BaP/BPDE suppresses human trophoblast cell migration/invasion and induces unexplained miscarriage by up-regulating a novel lnc-HZ11 in extracellular vesicles: An intercellular study.

Extracellular vesicles (EVs) mediate the intercellular crosstalk by transferring functional cargoes. Recently, we have discovered that BaP/BPDE exposure suppresses trophoblast cell migration/invasion and induces miscarriage, which are also regulate by lncRNAs at intracelluar levels. However, the EVs-mediated intercellular regulatory mechanisms are completely unexplored. Specifically, whether EVs might transfer BPDE-induced toxic lncRNA to fresh recipient trophoblast cells and suppress their migration/invasion to further induce miscarriage is completely unknown. In this study, we find that BPDE exposure up-regulates a novel lnc-HZ11, which suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion of trophoblast cells. Intercellular studies show that EV-HZ11 (lnc-HZ11 in EVs), which is highly expressed in BPDE-exposed donor cells, suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion in recipient cells by transferring lnc-HZ11 through EVs. Analysis of villous tissues collected from UM (unexplained miscarriage) patients and HC (healthy control) group shows that the levels of BPDE-DNA adducts, lnc-HZ11 or EV-lnc-HZ11, and EGR1/NF-κB/CXCL12 pathway are all associated with miscarriage. Mouse assays show that BaP exposure up-regulates the levels of lnc-Hz11 or EV-Hz11, suppresses Egr1/Nf-κb/Cxcl12 pathway, and eventually induces miscarriage. Knockdown of lnc-Hz11 by injecting EV-AS-Hz11 could effectively alleviate miscarriage in BaP-exposed mice. Furthermore, EV-HZ11 in serum samples could well predict the risk of miscarriage. Collectively, this study not only discovers EVs-HZ11-mediated intercellular mechanisms that BaP/BPDE suppresses trophoblast cell migration/invasion and induces miscarriage but also provides new approach for treatment against unexplained miscarriage through EV-HZ11.

Construction of 5-Fluorouracil and Gallium Corrole Conjugates for Enhanced Photodynamic Therapy.

Molecular hybridization is a well-established strategy for developing new drugs. In the pursuit of promising photosensitizers (PSs) with enhanced photodynamic therapy (PDT) efficiency, a series of novel 5-fluorouracil (5FU) gallium corrole conjugates (1-Ga-4-Ga) were designed and synthesized by hybridizing a chemotherapeutic drug and PSs. Their photodynamic antitumor activity was also evaluated. The most active complex (2-Ga) possesses a low IC50 value of 0.185 µM and a phototoxic index of 541 against HepG2 cells. Additionally, the 5FU-gallium corrole conjugate (2-Ga) exhibited a synergistic increase in cytotoxicity under irradiation. Excitedly, treatment of HepG2 tumor-bearing mice with 2-Ga under irradiation could completely ablate tumors without harming normal tissues. 2-Ga-mediated PDT could disrupt mitochondrial function, cause cell cycle arrest in the sub-G1 phase, and activate the cell apoptosis pathway by upregulating the cleaved PARP expression and the Bax/Bcl-2 ratios. This work provides a useful strategy for the design of new corrole-based chemo-photodynamic therapy drugs.

A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness.

BACKGROUND: Due to the high mortality and disability rate of intracranial hemorrhage, headache is not the main focus of research on cerebral arteriovenous malformation (AVM), so research on headaches in AVM is still scarce, and the clinical understanding is shallow. This study aims to delineate the risk factors associated with headaches in AVM and to compare the effectiveness of various intervention treatments versus conservative treatment in alleviating headache symptoms. METHODS: This study conducted a retrospective analysis of AVMs who were treated in our institution from August 2011 to December 2021. Multivariable logistic regression analysis was employed to assess the risk factors for headaches in AVMs with unruptured, non-epileptic. Additionally, the effectiveness of different intervention treatments compared to conservative management in alleviating headaches was evaluated through propensity score matching (PSM). RESULTS: A total of 946 patients were included in the analysis of risk factors for headaches. Multivariate logistic regression analysis identified that female (OR 1.532, 95% CI 1.173-2.001, p = 0.002), supply artery dilatation (OR 1.423, 95% CI 1.082-1.872, p = 0.012), and occipital lobe (OR 1.785, 95% CI 1.307-2.439, p < 0.001) as independent risk factors for the occurrence of headaches. There were 443 AVMs with headache symptoms. After propensity score matching, the microsurgery group (OR 7.27, 95% CI 2.82-18.7 p < 0.001), stereotactic radiosurgery group(OR 9.46, 95% CI 2.26-39.6, p = 0.002), and multimodality treatment group (OR 8.34 95% CI 2.87-24.3, p < 0.001) demonstrate significant headache relief compared to the conservative group. However, there was no significant difference between the embolization group (OR 2.24 95% CI 0.88-5.69, p = 0.091) and the conservative group. CONCLUSIONS: This study identified potential risk factors for headaches in AVMs and found that microsurgery, stereotactic radiosurgery, and multimodal therapy had significant benefits in headache relief compared to conservative treatment. These findings provide important guidance for clinicians when developing treatment options that can help improve overall treatment outcomes and quality of life for patients.

Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer.

Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.

Bulk and single cells transcriptomes with experimental validation identify USP18 as a novel glioma prognosis and proliferation indicator.

The mechanism by which ubiquitin-specific protease 18 (USP18) (enzyme commission: 3.4.19.12) inhibition in cancer promotes cell pyroptosis via the induction of interferon (IFN)-stimulated genes has been recently demonstrated. It is also known that USP18 influences the epithelial-mesenchymal transition of glioma cells. In the present study, the upregulation of USP18 in glioma was revealed through bulk transcriptome analysis, which was associated with poor prognosis in patients with glioma. Furthermore, USP18 levels affected the response to immunotherapy in patients with glioma. Single-cell transcriptome and enrichment analyses demonstrated that USP18 was associated with type 1 IFN responses in glioma T cells. To demonstrate the effect of USP18 expression levels on glioma cells, USP18 expression was knocked down in U251 and U87MG ATCC cell lines. A subsequent Cell Counting Kit-8 assay revealed that glioma cell viability was significantly decreased 4 days after USP18 knockdown. In addition, the knockdown of USP18 expression significantly inhibited the clonogenicity of U251 and U87MG ATCC cells. In conclusion, the present study demonstrated that knockdown of USP18 expression inhibited the proliferation of glioma cells, which may be mediated by the effect of USP18 on the IFN-I response.

Integrated bioinformatics analysis and experimental validation identified CDCA families as prognostic biomarkers and sensitive indicators for rapamycin treatment of glioma.

The cell division cycle associated (CDCA) genes regulate the cell cycle; however, their relationship with prognosis in glioma has been poorly reported in the literature. The Cancer Genome Atlas (TCGA) was utilized to probe the CDCA family in relation to the adverse clinical features of glioma. Glioma single-cell atlas reveals specific expression of CDCA3, 4, 5, 8 in malignant cells and CDCA7 in neural progenitor cells (NPC)-like malignant cells. Glioma data from TCGA, the China Glioma Genome Atlas Project (CGGA) and the gene expression omnibus (GEO) database all demonstrated that CDCA2, 3, 4, 5, 7 and 8 are prognostic markers for glioma. Further analysis identified CDCA2, 5 and 8 as independent prognostic factors for glioma. Lasso regression-based risk models for CDCA families demonstrated that high-risk patients were characterized by high tumor mutational burden (TMB), low levels of microsatellite instability (MSI), and low tumor immune dysfunction and rejection (TIDE) scores. These pointed to immunotherapy for glioma as a potentially viable treatment option Further CDCA clustering suggested that the high CDCA subtype exhibited a high macrophage phenotype and was associated with a higher antigen presentation capacity and high levels of immune escape. In addition, hsa-mir-15b-5p was predicted to be common regulator of CDCA3 and CDCA4, which was validated in U87 and U251 cells. Importantly, we found that CDCAs may indicate response to drug treatment, especially rapamycin, in glioma. In summary, our results suggest that CDCAs have potential applications in clinical diagnosis and as drug sensitivity markers in glioma.

DTX2 promotes glioma development via regulation of HLTF.

BACKGROUND: Human Deltex 2 (DTX2) is a ubiquitin E3 ligase that functions as an oncogene and has been shown to participate in many human cancers. However, the role of DTX2 in glioma progression has remained obscure. In this study, we explore the mechanism underlying the function of DTX2 in glioma progression. METHODS: The associations between DTX2 expression and clinical characteristics of glioma were determined by bioinformatic analysis of data from The Cancer Genome Atlas and Human Protein Atlas. The expression of DTX2 in glioma tissues was detected using immunohistochemistry and western blotting. Lentivirus-mediated gene knockdown and overexpression were used to determine the effects of DTX2 and helicase-like transcription element (HLTF) on glioma cell proliferation and migration with CCK-8, cell colony formation, transwell, and wound healing assays; flow cytometry in vitro; and animal models in vivo. The interaction of the DTX2 and HLTF proteins was verified by immunoprecipitation assay and confocal microscopy. RESULTS: DTX2 was highly expressed in glioma samples, and this was correlated with worse overall survival. Silencing of DTX2 suppressed glioma cell viability, colony formation, and migration and induced cell apoptosis. In vitro ubiquitination assays confirmed that DTX2 could downregulate HLTF protein levels by increasing ubiquitination of the HLTF protein. We also observed that HLTF inhibited proliferation and migration of glioma cells. Subcutaneous xenografts with DTX2-overexpressing U87 cells showed significantly increased tumor volumes and weights. CONCLUSIONS: We have identified DTX2/HLTF as a new axis in the development of glioma that could serve as a prognostic or therapeutic marker.

Azide-modified corrole phosphorus complexes for endoplasmic reticulum-targeted fluorescence bioimaging and effective cancer photodynamic therapy.

Study on corrole photosensitizers (PSs) for photodynamic therapy (PDT) has made remarkable progress. Targeted delivery of PSs is of great significance for enhancing therapeutic efficiency, decreasing the dosage, and reducing systemic toxicity during PDT. The development of PSs that can be specifically delivered to the subcellular organelle is still an attractive and challenging work. Herein, we synthesize a series of azide-modified corrole phosphorus and gallium complex PSs, in which phosphorus corrole 2-P could not only precisely target the endoplasmic reticulum (ER) with a Pearson correlation coefficient (PCC) up to 0.92 but also possesses the highest singlet oxygen quantum yields (ΦΔ = 0.75). This renders it remarkable PDT activity at a very low dosage (IC50 = 23 nM) towards HepG2 tumor cell line while ablating solid tumors in vivo with excellent biosecurity. Furthermore, 2-P exhibits intense red fluorescence (ΦF = 0.25), outstanding photostability, and a large Stokes shift (190 nm), making it a promising fluorescent probe for ER. This study provides a clinically potential photosensitizer for cancer photodynamic therapy and a promising ER fluorescent probe for bioimaging.

Estimation of annual soil CO2 efflux under the erosion and deposition conditions by measuring and modeling its respiration rate in southern China.

Soil respiration (Rs) is a crucial ecological process of carbon (C) cycling in the terrestrial ecosystems, and soil erosion has a significant impact on its C budget and balance. However, the variations of Rs rate and their CO2 efflux induced by erosion are currently poorly understood. To this end, four landscape positions (top, up, middle and toe) with different erosional and depositional characteristics were selected on a typical eroded slope in southern China to conduct field experiments, aiming to explore the effects of erosion and deposition on Rs among various sites. From March 2021 to February 2022, the in-situ Rs were measured using an automated soil respiration system, together with soil temperature at 5 cm depth (Ts5) and water content at 10 cm depth (SWC10). We initially constructed various Rs models across a one-year period, based on its relationships with Ts5 and SWC10. Subsequently, the seasonal changes of Rs at different erosional sites were simulated by the optimum models, and their annual CO2 fluxes were further estimated. The results showed that Rs rates at all sites displayed a bimodal seasonal pattern, with the highest values in May and August. And the measured Rs of the eroding and depositional sites were 0.05-7.71 and 1.47-13.03 µmol m-2 s-1, respectively. Also, remarkably higher Ts5 and SWC10 were observed in depositional sites versus the eroding sites (P < 0.05). Additionally, Rs rates at all sites were positively correlated with SOC and Ts5, but negatively correlated with SWC10. Herein, Rs models to single- and double-variable were established at different positions, and we found that the fitted R2 and AIC differed on various sites, primarily in erosional and depositional sites. Furthermore, through the best-fitting models (higher R2 and lowest AIC) we screened, the average Rs values of 3.03 and 4.46 µmol m-2 s-1 were quantitatively estimated for the eroding and depositional sites, respectively. Finally, it could be further assessed that the mean annual soil CO2-C efflux of eroded site (1104.14 g m-2) was significantly lower than that of depositional site (1629.46 g m-2). These findings highlighted the effect of erosion and deposition on Rs, which will facilitate a better understanding of C cycling in terrestrial ecosystems.

Long-Term Effects of Ecological Restoration Projects on Ecosystem Services and Their Spatial Interactions: A Case Study of Hainan Tropical Forest Park in China.

Ecological restoration projects aim to comprehensively intervene in damaged or deteriorating ecosystems, restore them, improve the provision of ecosystem services, and achieve harmonious coexistence between humans and nature. Implementing ecological restoration projects leads to continuous changes in land use/land cover. Studying the long-term changes in land use/land cover and their impacts on ecosystem services, as well as the trade-off and synergy between these services, helps evaluate the long-term effectiveness of ecological restoration projects in restoring ecosystems. Therefore, this study analyzes the land use/land cover, and ecosystem services of the Hainan Tropical Forest Park in China to address this. Since 2000, the area has undergone multiple ecological restoration projects, divided roughly into two stages: 2003-2013 and 2013-2021. The InVEST model is used to quantify three essential ecosystem services in mountainous regions (water yield, carbon storage, and soil conservation), and redundancy analysis identifies the primary driving factors influencing their changes. We conducted spatial autocorrelation analysis to examine the interplay among ecosystem services under long-term land use/land cover change. The results indicate a decrease in the total supply of water yield (-5.14%) and carbon storage (-3.21%) in the first phase. However, the second phase shows an improvement in ecosystem services, with an increase in the total supply of water yield (11.45%), carbon storage (27.58%), and soil conservation (21.95%). The redundancy analysis results reveal that land use/land cover are the primary driving factors influencing the changes in ecosystem services. Furthermore, there is a shift in the trade-off and synergy between ecosystem services at different stages, with significant differences in spatial distribution. The findings of this study provide more spatially targeted suggestions for the restoration and management of tropical montane rainforests in the future.

Recurrence of Cerebral Arteriovenous Malformation Following Complete Obliteration Through Endovascular Embolization.

Arteriovenous malformation (AVM) recurrence after embolization was rarely reported. This study aimed to explore the potential risk factors of recurrence in angiographically obliterated AVMs treated with endovascular embolization. This study reviewed AVMs treated with embolization only in a prospective multicenter registry from August 2011 to December 2021, and ultimately included 92 AVMs who had achieved angiographic obliteration. Recurrence was assessed by follow-up digital subtraction angiography (DSA) or magnetic resonance imaging (MRI). Hazard ratios (HRs) with 95% confidence intervals were calculated using Cox proportional hazards regression models. Nineteen AVMs exhibited recurrence on follow-up imaging. The recurrence rates after complete obliteration at 6 months, 1 year, and 2 years were 4.35%, 9.78%, and 13.0%, respectively. Multivariate Cox regression analysis identified diffuse nidus (HR 3.208, 95% CI 1.030-9.997, p=0.044) as an independent risk factor for recurrence. Kaplan-Meier analysis confirmed a higher cumulative risk of recurrence with diffuse nidus (log-rank, p=0.016). Further, in the exploratory analysis of the effect of embolization timing after AVM rupture on recurrence after the complete obliteration, embolization within 7 days of the hemorrhage was found as an independent risk factor (HR 4.797, 95% CI 1.379-16.689, p=0.014). Kaplan-Meier analysis confirmed that embolization within 7 days of the hemorrhage was associated with a higher cumulative risk of recurrence in ruptured AVMs (log-rank, p<0.0001). This study highlights the significance of diffuse nidus as an independent risk factor for recurrence after complete embolization of AVMs. In addition, we identified a potential recurrent risk associated with early embolization in ruptured AVMs.

Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance.

Posttranslational modification dramatically enhances protein complexity, but the function and precise mechanism of novel lysine acylation modifications remain unknown. Chemoresistance remains a daunting challenge to successful treatment. We found that lysine butyrylation (Kbu) is specifically upregulated in chemoresistant tumor cells and tissues. By integrating butyrylome profiling and gain/loss-of-function experiments, lysine 754 in HSP90 (HSP90 K754) was identified as a substrate for Kbu. Kbu modification leads to overexpression of HSP90 in esophageal squamous cell carcinoma (ESCC) and its further increase in relapse samples. Upregulation of HSP90 contributes to 5-FU resistance and can predict poor prognosis in cancer patients. Mechanistically, HSP90 K754 is regulated by the cooperation of KAT8 and HDAC11 as the writer and eraser, respectively; SDCBP increases the Kbu level and stability of HSP90 by binding competitively to HDAC11. Furthermore, SDCBP blockade with the lead compound V020-9974 can target HSP90 K754 to overcome 5-FU resistance, constituting a potential therapeutic strategy.

National Brain Tumour Registry of China (NBTRC) statistical report of primary brain tumours diagnosed in China in years 2019-2020.

Background: The lack of a well-designed brain tumour registry with standardized pathological diagnoses in underdeveloped countries hinders the ability to compare epidemiologic data across the globe. The National Brain Tumour Registry of China (NBTRC), created in January 2018, is the first multi-hospital-based brain tumour registry in China. Patient data reported to the NBTRC in years 2019-2020 were assessed. Methods: Tumour pathology was based on the 2016 World Health Organization (WHO) classification of tumours of the central nervous system and ICD-O-3. The anatomical site was coded per the Surveillance, Epidemiology, and End Results (SEER) solid tumour module (version of July 2019). The cases were tabulated by histology and anatomical site. Categorical variables were reported as numbers (percentages). The distribution of tumours by age (0-14, 15-19, 20-39, 40-64, and 65+ years) was analysed. Findings: There were a total of 25,537 brain tumours, foremost among them meningioma (23.63%), followed by tumours of the pituitary (23.42%), and nerve sheath tumours (9.09%). Glioblastoma, the most common and lethal form of primary brain cancer in adults, represented 8.56% of all cases. Of note, 6.48% of the malignant tumours were located in the brain stem. The percentage of malignant brain tumours decreased with increasing age, 24.08% in adults (40+ years), 30.25% in young adults (20-39 years), 35.27% in adolescents (15-19 years), and 49.83% in children (0-14 years). Among the 2107 paediatric patients, the most common sites were ventricle (17.19%), brainstem (14.03%), pituitary and craniopharyngeal duct (13.4%), and cerebellum (12.3%), a distribution that differed from that of the entire cohort. The histology distribution was also unique in children, with glioblastoma much less incident compared to the whole cohort (3% vs. 8.47%, p < 0.01). 58.80% of all patients chose higher-level neurosurgical hospitals outside of their province of residence. The median in-hospital length of stay (LOS) for the various pathologies ranged from 11 to 19 days. Interpretation: The histological and anatomical site distribution of brain tumours in the NBTRC was statistically different in the subgroup of children (0-14 years). Patient choice of pursuing trans-provincial treatment was common and the in-hospital LOS was longer compared to that reported in similar European and American patient populations, which merits further attention. Funding: The National Key Research and Development Program of China (2015BAI12B04, 2013BAI09B03, 2014BAI04B01, and 2021YFF1201104) and Chinese National Natural Science Foundation of China (81971668).

The value of basement membrane-associated genes in the prognosis and immune regulation of glioma.

Gliomas have a high incidence rate in central nervous tumors. Although many breakthroughs have been made in the pathogenesis and treatment of glioma, the recurrence and metastasis rates of patients have not been improved based on the uniqueness of glioma. Glioma destroys the surrounding basement membrane (BM), leading to local infiltration, resulting in the corresponding clinical and neurological symptoms. Therefore, exploring the biological roles played by BM associated genes in glioma is particularly necessary for a comprehensive understanding of the biological processes of glioma and its treatment. Differential expression and univariate COX regression analyses were used to identify the basement membrane genes (BMGs) to be included in the model. LASSO regression was used to construct the BMG model. The Kaplan-Meier (KM) survival analysis model was used to assess the prognosis discrimination between training sets, validation sets, and clinical subgroups. Receiver-operating characteristic (ROC) analysis was used to test the prognostic efficacy of the model. Use calibration curves to verify the accuracy of nomograms. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and gene set enrichment analysis (GSEA) were used to analyze the function and pathway enrichment among the model groups. ESTIMATE and other 7 algorithms including CIBERSORT were used to evaluate the immune microenvironment. "pRRophetic" was used to evaluate drug sensitivity. This study demonstrated that high-risk genes (LAMB4, MMP1, MMP7) promote glioma progression and negatively correlate with patient prognosis. In the tumor microenvironment (TME), high-risk genes have increased scores of macrophages, neutrophils, immune checkpoints, chemokines, and chemokine receptors. This study suggests that BMGs, especially high-risk-related genes, are potential sites for glioma therapy, a new prospect for comprehensively understanding the molecular mechanism of glioma.

Extracranial-intracranial bypass surgery for intracranial aneurysm of the anterior cerebral circulation: A systematic review and meta-analysis.

Background: The safety of extracranial-intracranial (EC-IC) bypass in the management of anterior circulation intracranial aneurysms (IAs) remains to be determined. This systematic review aims to summarize the existing evidence and provide guidance for the precise management of IAs. Data source: We constructed search strategies and comprehensively searched Pubmed, Medline, Embase, Web of science, and Cochrane library. Methods: This systematic review was actualized according to the PRISMA statement. We evaluated study quality using the methodological index for non-randomized study (MINORS). Effect sizes were pooled using a random-effects model. Heterogeneity between studies was assessed using the I 2 test. Publication bias was assessed using the Egger's test. The registration number for this systematic review is CRD42023396730. Result: This systematic review included a total of 21 articles, involving 915 patients. Postoperative bypass patency rate was 99% (95% CI 0.98-1.00); short-term follow-up was 98% (95% CI 0.94-1.00); long-term follow-up was 95% (95% CI 0.93-0.97). The long-term follow-up occlusion rate of saphenous vein was higher than that of radial artery (OR 6.10 95% CI 1.04-35.59). Short-term surgery-related mortality was 0.3% (95% CI 0.000-0.012); long-term follow-up was 0.4% (95% CI 0.000-0.013); The proportion of patients with a score of 0-2 on the modified Rankin Scale (mRS) during long-term follow-up was 92% (95% CI 0.86-0.98). The incidence rates of long-term follow-up complications were: ischemic 3% (95% CI 0.01-0.06); hemorrhagic 1% (95% CI 0.00-0.03); neurological deficit 1% (95% CI 0.00-0.03); other 3% (95% CI 0.01-0.06). Limitation: Most of the included studies were retrospective studies. Studies reporting preoperative status were not sufficient to demonstrate postoperative improvement. Lack of sufficient subgroup information such as aneurysm rupture status. Conclusion: EC-IC therapy for anterior circulation IAs has a high safety profile. Higher level of evidence is still needed to support clinical decision. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023396730, identifier: CRD42023396730.

Studies on the Therapeutic and Prognostic Biomarkers of Glioma Using a Novel Cuproptosis-Related IncRNA Signature and Validation in Glioma.

Glioma is the most common tumor of the central nervous system (CNS). Drug resistance, and lack of effective treatment methods make the treatment effect of glioma patients unsatisfactory. The recent discovery of cuproptosis has led to new thinking about the therapeutic and prognostic targets of glioma. The transcripts and clinical data of glioma samples were obtained from The cancer genome atlas (TCGA). The cuproptosis-related lncRNA (CRL)-based glioma prognostic models were built through least absolute shrinkage and selection operator (LASSO) regression analysis in the train set and validated in the test set. Kaplan-Meier survival curve, risk curve analysis, and time-dependent receiver operating characteristic (ROC) curve were used to assess the predictive ability and risk differentiation ability of the models. Univariate and multivariate COX regression analyses were conducted on the models and various clinical features, and then nomograms were constructed to verify their predictive efficacy and accuracy. Finally, we explored potential associations of the models with immune function, drug sensitivity, and the tumor mutational burden of glioma. Four CRLs were selected from the training set of 255 LGG samples and the other four CRLs were selected from the training set of 79 GBM samples to construct the models. Follow-up analysis showed that the models have commendable prognostic value and accuracy for glioma. Notably, the models were also associated with the immune function, drug sensitivity, and tumor mutational burden of gliomas. Our study showed that CRLs were prognostic biomarkers of glioma, closely related to glioma immune function. CRLs may affect uniquely the sensitivity of glioma treatment. It will be a potential therapeutic target for glioma. CRLs will offer new perspectives on the prognosis and therapy of gliomas.

Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner.

Posttranslational modifications add tremendous complexity to proteomes; however, gaps remain in knowledge regarding the function and regulatory mechanism of newly discovered lysine acylation modifications. Here, we compared a panel of non-histone lysine acylation patterns in metastasis models and clinical samples, and focused on 2-hydroxyisobutyrylation (Khib) due to its significant upregulation in cancer metastases. By the integration of systemic Khib proteome profiling in 20 paired primary esophageal tumor and metastatic tumor tissues with CRISPR/Cas9 functional screening, we identified N-acetyltransferase 10 (NAT10) as a substrate for Khib modification. We further showed that Khib modification at lysine 823 in NAT10 functionally contribute to metastasis. Mechanistically, NAT10 Khib modification enhances its interaction with deubiquitinase USP39, resulting in increased NAT10 protein stability. NAT10 in turn promotes metastasis by increasing NOTCH3 mRNA stability in an N4-acetylcytidine-dependent manner. Furthermore, we discovered a lead compound #7586-3507 that inhibited NAT10 Khib modification and showed efficacy in tumor models in vivo at a low concentration. Together, our findings bridge newly identified lysine acylation modifications with RNA modifications, thus providing novel insights into epigenetic regulation in human cancer. We propose that pharmacological inhibition of NAT10 K823 Khib modification constitutes a potential anti-metastasis strategy.

ANO1 Reprograms Cholesterol Metabolism and the Tumor Microenvironment to Promote Cancer Metastasis.

SIGNIFICANCE: Metastatic cancer cells upregulate ANO1 to activate cell-intrinsic and -extrinsic mechanisms that alter cholesterol metabolism and stimulate fibroblasts, which can be targeted with ANO1 inhibitors to inhibit metastatic growth. See related commentary by Singh and Mehla, p. 1759.

Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed. Here, a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs. A series of functional assays showed that desloratadine, an antiallergic drug, can repress proliferation in HCC cell lines, cell-derived xenograft (CDX), patient-derived organoid (PDO) and patient-derived xenograft (PDX) models. N-myristoyl transferase 1 (NMT1) was identified as a target protein of desloratadine by drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) assays. Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo. Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3 (VILIP3) was a new substrate of NMT1 in protein N-myristoylation modification, and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC. Mechanistically, desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity, disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling. Conclusively, this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.

Effect of Surgical Clipping versus Endovascular Coiling on the Incidence of Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Observational Cohort Study with Propensity Score Matching.

OBJECTIVE: The effect of surgical clipping (SC) and endovascular coiling (EC) on the incidence of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) has always been a controversial topic. Hence, it is necessary to reanalyze the effects of the 2 surgical methods on DCI, which determines the choice of the most favorable method for patients who are suitable for both surgical modalities. METHODS: A multicenter retrospective observational cohort study was performed to evaluate all consecutive patients with aSAH admitted to 5 medical centers in China between April 2019 and June 2021. Univariable and multivariable analyses were used to confirm risk factors of DCI after aSAH. A 1:1 propensity score matching model was generated in the EC and SC groups to reduce the influence of all confounding factors on DCI. RESULTS: A total of 412 patients were included, and 115 patients (27.9%) developed DCI. After propensity score matching for controlling demographic information, past medical history, admission clinical status, aneurysm characteristics, and inflammatory factors associated with DCI, 133 patients with SC and 133 patients with EC treatment were matched. The results of the matched cohorts indicate a significantly lower incidence of DCI when patients received EC than SC (31.9% vs. 20%; adjusted odds ratio, 1.87; 95% confidence interval, 1.08-3.29; P = 0.027). CONCLUSIONS: The study found that the patients who received SC treatment had a higher incidence of DCI than did those who received EC and suggested that ruptured intracerebral aneurysm is preferentially coiled rather than clipped if the aneurysm is suitable for both surgical modalities.