Association of Mismatch Profiles and Clinical Outcome from Endovascular Therapy in Large Infarct: A Post-Hoc Analysis of the ANGEL-ASPECT Trial.

OBJECTIVES: We investigated whether patients with large infarct and the presence or absence of perfusion mismatch are associated with endovascular treatment benefit. METHODS: This is a post-hoc analysis of the Endovascular Therapy in Anterior Circulation Large Vessel Occlusion with a Large Infarct (ANGEL-ASPECT) randomized trial, which enrolled patients within 24 hours of onset with ASPECTS 3 to 5 or ASPECTS 0 to 2 with an infarct core 70 to 100 ml. Mismatch ratio was defined as time-to-maximum (Tmax) >6 s cerebral volume/ischemic core volume, and mismatch volume was defined as Tmax >6 s volume minus ischemic core volume. We divided patients into mismatch ratio ≥1.2 and mismatch volume ≥10 ml, and mismatch ratio ≥1.8 and mismatch volume ≥15 ml groups. The primary outcome was the 90-day modified Rankin Scale score ordinal distribution. Safety outcomes were symptomatic intracranial hemorrhage and 90-day mortality. RESULTS: There were 425 patients included. In both the mismatch ratio ≥1.2 and mismatch volume ≥10 ml (mismatch+, n = 395; mismatch-, n = 31) and mismatch ratio ≥1.8 and mismatch volume ≥15 ml groups (mismatch+, n = 346; mismatch-, n = 80), better 90-day modified Rankin Scale outcomes were found in the endovascular treatment group compared with the MM group (4 [2-5] vs 4 [3-5], common odds ratio [cOR], 1.9, 95% confidence interval [CI] 1.3-2.7, p = 0.001; 4 [2-5] vs 4 [3-5], cOR, 1.9, 95% CI 1.3-2.8, p = 0.001, respectively), but not in patients without mismatch ratio ≥1.2 and mismatch volume ≥10 ml (5 [3-6] vs 5 [4-6], cOR, 1.2, 95% CI 0.3-4.1, p = 0.83), and mismatch ratio ≥1.8 and mismatch volume ≥15 ml (4 [3-6] vs 5 [3-6], cOR, 1.2, 95% CI 0.6-2.7, p = 0.60). However, no interaction effect was found in both subgroups (p interaction >0.10). CONCLUSION: Endovascular treatment was more efficacious than MM in patients with mismatch profiles, but no treatment effect or interaction was noted in the no mismatch profile patients. However, the small sample size of patients with no mismatch may have underpowered our analysis. A pooled analysis of large core trials stratified by mismatch is warranted. ANN NEUROL 2024.

Immune Cell Infiltration Types as Biomarkers for the Recurrence Diagnosis and Prognosis of Bladder Cancer.

This study aimed to investigate the role of infiltrating immune cell types in diagnosing and predicting bladder cancer recurrence. This study mainly applied some algorithms, including Estimate the Proportion of Immune and Cancer Cells (EPIC), support vector machine-recursive feature elimination (SVM-RFE), random forest out-of-bag (RF-OOB) and least absolute shrinkage and selection operator (LASSO)-Cox regression analysis. We found six immune infiltrating cell types significantly associated with recurrence prognosis and two independent clinical prognostic factors. Infiltrating immune cell types (IICTs) based on the prognostic immune risk score (pIRS) models may provide significant biomarkers for the diagnosis and prognostic prediction of bladder cancer recurrence.

Modification effects of long-term air pollution levels on the relationship between short-term exposure to meteorological factors and hand, foot, and mouth disease: A distributed lag non-linear model-based study in Shandong Province, China.

The occurrence of hand, foot, and mouth disease (HFMD) is closely related to meteorological factors. However, location-specific characteristics, such as persistent air pollution, may increase the complexity of the impact of meteorological factors on HFMD, and studies across different areas and populations are largely lacking. In this study, a two-stage multisite time-series analysis was conducted using data from 16 cities in Shandong Province from 2015 to 2019. In the first stage, we obtained the cumulative exposure-response curves of meteorological factors and the number of HFMD cases for each city. In the second stage, we merged the estimations from the first stage and included city-specific air pollution variables to identify significant effect modifiers and how they modified the short-term relationship between HFMD and meteorological factors. High concentrations of air pollutants may reduce the risk effects of high average temperature on HFMD and lead to a distinct peak in the cumulative exposure-response curve, while lower concentrations may increase the risk effects of high relative humidity. Furthermore, the effects of average wind speed on HFMD were different at different levels of air pollution. The differences in modification effects between subgroups were mainly manifested in the diversity and quantity of significant modifiers. The modification effects of long-term air pollution levels on the relationship between sunshine hours and HFMD may vary significantly depending on geographical location. The people in age＜3 and male groups were more susceptible to long-term air pollution. These findings contribute to a deepening understanding of the relationship between meteorological factors and HFMD and provide evidence for relevant public health decision-making.

Outcomes of antiplatelet therapy before endovascular treatment of acute large vessel occlusion: Data from the ANGEL-ACT registry.

OBJECTIVES: To investigate whether single or dual antiplatelet therapy (SAPT or DAPT) within 24 hours before endovascular treatment (EVT) could improve the clinical outcomes of patients with large vessel occlusion (LVO). METHODS: Patients from the ANGEL-ACT registry were divided into antiplatelet therapy (APT) and non-APT groups. The APT group was divided into SAPT and DAPT groups. Outcome measurement included 90-day modified Rankin Scale (mRS) distribution, change in the NIHSS at 7 days or discharge, number of passes, modified first pass effect (mFPE), symptomatic intracranial hemorrhage (SICH), and mortality within 90 days. To compare the outcomes, we performed multivariable analyses by adjusting for the propensity score calculated by the logistic regression model. RESULTS: Of 1611 patients, 1349 were in the non-APT group, while 262 (16.3 %) were in the APT group (122 [46.6 %] received SAPT, 140 [53.4 %] received DAPT). APT, SAPT or DAPT were not associated with a shift to better outcomes (non-APT vs. APT, 3[0-5] vs. 3[0-5], common odds ratio [OR], 1.04, 95 %confidence interval [CI]:0.82-1.34, P = 0.734). DAPT was associated with mFPE (OR,2.05, 95 %CI:1.39-3.01, P<0.001), more NIHSS reduction at 7 days or discharge (ß, -2.13, 95 %CI: -4.02--0.24, P = 0.028), lower number of passes (ß, -0.40, 95 %CI: -0.68--0.12, P=0.006), and shorter procedure duration (ß, -12.4, 95 %CI: -23.74--1.05, P = 0.032) without increasing odds of successful recanalization, PH within 24 hours and mortality with 90 days . CONCLUSIONS: APT before MT for AIS due to LVO does not affect clinical outcome in 90 days despite a tendency to reduce MT procedure time and number of passes. APT before MT in LVO does not increase SICH or mortality rates.

Sex-Related Differences in Outcomes of Endovascular Treatment for Anterior Circulation Large Vessel Occlusion.

BACKGROUND: Sex disparities in acute large vessel occlusion (LVO) following endovascular treatment (EVT) have been recently reported. However, there is uncertainty about the effect of sex differences on functional outcomes after EVT, particularly in an Asian population. The present study aimed to compare the clinical and safety outcomes between men and women with anterior circulation LVO treated with EVT. METHODS: We analyzed data from the ANGEL-ACT (Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke: a Prospective Multicenter Registry Study) Registry, which was conducted at 111 hospitals from 26 provinces in China between November 2017 and March 2019. Men and women with anterior circulation LVO treated with EVT were matched using propensity scores. After a 1:1 propensity score matching, we compared the clinical outcomes including 90-day ordinal modified Rankin Scale distribution (primary outcome), procedure duration, successful reperfusion, symptomatic intracranial hemorrhage, and mortality. Furthermore, we explored sex modification on the primary outcome in subgroup analysis. RESULTS: Of 1321 patients, 483 (36.6%) were women and 838 (63.4%) were men. The mean age for women and men were 68 and 62 years old, respectively. Among 578 patients identified after matching, there were no sex differences (men versus women) in 90-day ordinal modified Rankin Scale distribution (median [interquartile range], 4 [1-5] versus 3 [1-5], P=0.464), successful reperfusion (86.5% versus 91.0%, P=0.089), symptomatic intracranial hemorrhage (6.5% versus 7.9%, P=0.512), and mortality within 90 days (17.7% versus 17.0%, P=0.826). However, men had a longer median procedure duration than women (86 [52-128] versus 72 [48-110] minutes, ß=14.51, [95% CI, 4.19-24.84]; P=0.006). Subgroup analysis showed that in patients with National Institutes of Health Stroke Scale score <15, women tended to have a better outcome than men, whereas there was no gender effect in those with National Institutes of Health Stroke Scale score ≥15 (P for interaction=0.032). CONCLUSIONS: Overall, this matched-control study from the ANGEL-ACT study showed similar clinical outcomes between men and women with anterior circulation LVO treated with EVT. However, in the subgroup of patients presenting with lower stroke severity (ie, National Institutes of Health Stroke Scale score <15), women tended to have a better outcome than men highlighting a potential sex disparity for further investigation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03370939.

Co-Administration of nalbuphine to improve morphine tolerance in mice with bone cancer pain.

BACKGROUND: Kappa-opioid receptor (KOR) agonists are known for having opposite and/or different effects compared with Mu-opioid receptor (MOR) agonists. This study is aimed at clarifying the analgesic effect and tolerance of nalbuphine combined with morphine, and quantifying the mRNA and protein expression of spinal MOR and KOR in a mouse bone cancer pain (BCP) model treated with nalbuphine and morphine. METHOD: BCP model was prepared in C3H/HeNCrlVr Mice by implanting the sarcoma cells into the intramedullary space of the femur. The paw withdrawal thermal latency (PWL) measured by thermal radiometer was used to assess thermal hyperalgesia. PWL testing was performed after implantation and drug administration according to the protocol. Hematoxylin-eosin staining in the spinal cord and x-ray in the femoral intramedullary canal was detected. Real-time PCR and western blot analysis played a role in detecting spinal MOR and KOR expression changes. RESULTS: In tumor-implanted mice, the spinal MOR and KOR protein and mRNA expression was down-regulated when compared to that in sham-implanted mice (p < 0.05). Morphine therapy can lead to a decrease in spinal µ receptor expression. Similarly, the nalbuphine therapy can lead to a decrease in the expression of κ receptor protein and mRNA at the spinal cord level (p < 0.05). Morphine, nalbuphine, or nalbuphine co-administration with morphine all can extend the paw withdrawal thermal latency (PWL) to radiant thermal stimulation in tumor-implanted mice (p < 0.05). Compared with the morphine treatment group, nalbuphine co-administration with morphine delayed the reduction of PWL value again (p < 0.05). DISCUSSION: BCP itself may induce down-regulation of the spinal MOR and KOR expression. A low dose of nalbuphine co-administration with morphine led to the delayed emergence of morphine tolerance. The part of the mechanism may be due to the regulation of spinal opioid receptors expression.

Serum thrombospondin-1 serves as a novel biomarker and agonist of gemcitabine-based chemotherapy in intrahepatic cholangiocarcinoma.

BACKGROUND: At present, the first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC) is gemcitabine combined with cisplatin, but a considerable portion of ICC patients exhibit resistance to gemcitabine. Therefore, finding sensitisers for gemcitabine chemotherapy in ICC patients and predicting molecular markers for chemotherapy efficacy have become urgent needs. METHODS: In this study, PDX models were established to conduct gemcitabine susceptibility tests. The selected PDX tissues of the chemotherapy-sensitive group and drug-resistant group were subjected to transcriptome sequencing and protein chip technology to identify the key genes. Sixty-one ICC patients treated with gemcitabine chemotherapy were recruited for clinical follow-up validation. RESULTS: We found that thrombospondin-1 (TSP1) can predict gemcitabine chemosensitivity in ICC patients. The expression level of TSP1 could reflect the sensitivity of ICC patients to gemcitabine chemotherapy. Functional experiments further confirmed that TSP1 can increase the efficacy of gemcitabine chemotherapy for ICC. A mechanism study showed that TSP1 may affect the intake of oleic acid by binding to the CD36 receptor. CONCLUSIONS: In summary, we found a key molecule-TSP1-that can predict and improve the sensitivity of ICC patients to gemcitabine chemotherapy, which is of great significance for the treatment of advanced cholangiocarcinoma.

History of Neurointervention.

In this review article, we aim to provide a summary of the discoveries and developments that were instrumental in the evolution of the Neurointerventional field. We begin with developments in the advent of Diagnostic Cerebral Angiography and progress to cerebral aneurysm treatment, embolization in AVMs and ischemic stroke treatment. In the process we discuss many persons who were key in the development and maturation of the field. A pivotal aspect to rapid growth in the field has been the multidisciplinary involvement of the different neuroscience specialties and therefore we close out our discussion with excitement about ongoing and future developments in the field with a focus on treatments in the non-cerebrovascular disease realm.

Endovascular Thrombectomy for Anterior Circulation Large Vessel Occlusion Stroke: An Evolution of Trials.

The last decade's progress in demonstrating the clinical benefit of endovascular thrombectomy (EVT) in patients with large vessel occlusion stroke has transformed the paradigm of care for these patients. This review presents the milestones in implementing EVT as standard of care, demonstrates the current state of evidence, provides guidance for identifying the candidate patient for EVT, and highlights unsolved and controversial issues. Ongoing trials investigate broadening of EVT indications for patients who present with large core infarction, adjunctive intra-arterial thrombolysis, medium vessel occlusion, low NIHSS, and tandem occlusion.

Endovascular Treatment for Acute Large Vessel Occlusion Due to Underlying Intracranial Atherosclerotic Disease.

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of acute ischemic stroke worldwide. Patients with acute large vessel occlusion due to underlying ICAD (ICAD-LVO) often do not achieve successful recanalization when undergoing mechanical thrombectomy (MT) alone, requiring rescue treatment, including intra-arterial thrombolysis, balloon angioplasty, and stenting. Therefore, early detection of ICAD-LVO before the procedure is important to enable physicians to select the optimal treatment strategy for ICAD-LVO to improve clinical outcomes. Early diagnosis of ICAD-LVO is challenging in the absence of consensus diagnostic criteria on noninvasive imaging and early digital subtraction angiography. In this review, we summarize the clinical and diagnostic criteria, prediction of ICAD-LVO prior to the procedure, and EVT strategy of ICAD-LVO and provide recommendations according to the current literature.

Predictors of poor outcome after endovascular treatment for acute vertebrobasilar occlusion: data from ANGEL-ACT registry.

PURPOSE: Acute vertebrobasilar artery occlusion (VBAO) is a catastrophic disease for patients. There is evidence that the eventual patient outcome depends on patient-specific and procedural factors. This study aimed to identify the incidence and independent predictors of the 90-day poor outcome in VBAO after endovascular treatment (EVT). METHODS: Subjects were selected from the ANGEL-ACT registry. The 90-day poor outcome was defined as a 90-day modified Rankin Scale (mRS) of 4 to 6. Logistic regression analyses were performed to determine the independent predictors of the 90-day poor outcome. RESULTS: Of the 347 enrolled patients with acute VBAO undergoing EVT, 176 (50.7%) experienced the 90-day poor outcome. Multivariate logistic regression indicated that only the use of general anesthesia (GA) (odds ratio [OR] = 2.04; 95% confidence interval [CI], 1.23-3.37; P = 0.006) and heparin during the procedure (OR =1.74; 95% CI, 1.06-2.86; P = 0.028), admission National Institute of Health Stroke Scale (NIHSS) ≥ 26 (OR=3.96; 95% CI, 2.37-6.61; P < 0.001), and time from onset to puncture (OTP) ≥ 395 min (OR=1.91; 95% CI, 1.14-3.20; P = 0.014) and procedure duration ≥ 102 min (OR = 1.70; 95% CI, 1.04-2.79; P = 0.036) were independent predictors of the 90-day poor outcome after EVT. Furthermore, admission NIHSS (OR > 36 vs. ≤ 11 = 9.01, P for trend < 0.001), OTP (OR > 441min vs. ≤ 210 min = 2.71, P for trend = 0.023), and procedure duration (OR > 145 min vs. ≤ 59 min = 2.77, P for trend = 0.031) were significantly associated with increasing risk of the 90-day poor outcome. CONCLUSIONS: Poor outcome after EVT at 90 days occurred in 50.7% of acute VBAO patients from the ANGEL-ACT registry. Our study found several predictors of the 90-day poor outcome which should be highly considered in daily practice to improve acute VBAO management. CLINICAL TRIAL REGISTRATION : http://www. CLINICALTRIALS: gov . Unique identifier: NCT03370939.

LncRNA PMS2L2 Is Downregulated in Sepsis-Induced Acute Kidney Injury and Inhibits LPS-Induced Apoptosis of Podocytes.

INTRODUCTION: Long noncoding RNA PMS2L2 can inhibit inflammation induced by LPS, while LPS plays an important role in sepsis, indicating the possible involvement of PMS2L2 in sepsis. METHODS: Expressions of miR-21 and PMS2L2 in patients with acute kidney injury (AKI), sepsis patients without induced AKI, and healthy controls were determined by performing RT-qPCR. Overexpression assay was performed to explore the crosstalk between miR-21 and PMS2L2. Methylation-specific PCR (MSP) was performed to explore the role of PMS2L2 in regulating the methylation of miR-21 gene. The role of miR-21 and PMS2L2 in the apoptosis of CIHP-1 cells induced by LPS was assessed by cell apoptosis assay. RESULTS: PMS2L2 was downregulated in AKI patients induced by sepsis compared to sepsis patients without AKI and healthy controls. MiR-21 was also downregulated in AKI induced by sepsis and positively correlated with PMS2L2. In addition, in cells of human podocyte cell line (CIHP-1), overexpression of PMS2L2 promoted the expression of miR-21, while miR-21 did not affect the expression of PMS2L2. MSP analysis showed that overexpression of PMS2L2 decreased methylation of miR-21. LPS treatment downregulated PMS2L2 and miR-21 in a time-dependent manner. PMS2L2 and miR-21 decreased the apoptosis of CIHP-1 cells induced by LPS, and co-overexpression of PMS2L2 and miR-21 showed stronger inhibitory effect. CONCLUSION: PMS2L2 is downregulated in AKI induced by sepsis and inhibits LPS-induced apoptosis of podocytes.

A sensitive approach to map genome-wide 5-hydroxymethylcytosine and 5-formylcytosine at single-base resolution.

Mapping genome-wide 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC) at single-base resolution is important to understand their biological functions. We present a cost-efficient mapping method that combines 5hmC-specific restriction enzyme PvuRts1I with a 5hmC chemical labeling enrichment method. The sensitive method enables detection of low-abundance 5hmC sites, providing a more complete 5hmC landscape than available bisulfite-based methods. This method generated a genome-wide 5fC map at single-base resolution. Parallel analyses revealed that 5hmC and 5fC in non-CpG context exhibit lower abundance, more dynamically, than those in CpG context. In the genic region, distribution of 5hmCpG and 5fCpG differed from 5hmCH and 5fCH (H = A, T, C). 5hmC and 5fC were distributed distinctly at regulatory protein-DNA binding sites, depleted in permissive transcription factor binding sites, and enriched at active and poised enhancers. This sensitive bisulfite conversion-free method can be applied to biological samples with limited starting material or low-abundance cytosine modifications.

Cryo-EM structure of influenza virus RNA polymerase complex at 4.3 Å resolution.

Replication and transcription of influenza virus genome mainly depend on its RNA-dependent RNA polymerase (RdRP), composed of the PA, PB1, and PB2 subunits. Although extensively studied, the underlying mechanism of the RdRP complex is still unclear. Here we report the biochemical characterization of influenza RdRP subcomplex comprising PA, PB1, and N terminus of PB2, which exist as dimer in solution and can assemble into a tetramer state, regulated by vRNA promoter. Using single-particle cryo-electron microscopy, we have reconstructed the RdRP tetramer complex at 4.3 Å, highlighting the assembly and interfaces between monomers within the tetrameric structure. The individual RdRP subcomplex contains all the characterized motifs and appears as a cage-like structure. High-throughput mutagenesis profiling revealed that residues involved in the oligomer state formation are critical for viral life cycle. Our results lay a solid base for understanding the mechanism of replication of influenza and other negative-stranded RNA viruses.

Delayed neurological improvement after endovascular treatment for acute large vessel occlusion: data from ANGEL-ACT registry.

BACKGROUND: A subgroup of patients with acute large vessel occlusion (ALVO) may experience delayed neurological improvement (DNI) after endovascular treatment (EVT). Our study aimed to investigate the incidence and independent predictors of DNI in patients with ALVO after EVT. METHODS: We selected subjects from ANGEL-ACT Registry. The definition of DNI is patients with ALVO who did not experience early neurological improvement (ENI) despite complete recanalization after EVT. These patients achieved a 90-day favorable outcome assessed by a modified Rankin Scale (mRS) score. We defined ENI as a ≥ 4-point decrease in the National Institutes of Health Stroke Scale (NIHSS) between baseline and 24 h or NIHSS of 0 or 1 at 24 h, with complete recanalization after EVT. We performed logistic regression analyses to determine the independent predictors of DNI. RESULTS: Among the 1056 enrolled patients, 406 (38.4%) did not experience ENI. 106 (26.1%) patients without ENI achieved DNI. On Multivariate analysis, lower admission NIHSS score (odds ratio [OR] = 1.17,95% confidence interval [CI]: 1.11-1.23, P < 0.001), underlying ICAD (OR = 2.03, 95% CI: 1.07-3.85, P = 0.029) and absence of general anesthesia (OR = 2.13, 95% CI: 1.24-3.64, P = 0.006) were independent predictors of DNI. CONCLUSION: DNI occurred in 26.1% of patients with ALVO who did not experience ENI after EVT. Our study identified several independent predictors of DNI that should be highly considered in daily clinical practice to improve ALVO management.

Development of preoperative prognostic models including radiological features for survival of singular nodular HCC patients.

BACKGROUND: Early singular nodular hepatocellular carcinoma (HCC) is an ideal surgical indication in clinical practice. However, almost half of the patients have tumor recurrence, and there is no reliable prognostic prediction tool. Besides, it is unclear whether preoperative neoadjuvant therapy is necessary for patients with early singular nodular HCC and which patient needs it. It is critical to identify the patients with high risk of recurrence and to treat these patients preoperatively with neoadjuvant therapy and thus, to improve the outcomes of these patients. The present study aimed to develop two prognostic models to preoperatively predict the recurrence-free survival (RFS) and overall survival (OS) in patients with singular nodular HCC by integrating the clinical data and radiological features. METHODS: We retrospective recruited 211 patients with singular nodular HCC from December 2009 to January 2019 at Eastern Hepatobiliary Surgery Hospital (EHBH). They all met the surgical indications and underwent radical resection. We randomly divided the patients into the training cohort (n =132) and the validation cohort (n = 79). We established and validated multivariate Cox proportional hazard models by the preoperative clinicopathologic factors and radiological features for association with RFS and OS. By analyzing the receiver operating characteristic (ROC) curve, the discrimination accuracy of the models was compared with that of the traditional predictive models. RESULTS: Our RFS model was based on HBV-DNA score, cirrhosis, tumor diameter and tumor capsule in imaging. RFS nomogram had fine calibration and discrimination capabilities, with a C-index of 0.74 (95% CI: 0.68-0.80). The OS nomogram, based on cirrhosis, tumor diameter and tumor capsule in imaging, had fine calibration and discrimination capabilities, with a C-index of 0.81 (95% CI: 0.74-0.87). The area under the receiver operating characteristic curve (AUC) of our model was larger than that of traditional liver cancer staging system, Korea model and Nomograms in Hepatectomy Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma, indicating better discrimination capability. According to the models, we fitted the linear prediction equations. These results were validated in the validation cohort. CONCLUSIONS: Compared with previous radiography model, the new-developed predictive model was concise and applicable to predict the postoperative survival of patients with singular nodular HCC. Our models may preoperatively identify patients with high risk of recurrence. These patients may benefit from neoadjuvant therapy which may improve the patients' outcomes.

Metabolomics-based classification reveals subtypes of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, and the prognosis varies due to its high heterogeneity, systematic evaluation of HCC is mainly based on genomic and transcriptomic features, metabolomics-based classification has yet to be reported. Here we performed RNA-seq on 50 paired samples and metabolomics analysis on 72 paired samples of both normal and tumor tissues from HCC patients. Through unsupervised hierarchical cluster analysis with train and test data sets, metabolic and gene expression signatures were identified. We found that most fluxes related to glutamate are attenuated, except for the glutamate-proline pathway. Three subgroups were identified with distinct survival, clinical observations, and metabolic/gene signatures. S1 is characterized by a relatively poor prognosis, a low concentration of the degradation products of phosphatidylcholine and phosphatidylethanolamine, an enrichment of specific genes related to focal adhesion, and an upregulation of genes on chromosome 6q27. Beyond commonly downregulated metabolites, S2 tumors are largely characterized by few alterations in metabolites and genes, as well as low incidence of mutations/loss of heterozygosity, the metabolite signature of this group consists of hexoses and their phosphates, and the prognosis is the best, with a 5-year survival rate of greater than 80%. S3 is characterized by the worst survival (an approximately 20% 5-year survival rate), unsaturated fatty acid metabolites, an upregulation of specific genes involved in metastasis, and an upregulation of genes on chromosome 1q21. The metabolite-based classifications are more stable and reproducible, with each subgroup characterized by a distinct molecular signature and disease prognosis.

HBV/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV-Related HCC Through Reciprocal Regulation With Insulin-Like Growth Factor 2 mRNA-Binding Protein 3.

BACKGROUND AND AIMS: HBV-pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV-pgRNA to HCC remain open for study. APPROACH AND RESULTS: Double-center cohorts of serum samples with undetectable serum HBV-DNA (below the lower limit of detection) were obtained from long-term NA-treated (≥48 weeks) HBV-related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long-term NA therapy with undetectable serum HBV-DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up-regulate the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a well-proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)-α-2a could degrade the stability of pgRNA through increasing its N6-methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long-term NA therapy with undetectable serum HBV-DNA; and the pgRNA-IGF2BP3 axis plays an important role in the development of HBV-related HCC. Moreover, IFN-α-2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV-related HCC. CONCLUSIONS: In conclusion, our studies reveal a significance and mechanism of HBV-pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV-related HCC.

Predictors of symptomatic intracranial hemorrhage after endovascular treatment for acute large vessel occlusion: data from ANGEL-ACT registry.

Symptomatic intracranial hemorrhage (SICH) is a catastrophic complication of endovascular treatment (EVT) for large vessel occlusion (LVO). We aimed to investigate the incidence and predictors of SICH after EVT. Patients were selected from the ANGEL-ACT registry. We diagnosed SICH according to the Heidelberg Bleeding Classification. Logistic regression analyses were performed to determine the independent predictors of SICH. Of the 1283 patients, SICH was observed in 116 patients (9.0%). On multivariable analysis, admission National Institutes of Health Stroke Scale (NIHSS) > 12 (odds ratio [OR] = 1.86, 95% confidence interval [CI]: 1.11-3.11, P = 0.018), admission Alberta Stroke Program Early CT Score (ASPECTS) < 6 (OR = 2.98, 95%CI: 1.68-5.29, P < 0.001), general anesthesia (OR = 1.81, 95%CI: 1.20-2.71, P = 0.004), prior intravenous thrombolysis (OR = 1.58, 95%CI: 1.04-2.40, P = 0.031), number of mechanical thrombectomy passes > 2 (OR = 1.68, 95%CI: 1.10-2.57, P = 0.016), and procedure duration > 96 min (OR = 1.82, 95%CI: 1.20-2.77, P = 0.005) were associated with high risk of SICH, whereas SICH was negatively associated with underlying intracranial atherosclerotic disease (OR = 0.45, 95%CI: 0.26-0.79, P = 0.021). The incidence of SICH after EVT for anterior LVO was 9.0% in ANGEL-ACT registry. Our study identified some predictors, which may assist doctors in identifying LVO patients with a high risk of SICH and making the optimal peri-procedural management strategies for such patients.

Prediction of intracranial atherosclerotic acute large vessel occlusion by severe hypoperfusion volume growth rate.

BACKGROUND AND PURPOSE: We aimed to investigate whether the time elapsed from stroke onset to imaging (OTI) combined with the parameters generated by automated computed tomography perfusion (CTP) could predict large vessel occlusion (LVO) patients with underlying intracranial atherosclerotic disease (ICAD) before endovascular treatment (EVT). METHODS: We performed a prospective cohort of LVO patients with automated CTP before EVT from two comprehensive stroke centers. Severe hypoperfusion volume growth rate was defined as the Time-to-Maximum (Tmax) > 10s divided by OTI. We performed receiver operating characteristic analyses to assess the ICAD prediction performance of all the automated CTP parameters, Delong test to compare the area under the curve (AUC) of severe hypoperfusion volume growth rate with the AUC of the other parameters, and logistic regression analysis to find the independent predictors of LVO with underlying ICAD. RESULTS: Of the 204 enrolled LVO patients, 95 ICAD patients and 109 non-ICAD patients were identified. The AUC of severe hypoperfusion volume growth rate was 0.86 (95% confidence interval [CI] 0.81 - 0.91, P < 0.001), the cut-off value with the highest Youden Index was ≤ 11.2 mL/h (sensitivity, 78.95%; specificity, 77.06%; accuracy 77.94%), which was larger than the other parameters except for hypoperfusion intensity ratio (HIR) (All P for Delong test < 0.05). Atrial fibrillation (odds ratio [OR]: 0.09, 95%CI: 0.03 - 0.26, P < 0.001), admission ASPECTS (1-point increased OR: 1.25, 95%CI: 1.03 - 1.53, P = 0.024), and severe hypoperfusion volume growth rate (1 mL/h increased OR: 0.94, 95%CI: 0.90 - 0.98, P = 0.003) were associated with underlying ICAD independently. CONCLUSIONS: Severe hypoperfusion volume growth rate showed the best performance for LVO with underlying ICAD prediction. Future larger studies for external validation are needed.