Tumor budding in pre-neoadjuvant biopsy and post-neoadjuvant resection specimens is associated with poor prognosis in intrahepatic cholangiocarcinoma-a cohort study of 147 cases by modified ITBCC criteria.

Tumor budding (TB) has been associated with poor survival in a variety of cancers including intrahepatic cholangiocarcinoma (iCCA). As tumor histomorphological features are significantly altered after neoadjuvant therapy (NAT), our study aims to assess the prognostic significance of TB in iCCA patients before and after NAT, by the modified International Tumor Budding Consensus Conference (ITBCC) criteria. 147 NAT-treated iCCA cases were included in this study. In biopsy specimens obtained before NAT, the TB-positive subgroup had lower overall survival (OS) in univariate analysis (P = 0.010). In resection specimens obtained after NAT, the TB-positive subgroup had reduced OS (P = 0.002) and recurrence-free survival (RFS) (P = 0.013) in univariate analysis. In multivariate analysis including TNM stage, lymphovascular invasion and perineural invasion, TB-positive in post-NAT resection was also found as an independent prognostic factor for both OS and RFS (OS, HR, 3.005; 95% CI, 1.333-6.775, P = 0.008; RFS, HR, 1.748; 95% CI, 1.085-2.816, P = 0.022). In conclusion, assessing the presence of TB by modified ITBCC criteria provides robust prognostic information in the NAT setting of iCCA patients and can be considered to be included in routine pathological reporting.

Clinical characteristics and outcomes of neonatal SARS-CoV-2 infection after the release of the epidemic situation of COVID-19.

BACKGROUND: With the release of the coronavirus disease 2019 (COVID-19) pandemic in late 2022 in China, the number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) roared, including neonatal cases. However, there were few studies on neonatal COVID-19, especially multi-center case reports. This study aimed to explore clinical characteristics and short-term outcomes of neonatal COVID-19 in China. METHODS: We reviewed 187 cases of neonatal COVID-19 between December 11, 2022, and January 12, 2023. The diagnosis was assessed by symptoms, laboratory tests, X-ray manifestations, and diagnosis code. Clinical characteristics and outcomes were evaluated. RESULTS: In 187 neonatal cases with COVID-19, 84 (44.9%) had severe SARS-CoV-2 infection. Most patients had confirmed exposure to SARS-CoV-2. Fever and respiratory symptoms were common (75.4% and 71.7%, respectively). Severe patients were more likely to have high alanine transaminase (ALT) (> 40U/L) (11.9% vs. 3.9%) and high N-terminal pro-brain natriuretic peptide (NT-proBNP) (> 2000pg/mL) (38.0% vs. 19.6%), compared with nonsevere ones (P < 0.05). None of the patients received COVID-19-specific medical interventions. A few severe patients received corticosteroids (1.1%), and immunoglobulin (0.5%), respectively. All patients were discharged home after the medical care with a median length of stay (LOS) of four days and none of them met the criteria of multisystem inflammatory syndrome in neonates (MIS-N). CONCLUSIONS: After the release of the epidemic situation of COVID-19 in late 2022 in China, more neonatal cases with severe COVID-19 had high ALT and NT-proBNP level. Few specific medical interventions were given, and the outcome was satisfying.

Clinical outcomes of the neonates with critical pulmonary stenosis: intrauterine versus postnatal transport.

Background: Pulmonary stenosis (PS) is one rare congenital heart disease (CHD) featuring obstruction of right ventricular outflow tract. Critical pulmonary stenosis (CPS) is neonatal PS having cyanosis and evidence of patent ductus arteriosus (PDA) dependency. There is limited data on the clinical outcomes of CPS with different modes of transportation. This study aimed to investigate clinical features and outcomes of CPS through the intrauterine transport (IT) and postnatal transport (PT). Methods: Single-center retrospective research was performed. Neonates with CPS were grouped into the IT group and PT group. Clinical characteristics and outcomes of the neonates were compared between the two groups. Results: Totally 110 neonates with PS were included in this study, 77 with CPS and 33 with non-CPS. In the infants with CPS, there were 53 and 24 in the IT and PT group respectively. Echocardiography showed that transvalvular pulmonary gradient (TVG) stayed lower in the IT group than that in the PT group {77.0 [interquartile range (IQR), 60.5-91.5] vs. 92.0 (IQR, 73.3-125.0) mmHg, P=0.006}. Levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin I also remained lower in the IT group than those in the PT group [2,256 (IQR, 1,054-4,527) vs. 3,708 (IQR, 2,138-6,789) pg/mL, P=0.02; 0.020 (IQR, 0.011-0.034) vs. 0.042 (IQR, 0.027-0.072) ng/mL, P<0.001, respectively]. All infants with CPS received percutaneous balloon pulmonary valvuloplasty (PBPV) therapy in neonatal period and were discharged from the hospital. Length of hospital stay remained shorter in the IT group than that in the PT group [13.0 (IQR, 11.0-15.0) vs. 15.5 (IQR, 10.8-22.8) days, P=0.03]. Conclusions: IT and early management after birth could effectively reduce the severity of CPS before PBPV treatment and shorten the length of hospital stay among neonates suffering from CPS.

SVIL promotes ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions through the TGF-ß/Smad pathway.

OBJECTIVE: Ovarian cancer is the malignant tumor with the highest mortality rate in gynecology. We aimed to identify novel genes that promote ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions. METHODS: We screened SVIL as a hypoxia-associated target in ovarian cancer and explored the related molecular mechanisms. We assessed the effects of SVIL on ovarian cancer progression and metastasis in clinical samples and cellular hypoxia models. Further, we investigated the relevant pathways of SVIL and confirmed the effects of SVIL on ovarian cancer progression by using nude mouse in situ tumor models. RESULTS: We found that SVIL was significantly highly expressed in the hypoxic environment of ovarian cancer, and SVIL expression correlated with patient prognosis.CCK8, Wound-healing assay, Transwell assay, Western Blot, and apoptosis assays revealed that knockdown of SVIL inhibited the activation of the TGFß1/smad2/3 pathway, which attenuated the progression and epithelial-mesenchymal transition(EMT) of ovarian cancer and alleviated cisplatin resistance by increasing cisplatin-induced apoptosis. Furthermore, in a nude mouse ovarian cancer in situ model, we found that the knockdown of SVIL significantly inhibited tumor growth and metastasis. CONCLUSION: SVIL highly expressed in the hypoxic microenvironment can increase ovarian cancer progression and cisplatin resistance by activating TGFß1/smad2/3 pathway. Our study demonstrated that SVIL may be a novel target for the treatment of ovarian cancer.

Lactate enhances NMNAT1 lactylation to sustain nuclear NAD+ salvage pathway and promote survival of pancreatic adenocarcinoma cells under glucose-deprived conditions.

The aim of this study was to investigate the underlying molecular mechanism behind the promotion of cell survival under conditions of glucose deprivation by l-lactate. To accomplish this, we performed tissue microarray and immunohistochemistry staining to analyze the correlation between the abundance of pan-Lysine lactylation and prognosis. In vivo evaluations of tumor growth were conducted using the KPC and nude mice xenograft tumor model. For mechanistic studies, multi-omics analysis, RNA interference, and site-directed mutagenesis techniques were utilized. Our findings robustly confirmed that l-lactate promotes cell survival under glucose deprivation conditions, primarily by relying on GLS1-mediated glutaminolysis to support mitochondrial respiration. Mechanistically, we discovered that l-lactate enhances the NMNAT1-mediated NAD+ salvage pathway while concurrently inactivating p-38 MAPK signaling and suppressing DDIT3 transcription. Notably, Pan-Kla abundance was significantly upregulated in patients with Pancreatic adenocarcinoma (PAAD) and associated with poor prognosis. We identified the 128th Lysine residue of NMNAT1 as a critical site for lactylation and revealed EP300 as a key lactyltransferase responsible for catalyzing lactylation. Importantly, we elucidated that lactylation of NMNAT1 enhances its nuclear localization and maintains enzymatic activity, thereby supporting the nuclear NAD+ salvage pathway and facilitating cancer growth. Finally, we demonstrated that the NMNAT1-dependent NAD+ salvage pathway promotes cell survival under glucose deprivation conditions and is reliant on the activity of Sirt1. Collectively, our study has unraveled a novel molecular mechanism by which l-lactate promotes cell survival under glucose deprivation conditions, presenting a promising strategy for targeting lactate and NAD+ metabolism in the treatment of PAAD.

Itaconic acid regulation of TFEB-mediated autophagy flux alleviates hyperoxia-induced bronchopulmonary dysplasia.

BACKGROUND: Premature infants often require oxygen supplementation, which can elicit bronchopulmonary dysplasia (BPD) and lead to mitochondrial dysfunction. Mitochondria play important roles in lung development, in both normal metabolism and apoptosis. Enhancing our comprehension of the underlying mechanisms in BPD development can facilitate the effective treatments. METHODS: Plasma samples from BPD and non-BPD infants were collected at 36 weeks post-menstrual age and used for metabolomic analysis. Based on hyperoxia-induced animal and cell models, changes in mitophagy and apoptosis were evaluated following treatment with itaconic acid (ITA). Finally, the mechanism of action of ITA in lung development was comprehensively demonstrated through rescue strategies and administration of corresponding inhibitors. RESULTS: An imbalance in the tricarboxylic acid (TCA) cycle significantly affected lung development, with ITA serving as a significant metabolic marker for the outcomes of lung development. ITA improved the morphological changes in BPD rats, promoted SP-C expression, and inhibited the degree of alveolar type II epithelial cells (AEC II) apoptosis. Mechanistically, ITA mainly promotes the nuclear translocation of transcription factor EB (TFEB) to facilitate dysfunctional mitochondrial clearance and reduces apoptosis in AEC II cells by regulating autophagic flux. CONCLUSION: The metabolic imbalance in the TCA cycle is closely related to lung development. ITA can improve lung development by regulating autophagic flux and promote the nuclear translocation of TFEB, implying its potential therapeutic utility in the treatment of BPD.

Early metabolic markers as predictors of respiratory complications in preterm infants with bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD), a common complication of premature birth, exerts considerable impact on the respiratory health of infants. This study aimed to identify the role of plasma metabolites in predicting respiratory outcomes in BPD-afflicted infants. METHODS: This was a case-control study including 15 BPD premature infants and 15 gestational age and birth weight matched no-BPD preterm infants. Plasma samples, obtained at 36 weeks postmenstrual age (PMA), were subjected to a comprehensive analysis of over 300 metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The respiratory outcomes of the infants were collected with the first 2 years of corrected postnatal age. RESULTS: The analysis revealed a significant upregulation of urea and downregulation of nine metabolites in BPD infants, including oxalacetic acid, cis-aconitic acid, itaconic acid, betaine, L-asparagine, L-alanine, picolinic acid, inositol, and purine (p < 0.05). These metabolites primarily pertained to the citrate cycle (TCA cycle), glyoxylate and dicarboxylate metabolism, and alanine, aspartate, and glutamate metabolism. Furthermore, seven metabolites demonstrated substantial predictive capacity for respiratory readmissions within the first two years of corrected postnatal age, achieving an area under curve (AUC) exceeding or equal to 0.8. These included chenodeoxycholic acid, dehydrolithocholic acid, glucaric acid, D-glucuronic acid, gamma-glutamylvaline, mevalonic acid, and 3-ureidopropionic acid. CONCLUSIONS: This study identified ten distinct plasma metabolites at 36 weeks PMA that differentiate BPD infants from their non-BPD counterparts, implicating three major metabolic pathways. Additionally, seven metabolites showed strong predictive value for heightened risk of respiratory readmission within two years, underscoring their potential utility in clinical prognostication and management strategies for BPD.

Single-cell landscape identifies the immunophenotypes and microenvironments of HBV-positive and HBV-negative liver cancer.

BACKGROUND: HBV infection leads to HCC and affects immunotherapy. We are exploring the tumor ecosystem in HCC to help gain a deeper understanding and design more effective immunotherapy strategies for patients with HCC with or without HBV infection. METHODS: Single-cell RNA sequencing series were integrated as a discovery cohort to interrogate the tumor microenvironment of HBV-positive (HBV+) HCC and HBV-negative (HBV-) HCC. We further dissect the intratumoral immune status of HBV+ HCC and HBV- HCC. An independent cohort, including samples treated with immune checkpoint blockade therapy, was used to validate the major finding and investigate the effect of HBV infection on response to immunotherapy. RESULTS: The interrogation of tumor microenvironment indicated that regulatory T cells, exhausted CD8+ T cells, and M1-like Macrophage_MMP9 were enriched in HBV+ HCC, while mucosa-associated invariant T cells were enriched in HBV- HCC. All subclusters of T cells showed high expression of immune checkpoint genes in HBV+ HCC. Regulatory T cells enriched in HBV+ HCC also showed more robust immunosuppressive properties, which was confirmed by cross talk between immune cell subsets. The ability of antigen presentation with major histocompatibility complex-II was downregulated in HBV+ HCC and this phenomenon can be reversed by immunotherapy. Two types of HCC also present different responses to immunotherapy. CONCLUSIONS: There is a more immunosuppressive and exhausted tumor microenvironment in HBV+ HCC than in HBV- HCC. This in-depth immunophenotyping strategy is critical to understanding the impact of HBV and the HCC immune microenvironment and helping develop more effective treatments in patients with HCC.

PLOD3 facilitated T cell activation in the colorectal tumor microenvironment and liver metastasis by the TNF-α/ NF-κB pathway.

BACKGROUND: Colorectal cancer (CRC) has been the third most prevalent cancer worldwide. Liver metastasis is the critical factor for the poor prognosis of CRC. Here, we investigated the expression and role of PLOD3 in CRC. METHODS: Different liver metastasis models were established by injecting PLOD3 stable knockdown or overexpression CT26 or MC38 mouse CRC cells into the spleen of mice to verify the tumorigenicity and metastasis ability in vivo. RESULTS: We identified PLOD3 is significantly overexpressed in liver metastasis samples of CRC. High expression of PLOD3 was significantly associated with poor survival of CRC patients. The knockdown of PLOD3 exhibited remarkable inhibition of proliferation, migration, and invasion in CRC cells, while the opposite results could be found in different PLOD3-overexpressed CRC cells. Stable knockdown of PLOD3 also significantly inhibited liver metastasis of CRC cells in different xenografts models, while stable overexpression of PLOD3 promotes liver metastasis and tumor progression. Further studies showed that PLOD3 facilitated the T cell activation in the tumor microenvironment and affected the TNF-α/ NF-κB pathway. CONCLUSIONS: This study revealed the essential biological functions of PLOD3 in colon cancer progression and metastasis, suggesting that PLOD3 is a promising translational medicine target and bioengineering targeting PLOD3 overcomes CRC liver metastasis.

SECTM1 promotes the development of glioblastoma and mesenchymal transition by regulating the TGFß1/Smad signaling pathway.

Objective: Secreted and transmembrane protein 1 (SECTM1) is a gene encoding a transmembrane protein. The role of SECTM1 in glioblastoma (GBM) is unclear. Here, we reported the abnormal expression of SECTM1 in GBM for the first time and studied the role and mechanism of SECTM1 in GBM. Methods: qRT-PCR, Western blotting and immunofluorescence were used to detect the expression of SECTM1 in gliomas of different grades and GBM cell lines. After the knockdown of SECTM1 expression in cell lines by shRNA, the effect of SECTM1 in GBM cell lines was verified by CCK-8, Transwell, EdU and wound healing experiments. We further investigated the effect and mechanism of SECTM1 on GBM in vitro and in vivo. The effect of SECTM1 on glioma growth was detected by subcutaneous tumor xenografts in nude mice in vivo. Results: The results showed that the knockdown of SECTM1 expression in cell lines significantly inhibited the proliferation, migration and invasion of GBM cells while inhibiting the progression of subcutaneous xenograft tumors in nude mice. However, the role and molecular mechanism of SECTM1 in GBM remain unclear. SECTM1 was found to promote GBM epithelial-mesenchymal transition (EMT) like processes. Bioinformatics analysis and Western blotting showed that SECTM1 regulates glioblastoma invasion and EMT-like processes mainly through the TGFß1/Smad signaling pathway. Conclusion: The low expression of SECTM1 has an inhibitory effect on GBM and is a potential target for GBM treatment. SECTM1 may also be a promising biomarker for the diagnosis and prognosis of GBM.

An in vitro-transcribed circular RNA targets the mitochondrial inner membrane cardiolipin to ablate EIF4G2+/PTBP1+ pan-adenocarcinoma.

In vitro-transcribed (IVT) mRNA has arisen as a rapid method for the production of nucleic acid drugs. Here, we have constructed an oncolytic IVT mRNA that utilizes human rhinovirus type 2 (HRV2) internal ribosomal entry sites (IRESs) to selectively trigger translation in cancer cells with high expression of EIF4G2 and PTBP1. The oncolytic effect was provided by a long hGSDMDc .825 T>A/c.884 A>G-F1LCT mutant mRNA sequence with mitochondrial inner membrane cardiolipin targeting toxicity that triggers mitophagy. Utilizing the permuted intron-exon (PIE) splicing circularization strategy and lipid nanoparticle (LNP) encapsulation reduced immunogenicity of the mRNA and enabled delivery to eukaryotic cells in vivo. Engineered HRV2 IRESs-GSDMDp.D275E/E295G-F1LCT circRNA-LNPs (GSDMDENG circRNA) successfully inhibited EIF4G2+/PTBP1+ pan-adenocarcinoma xenografts growth. Importantly, in a spontaneous tumor model with abnormal EIF4G2 and PTBP1 caused by KRAS G12D mutation, GSDMDENG circRNA significantly prevented the occurrence of pancreatic, lung and colon adenocarcinoma, improved the survival rate and induced persistent KRAS G12D tumor antigen-specific cytotoxic T lymphocyte responses.

Hollow Cu2MoS4 nanoparticles loaded with immune checkpoint inhibitors reshape the tumor microenvironment to enhance immunotherapy for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease that responds poorly to single-drug immunotherapy with PD-L1 (CD274) inhibitors. Here, we prepared mesoporous nanomaterials Cu2MoS4 (CMS)/PEG loaded with PD-L1 inhibitor BMS-1 and CXCR4 inhibitor Plerixafor to form the nanodrug CMS/PEG-B-P. In vitro experiments, CMS/PEG-B-P have a more substantial inhibitory effect on the expression of PD-L1 and CXCR4 as well as to promote the apoptosis of pancreatic cancer cells KPC and suppressed KPC cell proliferation were detected by flow cytometry, qPCR and Western blotting (WB). Promotes the release of the cytotoxic substance reactive oxygen species (ROS) and the production of the immunogenic cell death (ICD) marker calreticulin (CRT) in KPC cells. CMS/PEG-B-P was also detected to have a certain activating effect on mouse immune cells, dendritic cells (mDC) and macrophage RAW264.7. Subcutaneous tumorigenicity experiments in C57BL/6 mice verified that CMS/PEG-B-P had an inhibitory effect on the growth of tumors and remodeling of the tumor immune microenvironment, including infiltration of CD4+ and CD8+ T cells and polarization of macrophages, as well as reduction of immunosuppressive cells. Meanwhile, CMS/PEG-B-P was found to have different effects on the release of cytokines in the tumor immune microenvironment, including The levels of immunostimulatory cytokines INF-γ and IL-12 are increased and the levels of immunosuppressive cytokines IL-6, IL-10 and IFN-α are decreased. In conclusion, nanomaterial-loaded immune checkpoint inhibitor therapies can enhance the immune response and reduce side effects, a combination that shows great potential as a new immunotherapeutic approach. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease that has a low response to single-drug immunotherapy with PD-L1 (CD274) inhibitors. We preared PEG-modified mesoporous nanomaterials Cu2MoS4 (CMS) loaded with PD-L1 inhibitor BMS-1 and CXCR4 inhibitor Plerixafor to form the nanodrug CMS/PEG-B-P. Our study demonstrated that Nanomaterial-loaded immune checkpoint inhibitor therapies can enhance the immune response and reduce side effects, a combination that shows great potential as a new immunotherapeutic approach.

Identification and validation of a novel necroptosis-related molecular signature to evaluate prognosis and immune features in breast cancer.

Necroptosis has been shown to play an important role in the development of tumors. However, the characteristics of the necroptosis-related subtypes and the associated immune cell infiltration in the tumor microenvironment (TME) of breast cancer (BRCA) remain unclear. In this study, we identified three clusters related to necroptosis using the expression patterns of necroptosis-relevant genes (NRGs), and found that these three clusters had different clinicopathological features, prognosis and immune cell infiltration in the TME. Cluster 2 was characterized by less infiltration of immune cells in the TME and was associated with a worse prognosis. Then, a necroptosis risk score (NRS) composed of 14 NRGs was constructed using the least absolute shrinkage and selection operator regression (LASSO) Cox regression method. Based on NRS, all BRCA patients in the TCGA datasets were classified into a low-risk group and a high-risk group. Patients in the low-risk group were characterized by longer overall survival (OS), lower mutation burden, and higher infiltration level of immune cells in the TME. Moreover, the NRS was significantly associated with chemotherapeutic drug sensitivity. Finally, the knockdown of VDAC1 reduced the proliferation and migration of BRCA cells, and promoted cell death induced by necroptosis inducer. This study identified a novel necroptosis-related subtype of BRCA, and a comprehensive analysis of NRGs in BRCA revealed its potential roles in prognosis, clinicopathological features, TME, chemotherapy, tumor proliferation, and tumor necroptosis. These results may improve our understanding of NRGs in BRCA and provide a reference for developing individualized therapeutic strategies.

RHOJ Induces Epithelial-to-Mesenchymal Transition by IL-6/STAT3 to Promote Invasion and Metastasis in Gastric Cancer.

Background: Recently, the molecular classification of gastric cancer (GC) promotes the advances of GC patients' precision therapy and prognosis prediction. According to the Asian Cancer Research Group (ACRG), GC is classified as microsatellite instable (MSI) subtype GC, microsatellite stable/epithelial-to-mesenchymal transition (MSS/EMT) subtype GC, MSS/TP53- subtype GC, and MSS/TP53+ subtype GC. Due to the easy metastasis of EMT-subtype GC, it has the worst prognosis, the highest recurrence rate, and the tendency to occur at a younger age. Therefore, it is curious and crucial for us to understand the molecular basis of EMT-subtype GC. Methods: The expression of RHOJ was detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) in GC cells and tissues. Western blotting and immunofluorescence (IF) were conducted to examine the effects of RHOJ on the EMT markers' expression of GC cells. The GC cells' migration and invasion were investigated by transwell assay. The tumor growth and metastasis were demonstrated correspondingly in different xenograft models. Results: Firstly, it was noticed that RHOJ was significantly upregulated in EMT-subtype GC and RHOJ has close relationships with the EMT process of GC, based on the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. Next, transwell assay and tail vein metastasis models were conducted to verify that RHOJ mediates the EMT to regulate the invasion and metastasis of GC in vitro and in vivo. In addition, weakened tumor angiogenesis was observed after RHOJ knockdown by the angiogenesis assay of HUVEC. RNA-seq and further study unveiled that RHOJ aggravates the malignant progression of GC by inducing EMT through IL-6/STAT3 to promote invasion and metastasis. Finally, blocking the IL-6/STAT3 signaling overcame RHOJ-mediated GC cells' growth and migration. Conclusions: These results indicate that the upregulation of RHOJ contributes to EMT-subtype GC invasion and metastasis via IL-6/STAT3 signaling, and RHOJ is expected to become a promising biomarker and therapeutic target for EMT-subtype GC patients.

STING-IRG1 inhibits liver metastasis of colorectal cancer by regulating the polarization of tumor-associated macrophages.

The liver is the main site of colorectal cancer (CRC) metastasis. Tumor-associated macrophages (TAMs) play a key role in tumor metastasis. Therefore, modulating the function of tumor-associated macrophages is a potential therapeutic strategy to control tumor metastasis. We found in vivo experiments that the activation of STING inhibited CRC liver metastasis in model mice and affected the macrophage phenotype in the tumor microenvironment. Mechanistically, STING affects TAM polarization and regulates macrophage function through IRG1. And STING activates IRG1 to promote the nuclear translocation of TFEB, affecting the ability of macrophages to suppress tumor metastasis.Therefore, this study highlights the critical role of the STING-IRG1 axis on TAM reprogramming and its role in the process of tumor liver metastasis, which may provide a promising therapeutic strategy for CRC liver metastasis.

Novel risk model based on angiogenesis-related lncRNAs for prognosis prediction of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death due to early metastasis or recurrence. Tumor angiogenesis plays an essential role in the tumorigenesis of HCC. Accumulated studies have validated the crucial role of lncRNAs in tumor angiogenesis. Here, we established an angiogenesis-related multi-lncRNAs risk model based on the machine learning for HCC prognosis prediction. Firstly, a total of 348 differential expression angiogenesis-related lncRNAs were identified by correlation analysis. Then, 20 of these lncRNAs were selected through univariate cox analysis and used for in-depth study of machine learning. After 1,000 random sampling cycles calculating by random forest algorithm, four lncRNAs were found to be highly associated with HCC prognosis, namely LUCAT1, AC010761.1, AC006504.7 and MIR210HG. Subsequently, the results from both the training and validation sets revealed that the four lncRNAs-based risk model was suitable for predicting HCC recurrence. Moreover, the infiltration of macrophages and CD8 T cells were shown to be closely associated with risk score and promotion of immune escape. The reliability of this model was validated by exploring the biological functions of lncRNA MIR210HG in HCC cells. The results showed that MIR210HG silence inhibited HCC growth and migration through upregulating PFKFB4 and SPAG4. Taken together, this angiogenesis-related risk model could serve as a reliable and promising tool to predict the prognosis of HCC.

Prognosis and outcome of intrauterine treatment of fetuses with critical congenital heart disease.

BACKGROUND: Intrauterine valvuloplasty is an innovative therapy, which promotes ventricular growth and function in some congenital heart diseases (CHDs). The technique remains challenging and can only be performed in a few centers. This study aimed to assess the feasibility and mid-term outcomes of fetal cardiac intervention (FCI) in fetuses with critical CHD in an experienced tertiary center. METHODS: Five fetal aortic valvuloplasty (FAV) or fetal pulmonary valvuloplasty (FPV) procedures were performed in our fetal heart center between August 2018 and May 2022. Technical success was defined as crossing the aortic or pulmonary valve and balloon inflation, followed by evidence of increased blood flow across the valve and/or new regurgitation. Follow-up clinical records and echocardiography were obtained during the prenatal and postnatal periods. RESULTS: Five fetuses received FAV or FPV, including critical aortic stenosis (n = 2) and pulmonary atresia with intact ventricular septum (n = 3). The mean maternal age was 33.0 ± 2.6 years. The median gestational age (GA) at diagnosis was 24 weeks (range, 22-26 weeks). The median GA at intervention was 29 weeks (range, 28-32 weeks). All five cases underwent successful or partially successful procedures. One patient had pulmonary valve perforation without balloon dilation. No procedure-related deaths or significant complications occurred. However, one neonatal death occurred due to heart and renal failure. The median follow-up period was 29.5 months (range, 8.0-48.0 months). The four surviving patients had achieved biventricular circulation, exhibited improved valve, and ventricular development at the last follow-up visit. CONCLUSION: Intrauterine FCI could be performed safely with good prognosis in critical CHD.

Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages.

Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease. Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis. However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown. Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE+ ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE+ ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs). We constructed the conditional knockout mice STIMATE sftpc , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE+ ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs. We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE+ ADEs supplementation. Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE+ ADEs. The immune and metabolic status of TRAMs in the lungs of STIMATE sftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders. STIMATE+ ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca2+ responsiveness and long-term Ca2+ signal transduction, which maintains M2-like immunophenotype and metabolism selection. This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding. In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE+ ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.

Engineered Apoptosis-Bioinspired Nanoparticles Initiate Immune Cascade for Cancer Immunotherapy of Malignant Ascites.

Malignant ascites (MA) is a common symptom of peritoneal metastasis in liver cancer. Cancer immunotherapy can modulate immune cells to induce antitumor immune efficiency. Reprogramming tumor immune microenvironment (TIME) is a momentous strategy to overcome immunosuppression and achieve immune functional normalization. Inspired by the inherent apoptotic bodies and vesicles, we proposed and systematically studied engineered apoptosis-bioinspired nanoparticles (EBN) for cancer immunotherapy of MA. Using both in vitro and in vivo experimental validations, we elucidated that EBN could be efficiently engulfed by the tumor-associated macrophages (TAMs) and manipulate their polarization. Moreover, a boosted immune cascade response as a result of heightening cytotoxic T-lymphocytes (CTLs) activity was investigated. Based on these results, EBN was confirmed to have strong immune cascade activation capability. Remarkably, the injection of EBN further reduced ascites volume and reformed immune cell subtypes, compared to the injection of either PBS or free TMP195 alone. In short, this novel nanodrug delivery system (NDDS) represents a prospective immunotherapeutic approach for clinical therapeutics of hepatoma ascites and other malignant effusion.