Comprehensive molecular classification predicted microenvironment profiles and therapy response for HCC.

BACKGROUND AND AIMS: Tumor microenvironment (TME) heterogeneity leads to a discrepancy in survival prognosis and clinical treatment response for patients with HCC. The clinical applications of documented molecular subtypes are constrained by several issues. APPROACH AND RESULTS: We integrated 3 single-cell data sets to describe the TME landscape and identified 6 prognosis-related cell subclusters. Unsupervised clustering of subcluster-specific markers was performed to generate transcriptomic subtypes. The predictive value of these molecular subtypes for prognosis and treatment response was explored in multiple external HCC cohorts and the Xiangya HCC cohort. TME features were estimated using single-cell immune repertoire sequencing, mass cytometry, and multiplex immunofluorescence. The prognosis-related score was constructed based on a machine-learning algorithm. Comprehensive single-cell analysis described TME heterogeneity in HCC. The 5 transcriptomic subtypes possessed different clinical prognoses, stemness characteristics, immune landscapes, and therapeutic responses. Class 1 exhibited an inflamed phenotype with better clinical outcomes, while classes 2 and 4 were characterized by a lack of T-cell infiltration. Classes 5 and 3 indicated an inhibitory tumor immune microenvironment. Analysis of multiple therapeutic cohorts suggested that classes 5 and 3 were sensitive to immune checkpoint blockade and targeted therapy, whereas classes 1 and 2 were more responsive to transcatheter arterial chemoembolization treatment. Class 4 displayed resistance to all conventional HCC therapies. Four potential therapeutic agents and 4 targets were further identified for high prognosis-related score patients with HCC. CONCLUSIONS: Our study generated a clinically valid molecular classification to guide precision medicine in patients with HCC.

Ultrasound in paediatric surgery: A meta-analysis review of its influence on postoperative wound healing and infection rates.

Ultrasound (US) has traditionally been recognised for its imaging capabilities, but its emerging role as a therapeutic modality in postoperative wound management, especially in paediatric care, has garnered significant attention. This meta-analysis aimed to evaluate the influence of US on postoperative wound healing and infection rates in paediatric patients. From an initial pool of 1236 articles, seven were deemed suitable for inclusion. Postoperative wound healing was assessed using the Redness, Edema, Ecchymosis, Discharge, and Approximation (REEDA) scale. Notably, there was a significant difference in wound healing patterns between the US-treated and control groups (I2 = 94%, standardized mean difference [SMD]: -4.60, 95% confidence intervals [CIs]: -6.32 to -2.88, p < 0.01), as illustrated in Figure 4. Additionally, a marked difference in wound infection rates was observed between the groups (I2 = 93%, SMD: -5.86, 95% CIs: -9.04 to -2.68, p < 0.01), as portrayed in Figure 5. The findings underscore the potential benefits of US in enhancing postoperative wound healing and reducing infection rates in paediatric surgical settings. However, the application of US should be judicious, considering the nuances of individual patient needs and clinical contexts.

Transcriptome analysis reveals the impact of NETs activation on airway epithelial cell EMT and inflammation in bronchiolitis obliterans.

Bronchiolitis obliterans (BO) is a chronic airway disease that was often indicated by the pathological presentation of narrowed and irreversible airways. However, the molecular mechanisms of BO pathogenesis remain unknown. Although neutrophil extracellular traps (NETs) can contribute to inflammatory disorders, their involvement in BO is unclear. This study aims to identify potential signaling pathways in BO by exploring the correlations between NETs and BO. GSE52761 and GSE137169 datasets were downloaded from gene expression omnibus (GEO) database. A series of bioinformatics analyses such as differential expression analysis, gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and gene set enrichment analysis (GSEA) were performed on GSE52761 and GSE137169 datasets to identify BO potential signaling pathways. Two different types of BO mouse models were constructed to verify NETs involvements in BO. Additional experiments and bioinformatics analysis using human small airway epithelial cells (SAECs) were also performed to further elucidate differential genes enrichment with their respective signaling pathways in BO. Our study identified 115 differentially expressed genes (DEGs) that were found up-regulated in BO. Pathway enrichment analysis revealed that these genes were primarily involved in inflammatory signaling processes. Besides, we found that neutrophil extracellular traps (NETs) were formed and activated during BO. Our western blot analysis on lung tissue from BO mice further confirmed NETs activation in BO, where neutrophil elastase (NE) and myeloperoxidase (MPO) expression were found significantly elevated. Transcriptomic and bioinformatics analysis of NETs treated-SAECs also revealed that NETs-DEGs were primarily associated through inflammatory and epithelial-to-mesenchymal transition (EMT) -related pathways. Our study provides novel clues towards the understanding of BO pathogenesis, in which NETs contribute to BO pathogenesis through the activation of inflammatory and EMT associated pathways. The completion of our study will provide the basis for potential novel therapeutic targets in BO treatment.

Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as potential predictive markers of treatment response in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: The role of platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) as independent prognostic markers in different tumors is well established. However, there is a limited review of the potential of NLR and PLR as predictors of treatment outcomes from immune checkpoint inhibitors (ICIs). Objective: To establish a correlation between NLR and PLR and the potential of clinical benefit from ICIs. Methods: The literature search was performed for studies that reported the association between NLR, PLR, and treatment outcomes among cancer patients treated with ICIs. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), and progressive disease (PD). ORR was the summation of patients who achieved complete response and partial response. DCR included patients who achieved stable disease. PD was the proportion of patients who progressed, relapsed, or discontinued the treatment. Statistical analysis was performed using the STATA 12.0 package. Heterogeneity was determined by the I2 value. Quality assessment was performed using the Newcastle-Ottawa Scale. Egger's test was used to establish publication bias and sensitivity analysis. Results: A total of 40 papers that met the inclusion criteria were included in the systematic review. However, only 17 studies were used in the meta-analysis to determine the correlation between NLR, PLR, and treatment response. We found that treatment with ICIs and monitoring of outcomes and adverse events using PLR and NLR parameters have been studied in different tumors. Our analysis showed that low NLR correlated with higher ORR (OR = 0.62 (95% CI 0.47-0.81, p = 0.001) and higher DCR (OR = 0.23, 95% CI 0.14-0.36, p < 0.001). Higher NLR predicted a higher probability of PD (OR = 3.12, 95% CI 1.44, 6.77, p = 0.004). Similarly, low PLR correlated with higher ORR (OR = 0.69, 95% CI 0.5, 0.95, p = 0.025). Generally, patients with low NLR and PLR were more likely to achieve clinical benefit and better response (p-value < 0.001). Meanwhile, patients with high ratios were more likely to progress (p-value < 0.005), although there was significant heterogeneity among studies. There was no significant publication bias observed. Conclusion: The study showed that high NLR and PLR either at baseline or during treatment is associated with poorer treatment outcome. Therefore, these ratios can be utilized in clinical practice with other markers to determine treatment efficacy from immunotherapy.

Gastric precancerous lesions:occurrence, development factors, and treatment.

Patients with gastric precancerous lesions (GPL) have a higher risk of gastric cancer (GC). However, the transformation of GPL into GC is an ongoing process that takes several years. At present, several factors including H.Pylori (Hp), flora imbalance, inflammatory factors, genetic variations, Claudin-4, gastric stem cells, solute carrier family member 26 (SLC26A9), bile reflux, exosomes, and miR-30a plays a considerable role in the transformation of GPL into GC. Moreover, timely intervention in the event of GPL can reduce the risk of GC. In clinical practice, GPL is mainly treated with endoscopy, acid suppression therapy, Hp eradication, a cyclooxygenase-2 inhibitor, aspirin, and diet. Currently, the use of traditional Chinese medicine (TCM) or combination with western medication to remove Hp and the use of TCM to treat GPL are common in Asia, particularly China, and have also demonstrated excellent clinical efficacy. This review thoroughly discussed the combining of TCM and Western therapy for the treatment of precancerous lesions as conditions allow. Consequently, this review also focuses on the causes of the development and progression of GPL, as well as its current treatment. This may help us understand GPL and related treatment.

A cancer-associated fibroblast subtypes-based signature enables the evaluation of immunotherapy response and prognosis in bladder cancer.

Bladder cancer (BLCA) is one of the most prevalent and heterogeneous urinary malignant tumors. Previous researches have reported a significant association between cancer-associated fibroblasts (CAFs) and poor prognosis of tumor patients. However, uncertainty surrounds the role of CAFs in the BLCA tumor microenvironment, necessitating further investigation into the CAFs-related gene signatures in BLCA. In this study, we identified three CAF subtypes in BLCA according to single-cell RNA-seq data and constructed CAFs-related risk score (CRRS) by screening 102,714 signatures. The survival analysis, ROC curves, and nomogram suggested that CRRS was a valuable predictor in 2,042 patients from 9 available public datasets and Xiangya real-world cohort. We further revealed the significant correlation between CRRS and clinicopathological characteristics, genome alterations, and epithelial-mesenchymal transition (EMT). A high CRRS indicated a non-inflamed phenotype and a lower remission rate of immunotherapy in BLCA. In conclusion, the CRRS had the potential to predict the prognosis and immunotherapy response of BLCA patients.

Identification of Hub Genes in the Pathogenesis of Bronchiolitis Obliterans via Bioinformatic Analysis and Experimental Verification.

Background: Bronchiolitis obliterans (BO) is a chronic disease that can arise as a complication of severe childhood pneumonia and can also impact the long-term survival of patients after lung transplantation. However, the precise molecular mechanism underlying BO remains unclear. We aimed to identify BO-associated hub genes and their molecular mechanisms. Methods: BO-associated transcriptome datasets (GSE52761, GSE137169, and GSE94557) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). Additional bioinformatics analyses, such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) analyses, were performed to determine functional roles and DEG-associated regulatory networks. Prediction of hub genes using the 12 algorithms available in the Cytohubba plugin of Cytoscape software was also performed. Verification was performed using the BO mouse model. Results: Our results revealed 57 DEGs associated with BO, of which 18 were down-regulated and 39 were up-regulated. The Cytohubba plugin data further narrowed down the 57 DEGs into 9 prominent hub genes (CCR2, CD1D, GM2A, TFEC, MPEG1, CTSS, GPNMB, BIRC2, and CTSZ). Genes such as CCR2, TFEC, MPEG1, CTSS, and CTSZ were dysregulated in 2,3-butanedione-induced BO mice, whereas TFEC, CTSS, and CTSZ were dysregulated in nitric acid-induced BO mouse models. Conclusion: Our study identified and validated four novel BO biomarkers, which may allow further investigation into the development of distinct BO diagnostic markers and novel therapeutic avenues.

A multi-omics analysis reveals CLSPN is associated with prognosis, immune microenvironment and drug resistance in cancers.

BACKGROUND: Immunotherapy is effective only in limited patients. It is urgent to discover a novel biomarker to predict immune cells infiltration status and immunotherapy response of different cancers. CLSPN has been reported to play a pivotal role in various biological processes. However, a comprehensive analysis of CLSPN in cancers has not been conducted. METHODS: To show the whole picture of CLSPN in cancers, a pan-cancer analysis was conducted in 9125 tumor samples across 33 cancer types by integrating transcriptomic, epigenomic and pharmacogenomics data. Moreover, the role of CLSPN in cancer was validated by CCK-8, EDU, colony formation and flow cytometry in vitro and tumor cell derived xenograft model in vivo. RESULTS: CLSPN expression was generally upregulated in most cancer types and was significantly associated with prognosis in different tumor samples. Moreover, elevated CLSPN expression was closely correlated with immune cells infiltration, TMB (tumor mutational burden), MSI (microsatellite instability), MMR (mismatch repair), DNA methylation and stemness score across 33 cancer types. Enrichment analysis of functional genes revealed that CLSPN participated in the regulation of numerous signaling pathways involved in cell cycle and inflammatory response. The expression of CLSPN in LUAD patients were further analyzed at the single-cell level. Knockdown CLSPN significantly inhibited cancer cell proliferation and cell cycle related cyclin-dependent kinase (CDK) family and Cyclin family expression in LUAD (lung adenocarcinoma) both in vitro and in vivo experiments. Finally, we conducted structure-based virtual screening by modelling the structure of CHK1 kinase domain and Claspin phosphopeptide complex. The top five hit compounds were screened and validated by molecular docking and Connectivity Map (CMap) analysis. CONCLUSION: Our multi-omics analysis offers a systematic understanding of the roles of CLSPN in pan-cancer and provides a potential target for future cancer treatment.

The Protective Effect of (-)-Tetrahydroalstonine against OGD/R-Induced Neuronal Injury via Autophagy Regulation.

Here, (-)-Tetrahydroalstonine (THA) was isolated from Alstonia scholaris and investigated for its neuroprotective effect towards oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal damage. In this study, primary cortical neurons were pre-treated with THA and then subjected to OGD/R induction. The cell viability was tested by the MTT assay, and the states of the autophagy-lysosomal pathway and Akt/mTOR pathway were monitored by Western blot analysis. The findings suggested that THA administration increased the cell viability of OGD/R-induced cortical neurons. Autophagic activity and lysosomal dysfunction were found at the early stage of OGD/R, which were significantly ameliorated by THA treatment. Meanwhile, the protective effect of THA was significantly reversed by the lysosome inhibitor. Additionally, THA significantly activated the Akt/mTOR pathway, which was suppressed after OGD/R induction. In summary, THA exhibited promising protective effects against OGD/R-induced neuronal injury by autophagy regulation through the Akt/mTOR pathway.

MTFR2 shapes a barrier of immune microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the world. Mitochondrial fission regulator 2 (MTFR2) is involved in the development of various cancers. However, the roles of MTFR2 in HCC remain unknown. In this study, we conducted a comprehensive analysis of MTFR2 in HCC, which was generated from integrative MTFR2 analyses of eight HCC cell lines, and three datasets (public dataset, real-world dataset, and immunotherapy dataset) derived from bulk HCC tissues, survival, and immunotherapy data. We demonstrated that the expression level of MTFR2 is upregulated in HCC, leading to poor prognosis. MTFR2 is positively correlated with the level of immune cell infiltration, multiple immune checkpoints and immunotherapy response prediction pathways, and acts as an important role in cancer-immunity cycle. In conclusion, our work indicates that MTFR2 can shape a barrier of immune microenvironment and result in poor prognosis in hepatocellular carcinoma, but the immune barrier may be broken by immunotherapy.

Translational patterns of ionotropic glutamate and GABA receptors during brain development and behavioral stimuli revealed by polysome profiling.

mRNA translation is critical for regulation of various aspects of the nervous system. Ionotropic glutamate and gamma-aminobutyric acid type A (GABAA ) receptors are fundamental synaptic ion channels that control excitatory and inhibitory synaptic transmission, respectively. However, little is known about the translation of these receptors during brain development and function. By utilizing polysome profiling, a powerful tool for investigating translational machinery and mRNA translational states, we characterized the translational patterns of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA), and GABAA receptor subunits, and compared them with total mRNA and protein levels during mouse brain development, in different brain regions, and in response to behavioral stimuli. Most of the receptor subunits exhibited developmental changes at total mRNA, translation, and protein levels, among which translation of Gria1, Gria2, Grin1, Grin2a, Gabra1, and Gabrg2 contributed greatly to their protein levels. Most of the receptor subunits also displayed differentiated levels of total mRNA, translation, and protein in the prefrontal cortex and hippocampus, among which translation of Gria1, Gria2, Gabrb2, and Gabrg2 contributed to their protein levels. Finally, we showed that acute foot shock stress had a rapid influence in both the prefrontal cortex and hippocampus, with the prefrontal cortex displaying more changes at translational and protein levels. Notably, Grin2a is translationally repressed by stress which was followed by a decrease of GluN2A protein in both brain regions. Together, this study provides a new understanding of the translational patterns of critical ionotropic synaptic receptors during brain development and behavioral stress.

Clinical findings, diagnosis and therapy of patent ductus venosus in children: a case series.

Background: Patent ductus venosus (PDV) is a rare form of congenital portosystemic shunt. Because of the diversity of clinical symptoms and insufficient knowledge of this condition, clinicians often fail to perform targeted examinations, resulting in missed diagnoses and misdiagnoses. This study summarized the clinical and radiological findings, as well as surgical methods, of PDV with the aim of improving early diagnosis and guiding treatment. Methods: Clinical, laboratory, and radiologic data of patients with PDV were analyzed retrospectively. In all, 9 patients with PDV were included in the study (7 male, 2 female; median age 1.6 years, age range 16 days to 16.5 years). Results: Data for all 9 patients with PDV were reviewed. The most common initial clinical presentations were jaundice and respiratory symptoms. Laboratory data revealed hypoxemia in 5 patients, hyperammonemia in 2, hyperbilirubinemia in 7, abnormal coagulation function in 6, abnormal myocardial enzymes in 4, hepatic dysfunction in 8, and renal dysfunction in 3. The direct imaging sign of PDV was a vascular structure connecting the left branch of the portal vein (LPV) to the inferior vena cava. Secondary imaging findings observed in all 9 patients were dilated right heart, pulmonary artery, and LPV, and an atrophic right branch of the portal vein. The main portal vein was dilated in 8 patients and shrunk in 1. Moreover, 8 patients had enlarged livers, and 3 presented with hypoperfusion in the right lobe of the liver. The spleen was enlarged in 8 patients but shrunk in 1. Renal imaging was abnormal in 2 patients. Hepatic encephalopathy was found in 4 patients; 7 patients had PDV combined with other malformations, with congenital heart disease and vascular abnormalities being the most common; 3 patients successfully underwent surgical ligation of PDV. Conclusions: PDV can lead to multisystem damage. Secondary radiological signs of PDV play an important role in early diagnosis and preoperative evaluation. Complications and coexisting malformations were common and should not be missed during preoperative evaluation. Early surgical closure for PDV is recommended.

Hsa_Circ_0066351 Acts as a Prognostic and Immunotherapeutic Biomarker in Colorectal Cancer.

Circular RNA (circRNA), a novel class of non-coding RNA, has been reported in various diseases, especially in tumors. However, the key signatures of circRNA-competitive endogenous RNA (ceRNA) network are largely unclear in colorectal cancer (CRC). We first characterized circRNAs profile by using circRNA-seq analysis from real-word dataset. The expression level of hsa_circ_0066351 in CRC tissues and cell lines was detected by quantitative real-time PCR. Then, cell proliferation assay was used to confirm the proliferation function of hsa_circ_0066351. Next, Cytoscape was used to construct circRNA-miRNA-mRNA networks. Last but not least, the landscape of hsa_circ_0066351-miRNA-mRNA in CRC had been investigated in the bulk tissue RNA-Seq level and single-cell Seq level. We proved that hsa_circ_0066351 was significantly downregulated in CRC cell lines and tissues (P < 0.001), and was negatively associated with distant metastasis (P < 0.01). Significantly, the expression of hsa_circ_0066351 was associated with better survival in patients with CRC. Function assays showed that hsa_circ_0066351 could inhibit CRC cells proliferation. In addition, a ceRNA network, including hsa_circ_0066351, two miRNAs, and ten mRNAs, was constructed. Our analyses showed that these ten mRNAs were consistently downregulated in pan-cancer and enriched in tumor suppressive function. A risk score model constructed by these ten downstream genes also indicated that they were related to the prognosis and immune response in CRC. In conclusion, we demonstrated that a novel circRNA (hsa_circ_0066351) inhibited CRC proliferation, and revealed a potential prognostic and immunotherapeutic biomarker in CRC.

The optimal first-line treatment for patients with left-sided RAS wild-type metastatic colorectal cancer: Double-drug regimen or triple-drug regimen therapy.

There are many treatments for metastatic colorectal cancer (mCRC). Among them, uncertainty remains especially concerning the clinical benefit of different regimens for left-sided RAS wild-type (WT) mCRC in the triple-drug therapy era. No studies have been conducted to answer this critical clinical issue. We performed a comprehensive analysis of published data and real-world data. First, we conducted analyses of the published trials to show the landscape of efficacy and safety in the treatments of left-sided RAS WT mCRC. Then, we initiated a multicenter real-world study as the validation dataset. This study included six published randomized controlled trials (RCTs) and a total of 1925 patients. The double-drug regimen plus cetuximab/panitumumab (D + C/P) achieved the longest overall survival (OS) in patients with left-sided mCRC (HR = 0.74, 95%CI: 0.57-0.98), while triple-drug regimen with bevacizumab (T + B, HR = 1.1, 95%CI: 0.63-2.0), compared with double-drug with bevacizumab (D + B). The D + C/P had the highest overall response rate (ORR) in patients with left-sided mCRC (OR = 1.8, 95%CI: 0.89-3.8), while T + B (OR = 1.8, 95%CI: 0.70-4.8), compared with D + B. The multicenter real-world cohort showed the double-drug regimen plus cetuximab had longer progression-free survival (PFS) in left-sided mCRC patients than the triple-drug regimen with bevacizumab. The safety analysis showed the incidence of the adverse events (grade≥3) in the triple-drug therapy plus bevacizumab was higher than that in the double-drug therapy plus cetuximab/panitumumab. This work demonstrates the ranking of three regimens for therapeutic efficacy and safety in patients with left-sided RAS WT mCRC. The double-drug regimen plus cetuximab/panitumumab appears more effective and safer than double-drug and triple-drug based regimens with bevacizumab. Further trials and cohort analyses on this topic would increase confidence in these results.

Single-Cell Transcriptional Profiling Reveals Low-Level Tragus Stimulation Improves Sepsis-Induced Myocardial Dysfunction by Promoting M2 Macrophage Polarization.

Background: Sepsis can lead to multiple organ damage, of which the heart is one of the most vulnerable organs. Vagal nerve stimulation can reduce myocardial injury in sepsis and improve survival rates. However, the potential impact of low-level tragus stimulation and disparate cell populations on sepsis-induced myocardial dysfunction remains undetermined. Methods: A cardiac single-cell transcriptomic approach was used for characterizing cardiac cell populations that form the heart. Single-cell mRNA sequencing data were used for selecting all cardiac macrophages from CD45+ cells. Then, echocardiography, western blot, flow cytometry, immunofluorescence, and immunohistochemistry were performed to verify the single-cell mRNA sequencing results. Results: Using single-cell mRNA sequencing data, we uncovered the multiple cell populations contributing to myocardial injury in sepsis under low-level tragus stimulation, thereby illustrating a comprehensive map of the cardiac cellular landscape. Pseudotiming analysis in single-cell sequencing showed that low-level vagal nerve stimulation played an anti-inflammatory role by promoting cardiac monocytes into M2 macrophages, which significantly increased α7nAChR expression in heart tissues. Echocardiography assessment indicated that low-level vagal nerve stimulation could also improve cardiac functions in mice with sepsis-induced myocardial dysfunction. In addition, the heart tissues of mice from the sepsis group with low-level tragus stimulation had significantly lower interleukin-1ß expression levels than those from the sepsis group. Flow cytometry analysis showed that different acetylcholine concentrations promoted cardiac monocytes into M2 macrophages in in vitro experiments. Conclusion: Low-level tragus stimulation could improve sepsis-induced myocardial dysfunction by promoting cardiac monocytes to M2 macrophages.

Prognostic stratification based on m5C regulators acts as a novel biomarker for immunotherapy in hepatocellular carcinoma.

Background: Immunotherapy is a promising anti-cancer strategy in hepatocellular carcinoma (HCC). However, a limited number of patients can benefit from it. There are currently no reliable biomarkers available to find the potential beneficiaries. Methylcytosine (m5C) is crucial in HCC, but its role in forecasting clinical responses to immunotherapy has not been fully clarified. Methods: In this study, we analyzed 371 HCC patients from The Cancer Genome Atlas (TCGA) database and investigated the expression of 18 m5C regulators. We selected 6 differentially expressed genes (DEGs) to construct a prognostic risk model as well as 2 m5C-related diagnostic models. Results: The 1-, 3-, and 5-year area under the curve (AUC) of m5C scores for the overall survival (OS) was 0.781/0.762/0.711, indicating the m5C score system had an ideal distinction of prognostic prediction for HCC. The survival analysis showed that patients with high-risk scores present a worse prognosis than the patients with low-risk scores (p< 0.0001). We got consistent results in 6 public cohorts and validated them in Xiangya real-world cohort by quantitative real-time PCR and immunohistochemical (IHC) assays. The high-m5C score group was predicted to be in an immune evasion state and showed low sensitivity to immunotherapy, but high sensitivity to chemotherapy and potential targeted drugs and agents, such as sepantronium bromide (YM-155), axitinib, vinblastine and docetaxel. Meanwhile, we also constructed two diagnostic models to distinguish HCC tumors from normal liver tissues or liver cirrhosis. Conclusion: In conclusion, our study helps to early screen HCC patients and select patients who can benefit from immunotherapy. Step forwardly, for the less likely beneficiaries, this study provides them with new potential targeted drugs and agents for choice to improve their prognosis.

Echocardiographic evaluation of total anomalous pulmonary venous connection: Comparison of obstructed and unobstructed type.

ABSTRACT: This study aims to compare the differences between obstructed and unobstructed total anomalous pulmonary venous connection (TAPVC) using echocardiography, and to evaluate the clinical and echocardiographic parameters associated with pulmonary venous obstruction (PVO).We conducted a retrospective study of 70 patients with TAPVC between 2014 and 2019. The morphologic and hemodynamic echocardiographic parameters of patients were observed and measured, and the parameters between obstructed and unobstructed TAPVC were compared. The clinical and echocardiographic parameter differences between the two groups were used for ROC curve analysis.Obstructed TAPVC was found in 30 (42.9%) of 70 patients. Between obstructed and unobstructed TAPVC, there were significant differences in atrial septal defect size, pulmonary artery maximum velocity (PA Vmax ), peak E velocity of mitral valve, left ventricular fractional shortening, left ventricular ejection fraction, stroke volume and the incidence of patent ductus arteriosus, but there was no significant difference in birth weight. The first diagnosis age of obstructed TAPVC was earlier than unobstructed type. The ROC curve analysis for the first diagnosis age showed the sensitivity and specificity were 76.7%, 80% respectively. The ROC curve analysis for the PA Vmax showed the sensitivity and specificity were 88.5%, 67.6% respectively.Patients with TAPVC had a high incidence of PVO. The presence of PVO can affect the size of atrial septal defect and the closure of the ductus arteriosus, cause significant changes in PA Vmax, peak E velocity of mitral valve, left ventricular fractional shortening, left ventricular ejection fraction, stroke volume, lead to earlier symptoms and earlier first diagnosis age. The first diagnosis age and PA Vmax were excellent values since they associated with PVO.

Identification of tumour immune infiltration-associated snoRNAs (TIIsno) for predicting prognosis and immune landscape in patients with colon cancer via a TIIsno score model.

BACKGROUND: Colon cancer (CC) is the leading cause of tumour-related death worldwide. SnoRNA plays a critical role in the tumour microenvironment. The tumour microenvironment can be shaped by tumour-infiltrating immune cells, which control the destiny of immunotherapy efficacy. This study uniquely focused on snoRNAs derived from immune cells to identify new biomarkers for immune landscape. METHODS: A novel computational framework was initiated for identifying tumour immune infiltration-associated snoRNAs (TIIsno) signatures and developed a TIIsno score model from integrative snoRNA profiling analysis of 21 purified immune cell lines, 43 colon cancer cell lines, and three datasets (training, test, real-world validation set). FINDINGS: Our study found that a high TIIsno score was associated with poor CC prognosis. TIIsno scores were seen to be negatively correlated with (I) the infiltration level of most immune cells, (II) the inhibitory immune checkpoints expression level, and (III) the immune score. These findings, taken together with the observation that TIIsno score is lower in MSI-H patients, suggests that patients with a low TIIsno score may have a better response to immunotherapy. INTERPRETATION: In conclusion, we successfully identified TIIsno and constructed a TIIsno score model, a new potential biomarker of immunotherapy response, which can effectively predict the prognosis of CC patients as well. FUNDING: National Key R & D Program of China, National Natural Science Foundation of China, key projects from the Nature Science Foundation of Hunan Province, projects from Beijing CSCO Clinical Oncology Research Foundation, Fundamental Research Funds for the Central Universities of Central South University.

tRF3008A suppresses the progression and metastasis of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner.

BACKGROUND: tRNA-derived fragments (tRFs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of tRFs to colorectal cancer (CRC) remain largely unknown. METHODS: tRF3008A (a tRFRNA derived from tRNAVal) was identified by RNA sequencing and validated by quantitative reverse transcription PCR. The role of tRF3008A in CRC progression was assessed both in vitro and in vivo, and its downstream target genes were identified and validated in CRC cells. RNA pull-down with mass spectrometry and AGO-RIP were used to confirm the interaction of tRF3008A and AGO proteins. The clinical implications of tRF3008A were assessed in CRC tissues and blood samples. RESULTS: The expression of tRF3008A was reduced in colorectal cancer, and its reduction was significantly correlated with advanced and metastatic disease in CRC. Patients with low tRF3008A expression showed significantly shorter DFS, and multivariate analysis identified tRF3008A as an independent prognostic biomarker in CRC. Functionally, tRF3008A inhibits the proliferation and migration of CRC in vivo and in vitro by repressing endogenous FOXK1, a positive regulator of the Wnt/ß-catenin pathway. Mechanistically, tRF3008A binds to AGO proteins as a guide to destabilize oncogenic FOXK1 transcript. CONCLUSIONS: tRF3008A suppresses the metastasis and progression of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner.