODS: Original articles investigating radiomics in OC published in PubMed, Embase, Web of Science, and the Cochrane Library between January 1, 2002, and January 6, 2023, were extracted. The methodological quality was evaluated using the radiomics quality score (RQS) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Pairwise correlation analyses were performed to compare the methodological quality, baseline information, and performance metrics. Additional meta-analyses of studies exploring differential diagnoses and prognostic prediction in patients with OC were performed separately. RESULTS: Fifty-seven studies encompassing 11,693 patients were included. The mean RQS was 30.7% (range - 4 to 22); less than 25% of studies had a high risk of bias and applicability concerns in each domain of QUADAS-2. A high RQS was significantly associated with a low QUADAS-2 risk and recent publication year. Significantly higher performance metrics were observed in studies examining differential diagnosis; 16 such studies as well as 13 exploring prognostic prediction were included in a separate meta-analysis, which revealed diagnostic odds ratios of 25.76 (95% confidence interval (CI) 13.50-49.13) and 12.55 (95% CI 8.38-18.77), respectively. CONCLUSION: Current evidence suggests that the methodological quality of OC-related radiomics studies is unsatisfactory. Radiomics analysis based on CT and MRI showed promising results in terms of differential diagnosis and prognostic prediction. CRITICAL RELEVANCE STATEMENT: Radiomics analysis has potential clinical utility; however, shortcomings persist in existing studies in terms of reproducibility. We suggest that future radiomics studies should be more standardized to better bridge the gap between concepts and clinical applications.

Chondroitin sulfate functionalized palmitic acid and cysteine cografted-quaternized chitosan for CD44 and gut microbiota dual-targeted delivery of curcumin.

Curcumin (CUR) has a regulatory effect on the gut microbiota (GM), and its significant anti-inflammatory properties make it a research hotspot for inflammatory bowel disease (IBD) treatment. However, the low bioavailability and poor pharmacokinetic properties of CUR limit its practical application. Herein, CD44 and GM dual-targeted nanoparticles (NPs) loaded with CUR (CUR@Chs-PNC NPs) were derived from a quaternized chitosan and surface functionalization with chondroitin sulfate (Chs). The generated CUR@Chs-PNC NPs had an ideal average particle size (238.9 â€‹nm), a uniform size distribution, and a positive surface charge (+41.93 â€‹mV). Strikingly, the CUR@Chs-PNC NPs had a good sustained-release effect in a simulated gastrointestinal environment and exhibited the full drug release when in a simulated colon environment. Moreover, Chs functionalization endowed the NPs with a notable CD44-targeted drug delivery ability and thereby enhanced the CUR content in the plasma of SD rats. The biodistribution of the CUR@Chs-PNC NPs in vivo indicated that the NPs could prolong the intestinal residence time, thereby promoting the interaction between CUR and GM. Most importantly, in a DSS-induced colitis mouse model, the CUR@Chs-PNC NPs decreased the disease activity index, improved the oxidative stress and inflammation condition, promoted the production of short-chain fatty acids (SCFAs), regulated immune cells, and maintained intestinal microbiome homeostasis. This study demonstrates that CUR@Chs-PNC NPs, which exhibit excellent biocompatibility and biodegradability, on-demand drug release property, and CD44 and GM dual-targeted capacities, have the potential for further application in the treatment of colitis.

Involvement of Rictor/mTORC2/Akt/GLUT4 pathway in the regulation of energy metabolism in the gastric smooth muscle of diabetic rats.

Diabetes mellitus can be accompanied by a variety of complications. The purpose of the present study was to characterize the Rictor/mTOR complex 2 (mTORC2)/Akt/glucose transporter 4 (GLUT4) pathway and its effects on energy metabolism in the gastric smooth muscle of diabetic rats. Diabetes was induced in rats using streptozotocin and their phenotype was compared with untreated rats. The relationship between gastric motility and energy metabolism was analyzed by comparing the contraction and ATP metabolism of muscle strips. Western blotting was used to detect the expression of key proteins in the pathway. The diabetic rats demonstrated less frequent and less powerful gastric smooth muscle contractions. The concentrations of ADP, AMP, and ATP, and the energy charge in gastric smooth muscle changed in different periods of diabetes, and these changes were consistent with changes in mechanistic target of rapamycin (mTOR) protein content. The expression of the key intermediates in signal transduction in the Rictor/mTORC2/Akt/GLUT4 pathway also underwent significant changes. Rictor protein expression increased during the development of diabetes, but the activation of mTORC2 did not increase with the increase in Rictor expression. GLUT4 translocation is regulated by Akt and its expression change during the development of diabetes. These findings suggest that altered energy metabolism is present in gastric smooth muscle that is associated with changes in the Rictor/mTORC2/Akt/GLUT4 pathway. Rictor/mTORC2/Akt/GLUT4 pathway may be involved in the regulation of energy metabolism in the gastric smooth muscle of diabetic rats and the development of diabetic gastroparesis.

Seeing beyond the tumor: computed tomography image-based radiomic analysis helps identify ovarian clear cell carcinoma subtype in epithelial ovarian cancer.

OBJECTIVE: To develop and validate a model that can preoperatively identify the ovarian clear cell carcinoma (OCCC) subtype in epithelial ovarian cancer (EOC) using CT imaging radiomics and clinical data. MATERIAL AND METHODS: We retrospectively analyzed data from 282 patients with EOC (training set = 225, testing set = 57) who underwent pre-surgery CT examinations. Patients were categorized into OCCC or other EOC subtypes based on postoperative pathology. Seven clinical characteristics (age, cancer antigen [CA]-125, CA-199, endometriosis, venous thromboembolism, hypercalcemia, stage) were collected. Primary tumors were manually delineated on portal venous-phase images, and 1218 radiomic features were extracted. The F-test-based feature selection method and logistic regression algorithm were used to build the radiomic signature, clinical model, and integrated model. To explore the effects of integrated model-assisted diagnosis, five radiologists independently interpreted images in the testing set and reevaluated cases two weeks later with knowledge of the integrated model's output. The diagnostic performances of the predictive models, radiologists, and radiologists aided by the integrated model were evaluated. RESULTS: The integrated model containing the radiomic signature (constructed by four wavelet radiomic features) and three clinical characteristics (CA-125, endometriosis, and hypercalcinemia), showed better diagnostic performance (AUC = 0.863 [0.762-0.964]) than the clinical model (AUC = 0.792 [0.630-0.953], p = 0.295) and the radiomic signature alone (AUC = 0.781 [0.636-0.926], p = 0.185). The diagnostic sensitivities of the radiologists were significantly improved when using the integrated model (p = 0.023-0.041), while the specificities and accuracies were maintained (p = 0.074-1.000). CONCLUSION: Our integrated model shows great potential to facilitate the early identification of the OCCC subtype in EOC, which may enhance subtype-specific therapy and clinical management.

Palmitic acid- and cysteine-functionalized nanoparticles overcome mucus and epithelial barrier for oral delivery of drug.

Nanoparticles (NPs) used for oral administration have greatly improved drug bioavailability and therapeutic efficacy. Nevertheless, NPs are limited by biological barriers, such as gastrointestinal degradation, mucus barrier, and epithelial barrier. To solve these problems, we developed the PA-N-2-HACC-Cys NPs loaded with anti-inflammatory hydrophobic drug curcumin (CUR) (CUR@PA-N-2-HACC-Cys NPs) by self-assembled amphiphilic polymer, composed of the N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC), hydrophobic palmitic acid (PA), and cysteine (Cys). After oral administration, the CUR@PA-N-2-HACC-Cys NPs had good stability and sustained release under gastrointestinal conditions, followed by adhering to the intestine to achieve drug mucosal delivery. Additionally, the NPs could penetrate mucus and epithelial barriers to promote cellular uptake. The CUR@PA-N-2-HACC-Cys NPs could open tight junctions between cells for transepithelial transport while striking a balance between mucus interaction and diffusion through mucus. Notably, the CUR@PA-N-2-HACC-Cys NPs improved the oral bioavailability of CUR, which remarkably relieved colitis symptoms and promoted mucosal epithelial repair. Our findings proved that the CUR@PA-N-2-HACC-Cys NPs had excellent biocompatibility, could overcome mucus and epithelial barriers, and had significant application prospects for oral delivery of the hydrophobic drugs.

Adjuvanted quaternized chitosan composite aluminum nanoparticles-based vaccine formulation promotes immune responses in chickens.

Aluminum adjuvant is a typical adjuvant that can promote humoral immune response, but it lacks the ability to effectively induce cellular immune response. The water-soluble N-2-Hydroxypropyl trimethyl ammonium chloride chitosan nanoparticles (N-2-HACC NPs) can enhance humoral and cellular immune responses of vaccines. To enable aluminum adjuvant to induce cellular immunity, the composite nano adjuvant N-2-HACC-Al NPs were synthesized by the N-2-HACC and aluminum sulfate (Al2(SO4)3). The particle size and zeta potential of the N-2-HACC-Al NPs were 300.70 ± 24.90 nm and 32.28 ± 0.52 mV, respectively. The N-2-HACC-Al NPs have good thermal stability and biodegradability and lower cytotoxicity. In addition, to investigate the immunogenicity of the composite nano adjuvant, the combined inactivated vaccine against Newcastle disease (ND) and H9N2 avian influenza (AI) was prepared with the N-2-HACC-Al NPs as a vaccine adjuvant. The immune effect of the vaccine (N-2-HACC-Al/NDV-AIV) was evaluated by chicken in vivo immunization. The vaccine induced higher levels of serum IgG, IL-4, and IFN-γ than those of the commercial combined inactivated vaccine against ND and H9N2 AI. The levels of IFN-γ were more than twice those of the commercial vaccine at 7 days post the immunization. The N-2-HACC-Al NPs could be used as an efficient nano adjuvant to enhance the effectiveness of vaccine and have immense application potential.