MOCAT: multi-omics integration with auxiliary classifiers enhanced autoencoder.

BACKGROUND: Integrating multi-omics data is emerging as a critical approach in enhancing our understanding of complex diseases. Innovative computational methods capable of managing high-dimensional and heterogeneous datasets are required to unlock the full potential of such rich and diverse data. METHODS: We propose a Multi-Omics integration framework with auxiliary Classifiers-enhanced AuToencoders (MOCAT) to utilize intra- and inter-omics information comprehensively. Additionally, attention mechanisms with confidence learning are incorporated for enhanced feature representation and trustworthy prediction. RESULTS: Extensive experiments were conducted on four benchmark datasets to evaluate the effectiveness of our proposed model, including BRCA, ROSMAP, LGG, and KIPAN. Our model significantly improved most evaluation measurements and consistently surpassed the state-of-the-art methods. Ablation studies showed that the auxiliary classifiers significantly boosted classification accuracy in the ROSMAP and LGG datasets. Moreover, the attention mechanisms and confidence evaluation block contributed to improvements in the predictive accuracy and generalizability of our model. CONCLUSIONS: The proposed framework exhibits superior performance in disease classification and biomarker discovery, establishing itself as a robust and versatile tool for analyzing multi-layer biological data. This study highlights the significance of elaborated designed deep learning methodologies in dissecting complex disease phenotypes and improving the accuracy of disease predictions.

Integration of scRNA and bulk RNA-sequence to construct the 5-gene molecular prognostic model based on the heterogeneity of thyroid carcinoma endothelial cell.

Thyroid cancer (TC) is a kind of cancer with high heterogeneity, which leads to significant difference in prognosis. The prognostic molecular processes are not well understood. Cancer cells and tumor microenvironment (TME) cells jointly determine the heterogeneity. However, quite a little attention was paid to cells in the TME in the past years. In this study, we not only reveal that endothelial cells (ECs) are strongly associated with the progress of papillary thyroid cancer (PTC) using single-cell RNA-seq (scRNA-seq) data downloaded from Gene Expression Omnibus (GEO) and WGCNA, but also screen 5 crucial genes of ECs: CLDN5, ABCG2, NOTCH4, PLAT, and TMEM47. Furthermore, the 5-gene molecular prognostic model is constructed, which can predict how well a patient will do on PD-L1 blockade immunotherapy for TC and evaluate prognosis. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrates that PLAT is decreased in TC and the increase of PLAT can restrain the migratory capacity of TC cells. Meanwhile, in TC cells, PLAT suppresses VEGFa/VEGFR2-mediated human umbilical vascular endothelial cell (HUVEC) proliferation and tube formation. Totally, we construct the 5-gene molecular prognostic model from the perspective of EC and provide a new idea for immunotherapy of TC.

Regulation of Hippo-YAP/CTGF signaling by combining an HDAC inhibitor and 5-fluorouracil in gastric cancer cells.

Histone deacetylase (HDAC) inhibitors diminish carcinogenesis, metastasis, and cancer cell proliferation by inducing death in cancer cells. Tissue regeneration and organ development are highly dependent on the Hippo signaling pathway. Targeting the dysregulated hippo pathway is an excellent approach for cancer treatment. According to the results of this study, the combination of panobinostat, a histone deacetylase inhibitor, and 5-fluorouracil (5-FU), a chemotherapy drug, can act synergistically to induce apoptosis in gastric cancer cells. The combination of panobinostat and 5-FU was more effective in inhibiting cell viability than either treatment alone by elevating the protein levels of cleaved PARP and cleaved caspase-9. By specifically targeting E-cadherin, vimentin, and MMP-9, the combination of panobinostat and 5-FU significantly inhibited cell migration. Additionally, panobinostat significantly increased the anticancer effects of 5-FU by activating Hippo signaling (Mst 1 and 2, Sav1, and Mob1) and inhibiting the Akt signaling pathway. As a consequence, there was a decrease in the amount of Yap protein. The combination therapy of panobinostat with 5-FU dramatically slowed the spread of gastric cancer in a xenograft animal model by deactivating the Akt pathway and supporting the Hippo pathway. Since combination treatment exhibits much higher anti-tumor potential than 5-FU alone, panobinostat effectively potentiates the anti-tumor efficacy of 5-FU. As a result, it is believed that panobinostat and 5-FU combination therapy will be useful as supplemental chemotherapy in the future.

Serum sCD25 is an indicator for rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: CD25 (IL-2Rα) is one of IL-2 receptor's polypeptide subunits, and its soluble form is increased in patients with various inflammatory or autoimmune diseases. This study aimed to evaluate the clinical correlation of serum soluble CD25 (sCD25) with interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. METHODS: 294 RA patients, including 72 in the discovery cohort (15 patients with ILD, 57 patients without ILD), 222 in the validation cohort (41 patients with ILD and 181 patients without ILD), and 58 healthy controls (HCs) were recruited. High-resolution computed tomography (HRCT) scan provided evidence and patterns of RA-ILD. Serum sCD25 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory data were recorded and the association with sCD25 was also analysed. RESULTS: In the discovery cohort, 16 RA-related molecules including cytokines, chemokines and functional soluble cell surface proteins were investigated. The results showed that sCD25 was significantly higher in RA-ILD than in RA-no-ILD group (p=0.004). ROC analysis also showed RA-ILD was discriminated with RA-no-ILD by sCD25 (AUC=0.695, 95% CI=0.541-0.849). Logistics regression demonstrated that sCD25 was one of the risk factors of RA-ILD. This result was further confirmed in validation cohort (p<0.001). According to the cut-off value in the discovery cohort, the sensitivity and specificity of sCD25 in RA-ILD were 51.2%, 77.3%, respectively. Compared with RA-no-ILD, serum level of sCD25 was also higher in different HRCT patterns including UIP, NSIP and RA-ILA. The ROC curves revealed sCD25 as diagnostic marker in UIP, NSIP and RA-ILA (with AUCs of 0.730, 0.761, and 0. 694, respectively, p<0.05). The result indicated that sCD25 was a biomarker for RA-ILD subtypes. Although sCD25 was not correlated with HRCT scores, it was significantly higher in consolidation pattern by HRCT. CONCLUSIONS: sCD25 was significantly elevated in RA-ILD (including UIP, NSIP and RA-ILA) compared to RA-no-ILD and HCs, which supports their value as a potential biomarker in RA-ILD screening and assessment.

[Bioinformatics analysis and identification to immune-related markers of osteoporosis].

Objective To identify immune-related dysregulation mechanisms and potential diagnostic predictive biomarkers in osteoporosis. Methods Gene expression data for both osteoporosis and control populations were retrieved from the GSE35958 and GSE56815 datasets. Immune-related differentially expressed genes (DEGs) were obtained by screening DEGs and were compared with the immunology database and analysis portal (ImmPort) database. Enrichment analysis of these immune-related DEGs was conducted using the Clusterprofiler software package. A protein-protein interaction network was built with the STRING database, which is a search tool for finding interacting genes/proteins, and the top 10 genes with the highest network connectivity were identified as candidate genes. Subsequently, the diagnostic predictive effect of candidate genes was evaluated using receiver operating characteristic (ROC) curves, logistic regression, and column plots. Finally, PCR and Western blot analysis were applied to detect the differential expression of these genes in bone marrow tissue of patients with osteoporosis. Results A total of 138 immune-related DEGs were obtained through intersection analysis. The results of the enrichment analysis indicated that these genes were involved in biological functions such as immune inflammation and signaling pathways including T cell receptors, mitogen activated protein kinase (MAPK), rat sarcoma virus oncogene homologs (Ras), osteoclast differentiation, and B cell receptors. In addition, among the candidate genes, upregulated vascular endothelial growth factor A (VEGFA) and epidermal growth factor receptor (EGFR) and downregulated AKT1, SRC, and JUN in osteoporosis showed the highest connectivity. Among them, VEGFA, EGFR, JUN, and AKT1 demonstrated the best diagnostic predictive value. Conclusion The screening of immune-related DEGs will enhance the understanding of osteoporosis and facilitate the development of immunotherapy targets.

A study on metabolic characteristics and metabolic markers of gastrointestinal tumors.

Tumor cells have significant heterogeneity in metabolism and are closely related to prognosis, gene mutation, and subtype. However, this association has not been demonstrated in reports of gastrointestinal tumors. In this study, we constructed four metabolic subtypes and identified four gene signatures using the expression data and clinical information of 252 metabolism-related genes from TCGA and NCBI databases for gastric adenocarcinoma (STAD) and colorectal cancer (COAD and READ). MC1 had the worst prognosis compared to other classifications. GSig1 was mainly related to drug metabolism and was the highest in MC1 with the worst prognosis, while the other subtypes were mainly related to glucose metabolism pathways. This difference also existed in other different malignant tumors. In addition, metabolic typing was associated with chemotherapeutic drug response and tumor heterogeneity, which indicated that monitoring metabolic typing could contribute to drug efficacy and gene-targeted therapy. In conclusion, we identified differences among subtypes in clinical characteristics such as prognosis and revealed the potential function of metabolic subtype in response to chemotherapeutic agents and oncogene mutations. This work highlighted the potential clinical meaning of metabolic subtype and characteristics in drug therapy and prognosis assessment of malignant tumors.

Construction of molecular typing in LIHC microenvironment based on lipid metabolism-related genes.

Consensus on the stage of liver hepatocellular carcinoma (LIHC) in patients is difficult, which restricts the diagnosis and treatment of liver cancer. Molecular typing based on genes related to the lipid metabolism pathways can reflect deeper characteristics of liver cancer and complement the deficiency of the clinical staging system. In this study, we constructed and verified two cell subtypes: C1 and C2 in LIHC, based on six lipid metabolic pathway-associated genes identified in two independent external validation cohorts comprising single-cell RNA-sequencing technology (scRNA-Seq) data and bulk RNA-seq data downloaded from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. The C2 subtype showed poorer prognosis, higher immune scores, and greater correlation with pathways associated with tumor progression as compared to the C1 subtype. Moreover, the sensitivity of many tested targeted drugs in C1 was relative to C2. Furthermore, Gene Set Enrichment Analysis (GSEA) revealed several significantly enriched oncological signatures and metabolic processes, which might help elucidate the underlying molecular mechanisms. At the same time, we identified there were significantly different metabolites in C1 and C2 subtypes using 11 LIHC tissue samples. In conclusion, we constructed two molecular subtypes based on the lipid metabolism-associated genes, which may provide valuable information to further study the pathogenesis and devise clinical management strategies for LIHC.

Inhibition of the interaction between Hippo/YAP and Akt signaling with ursolic acid and 3'3-diindolylmethane suppresses esophageal cancer tumorigenesis.

Hippo/YAP signaling hinders cancer progression. Inactivation of this pathway contributes to the development of esophageal cancer by activation of Akt. However, the possible interaction between Akt and Hippo/YAP pathways in esophageal cancer progression is unclear. In this study, we found that ursolic acid (UA) plus 3'3-diindolylmethane (DIM) efficiently suppressed the oncogenic Akt/Gsk-3ß signaling pathway while activating the Hippo tumor suppressor pathway in esophageal cancer cells. Moreover, the addition of the Akt inhibitor LY294002 and the PI3K inhibitor 3-methyladenine enhanced the inhibitory effects of UA plus DIM on Akt pathway activation and further stimulated the Hippo pathway, including the suppression of YAP nuclear translocation in esophageal cancer cells. Silencing YAP under UA plus DIM conditions significantly increased the activation of the tumor suppressor PTEN in esophageal cancer cells, while decreasing p-Akt activation, indicating that the Akt signaling pathway could be down-regulated in esophageal cancer cells by targeting PTEN. Furthermore, in a xenograft nude mice model, UA plus DIM treatment effectively diminished esophageal tumors by inactivating the Akt pathway and stimulating the Hippo signaling pathway. Thus, our study highlights a feedback loop between the PI3K/Akt and Hippo signaling pathways in esophageal cancer cells, implying that a low dose of UA plus DIM could serve as a promising chemotherapeutic combination strategy in the treatment of esophageal cancer.

Systematic and Comprehensive Analysis of tRNA-Derived Small RNAs Reveals Their Potential Regulatory Roles and Clinical Relevance in Sarcoidosis.

Introduction: The pathogenesis of sarcoidosis, which involves several systems, is unclear, and its pathological type is non-caseating epithelioid granulomas. tRNA-derived small RNA (tsRNA) is a novel class of short non-coding RNAs with potential regulatory functions. However, whether tsRNA contributes to sarcoidosis pathogenesis remains unclear. Methods: Deep sequencing technology was used to identify alterations in tsRNA relative abundance profiles between patients with sarcoidosis and healthy controls and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate. The clinical parameters were analysis to evaluate the clinical feature correlations initially. Target prediction and bioinformatics analysis of validated tsRNA were conducted to explore the mechanisms of tsRNAs in sarcoidosis pathogenesis. Results: A total of 360 tsRNAs were identified for exact matches. Among them, the relative abundance of three tRNAs (tiRNA-Glu-TTC-001, tiRNA-Lys-CTT-003, and tRF-Ser-TGA-007) was markedly regulated in sarcoidosis. The levels of various tsRNAs were significantly correlated with age, the number of affected systems, and calcium levels in the blood. Additionally, target prediction and bioinformatics analyses revealed that these tsRNAs may play roles in chemokine, cAMP, cGMP-PKG, retrograde endorphin, and FoxO signalling pathways. The related genes, APP, PRKACB, ARRB2, and NR5A1 finding may participate in the occurrence and development of sarcoidosis through immune inflammation. Conclusion: This study provides novel insights to explore tsRNA as a novel and efficacious pathogenic target of sarcoidosis.

Development of Prognostic Features of Hepatocellular Carcinoma Based on Metabolic Gene Classification and Immune and Oxidative Stress Characteristic Analysis.

Background: The molecular classification of HCC premised on metabolic genes might give assistance for diagnosis, therapy, prognosis prediction, immune infiltration, and oxidative stress in addition to supplementing the limitations of the clinical staging system. This would help to better represent the deeper features of HCC. Methods: TCGA datasets combined with GSE14520 and HCCDB18 datasets were used to determine the metabolic subtype (MC) using ConsensusClusterPlus. ssGSEA method was used to calculate the IFNγ score, the oxidative stress pathway scores, and the score distribution of 22 distinct immune cells, and their differential expressions were assessed with the use of CIBERSORT. To generate a subtype classification feature index, LDA was utilized. Screening of the metabolic gene coexpression modules was done with the help of WGCNA. Results: Three MCs (MC1, MC2, and MC3) were identified and showed different prognoses (MC2-poor and MC1-better). Although MC2 had a high immune microenvironment infiltration, T cell exhaustion markers were expressed at a high level in MC2 in contrast with MC1. Most oxidative stress-related pathways are inhibited in the MC2 subtype and activated in the MC1 subtype. The immunophenotyping of pan-cancer showed that the C1 and C2 subtypes with poor prognosis accounted for significantly higher proportions of MC2 and MC3 subtypes than MC1, while the better prognostic C3 subtype accounted for significantly lower proportions of MC2 than MC1. As per the findings of the TIDE analysis, MC1 had a greater likelihood of benefiting from immunotherapeutic regimens. MC2 was found to have a greater sensitivity to traditional chemotherapy drugs. Finally, 7 potential gene markers indicate HCC prognosis. Conclusion: The difference (variation) in tumor microenvironment and oxidative stress among metabolic subtypes of HCC was compared from multiple angles and levels. A complete and thorough clarification of the molecular pathological properties of HCC, the exploration of reliable markers for diagnosis, the improvement of the cancer staging system, and the guiding of individualized treatment of HCC all gain benefit greatly from molecular classification associated with metabolism.

3,3'-Diindolylmethane Augments 5-Fluorouracil-InducedGrowth Suppression in Gastric Cancer Cells through Suppression of the Akt/GSK-3ß and WNT/Beta-Catenin.

Gastric cancer (GC) is one of the most lethal cancers in South Korea, and it is a cancer of concern worldwide. 5-fluorouracil (5-Fu) is commonly used as the first-line therapy for advanced GC; however, its side effects often limit the dosage range and impair patients' quality of life. Due to the limitations of current chemotherapy, new anticancer therapies are urgently needed. 3,3'-diindolylmethane (DIM) has been reported to have the ability to protect against various types of cancer. Our study aimed to elucidate the anticancer effect of DIM in GC when treated with the chemotherapeutic agent 5-Fu. In our results, combined treatment with DIM and 5-Fu resulted in higher apoptosis and lower cell proliferation than treatment with 5-Fu in SNU484 and SNU638 cell lines. Furthermore, when DIM and 5-Fu were administered together, cell invasion was diminished by mediated E-cadherin, MMP-9, and uPA; p-Akt and p-GSK-3ß levels were reduced more significantly than when 5-Fu was administered alone. Moreover, in the Wnt signaling pathway, combined treatment of DIM and 5-Fu diminished ß-catenin levels in the nucleus and inhibited cyclin D1and c-Myc protein levels. The Akt inhibitor, wortmannin, further inhibited the levels of ß-catenin and c-Myc that were inhibited by DIM and 5-Fu. Furthermore, an animal xenograft model demonstrated that DIM combined with 5-Fu considerably reduced tumor growth without any toxic effects by regulating the Akt/GSK-3ß and ß-catenin levels. Our findings suggest that DIM significantly potentiates the anticancer effects of 5-Fu by targeting the Akt/GSK-3ß and WNT/ß-catenin because the combination therapy is more effective than 5-Fu alone, thereby offering an innovative potential therapy for patients with GC.

RBM10 recruits METTL3 to induce N6-methyladenosine-MALAT1-dependent modification, inhibiting the invasion and migration of NSCLC.

AIMS: Previous studies have shown that RNA binding motif 10 (RBM10) is a potential tumor suppressor protein that can inhibit proliferation and promote apoptosis of non-small cell lung cancer (NSCLC). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in promoting the development of lung cancer. Inhibiting its m6A methylation can effectively inhibit the invasion and metastasis of lung cancer. There is concern that RBM10 could affect MALAT1 m6A methylation for the invasion and migration of NSCLC. MAIN METHODS AND FINDINGS: Transwell and wound healing assays showed that RBM10 significantly inhibited the invasion and migration of NSCLC. CLIP-Seq showed that among all RBM10 binding RNAs, MALAT1 had the highest binding peak among all non-coding RNAs. RNA immunoprecipitation verified the direct combination of RBM10 and MALAT1. The rescue experiment confirmed that RBM10 affected the phosphorylation of the PI3K/AKT/mTOR pathway protein as well as the invasion and migration ability by regulating MALAT1. MeRIP-qPCR confirmed that RBM10 could inhibit the MALAT1 m6A methylation level by recruiting Methyltransferase Like 3 (METTL3). SIGNIFICANCE: The study suggests that RBM10, as an RNA-binding protein, may inhibit the m6A methylation of MALAT1 by recruiting METTL3 and affecting phosphorylation of the downstream PI3K/AKT/mTOR pathway by binding and regulating MALAT1, ultimately affecting the invasion and migration of NSCLC.

Saussurea involucrata oral liquid regulates gut microbiota and serum metabolism during alleviation of collagen-induced arthritis in rats.

Saussurea involucrata oral liquid (SIOL) can clinically relieve symptoms, such as joint pain and swelling, and morning stiffness, in patients with rheumatoid arthritis (RA). However, the mechanism of action remains unclear. This study used a combination of gut microbiota and serum metabolomics analysis to investigate the effects and potential mechanisms of SIOL intervention on rats with RA induced by type II bovine collagen and Freund's complete adjuvant. Results showed that SIOL treatment consequently improved the degree of ankle joint swelling, joint histopathological changes, joint pathological score, and expression of serum-related inflammatory cytokines (interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor-α) in RA model rats. 16 S rRNA sequencing results showed that SIOL increased the relative richness of the Lactobacillus and Bacteroides genus and decreased the relative richness of Romboutsia, Alloprevotella, Blautia, and Helicobacter genus. Serum nontargeted metabolomic results indicated that SIOL could regulate metabolites related to metabolic pathways, such as glycine, serine, threonine, galactose, cysteine, and methionine metabolism. Spearman correlation analysis showed that the regulatory effects of SIOL on the tricarboxylic acid (TCA) cycle, phenylalanine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, and glyoxylate and dicarboxylate metabolism pathways were correlated with changes in the richness of the Lactobacillus, Romboutsia, Bacteroides, and Alloprevotella genus in the gut microbiome. In conclusion, this study revealed the ameliorative effects of SIOL on RA and suggested that the therapeutic effects of SIOL on RA may be related to the regulation of the community richness of the Lactobacillus, Romboutsia, Bacteroides, and Alloprevotella genus, thereby improving the TCA cycle; phenylalanine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis, and glyoxylate and dicarboxylate metabolism-related pathways.

Analysis of the key ligand receptor CADM1_CADM1 in the regulation of thyroid cancer based on scRNA-seq and bulk RNA-seq data.

Introduction: Advanced papillary thyroid cancer (PTC) has a poor prognosis, 60~70% of which become radio iodine refractory (RAI-R), but the molecular markers that assess PTC progress to advanced PTC remain unclear. Meanwhile, current targeted therapies are badly effective due to drug resistance and adverse side effects. Ligand-receptor pairs (L/R pairs) play an important role in the interactions between tumor cells and other cells in the tumor microenvironment (TME). Nowadays, therapies targeting ligand-receptor pairs in the TME are advancing rapidly in the treatment of advanced cancers. However, therapies targeting L/R pairs applied to advanced PTC remains challenging because of limited knowledge about L/R pairs in PTC. Methods: We screened the critical L/R pair: CADM1-CADM1 using 65311 single-cell RNA sequencing (scRNA-seq) samples from 7 patients in different stage of PTC and bulk RNA-seq datasets containing data from 487 tumor samples and 58 para-carcinoma samples. Moreover, the expression levels of CADM1-CADM1 was assessed by quantitative real time polymerase chain reaction (qRT-PCR) and the function was analyzed using Transwell immigration assay. Results: We found that CADM1_CADM1 could be regarded as a biomarker representing a good prognosis of PTC. In addition, the high expression of CADM1_CADM1 can strongly increase the sensitivity of many targeted drugs, which can alleviate drug resistance. And the results of qRT-PCR showed us that the expression of CADM1_CADM1 in PTC was down-regulated and overexpression of CADM1 could suppresses tumor cell invasion migration. Conclusion: Our study identified that CADM1_CADM1 played an essential role in the progression of PTC for the first time and our findings provide a new potential prognostic and therapeutic ligand-receptor pair for advanced PTC.

RBM10 regulates alternative splicing of lncRNA Neat1 to inhibit the invasion and metastasis of NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 85% of the total cases with lung cancer. NSCLC is characterized by easy metastasis, which often spreads to bones, brains and livers. RNA-binding motif protein 10 (RBM10) is an alternative splicing (AS) regulator frequently mutated in NSCLC. We found that there were multiple peak binding sites between RBM10 and long non-coding RNA nuclear enriched abundant transcript 1 (LncRNA Neat1) by crosslinking-immunprecipitation and high-throughput sequencing (Clip-Seq). LncRNA Neat1 plays an indispensable role in promoting cancer in a variety of tumors and produces two splicing variants: Neat1_1 and Neat1_2. This study aims to explore the mechanism of RBM10 and LncRNA Neat1 in invasion and metastasis of NSCLC. METHODS: Through histological and cytological experiments, we assessed the expression level of RBM10 protein expression. The interaction between RBM10 and Neat1 was evaluated via Clip-Seq and RNA immunoprecipitation assay. The effect of RBM10 on Neat1 and its splicing variants was identified by RT-qPCR. The effect of RBM10 and Neat1 on invasive and metastasis phenotypes of NSCLC was analyzed using transwell invasion assay and scratch test. Additionally, downstream signaling pathway of RBM10 were identified by immunofluorescence and western blot. RESULTS: RBM10 exhibited low levels of expression in NSCLC tissues and cells. RBM10 inhibited the invasion and metastasis of NSCLC and recruited Neat1 and Neat1_2. Overexpression of RBM10 simultaneously inhibited Neat1 and Neat1_2, and promoted the expression of Neat1_1. On the other hand, silencing RBM10 promoted Neat1 and Neat1_2, and inhibited the expression of Neat1_1. From this, we concluded that RBM10 regulated AS of Neat1, and the tumor-promoting effect of Neat1 was mainly attributed to Neat1_2. RBM10 had a negative correlation with Neat1_2. In addition, RBM10 upregulated the expression of PTEN and downregulated the phosphorylation of PI3K/AKT/mTOR through Neat1_2, which ultimately inhibited the invasion and metastasis of NSCLC. CONCLUSION: The RBM10 regulated AS of Neat1 to cause the imbalance of Neat1_1 and Neat1_2, and RBM10 suppressed the activation of the PTEN/PI3K/AKT/mTOR signal by downregulating Neat1_2, finally affected the invasion and metastasis of NSCLC.

Reshaping hypoxia and silencing CD73 via biomimetic gelatin nanotherapeutics to boost immunotherapy.

The ubiquitous hypoxic microenvironment at the tumor site helps to regulate hypoxic inducible factor (HIF-1α), up-regulate downstream CD73-adenosine (CD73-ADO) pathways, and further result in effector T cell function exhaustion, which is regarded as a crucial adverse factor in the poor clinical efficacy of immune checkpoint blockade therapy (ICB). How to reshape hypoxic microenvironment and silence CD73 remains a huge challenge to improve ICB therapeutic outcomes. In this study, cancer cell membrane-camouflaged gelatin nanoparticles (CSG@B16F10) were designed to co-deliver oxygen-generating agent catalase (CAT) and CD73siRNA, thus enhancing tumor oxygenation and alleviating CD73-ADO pathway-mediated T cell immunosuppression. The fabricated biomimetic nanoparticles could efficiently achieve immune evading and homologous targeting by virtue of the retention of cancer cell membrane protein. Matrix metalloproteinases (MMP)-responsive gelatin nanoparticles were gradually disintegrated to accelerate the release of payloads. Rapidly released CAT was found to relieve tumor hypoxia by generating endogenous oxygen, while CD73siRNA effectively silenced target gene, synergically inhibiting CD73 protein expression and facilitating T-cell-specific immunity. Upon introduction of CSG@B16F10 in melanoma-bearing mice, PD-L1 checkpoint blockade achieved optimal tumor suppression (∼83%). The enhanced immune efficacy was mainly manifested by enhanced cytotoxic T cell (CTL), reduced regulatory T cells (Tregs), and increased anti-tumor cytokine secretion. This work presents a new paradigm for the ideal design of biomimetic nanoplatforms and the synergistic treatment of hypoxia alleviation and CD73 silence, greatly promising for enhancing clinical immune potency of PD-1/PD-L1 immune checkpoint blockade.

Effect of Salvia Miltiorrhiza Polyphenolic Acid Injection on Improving Limb Use and Cognitive Impairment in Patients with Acute Stroke.

Aims: To investigate the effect of injectable salvia polyphenolic acid on the improvement of limb movement and cognitive dysfunction in acute stroke patients. Materials and Methods: The clinical data of 90 acute stroke patients were collected for retrospective study and divided into 45 cases each in the comparison group and the observation group according to the different treatment methods; using basic treatment + salvianolic acid, the comparison group implemented conventional alteplase and butalbital treatment, and the observation group used injectable salvianolic acid treatment, to observe and compare the clinical efficacy, changes in neurological deficits, cognitive function, and motor function scores before and after treatment in the two groups. Results: The NIHSS (National Institute of Health stroke scale) score, cerebral infarct volume, NSE (neuron-specific enolase), and S100ß (A neurotrophic factor) levels were reduced after treatment compared with those before treatment in this group, and the NIHSS score, cerebral infarct volume, NSE, and S100ß levels in the observation group were lower than those in the comparison group after treatment, and the difference was statistically significant (P < 0.05). Compared with the clinical efficacy of the comparison group and the observation group, the treatment effect of the observation group was better than that of the comparison group, and the difference was statistically significant (P < 0.05). After treatment, the cognitive function and motor function scores of both groups were significantly improved compared with those before treatment, and the degree of improvement of each score in the observation group was significantly better than that in the comparison group (P < 0.05). During the trial, two patients in the comparison group developed a generalized rash and withdrew from the experiment, and the rash subsided after anti-allergic treatment, and no significant adverse events were observed in the remaining participants. There was no statistically significant difference in liver and kidney function and cardiac enzyme test indexes between the two groups of patients at 14 days of treatment (P > 0.05). Conclusion: Danshen polyphenolic acid for injection has definite clinical efficacy in the treatment of acute ischemic stroke, and it can effectively improve cognitive and motor functions and promote neurological recovery in patients with high safety.

Long-Term Prognostic Factors in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A 15-Year Multicenter Retrospective Study.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multisystem autoimmune disease with small-vessel involvement. In AAV, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are major clinicopathologic variants. In addition, myeloperoxidase (MPO) and proteinase 3 (PR3) are major target antigens. The objective of the study was to explore the predictive factors for long-term survival in AAV patients. Materials and Methods: A multicenter retrospective study was carried out on 407 patients between 2005 and 2020. Clinical parameters were obtained from laboratory tests including the ANCA types, antinuclear antibody (ANA), extractable nuclear antigen (ENA), anti-streptolysin O (ASO), glomerular filtration rate (GFR), and the laboratory examinations for the blood routine, liver function, renal function, and immunity, etc. The data for clinical parameters were collected from electronic medical records (EMRs), and the data for patient survival were acquired through regular follow-up. The association of clinical parameters with overall survival (OS) along with 3-year and 5-year survival rates was analyzed, and the nomogram as a predictive model was established according to the analysis results. Results: In the present study, 336 (82.6%) patients and 46 (11.3%) patients were diagnosed with MPA and GPA, respectively. The mean and median OS for all the patients were 2,285 and 2,290 days, respectively. The 1-year, 3-year, 5-year, and 10-year cumulative survival rates for all the patients were 84.2%, 76.3%, 57.2%, and 32.4%, respectively. Univariate and multivariate survival analyses indicated that the independent prognostic factors included age, pathological categories (MPA, GPA, and other types), serum ANCA types (negative or positive for MPO and/or PR3), ANA, ASO, GFR, lymphocyte, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and these clinical parameters except for ASO were used to construct a nomogram. The nomogram for 3-year and 5-year survival rates had a C-index of 0.721 (95% CI 0.676-0.766). The calibration curves showed that the predicted values of the nomogram for 3-year and 5-year survival rates were generally consistent with practical observed values, and decision curve analysis (DCA) further demonstrated the practicability and accuracy of the predictive model. Conclusion: Laboratory tests at diagnosis have great significance in the prediction of long-term survival in AAV patients.

From COVID-19 to Sarcoidosis: How Similar Are These Two Diseases?

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leads to the dysregulation of the immune system, exacerbates inflammatory responses, and even causes multiple organ dysfunction syndrome in patients with severe disease. Sarcoidosis is an idiopathic granulomatous multisystem disease characterized by dense epithelioid non-necrotizing lesions with varying degrees of lymphocytic inflammation. These two diseases have similar clinical manifestations and may also influence each other and affect their clinical courses. In this study, we analyzed some possible connections between sarcoidosis and COVID-19, including the role of the renin-angiotensin system in the respiratory system, immune response, and cell death pathways, to understand the underlying mechanisms of SARS-CoV-2 infection, predisposing patients to severe forms of COVID-19. This review will provide a new prospect for the treatment of COVID-19 and an opportunity to explore the pathogenesis and development of sarcoidosis.

MMP-responsive transformation nanomaterials with IAP antagonist to boost immune checkpoint therapy.

The clinical effect of immune checkpoint therapy is limited by the poor blocking efficiency of immune checkpoints and the insufficient infiltration of tumor-specific T cells. Here, we constructed enzyme-responsive PVA-peptide conjugates (PPCs) to achieve re-assembly with enhanced accumulation in the tumor region, enable enhanced PD-L1 occupancy and improve the blocking efficiency. The self-assembled PPC-1 nanoparticles can enter tumor environment, whereas the enzyme-cleavable peptide was digested under overgenerated matrix metalloproteinases (MMP). The accumulated PPC-1 simultaneously transformed into ß-sheet fibrous structures around the solid tumor and remained stable for over 96 h, which led to efficiently interrupting the PD-1/PD-L1 interaction. Upon introduction of the IAP antagonists, the non-classical NF-κB pathway of dendritic cells was activated and increased the infiltration of T cells in tumors. With the synergistic contribution of IAP antagonists from the substantial increase in expression of chemokines (CCL5 and CXCL9) and adequate T-cell infiltration in tumor sites, PPC-1 improved the biodistribution and accumulation of PD-L1 antagonists in tumor regions ultimately realizing higher-performance (P < 0.01) tumor growth inhibition efficiency (~80%) than PPC-2 group (~58%) in B16F10 tumor-bearing mice. The growth of the second tumor at the distal end was obviously inhibited (P < 0.01) after the resection of the primary tumor. The combined efficacy was similar to that observed in a Pan02 pancreatic cancer tumor model. This strategy aims to offer novel perspective for the development of locational assembly platforms in vivo and the optimal design of immune checkpoint combination therapy.