Development and validation of nomograms for predicting prognosis in patients with solitary HCC: A TRIPOD-Compliant study.

Objective: To develop and validate nomograms for predicting the OS and CSS of patients with Solitary Hepatocellular Carcinoma (HCC). Methods: Using the TRIPOD guidelines, this study identified 5206 patients in the Surveillance, Epidemiology, and End Results (SEER) 17 registry database. All patients were randomly divided in a ratio of 7:3 into a training cohort (n = 3646) and a validation cohort (n = 1560), and the Chinese independent cohort (n = 307) constituted the external validation group. The prognosis-related risk factors were selected using univariate Cox regression analysis, and the independent prognostic factors of OS and CSS were identified using the Lasso-Cox regression model. The nomograms for predicting the OS and CSS of the patients were constructed based on the identified prognostic factors. Their prediction ability was evaluated using the concordance index (C-index), receiver operating characteristic (ROC) curve, and calibration curve in both the training and validation cohorts. Results: We identified factors that predict OS and CSS and constructed two nomograms based on the data. The ROC analysis, C-index analysis, and calibration analysis indicated that the two nomograms performed well over the 1, 3, and 5-year OS and CSS periods in both the training and validation cohorts. Additionally, these results were confirmed in the external validation group. Decision curve analysis (DCA) demonstrated that the two nomograms were clinically valuable and superior to the TNM stage system. Conclusion: We established and validated nomograms to predict 1,3, and 5-year OS and CSS in solitary HCC patients, and our results may also be helpful for clinical decision-making.

Genistin: A Novel Estrogen Analogue Targeting ERß to Alleviate Thrombocytopenia.

Thrombocytopenia, a prevalent hematologic challenge, correlates directly with the mortality of numerous ailments. Current therapeutic avenues for thrombocytopenia are not without limitations. Here, we identify genistin, an estrogen analogue, as a promising candidate for thrombocytopenia intervention, discovered through AI-driven compound library screening. While estrogen's involvement in diverse biological processes is recognized, its role in thrombopoiesis remains underexplored. Our findings elucidate genistin's ability to enhance megakaryocyte differentiation, thereby augmenting platelet formation and production. In vivo assessments further underscore genistin's remedial potential against radiation-induced thrombocytopenia. Mechanistically, genistin's efficacy is attributed to its direct interaction with estrogen receptor ß (ERß), with subsequent activation of both ERK1/2 and the Akt signaling pathways membrane ERß. Collectively, our study positions genistin as a prospective therapeutic strategy for thrombocytopenia, shedding light on novel interplays between platelet production and ERß.

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia.

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.

Immune Regulatory Networks and Therapy of γδ T Cells in Liver Cancer: Recent Trends and Advancements.

The roles of γδ T cells in liver cancer, especially in the potential function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines, have aroused research interest. This review briefly describes the basic characteristics of γδ T cells, focusing on their diverse effects on liver cancer. In particular, different subtypes of γδ T cells have diverse or even opposite effects on liver cancer. We provide a detailed description of the immune regulatory network of γδ T cells in liver cancer from two aspects: immune components and nonimmune components. The interactions between various components in this immune regulatory network are dynamic and pluralistic, ultimately determining the biological effects of γδ T cells in liver cancer. We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment, emphasizing the potential of these cells in liver cancer immunotherapy.

Characterization and mitigation of artifacts derived from NGS library preparation due to structure-specific sequences in the human genome.

BACKGROUND: Hybridization capture-based targeted next generation sequencing (NGS) is gaining importance in routine cancer clinical practice. DNA library preparation is a fundamental step to produce high-quality sequencing data. Numerous unexpected, low variant allele frequency calls were observed in libraries using sonication fragmentation and enzymatic fragmentation. In this study, we investigated the characteristics of the artifact reads induced by sonication and enzymatic fragmentation. We also developed a bioinformatic algorithm to filter these sequencing errors. RESULTS: We used pairwise comparisons of somatic single nucleotide variants (SNVs) and insertions and deletions (indels) of the same tumor DNA samples prepared using both ultrasonic and enzymatic fragmentation protocols. Our analysis revealed that the number of artifact variants was significantly greater in the samples generated using enzymatic fragmentation than using sonication. Most of the artifacts derived from the sonication-treated libraries were chimeric artifact reads containing both cis- and trans-inverted repeat sequences of the genomic DNA. In contrast, chimeric artifact reads of endonuclease-treated libraries contained palindromic sequences with mismatched bases. Based on these distinctive features, we proposed a mechanistic hypothesis model, PDSM (pairing of partial single strands derived from a similar molecule), by which these sequencing errors derive from ultrasonication and enzymatic fragmentation library preparation. We developed a bioinformatic algorithm to generate a custom mutation "blacklist" in the BED region to reduce errors in downstream analyses. CONCLUSIONS: We first proposed a mechanistic hypothesis model (PDSM) of sequencing errors caused by specific structures of inverted repeat sequences and palindromic sequences in the natural genome. This new hypothesis predicts the existence of chimeric reads that could not be explained by previous models, and provides a new direction for further improving NGS analysis accuracy. A bioinformatic algorithm, ArtifactsFinder, was developed and used to reduce the sequencing errors in libraries produced using sonication and enzymatic fragmentation.

The immune response of hepatocellular carcinoma after locoregional and systemic therapies: The available combination option for immunotherapy.

Hepatocellular carcinoma (HCC) is associated with a highly heterogeneous immune environment that produces an immune response to various locoregional treatments (LRTs), which in turn affects the effectiveness of immunotherapy. Although LRTs still dominate HCC therapies, 50-60% of patients will ultimately be treated with systemic therapies and might receive those treatments for the rest of their life. TACE, SIRT, and thermal ablation can dramatically increase the immunosuppressive state of HCC, a condition that can be addressed by combination with immunotherapy to restore the activity of lymphocytes and the secretion of cellular immune factors. Immune treatment with locoregional and systemic treatments has dramatically changed the management of HCC. In this review, we examine the research on the changes in the immune microenvironment after locoregional or systemic treatment. We also summarize the regulation of various immune cells and immune factors in the tumor microenvironment and discuss the different infiltration degrees of immune cells and factors on the prognosis of HCC to better compare the efficacy between different treatment methods from the perspective of the tumor microenvironment. This information can be used to help develop treatment options for the upcoming new era of HCC treatment in the future.

Novel synergistically effects of palladium-iron bimetal and manganese carbonate carrier for catalytic oxidation of formaldehyde at room temperature.

The elimination of formaldehyde at room temperature holds immense potential for various applications, and the incorporation of a catalyst rich in surface hydroxyl groups and oxygen significantly enhances its catalytic activity towards formaldehyde oxidation. By employing a coprecipitation method, we successfully achieved a palladium domain confined within the manganese carbonate lattice and doped with iron. This synergistic effect between highly dispersed palladium and iron greatly amplifies the concentration of surface hydroxyl groups and oxygen on the catalyst, thereby enabling complete oxidation of formaldehyde at ambient conditions. The proposed method facilitates the formation of domain-limited palladium within the MnCO3 lattice, thereby enhancing the dispersion of palladium and facilitating its partial incorporation into the MnCO3 lattice. Consequently, this approach promotes increased exposure of active sites and enhances the catalyst's capacity for oxygen activation. The co-doping of iron effectively splits the doping sites of palladium to further enhance its dispersion, while simultaneously modifying the electronic modification of the catalyst to alter formaldehyde's adsorption strength on it. Manganese carbonate exhibits superior adsorption capability for activated surface hydroxyl groups due to the presence of carbonate. In situ infrared testing revealed that dioxymethylene and formate are primary products resulting from catalytic oxidation of formaldehyde, with catalyst surface oxygen and hydroxyl groups playing a crucial role in intermediate product decomposition and oxidation. This study provides novel insights for designing palladium-based catalysts.

BCL11B and the NuRD complex cooperatively guard T-cell fate and inhibit OPA1-mediated mitochondrial fusion in T cells.

The nucleosome remodeling and histone deacetylase (NuRD) complex physically associates with BCL11B to regulate murine T-cell development. However, the function of NuRD complex in mature T cells remains unclear. Here, we characterize the fate and metabolism of human T cells in which key subunits of the NuRD complex or BCL11B are ablated. BCL11B and the NuRD complex bind to each other and repress natural killer (NK)-cell fate in T cells. In addition, T cells upregulate the NK cell-associated receptors and transcription factors, lyse NK-cell targets, and are reprogrammed into NK-like cells (ITNKs) upon deletion of MTA2, MBD2, CHD4, or BCL11B. ITNKs increase OPA1 expression and exhibit characteristically elongated mitochondria with augmented oxidative phosphorylation (OXPHOS) activity. OPA1-mediated elevated OXPHOS enhances cellular acetyl-CoA levels, thereby promoting the reprogramming efficiency and antitumor effects of ITNKs via regulating H3K27 acetylation at specific targets. In conclusion, our findings demonstrate that the NuRD complex and BCL11B cooperatively maintain T-cell fate directly by repressing NK cell-associated transcription and indirectly through a metabolic-epigenetic axis, providing strategies to improve the reprogramming efficiency and antitumor effects of ITNKs.

Dual-Targeting Biomimetic Nanomaterials for Photo-/Chemo-/Antiangiogenic Synergistic Therapy.

Avoiding the low specificity of phototheranostic reagents at the tumor site is a major challenge in cancer phototherapy. Meanwhile, angiogenesis in the tumor is not only the premise of tumor occurrence but also the basis of tumor growth, invasion, and metastasis, making it an ideal strategy for tumor therapy. Herein, biomimetic cancer cell membrane-coated nanodrugs (mBPP NPs) have been prepared by integrating (i) homotypic cancer cell membranes for evading immune cell phagocytosis to increase drug accumulation, (ii) protocatechuic acid for tumor vascular targeting along with chemotherapy effect, and (iii) near-infrared phototherapeutic agent diketopyrrolopyrrole derivative for photodynamic/photothermal synergetic therapy. The mBPP NPs exhibit high biocompatibility, superb phototoxicity, excellent antiangiogenic ability, and double-trigging cancer cell apoptosis in vitro. More significantly, mBPP NPs could specifically bind to tumor cells and vasculature after intravenous injection, inducing fluorescence and photothermal imaging-guided tumor ablation without recurrence and side effects in vivo. The biomimetic mBPP NPs could cause drug accumulation at the tumor site, inhibit tumor neovascularization, and improve phototherapy efficiency, providing a novel avenue for cancer treatment.

The combination of a prolonged treatment time window and alpha-fetoprotein benefits the tumor response of hepatocellular carcinoma patients as evaluated by the imRECIST: a single-center, retrospective study.

Background: The combined immunotargeting therapy of hepatocellular carcinoma (HCC) have brought remarkable results. There are still some drawbacks to the application of the immune-modified Response Evaluation Criteria in Solid Tumors to Immunotherapy (imRECIST). How many weeks does it take to confirm the true disease progression for HCC patients who had reported disease progression for the first time based on imRECIST. Whether alpha-fetoprotein (AFP), an important indicator in the progression and prognosis of liver cancer, has the same value in immunotherapy. This prompted more clinical data to gather evidence that the immunotherapy time window issue contradicts the potential benefit of therapy. Methods: This study retrospectively analyzed the clinical data of 32 patients who had undergone immunotherapy plus targeted therapy at the First Affiliated Hospital of Chongqing Medical University from June 2019 to June 2022. ImRECIST was used to evaluate the therapeutic efficacy among the patients. Before initial treatment and each immunotherapy cycle, each patient underwent standard abdominal computed tomography (CT) imaging and some biochemical indicators to assess physical condition and tumor response. All patients included will be divided into 8 groups. The differences in the survival outcomes of each treatment group were analysed. Results: Among the 32 advanced HCC patients, 9 patients achieved stable disease (SD), 12 patients showed progressive disease (PD), 3 patients showed a complete response (CR), and 8 patients showed a partial response (PR). There is no difference in baseline characteristics between subgroups. In relation to patients with PD, a prolonged therapeutic time window and the provision of continuous medication may lead to a PR, prolonging their overall survival (P=0.5864). Compared to the patients with continuous PD, there was no significant difference in the survival of patients with increased AFP concentrations after treatment who achieved PR or SD and ultimately showed PD (P=0.6600). Conclusions: In our study, the time window for treatment may need to be extended in the process of immunotherapy for HCC patients. An analysis of AFP may assist the imRECIST by providing a more accurate evaluation of tumor progression.

Integrated proteogenomic characterization reveals an imbalanced hepatocellular carcinoma microenvironment after incomplete radiofrequency ablation.

BACKGROUND: Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA. METHODS: Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC. RESULTS: Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of CD4+ T cells, CD4+CD8+ T cells, and CD4+CD25+CD127- Tregs and significantly decreased the levels of CD16+CD56+ natural killer cells on day 5 after cRFA (p < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways. CONCLUSIONS: This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA. TRIAL REGISTRATION: ChiCTR2200055606, http://www.chictr.org.cn/showproj.aspx?proj=32588 .

Reduction-Hypersensitive Podophyllotoxin Prodrug Self-Assembled Nanoparticles for Cancer Treatment.

Podophyllotoxin (PPT) has shown strong antitumor effects on various types of cancers. However, the non-specific toxicity and poor solubility severely limits its clinical transformation. In order to overcome the adverse properties of PPT and explore its clinical potential, three novel PTT-fluorene methanol prodrugs linked by different lengths of disulfide bonds were designed and synthesized. Interestingly, the lengths of the disulfide bond affected the drug release, cytotoxicity, pharmacokinetic characteristics, in vivo biodistribution and antitumor efficacy of prodrug NPs. To be more specific, all three PPT prodrugs could self-assemble into uniform nanoparticles (NPs) with high drug loading (>40%) via the one-step nano precipitation method, which not only avoids the use of surfactants and cosurfactants, but also reduces the systemic toxicity of PPT and increases the tolerated dose. Among the three prodrug NPs, FAP NPs containing α-disulfide bond showed the most sensitive tumor-specific response and fastest drug release rate, thus demonstrating the strongest in vitro cytotoxicity. In addition, three prodrug NPs showed prolonged blood circulation and higher tumor accumulation. Finally, FAP NPs demonstrated the strongest in vivo antitumor activity. Our work will advance the pace of podophyllotoxin towards clinical cancer treatment.

Exosomes derived from human adipose-derived stem cells alleviate hepatic ischemia-reperfusion (I/R) injury through the miR-183/ALOX5 axis.

Ischemia-reperfusion (I/R) injury is a crucial factor causing liver injury in the clinic. Recent research has confirmed that human adipose-derived stem cells (ADSCs) can differentiate into functional hepatocytes. However, the mechanism of the effects of ADSCs in the treatment of liver injury remains unclear. The characteristics of ADSCs were first identified, and exosome-derived ADSCs were isolated and characterized. The function and mechanism of action of miR-183 and arachidonate 5-lipoxygenase (ALOX5) were investigated by functional experiments in HL-7702 cells with I/R injury and in I/R rats. Our data disclosed that exosome release from ADSCs induced proliferation and inhibited apoptosis in HL-7702 cells with I/R injury. The effect of miR-183 was similar to that of exosomes derived from ADSCs. In addition, ALOX5, as a target gene of miR-183, was involved in the related functions of miR-183. Moreover, in vivo experiments confirmed that miR-183 and exosomes from ADSCs could improve liver injury in rats and inhibit the MAPK and NF-κB pathways. All of these findings demonstrate that exosomes derived from ADSCs have a significant protective effect on hepatic I/R injury by regulating the miR-183/ALOX5 axis, which might provide a therapeutic strategy for liver injury.

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases.

Hepatic stellate cells (HSCs) play an essential role in various liver diseases, and exosomes are critical mediators of intercellular communication in local and distant microenvironments. Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells promotes or inhibits the activation of HSCs. Substantial evidence has revealed that HSC-derived exosomes are involved in the occurrence and development of liver diseases through the regulation of retinoid metabolism, lipid metabolism, glucose metabolism, protein metabolism, and mitochondrial metabolism. HSC-derived exosomes are underpinned by vehicle molecules, such as mRNAs and microRNAs, that function in, and significantly affect, the processes of various liver diseases, such as acute liver injury, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, fibrosis, and cancer. As such, numerous exosomes derived from HSCs or HSC-associated exosomes have attracted attention because of their biological roles and translational applications as potential targets for therapeutic targets. Herein, we review the pathophysiological and metabolic processes associated with HSC-derived exosomes, their roles in various liver diseases and their potential clinical application.

Reduction-Responsive Stearyl Alcohol-Cabazitaxel Prodrug Nanoassemblies for Cancer Chemotherapy.

Cabazitaxel (CTX) has distinct therapeutic merits for advanced and metastatic cancer. However, the present clinical formulation (Jevtana®) has several defects, especially for undesirable tumor-targeting and serious side effects, greatly limiting the therapeutic efficacy. Small-molecule prodrug-based nanoassemblies integrate the advantages of both prodrug strategy and nanotechnology, emerging as a promising treatment modality. Herein, disulfide bonds with different lengths were employed as linkages to elaborately synthesize three redox-sensitive stearyl alcohol (SAT)-CTX prodrug-based nanoassemblies (SAC NPs, SBC NPs and SGC NPs) for seeking optimal chemotherapeutical treatment. All the prodrug-based nanoassemblies exhibited impressive drug-loading efficiency, superior self-assembly capability and excellent colloidal stability. Interestingly, the drug release behaviors of three prodrug-nanoassemblies in the same reductive environment were different owing to tiny changes in the carbon chain length of disulfide bonds, resulting in disparate cytotoxicity effects, pharmacokinetic outcomes and in vivo antitumor efficacies. Among them, SAC NPs displayed rapid drug release, excellent cytotoxicity, long blood circulation and enhanced tumor accumulation, thus showing strong tumor inhibition in the 4T1-bearing mouse model. Our study shed light on the vital role of connecting bonds in designing high-efficiency, low-toxicity prodrug nanoassemblies.

A clinical observational study on the application of enhanced recovery after laparoscopic pancreaticoduodenectomy.

Purpose: The safety and feasibility of enhanced recovery after surgery (ERAS) for laparoscopic pancreaticoduodenectomy (LPD) are unclear. The aim of this retrospective clinical study was to evaluate the impact of ERAS protocols for LPD. Patients and methods: Between March 2016 and December 2018, a total of 34 consecutive patients with ERAS for LPD were prospectively enrolled and compared with 68 consecutive patients previously treated for non-ERAS after LPD during an equal time frame. The intraoperative and postoperative data were collected and comparatively analyzed. Results: The mean length of postoperative hospital stay (15.8 ± 3.4 and 23.1 ± 5.1 days, P < 0.001) was reduced significantly in ER group than those in non-ER group. The operation time (462.7 ± 117.0 vs. 450.9 ± 109.8 min, P = 0.627) and intraoperative blood loss (523.5 ± 270.0 vs. 537.5 ± 241.8 ml, P = 0.800) were similar in the two groups. The complications (ER: 32.4% vs. non-ER: 35.3%, P > 0.05) and their severities (Clavien-Dindo grade ≥3 complications, 2 vs. 5 patients; P = 0.783) of patients with ERAS protocols were not increased. No difference in mortality and readmission rates was found. Finally, the total medical costs ($2.1 ± 0.7 × 104 and $2.3 ± 0.7 × 104, P = 0.017) in ER group were lower than those in non-ER group. Conclusion: the ERAS is safe and effective in the perioperative period of LPD. It could effectively reduce the length of postoperative stay and medical costs, and does not increase the incidence of postoperative complications.

[Clinicopathological Features of Meningiomas in Tibet].

Objective To analyze the clinicopathological features and immunohistochemical expression of meningiomas in the Tibetan population in Tibet,and improve the understanding of meningiomas. Methods The clinical and pathological data of all the meningiomas diagnosed by pathology in Tibet Autonomous Region People's Hospital from April 2013 to March 2021 were analyzed retrospectively.All the cases underwent immunohistochemical staining of trimethylation of lysine 27 on histone H3 (H3K27me3),mucin 4 (MUC4),somatostatin receptor 2 (SSTR2),progesterone receptor,epithelial membrane antigen,glial fibrillary acidic protein,vimentin,S-100,P53,and Ki-67.The histopathological features and the staining results were observed under a light microscope. Results A total of 116 cases of meningiomas were included in this study,with the male-to-female ratio of 1.0∶2.6 and the age of 4-73 years.The main clinical symptom was headache.The imaging examination showed that 114 cases had single lesions and 2 cases had multiple lesions.The tumors were located in the cranium (108 cases) and spinal canal (8 cases).The maximum diameter of the tumors ranged from 0.3 cm to 10.0 cm,with a mean of (5.7±2.2) cm.In terms of microscopic grading and histological types,the 116 cases included 111 cases of WHO grade Ⅰ (including 53 cases of fibrous type,20 cases of meningothelial type,24 cases of transitional type,10 cases of psammomatous type,etc.),4 cases of WHO grade Ⅱ (3 cases of atypical type and 1 case of clear cell type),and 1 case of WHO grade Ⅲ (papillary type).The immunohistochemical staining showed H3K27me3 expression absent in 9 cases (9/116,7.8%),MUC4 positive in 64 cases (64/116,55.2%),SSTR2 positive in 101 cases (101/116,87.1%).Eighty cases had follow-up results,among which 71 cases had no recurrence,while 9 cases recurred. Conclusions Meningioma is the most common tumor in the central nervous system in the pathological file of Tibet.It mainly attacks the middle-aged female patients,occupying the parasagittal sinus,falx,and convex surface of the brain.Fibrous meningioma of WHO grade Ⅰ is common,while the meningiomas of WHO grades Ⅱ and Ⅲ are rare.The expression degree of MUC4 is higher in meningothelial and transitional meningiomas but lower in fibrous meningiomas.There may be no correlation between the absence of H3K27me3 expression and prognosis.

A well-matched marriage of immunotherapy and radiofrequency ablation to reduce the relapse and progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a health challenge with increasing incidence worldwide. Radiofrequency ablation (RFA) is a potentially curative option for patients with early-stage HCC. However, the high rate of tumor recurrence limits long-term survival when the tumors are larger than 2 cm and undergoing insufficient RFA (iRFA). Notably, in situ tumor necrosis due to thermal ablation is assumed to be a source of antigens that induce antitumor immunity. Therefore, mounting studies and trials have attempted to provide a rational and effective therapeutic strategy combining RFA and immunotherapy to treat HCC. Nowadays, many controversies and challenges with this combined therapeutic strategy remain to be resolved, such as the indications for adjuvant immunotherapy along with RFA in early HCC, the sequence of the two treatments in advanced HCC, and the optimal timing of immunotherapy before or after RFA. In addition, individualized treatment strategies need to be perfected for patients with HCC.

Hepatic stellate cell exosome-derived circWDR25 promotes the progression of hepatocellular carcinoma via the miRNA-4474-3P-ALOX-15 and EMT axes.

Recently, the emerging role of circular RNAs (circRNAs) in tumor development and progression has been a topic of great interest. Nevertheless, the effects of hepatic stellate cell (HSC)-derived exosomes in hepatocellular carcinoma (HCC) remain unclear. Here, we aim to explore the potential effect of HSC exosome-derived circWDR25 on the aggressiveness of HCC. Firstly, a microarray analysis of circRNAs was performed to profile and identify the differentially expressed circRNAs derived from HSC exosomes activated by HCC cells. Subsequently, the roles of circWDR25 in HCC tumor growth and aggressiveness were confirmed through in vitro and in vivo functional experiments. Moreover, RNA pull-down, dual-luciferase reporter assays, and fluorescent in situ hybridization (FISH) were performed to determine interactions in the circWDR25-miR-4474-3p-ALOX15 loop. Immunohistochemical analysis was also performed on a microarray of HCC tissues and peritumoral tissues. We found that overexpressed peritumoral circWDR25 was associated with survival and recurrence in patients with HCC and promoted the progression of HCC cells both in vitro and in vivo. Mechanistically, both exogenous and HSC exosomal-derived circWDR25 regulated the expression of ALOX15 by sponging miR-4474-3p and ultimately inducing an epithelial-to-mesenchymal transition (EMT) in HCC cells. Moreover, exogenous and HSC exosomal-derived circWDR25 promoted the expression of CTLA-4 in HSCs and PD-L1 in HCC cells. In conclusion, circWDR25 facilitated HCC cell proliferation and invasion via the circWDR25/miR-4474-3p/ALOX15 and EMT axes and it promoted the expression of CTLA-4 in HSCs and PD-L1 in HCC cells, thus providing insights into the mechanism of tumor aggressiveness mediated by HSC-derived exosomal circWDR25.