Prognostic and Immune Landscape Analysis of Ubiquitination-related Genes in Hepatocellular Carcinoma: Based on Bulk and Single-cell RNA Sequencing Data.

Background: Despite significant advances in tumor immunotherapy, hepatocellular carcinoma (HCC) remains a malignancy with a challenging prognosis. The increasing research emphasizes the crucial role of ubiquitination in tumor immunotherapy. However, the establishment of prognostic signatures based on ubiquitination-related genes (UbRGs) and their role in immunotherapy are still lacking in HCC. Methods: We employed datasets from TCGA and GEO for transcriptome differential expression analysis and single-cell RNA sequencing analysis. Applying weighted gene co-expression network analysis, cox regression, lasso, selection and visualization of the most relevant features, and gradient boosting machine, we identified hub UbRGs as a gene signature to develop a prognostic model. We evaluated the predictive utility concerning clinical characteristics as well as its role in the immune landscape and immunotherapy potential. Additionally, western blotting, reverse transcription-quantitative PCR, and immunofluorescence were employed to detect the expression and sub-localization of hub genes. Results: Three hub UbRGs (BOP1, CDC20, and UBE2S) were identified as a gene signature. In particular, the high-risk group exhibited notable characteristics, including higher tumor mutation burden, enrichment in immune-related pathways, up-regulation immune checkpoint, and higher immunity scores. Treatment response to immunotherapy varied based on the expression of PD-1 and CTLA-4. Furthermore, single-cell data analysis revealed heterogeneous expression of hub UbRGs across different cell subtypes, while cytological experiments provided additional confirmation of the high expression of hub UbRGs in HCC. Conclusion: Our study provides valuable insights into the identification of novel ubiquitination-related biomarkers with potential applications for prognosis, immunotherapy prediction, and drug sensitivity in HCC.

Disulfidptosis-related genes of prognostic signature and immune infiltration features in hepatocellular carcinoma supported by bulk and single-cell RNA sequencing data.

Background: Disulfidptosis is a new type of cellular death triggered in response to disulfide stress and is strongly linked to the progression of malignancies. Hepatocellular carcinoma (HCC) is a very common malignancy. Some reports have suggested a link between disulfidptosis-related genes (DRGs) and cancer; however, further research needs to be conducted. Methods: In this study, HCC data from the Cancer Genome Atlas-Liver Hepatocellular Carcinoma and Gene Expression Omnibus data sets were collected and analyzed. A univariate Cox regression analysis, least absolute shrinkage and selection operator, and multivariate Cox regression analysis were conducted to identify the hub DRGs signature for prognosis. The HCC patients were allocated to high- and low-risk groups based on their disulfidptosis risk scores. The model was validated with a high degree of precision using both internal and external validation data sets. "ESTIMATE" and "CIBERSORT" packages were employed to assess the immunological landscapes and immune cell infiltration. The IMvigor210 cohort was chosen to validate the immunotherapy results. A drug sensitivity analysis was conducted to identify targeted medications. The expression of the hub DRGs in the HCC cells was confirmed using cytological techniques. Results: The bioinformatic analysis revealed that 16 genes showed differential expression. A prognostic model was developed based on four genes: RPN1, SLC2A1, SLC2A4, and SLC7A11. A notable difference in prognosis was observed between the two risk groups. Based on the results of the immune microenvironment, tumor mutation burden, immunotherapy, and drug screening analyses, the DRGs signature can be employed in HCC immunotherapy decision making. Further, the expression levels of the hub DRGs were significantly upregulated in the HCC cells. Conclusions: Our four-DRGs signature could be used to predict HCC prognosis. Further, this study showed that the hub DRGs could serve as biomarkers for immunotherapy prediction and could potentially guide targeted therapies.

USP40 promotes hepatocellular carcinoma cell proliferation, migration and stemness by deubiquitinating and stabilizing Claudin1.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignant tumor that poses a major threat to people's lives and health. Previous studies have found that multiple deubiquitinating enzymes are involved in the pathogenesis of HCC. The purpose of this work was to elucidate the function and mechanism of the deubiquitinating enzyme USP40 in HCC progression. METHODS: The expression of USP40 in human HCC tissues and HCC cell lines was investigated using RT-qPCR, western blotting and immunohistochemistry (IHC). Both in vitro and in vivo experiments were conducted to determine the crucial role of USP40 in HCC progression. The interaction between USP40 and Claudin1 was identified by immunofluorescence, co-immunoprecipitation and ubiquitination assays. RESULTS: We discovered that USP40 is elevated in HCC tissues and predicts poor prognosis in HCC patients. USP40 knockdown inhibits HCC cell proliferation, migration and stemness, whereas USP40 overexpression shows the opposite impact. Furthermore, we confirmed that Claudin1 is a downstream gene of USP40. Mechanistically, USP40 interacts with Claudin1 and inhibits its polyubiquitination to stabilize Claudin1 protein. CONCLUSIONS: Our study reveals that USP40 enhances HCC malignant development by deubiquitinating and stabilizing Claudin1, suggesting that targeting USP40 may be a novel approach for HCC therapy.

A novel peroxisome-related gene signature predicts clinical prognosis and is associated with immune microenvironment in low-grade glioma.

Low-grade glioma (LGG), a common primary tumor, mainly originates from astrocytes and oligodendrocytes. Increasing evidence has shown that peroxisomes function in the regulation of tumorigenesis and development of cancer. However, the prognostic value of peroxisome-related genes (PRGs) in LGG has not been reported. Therefore, it is necessary to construct a prognostic risk model for LGG patients based on the expression profiles of peroxisome-related genes. Our study mainly concentrated on developing a peroxisome-related gene signature for overall survival (OS) prediction in LGG patients. First, according to these peroxisome-related genes, all LGG patients from The Cancer Genome Atlas (TCGA) database could be divided into two subtypes. Univariate Cox regression analysis was used to find prognostic peroxisome-related genes in TCGA_LGG dataset, and least absolute shrinkage and selection operator Cox regression analysis was employed to establish a 14-gene signature. The risk score based on the signature was positively associated with unfavorable prognosis. Then, multivariate Cox regression incorporating additional clinical characteristics showed that the 14-gene signature was an independent predictor of LGG. Time-dependent ROC curves revealed good performance of this prognostic signature in LGG patients. The performance about predicting OS of LGG was validated using the GSE107850 dataset derived from the Gene Expression Omnibus (GEO) database. Furethermore, we constructed a nomogram model based on the gene signature and age, which showed a better prognostic power. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses showed that neuroactive ligand-receptor interaction and phagosome were enriched and that the immune status was decreased in the high-risk group. Finally, cell counting kit-8 (CCK8) were used to detect cell proliferation of U251 and A172 cells. Inhibition of ATAD1 (ATPase family AAA domain-containing 1) and ACBD5 (Acyl-CoA binding-domain-containing-5) expression led to significant inhibition of U251 and A172 cell proliferation. Flow cytometry detection showed that ATAD1 and ACBD5 could induce apoptosis of U251 and A172 cells. Therefore, through bioinformatics methods and cell experiments, our study developed a new peroxisome-related gene signature that migh t help improve personalized OS prediction in LGG patients.

Carbon dot nanozymes as free radicals scavengers for the management of hepatic ischemia-reperfusion injury by regulating the liver inflammatory network and inhibiting apoptosis.

BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) is a pathophysiological process during liver transplantation, characterized by insufficient oxygen supply and subsequent restoration of blood flow leading to an overproduction of reactive oxygen species (ROS), which in turn activates the inflammatory response and leads to cellular damage. Therefore, reducing excess ROS production in the hepatic microenvironment would provide an effective way to mitigate oxidative stress injury and apoptosis during HIRI. Nanozymes with outstanding free radical scavenging activities have aroused great interest and enthusiasm in oxidative stress treatment. RESULTS: We previously demonstrated that carbon-dots (C-dots) nanozymes with SOD-like activity could serve as free radicals scavengers. Herein, we proposed that C-dots could protect the liver from ROS-mediated inflammatory responses and apoptosis in HIRI, thereby improving the therapeutic effect. We demonstrated that C-dots with anti-oxidative stress and anti-inflammatory properties improved the survival of L-02 cells under H2O2 and LPS-treated conditions. In the animal model, Our results showed that the impregnation of C-dots could effectively scavenge ROS and reduce the expression of inflammatory cytokines, such as IL-1ß, IL-6, IL-12, and TNF-α, resulting in a profound therapeutic effect in the HIRI. To reveal the potential therapeutic mechanism, transcriptome sequencing was performed and the relevant genes were validated, showing that the C-dots exert hepatoprotective effects by modulating the hepatic inflammatory network and inhibiting apoptosis. CONCLUSIONS: With negligible systemic toxicity, our findings substantiate the potential of C-dots as a therapeutic approach for HIRI, thereby offering a promising intervention strategy for clinical implementation.

Neotuberostemonine and tuberostemonine ameliorate pulmonary fibrosis through suppressing TGF-ß and SDF-1 secreted by macrophages and fibroblasts via the PI3K-dependent AKT and ERK pathways.

Activated fibroblasts and M2-polarized macrophages may contribute to the progression of pulmonary fibrosis by forming a positive feedback loop. This study was aimed to investigate whether fibroblasts and macrophages form this loop by secreting SDF-1 and TGF-ß and the impacts of neotuberostemonine (NTS) and tuberostemonine (TS). Mice were intratracheally injected with 3 U·kg-1 bleomycin and orally administered with 30 mg·kg-1 NTS or TS. Primary pulmonary fibroblasts (PFBs) and MH-S cells (alveolar macrophages) were used in vitro. The animal experiments showed that NTS and TS improved fibrosis related indicators, inhibited fibroblast activation and macrophage M2 polarization, and reduced the levels of TGF-ß and SDF-1 in alveolar lavage fluid. Cell experiments showed that TGF-ß1 may activated fibroblasts into myofibroblasts secreting SDF-1 by activating the PI3K/AKT/HIF-1α and PI3K/PAK/RAF/ERK/HIF-1α pathways. It was also found for the first time that SDF-1 was able to directly polarize macrophages into M2 phenotype secreting TGF-ß through the same pathways as mentioned above. Moreover, the results of the cell coculture confirmed that fibroblasts and macrophages actually developed a feedback loop to promote fibrosis, and the secretion of TGF-ß and SDF-1 was crucial for maintaining this loop. NTS and TS may disturb this loop through inhibiting both the PI3K/AKT/HIF-1α and PI3K/PAK/RAF/ERK/HIF-1α pathways to improve pulmonary fibrosis. NTS and TS are stereoisomeric alkaloids with pyrrole[1,2-a]azapine skeleton, and their effect on improving pulmonary fibrosis may be largely attributed to their parent nucleus. Moreover, this study found that inhibition of both the AKT and ERK pathways is essential for maximizing the improvement of pulmonary fibrosis.

Pituitary adenoma with cavernous sinus compartment penetration and intracranial extension: surgical anatomy, approach, and outcomes.

Objectives: To understand the different characteristics and growth corridors of knosp grade 4 pituitary adenomas (Knosp4PA) with cavernous sinus (CS) compartments penetration and intracranial extension, aiming to improve the safety, effectiveness, and total resection rate of surgery. Methods: A case series of 120 Knosp4PA patients with 187 invaded compartments were retrospectively reviewed. A novel surgery-relevant grading system was proposed according to the CS penetrating features. The details of approach drafting, risk prediction, and complication avoidance were analyzed and integrated through illustrated cases. Results: All enrolled tumor was Knosp4PA which was derived from Knosp subgrades 3A(62.5%) and 3B(37.5%). Based on the tumor growth pathway and its relevant features, five subclassifications of intracranial extension(n=98,81.7%) were classified, which derived from the superior (Dolenc's and Oculomotor subtype, 5% and 24.2%), lateral (Parkinson's subtype,18.3%), and posterior (cerebral peduncle and Dorello's subtype, 5.8% and 1.7%) CS compartment penetration. The size of intracranial extension is assessed by Lou's scale proposed here based on preoperative MRI characteristics. Under Lou's scale, the gross total rate (GTR) decreased (82%, 53%, 22%, and 19%) with grades increased (grade 0,1,2,3, respectively), and presents significant difference between the four groups (p=0.000), as well as between single and multiple compartments involved (p=0.001). Preoperative cranial nerve deficits included the optic nerve (53%), oculomotor nerve (24.2%), and abducent nerve (4.2%), with an overall rate of visual function improvement in 68.1%. Postoperative complications of transient diabetes insipidus, cerebrospinal fluid (CSF) leakage, and cranial nerve deficits were 6.7%, 0.8%, and 0%. No new cranial nerve deficits occurred. The mortality rate was 0.8%. Conclusion: The concept of "penetration" refines the extracavernous growth pattern, and the five intracranial subclassifications help to understand the potential extension corridors, enhancing adequate exposure and targeted resection of Knosp4PA. This grading system may benefit from its predictive and prognostic value, from which a higher GTR rate can be achieved.

Real-world systemic sequential therapy with regorafenib for recurrent hepatocellular carcinoma: analysis of 93 cases from a single center.

BACKGROUND: Regorafenib is an oral multikinase inhibitor and became the first second-line systemic treatment for hepatocellular carcinoma (HCC) following the phase III RESORCE trial. This single-center study retrospectively analyzed the clinical data and follow-up results of patients with recurrent HCC treated with regorafenib and discussed the prognostic factors to provide guidance for clinical treatment. METHODS: Ninety-three recurrent HCC patients were enrolled in the research and follow up from December 2017 to December 2020. Clinical and pathological data were collected. SPSS software v26.0 was used (Chicago, IL, USA) for statistical analysis. A two-sided P < 0.05 was considered statistically significant. RESULTS: The patients included 81 males and 12 females with a median age of 57 years. Eighty-seven patients had hepatitis B virus (HBV) infection. The objective response rate (ORR) was 14.0%, and the disease control rate (DCR) was 62.4%. The median overall survival (mOS) and median time to progression (mTTP) were 15.9 and 5.0 months. Multivariate analysis showed that Child-Pugh classification, the Eastern Cooperative Oncology Group performance status (ECOG PS), the neutrophil-to-lymphocyte ratio (NLR), combined treatment, and the time from first diagnosis of HCC to second-line treatment were independent factors affecting the prognosis of recurrent HCC patients. CONCLUSIONS: This real-world study demonstrated similar findings to those of the RESORCE trial. Regorafenib could effectively improve the prognosis of patients after first-line treatment failure. Combination therapy under multidisciplinary treatment (MDT) team guidance could be effective in impeding tumor progression and improving the prognosis of recurrent HCC patients.

SLC11A1 as a stratification indicator for immunotherapy or chemotherapy in patients with glioma.

Background: Glioma is a fatal tumor originating from the brain, which accounts for most intracranial malignancies. Currently, Immunotherapy has turned into a novel and promising treatment in glioma patients. however, there are still few effective biomarkers to mirror the reaction to immunotherapy in patients with glioma. Therefore, we intended to elucidate the evaluable efficacy of SLC11A1 in glioma patients. Methods: In this study, samples from Shanghai General Hospital and data from TCGA, GEO, CGGA datasets were used to investigate and validate the relationship between SLC11A1 and the progression of glioma. We evaluated the predictive value of SLC11A1 on the prognosis of glioma with cox regression analysis. Then the relationship between immune infiltration and SLC11A1 was also analyzed. Ultimately, we performed the prediction on the immunotherapeutic response and therapeutic drugs according to the expression of SLC11A1. Results: Expression of SLC11A1 increased with progression and predicted unfavorable prognosis for glioma patients. The hazard ratio for SLC11A1 expression was 2.33 with 95% CI (1.92-2.58) (P < 0.001) in cox analysis. And based on expression, we found SLC11A1 stratified glioma patients into subgroups with different immune activation statuses. Moreover, we observed that patients with higher SLC11A1 levels companied with better immunotherapeutic response, while those with lower SLC11A1 levels may respond better to temozolomide. Conclusion: This study provided evidence that SLC11A1 was a novel prognostic marker and immunotherapy response indicator for gliomas. In some cases, SLC11A1 could be an effective marker for identifying patients who might benefit from immunotherapy or chemotherapy.

SARS-CoV-2 down-regulates ACE2 through lysosomal degradation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its Spike (S) glycoprotein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry. ACE2 is a critical negative regulator of the renin-angiotensin system and plays a protective role in preventing tissue injury. Expression of ACE2 has been shown to decrease upon infection by SARS-CoV. However, whether SARS-CoV-2 down-regulates ACE2 and the underlying mechanism and biological impact of this down-regulation have not been well defined. Here we show that the SARS-CoV-2 infection down-regulates ACE2 in vivo in an animal model, and in cultured cells in vitro, by inducing clathrin- and AP2-dependent endocytosis, leading to its degradation in the lysosome. SARS-CoV-2 S-treated cells and ACE2 knockdown cells exhibit similar alterations in downstream gene expression, with a pattern indicative of activated cytokine signaling that is associated with respiratory distress and inflammatory diseases often observed in COVID-19 patients. Finally, we have identified a soluble ACE2 fragment with a stronger binding to SARS-CoV-2 S that can efficiently block ACE2 down-regulation and viral infection. Thus, our study suggests that ACE2 down-regulation represents an important mechanism underlying SARS-CoV-2-associated pathology, and blocking this process could be a promising therapeutic strategy.

Corrigendum: Endoscope-Assisted Retrosigmoid Approach for Vestibular Schwannomas with Intracanalicular Extensions: Facial Nerve Outcomes.

[This corrects the article DOI: 10.3389/fonc.2021.774462.].

Association Rule Analysis of Influencing Factors of Literature Curriculum Interest Based on Data Mining.

In recent years, the amount of educational data in colleges and universities has increased rapidly. Each university has set up multiple courses to recruit talents. Students cannot choose courses. The emergence of data mining technology and its application in college teaching and curriculum has been preferred particularly to streamline these activities. When analyzing the correlation of courses based on data mining technology, we usually use the correlation between the scores of various subjects to analyze the correlation between courses. Correlation among various courses that are offered at colleges or universities is reflected through many different aspects such as factors or metrics, which are affecting course interest, course content, course arrangement, etc. In this article, we have thoroughly analyzed various factors that are affecting students' interest in literature courses with the help of association rules of data mining technology. Through the collected original data, this article uses Apriori algorithm to screen the association rules affecting students' interest in literature courses and combines them with the current teaching situation to complete the rule analysis. The results of rule analysis show that the most relevant factors affecting students' interest in literature curriculum mainly include the space-time dimension of textbook selection and compilation, the processing method of selected reading, and the evaluation method. The reading content is effectively processed by using the counterpoint reading method, and the literature curriculum textbooks are compiled from the perspective of cross-cultural communication, to enhance students' interest in the literature curriculum.

Assessing the potential to use CDOM as an indicator of water quality for the sediment-laden Yellow river, China.

Chromophoric dissolved organic matter (CDOM) in rivers is mainly affected by natural conditions and human activities and can reflect the watershed pollution status to a certain extent. The Yellow River is one of the largest contributors to the global riverine sediment flux from the land to ocean, and there is a paucity of information on how the optical properties of CDOM have the potential to serve as an indicator of water quality for the sediment-laden Yellow River. In this study, a three-dimensional fluorescence parallel factor (PARAFAC) analysis method was applied to investigate the seasonal and spatial variations in CDOM fluorescence components and spectral characteristics from the source region to the estuary in the mainstream of Yellow River. The relationships of CDOM with water quality indicators and trophic state were also analyzed. Six PARAFAC components (C1-C6) were identified and grouped into two categories: humic-like components (C1-C4), which accounted for 85.8 %, and protein-like components (C5 and C6), which accounted for only 14.2 %. The CDOM components, spectral parameters, and their clear correlations with the main ions (Na+ and Cl-) all indicated that the humic-like components may be primarily derived from nonpoint source erosion, and the protein-like components were mainly derived from point source discharges in the watershed. The combination of the CDOM absorption coefficient at 254 nm (a(254)), spectral slope ratio (SR), specific UV absorbance SUVA254, and fluorescence index (FI) had a good predictive ability for the key water quality indicators (total nitrogen (TN), dissolved total nitrogen (DTN), total phosphorus (TP), dissolved total phosphorus (DTP), and chlorophyll a (Chl a)) and trophic state index (TSI). Therefore, some fluorophores and UV spectral parameters of CDOM in the Yellow River can be used for rapid water quality monitoring and pollution source indication, especially pollutants related to nitrogen and phosphorus nutrients in the basin.

The Phenomenon of Gene Rearrangement is Frequently Associated with TP53 Mutations and Poor Disease-Free Survival in Hepatocellular Carcinoma.

PURPOSE: Gene rearrangements (GRs) have been reported to be related to adverse prognosis in some tumours, but the relationship in hepatocellular carcinoma (HCC) remains less studied. The objective of our study was to explore the clinicopathological characteristics and prognosis of HCC patients (HCCs) with GRs (GR-HCCs). PATIENTS AND METHODS: This retrospective study included 297 HCCs who underwent hepatectomy and had their tumours sequenced by next-generation sequencing. Categorical variables between groups were compared by the chi-square test. The impact of variables on disease-free survival (DFS) and survival after relapse (SAR) was analysed by the Kaplan-Meier method and Cox regression. RESULTS: We observed four repetitive GR events in 297 HCCs: BRD9/TERT, ARID2/intergenic, CDKN2A/intergenic and OBSCN truncation. GR-HCCs frequently presented with low tumour differentiation, tumour necrosis, microvascular invasion, elevated AFP and gene mutations (TP53, NTRK3 and BRD9). The 1-, 2-, and 3-year cumulative DFS rates in GR-HCCs were 45.1%, 31.9%, 31.9%, respectively, which were significantly lower than those of GR-negative HCCs (NGR-HCCs) (72.5%, 57.9%, and 49.0%, respectively; P = 0.001). GR was identified as an independent risk factor for inferior DFS in HCCs (HR = 1.980, 95% CI = 1.246-3.147; P = 0.004). However, there was no significant difference in SAR between GR-HCCs and NGR-HCCs receiving targeted therapy or immunotherapy. CONCLUSION: GR is frequently associated with TP53 mutations and significantly affects DFS following radical resection for HCC. We recommend that GR-HCCs should be closely followed up as a high-risk group for postoperative recurrence.

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17.

Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion. Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo. Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs. Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.

TSC2 Mutations Were Associated with the Early Recurrence of Patients with HCC Underwent Hepatectomy.

PURPOSE: To explore the value of Tuberous sclerosis complex 2 (TSC2) mutations in evaluating the early recurrence of hepatocellular carcinoma (HCC) patients underwent hepatectomy. PATIENTS AND METHODS: A total of 183 HCC patients were enrolled. Next-generation sequencing was performed on tumor tissues to analyze genomic alterations, tumor mutational burden and variant allele fraction (VAF). The associations between TSC2 mutations and recurrence rate within 1 year, RFS and OS after hepatectomy were analyzed. RESULTS: Our results showed that TSC2 mutation frequency in HCC was 12.6%. Compared to patients without TSC2 mutation, the proportion of microvascular invasion (MVI) and Edmondson grade III-IV was significantly higher in patients with a TSC2 mutation (p<0.05). The VAF of mutated TSC2 was higher in patients with maximum diameter of tumor >5cm or MVI than that of other patients (p<0.05). The frequency of TP53 mutation was significantly higher in patients with a TSC2 mutation than those without TSC2 mutation (p=0.003). Follow-up analysis showed that patients with a TSC2 mutation had significantly higher recurrence rate within 1 year (p=0.015) and poorer median recurrence-free survival (RFS) (p=0.010) than patients without TSC2 mutation. TSC2 mutations did not significantly affect overall survival of patients (p=0.480). The multivariate analysis results showed that the Barcelona Clinic Liver Cancer (BCLC) B-C stage, TSC2 mutations and preoperative serum alpha-fetoprotein level ≥400µg/L were independently associated with recurrence within 1 year after hepatectomy (HR=8.628, 95% CI: 3.836-19.405, p=0.000; HR=3.885, 95% CI: 1.295-11.653, p=0.015; HR=2.327, 95% CI: 1.018-5.323, p=0.045; respectively), and poorer RFS after hepatectomy (HR=3.070, 95% CI: 1.971-4.783, p=0.000; HR=1.861, 95% CI: 1.061-3.267, p=0.030; HR=1.715, 95% CI: 1.093-2.693, p=0.019; respectively). CONCLUSION: TSC2 mutations were significantly associated with MVI in liver para-carcinoma tissue and Edmondson grade III-IV in patients with HCC and were independently associated with recurrence within 1 year and poorer RFS after hepatectomy. The TSC2 mutation may be a potential predictor for early recurrence in HCC patients underwent hepatectomy.

Prognostic and predictive value of FCER1G in glioma outcomes and response to immunotherapy.

PURPOSE: Glioma is the most prevalent malignant form of brain tumors, with a dismal prognosis. Currently, cancer immunotherapy has emerged as a revolutionary treatment for patients with advanced highly aggressive therapy-resistant tumors. However, there is no effective biomarker to reflect the response to immunotherapy in glioma patient so far. So we aim to assess the clinical predictive value of FCER1G in patients with glioma. METHODS: The expression level and correlation between clinical prognosis and FER1G levels were analyzed with the data from CGGA, TCGA, and GEO database. Univariate and multivariate cox regression model was built to predict the prognosis of glioma patients with multiple factors. Then the correlation between FCER1G with immune cell infiltration and activation was analyzed. At last, we predict the immunotherapeutic response in both high and low FCER1G expression subgroups. RESULTS: FCER1G was significantly higher in glioma with greater malignancy and predicted poor prognosis. In multivariate analysis, the hazard ratio of FCER1G expression (Low versus High) was 0.66 and 95 % CI is 0.54 to 0.79 (P < 0.001), whereas age (HR = 1.26, 95 % CI 1.04-1.52), grade (HR = 2.75, 95 % CI 2.06-3.68), tumor recurrence (HR = 2.17, 95 % CI 1.81-2.62), IDH mutant (HR = 2.46, 95 % CI 1.97-3.01) and chemotherapeutic status (HR = 1.4, 95 % CI 1.20-1.80) are also included. Furthermore, we illustrated that gene FCER1G stratified glioma cases into high and low FCER1G expression subgroups that demonstrated with distinct clinical outcomes and T cell activation. At last, we demonstrated that high FCER1G levels presented great immunotherapeutic response in glioma patients. CONCLUSIONS: This study demonstrated FCER1G as a novel predictor for clinical diagnosis, prognosis, and response to immunotherapy in glioma patient. Assess expression of FCER1G is a promising method to discover patients that may benefit from immunotherapy.

Endoscope-Assisted Retrosigmoid Approach for Vestibular Schwannomas With Intracanalicular Extensions: Facial Nerve Outcomes.

OBJECTIVE: To explore the role of neuroendoscope assistance during surgical resection of the intracanalicular portion of vestibular schwannomas via the retrosigmoid approach and the subsequent early facial nerve outcomes. METHODS: Patients of vestibular schwannoma with intracanalicular extensions undergoing retrosigmoid dissection at a single institution were retrospectively analyzed in this study. Several surgical techniques were applied to ensure maximal and safe removal of tumors. Tumors extending less than 10 mm into the internal acoustic canal (IAC) were classified as Grade A, while those extending over 10 mm into IAC were taken as Grade B. Neuroendoscope was applied at the end of microscopic phase to search for potential remnants for Grade B tumors. Absolute tumor extension was defined and measured. House and Brackmann (HB) scale was used to evaluate immediate CN VII outcomes. RESULTS: Of the 61 patients, there were 38 females and 23 males. A total of 18 (29.51%) cases were Koos Grade II, 12 (19.67%) cases Koos Grade III, and 31 (50.82%) cases Koos Grade IV. There were 38 cases (62.30%) of Grade A and 23 cases (37.70%) of Grade B. Gross total resection was achieved in 60 cases (98.36%). Four cases of intracanalicular remnants were detected and completely removed under endoscopic visualizations. There was a significantly higher proportion (17%, p = 0.02) of intracanalicular remnants in Grade B than Grade A. CN VII and VIII were anatomically preserved in all cases. A total of 55 cases (90.16%) retained good (HB Grades 1 and 2) facial nerve outcomes. CONCLUSIONS: In Grade B vestibular schwannomas, after maximal microsurgical removal, endoscopic evaluation of the intracanalicular portion revealed residual tumors in 17% of the patients. Hence endoscopic evaluation of the potential intracanalicular remnants for tumor extending over 10 mm within IAC (Grade B) is recommended.

Endoscopic endonasal resection of sinonasal teratocarcinosarcoma with intracranial breakthrough: illustrative case.

BACKGROUND: Teratocarcinosarcoma traversing the anterior skull base is rarely reported in literature. The heterogenous and invasive features of the tumor pose challenges for surgical planning. With technological advancements, the endoscopic endonasal approach (EEA) has been emerging as a workhorse of anterior skull base lesions. To date, no case has been reported of EEA totally removing teratocarcinosarcomas with intracranial extensions. OBSERVATIONS: The authors provided an illustrative case of a 50-year-old otherwise healthy man who presented with left-sided epistaxis for a year. Imaging studies revealed a 31 × 60-mm communicating lesion of the anterior skull base. Gross total resection via EEA was achieved, and multilayered skull base reconstruction was performed. LESSONS: The endoscopic approach may be safe and effective for resection of extensive teratocarcinosarcoma of the anterior skull base. To minimize the risk of postoperative cerebrospinal fluid leaks, multilayered skull base reconstruction and placement of lumbar drainage are vitally important.

Small extracellular vesicles secreted by human iPSC-derived MSC enhance angiogenesis through inhibiting STAT3-dependent autophagy in ischemic stroke.

BACKGROUND: Small extracellular vesicles (sEV) secreted by mesenchymal stem cells (MSC) derived from human induced pluripotent stem cells (iPSC, iMSC-sEV) are considered to have great potential in treating ischemic diseases. Angiogenesis play an important role in post-stroke recovery. However, no studies have yet been conducted to systemically examine the effect and the underlying mechanism of iMSC-sEV on angiogenesis under brain ischemia conditions. METHODS: Ischemic stroke model was performed in rats induced by middle cerebral artery occlusion (MCAO), and the pro-angiogenic capacity of iMSC-sEV was measured. The in vitro effects of iMSC-sEV on the migration and tube formation of endothelial cells were investigated, respectively. Autophagy and autophagy-related signaling pathway were detected in vivo and in vitro. RESULTS: We found that iMSC-sEV significantly reduced infarct volume, enhanced angiogenesis, and alleviated long-term neurological deficits in rats after stroke. We also demonstrated that iMSC-sEV increased migration and tube formation of endothelial cells in vitro. A further mechanism study revealed that the pro-angiogenic effect of iMSC-sEV was correlated with a reduction in autophagy. Furthermore, iMSC-sEV significantly activated signal transducer and activator of transcription 3 (STAT3), and suppression of STAT3 abolished iMSC-sEV-induced inhibition of autophagy and promotion of angiogenesis in vivo and in vitro. CONCLUSIONS: Taken together, our data indicate that iMSC-sEV promote angiogenesis after ischemic stroke, potentially, by inhibiting autophagy, a process that is partially dependent on STAT3 activation.