Transarterial chemoembolization combined with radiofrequency ablation for medium and large hepatocellular carcinoma: insufficient ablation is associated with intrahepatic distant metastasis and extrahepatic metastasis.

Purpose: To compare the prognosis of complete and insufficient ablation of transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) in treating medium and large hepatocellular carcinoma (HCC) and to explore the differences in recurrence patterns between the two groups. Patients and methods: Patients´ medical records and imaging data of patients with confirmed HCC from January 2014 to January 2022 were collected. These patients were divided into 2 groups: complete ablation (n=172) and insufficient ablation (n=171). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier curve and the log-rank test was used to compared. Fisher's exact test was used to compare recurrence patterns between the two groups. Results: The median OS time was 72.8 months (95%CI:69.5-76.1) and 62.0 months (95%CI: 55.3-68.7) in the complete and insufficient ablation groups, respectively. The median PFS time in the complete ablation group was 67.8 months (95% CI: 65.2-70.4) and 38.6 months (95%CI: 29.8-47.4) in the insufficient ablation group. The OS and PFS rates of the complete ablation group were significantly better than those of the insufficient ablation group (P<0.001). In the complete ablation group, 25(41%) patients experienced local tumor progression(LTP), 36(59%) experienced intrahepatic distant progression(IDP), and 0(0%) experienced extrahepatic progression (EP). In the insufficient ablation group, 51 (32.1%) patients experienced LTP, 96 (60.4%) experienced IDP, and 12 (7.5%) experienced EP. The progression patterns of the two groups were statistically significant (P=0.039). Conclusion: Insufficient ablation indicates a poor survival outcome of TACE combined with RFA for medium and large HCC and can promote intrahepatic distant and extrahepatic metastasis.

A Novel Gene Pair CSTF2/DPE2A Impacts Prognosis and Cell Cycle of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC), one of the commonest cancers at present, possesses elevated mortality. This study explored the predictive value of CSTF2/PDE2A for HCC prognosis. Methods: In this study, clinical information and RNA sequencing expression profiles of HCC patients were acquired from common databases. Kaplan-Meier curve compound with time-dependent ROC curve, nomogram model, and univariate/multivariate Cox analysis were carried out to access the prediction capacity of CSTF2/PDE2A. The immune status, tumor microenvironment, drug sensitivity, biological function and pathway between HCC and adjacent non-tumorous tissue were analyzed and compared. Finally, RT-qPCR, Western blot, and apoptosis assays were performed to verify the effect on HCC cells of CSTF2/PDE2A. Results: The optimal cut-off value of CSTF2, PDE2A and CSTF2/PDE2A was 6.95, 0.95 and 3.63, respectively. In TCGA and ICGC cohorts, the high group of CSTF2/PDE2A presented higher OS compared to low group. The area under the curve (AUC) for OS at 1-, 2-, and 3-years predicted by CSTF2/PDE2A were 0.731/0.695, 0.713/0.732 and 0.689/0.755, higher than the counterparts of the single gene CSTF2 and PDE2A. Multivariate Cox analysis revealed that CSTF2/PDE2A (HR = 1.860/3.236, 95% CI = 1.265-2.733/1.575-6.645) was an independent prognostic factor for HCC. The OS nomogram model created according to five independent factors including CSTF2/PDE2A showed excellent capacity for HCC prognosis. Furthermore, the immune status of the CSTF2/PDE2A high group was deleted, cell cycle-related genes and chemotherapy resistance were increased. Finally, cell experiments revealed distinct differences in the proliferation, apoptosis, protein and mRNA expression of HCC cells after si-CSTF2 transfection compared with the negative control. Conclusion: Taken together, the gene pair CSTF2/PDE2A is able to forecast the prognosis of HCC and regulates cell cycle, which is promising as a novel prognostic predictor of HCC.

Characterization of neutrophil extracellular traps related gene pair for predicting prognosis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant disease with a high incidence rate, high mortality and poor prognosis. Neutrophil extracellular traps (NETs), as an extracellular reticular structure, promote the development and progression of cancer in the tumor microenvironment, and have a promising prospect as a prognostic indicator. In the present study, we elucidated the prognostic value of NET-related genes. METHODS: The NETs gene pair of The Cancer Genome Atlas cohort was constructed by least absolute shrinkage and selection operator analysis. Samples from the International Cancer Genome Consortium were performed to verify its feasibility. Kaplan-Meier analysis was used to compare the overall survival (OS) rate of the two subgroups. The independent predictors of OS were determined by univariate and multivariate Cox analysis. Furthermore, Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway were analyzed by gene set enrichment analysis. The single sample gene set enrichment analysis method was performed to deplore the relationship of risk score with tumor immune microenvironment. The GSE149614 dataset was applied as single cell RNA level validation. PCR was performed to the detect mRNA expression profiles of NETs-related genes. RESULTS: Our analysis of the NETs-related model provides a promising prospect as a prognostic indicator. The OS of high-risk group patients was significantly reduced. The risk score was an important independent predictor of HCC prognosis. The Nomogram model suggested a favorable classification performance. The drug resistance and sensitivity of tumor cells to chemotherapeutics was significantly correlated with the prognostic gene expression. The immune status of the two risk groups showed a marked difference. CONCLUSIONS: The novel prognostic gene pair and immune landscape could predict the prognosis of HCC patients and provide a new understanding of immunotherapy in HCC.

Disconnection of Network Hubs Underlying the Executive Function Deficit in Patients with Ischemic Leukoaraiosis.

BACKGROUND: Cognitive impairment is the most common clinical manifestation of ischemic leukoaraiosis (ILA), but the underlying neurobiological pathways have not been well elucidated. Recently, it was thought that ILA is a "disconnection syndrome". Disorganized brain connectome were considered the key neuropathology underlying cognitive deficits in ILA patients. OBJECTIVE: We aimed to detect the disruption of network hubs in ILA patients using a new analytical method called voxel-based eigenvector centrality (EC) mapping. METHODS: Subjects with moderate to severe white matters hyperintensities (Fazekas score ≥3) and healthy controls (HCs) (Fazekas score = 0) were included in the study. The resting-state functional magnetic resonance imaging and the EC mapping approach were performed to explore the alteration of whole-brain network connectivity in ILA patients. RESULTS: Relative to the HCs, the ILA patients exhibited poorer cognitive performance in episodic memory, information processing speed, and executive function (all ps < 0.0125). Additionally, compared with HCs, the ILA patients had lower functional connectivity (i.e., EC values) in the medial parts of default-mode network (i.e., bilateral posterior cingulate gyrus and ventral medial prefrontal cortex [vMPFC]). Intriguingly, the functional connectivity strength at the right vMPFC was positively correlated with executive function deficit in the ILA patients. CONCLUSION: The findings suggested disorganization of the hierarchy of the default-mode regions within the whole-brain network in patients with ILA and advanced our understanding of the neurobiological mechanism underlying executive function deficit in ILA.

Polydatin relieves paraquat-induced human MRC-5 fibroblast injury through inhibiting the activation of the NLRP3 inflammasome.

BACKGROUND: Paraquat (PQ) is a herbicide that is highly toxic to the lungs and kidneys. When it enters the body, it will disrupt the balance of the microenvironment in the body, induce a large number of inflammatory factors and cause cell damage. Polydatin (PD), resveratrol glycoside, has multiple pharmacological effects. However, the protective effect of PD on human embryo lung fibroblast damage caused by PQ poisoning has not been reported. The purpose of this study was to investigate the regulatory effect of PD on human embryo lung fibroblast damage caused by PQ poisoning. METHOD: The optimal experimental concentration of PQ for human embryonic lung fibroblast MRC-5 was 100 µmol/L, and then the cells of 100 µmol/L PQ group were treated with different concentrations of PD for 24 h. MTT assay to detect MRC-5 cell viability and flow cytometry to detect apoptosis. The corresponding kit was used to detect the contents of glutathione peroxidase (GSH-PX), malondialdehyde (MDA) and superoxide dismutase (SOD). Enzyme-linked immunosorbent assay (ELISA) to detect the levels of related inflammatory factors tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-ß), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6). Western blot detection of NLRP3 inflammatory body activation-related protein expression. RESULTS: Compared with the PQ group, cell activity, GSH-Px content, and SOD content in PD intervention group were significantly increased, while apoptosis, MDA content, inflammatory factor level, and activation-related proteins of the NLRP3 inflammasome were significantly reduced and were dose-dependent. CONCLUSIONS: PD can relieve PQ-induced human MRC-5 fibroblasts injury by reducing the inflammatory response, improving the antioxidant stress capacity, and inhibiting the activation of the NLRP3 inflammasome.

N6-Methyladenosine Modification of Fatty Acid Amide Hydrolase Messenger RNA in Circular RNA STAG1-Regulated Astrocyte Dysfunction and Depressive-like Behaviors.

BACKGROUND: N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic messenger RNAs and is essential for multiple RNA processing events in physiological and pathological processes. However, precisely how m6A methylation is involved in major depressive disorder (MDD) is not fully understood. METHODS: Circular RNA STAG1 (circSTAG1) was screened from the hippocampus of chronic unpredictable stress-treated mice using high-throughput RNA sequencing. Microinjection of circSTAG1 lentivirus into the mouse hippocampus was used to observe the role of circSTAG1 in depression. Sucrose preference, forced swim, and tail suspension tests were performed to evaluate the depressive-like behaviors of mice. Astrocyte dysfunction was examined by GFAP immunostaining and 3D reconstruction. Methylated RNA immunoprecipitation sequence analysis was used to identify downstream targets of circSTAG1/ALKBH5 (alkB homolog 5) axis. Cell Counting Kit-8 assay was performed to evaluate astrocyte viability in vitro. RESULTS: circSTAG1 was significantly decreased in the chronic unpredictable stress-treated mouse hippocampus and in peripheral blood of patients with MDD. Overexpression of circSTAG1 notably attenuated astrocyte dysfunction and depressive-like behaviors induced by chronic unpredictable stress. Further examination indicated that overexpressed circSTAG1 captured ALKBH5 and decreased the translocation of ALKBH5 into the nucleus, leading to increased m6A methylation of fatty acid amide hydrolase (FAAH) messenger RNA and degradation of FAAH in astrocytes with subsequent attenuation of depressive-like behaviors and astrocyte loss induced by corticosterone in vitro. CONCLUSIONS: Our findings dissect the functional link between circSTAG1 and m6A methylation in the context of MDD, providing evidence that circSTAG1 may be a novel therapeutic target for MDD.

Fatal and Rapid Progressive Isolated Cerebral Mucormycosis Involving the Bilateral Basal Ganglia: A Case Report.

Isolated cerebral mucormycosis is a clinical type of mucormycosis that is estimated to account for 8% of all mucormycosis cases. The clinical symptoms of isolated cerebral mucormycosis are elusive, and thus conventional techniques often lake sensitivity and specificity. Moreover, cultures are often negative, even when direct microscopy examination is positive. Although histopathology will probably remain the gold standard for the diagnosis of mucormycosis, obtaining a biopsy specimen is not always feasible in most vulnerable populations. Thus, molecular approaches are currently used as an advantageous assistant examination method to improve the early identification of the causative agent and subsequently guide therapy to improve the prognosis of patients. Here, we report a case of isolated cerebral mucormycosis caused by Rhizopus microspores in a healthy young adult that was identified using next-generation sequencing technology.

Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease.

Muscle wasting and diminished physical performance contribute to the morbidity and mortality of chronic kidney disease (CKD), for which no curative therapy exists. Accumulating evidence indicates that impaired angiogenesis occurs in the muscles of CKD models. Therefore, proangiogenesis therapy is considered a potentially effective strategy for limiting CKD-associated myopathy. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF and enhances muscle angiogenesis during acute ischemia; however, little evidence was available from CKD models. Here, we assessed whether pharmacological activation of HIF by MK-8617 (MK), a novel orally active HIF-PHI, improves CKD-associated myopathy. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. These results indicate that HIF-PHI provides a potential therapeutic strategy to improve CKD-associated myopathy.

Clinical efficacy of percutaneous transluminal renal artery stenting for the treatment of renovascular hypertension associated with Takayasu arteritis.

BACKGROUND: This study aims to observe and analyze the clinical efficacy of interventional therapy for patients with Takayasu arteritis (TA) experiencing renovascular hypertension (RH). METHODS: Eight TA patients with RH underwent percutaneous transluminal renal artery stenting (PTRAS). Patients were followed up 1, 6, 12, and 24 months postoperatively for levels of blood pressure, number of antihypertensive drugs being taken, levels of serum creatinine, and the presence of renal artery restenosis. RESULTS: All 8 patients were successfully followed up 1, 6, and 12 months postoperatively, but 1 was lost to follow-up at 24 months. All patients had significantly lower average blood pressure levels compared with those at baseline (P < 0.05); treatment efficacy rates (recovery or improvement) at 1, 6, 12, and 24 months were 94%, 90%, 80%, and 80%, respectively. The average number of antihypertensive drugs being taken was 3.5 at baseline, 1.0 at 1 month, 0.5 at 6 months, 1.0 at 12 months, and 1.5 at 24 months. Serum creatinine levels during the follow-up period were not significantly different from those at the baseline. No patient developed renal artery restenosis during the follow-up period. CONCLUSIONS: PTRAS is a safe and effective treatment for TA-associated RH, with a high technical success rate and a low complication rate. This interventional therapy can effectively control TA-related hypertension and can also preserve and even improve kidney function.

Altered intrinsic hippocmapus declarative memory network and its association with impulsivity in abstinent heroin dependent subjects.

Converging evidence suggests that addiction can be considered a disease of aberrant learning and memory with impulsive decision-making. In the past decades, numerous studies have demonstrated that drug addiction is involved in multiple memory systems such as classical conditioned drug memory, instrumental learning memory and the habitual learning memory. However, most of these studies have focused on the contributions of non-declarative memory, and declarative memory has largely been neglected in the research of addiction. Based on a recent finding that hippocampus, as a core functioning region of declarative memory, was proved biased the decision-making process based on past experiences by spreading associated reward values throughout memory. Our present study focused on the hippocampus. By utilizing seed-based network analysis on the resting-state functional MRI datasets with the seed hippocampus we tested how the intrinsic hippocampal memory network altered toward drug addiction, and examined how the functional connectivity strength within the altered hippocampal network correlated with behavioral index 'impulsivity'. Our results demonstrated that HD group showed enhanced coherence between hippocampus which represents declarative memory system and non-declarative reward-guided learning memory system, and also showed attenuated intrinsic functional link between hippocampus and top-down control system, compared to the CN group. This alteration was furthered found to have behavioral significance over the behavioral index 'impulsivity' measured with Barratt Impulsiveness Scale (BIS). These results provide insights into the mechanism of declarative memory underlying the impulsive behavior in drug addiction.

Clinical Outcomes After Computer-assisted Versus Conventional Total Knee Arthroplasty.

The purpose of this study was to determine whether the use of computer-assisted surgery can improve the clinical results in total knee arthroplasty (TKA) compared with conventional methods of TKA.A literature search of PubMed (1966 to August 2011), CENTRAL (Cochrane Controlled Trials Register; issue 3, 2011), and EMBASE (1984 to August 2011) was conducted. Randomized, controlled trials detecting the clinical outcomes of TKA with or without the use of computer-assisted surgery were identified. A meta-analysis of these clinical trials was then performed. Twenty-one articles were included in the meta-analysis. The results confirmed that operative time was significantly increased with the use of computer-assisted TKA (mean standard difference, 14.68; 95% confidence interval [CI], 11.74 to 17.62; P<.00001], whereas no significant difference existed between the 2 groups regarding the total operative blood loss (mean standard difference, -54.38; 95% CI, -119.76 to 11.00; P=.10). As for other clinical outcomes, including the Knee Society Score (mean standard difference, 4.47; 95% CI, -1.05 to 9.99; P=.36) and range of motion (mean standard difference, 1.38; 95% CI, -1.43 to 4.18; P=.34), the use of computer-assisted TKA did not help to improve function recovery postoperatively.

Identification of hyperactive intrinsic amygdala network connectivity associated with impulsivity in abstinent heroin addicts.

Impulsivity is a pathological hallmark of drug addiction. However, little is known about the neuropsychological underpinnings of this impaired impulsive control network on drug addiction. Twenty two abstinent heroin dependent (HD) subjects and 15 cognitively normal (CN) subjects participated in this study. Resting-state functional connectivity MRI was employed to measure abnormalities in the intrinsic amygdala functional connectivity (iAFC) network activity and the Barratt Impulsive Scale, 11th version was used to measure impulsivity. Linear regression analysis was applied to detect the neural constructs underlying impulsivity by correlating iAFC network activity with impulsive scores. In the HD group, higher impulsivity scores and significantly enhanced iAFC network activity were found, especially in bilateral thalamus, right insula, and inferior frontal gyrus. Markedly decreased anticorrelated iAFC network activity was seen in the left precuneus, and even switched to positive correlation pattern in right precuneus, relative to the CN group. The iAFC network strengths in the HD group were positively correlated with impulsivity in the right subcallosal gyrus, insula, thalamus and posterior cingulate cortex, and negatively correlated in left fusiform area. In the CN group, the left pre-somamotor area-amygdala connectivity was positively correlated, and right orbital frontal cortex-amygdala and precuneus-amygdala connectivity were negatively correlated with impulsivity scores. Our study demonstrates different constructs of the impulsive network in HD and CN subjects. Altered iAFC network connectivity in HD subjects may contribute to the loss of impulsive control. This further facilitates our understanding of the neural underpinnings of behavior dysfunction in addiction.

Dynamic neural responses to cue-reactivity paradigms in heroin-dependent users: an fMRI study.

Neuroimaging methods have been employed to study cue-reactivity-induced neural correlates in the human brain. However, very few studies have focused on characterizing the dynamic neural responses to the factorial interactions between the cues and the subjects. Fifteen right-handed heroin-dependent subjects and 12 age-matched nondrug using subjects participated in this study. Cue-reactivity paradigms were employed, while changes in blood oxygenation level-dependent (BOLD) signals were acquired by functional MRI (fMRI). The fMRI datasets were analyzed with AFNI software and repeated two-way ANOVA was employed for factorial analyses. Neural correlates of factorial interactions between cue-factor and subject-factor were identified in the regions of the ventral tegmental area (VTA), the left and right amygdala, the left and right fusiform cortex, and the precuneus in the mesocorticolimbic system, and in the superior frontal, dorsal lateral prefrontal, and orbitofrontal cortices in the prefrontal cortex system. The neural response patterns in the prefrontal systems are dynamic: decreased response to neutral-cues and increased response to heroin-cues. Further, heroin-cue-induced neural responses within the subregions in the PFC system are significantly intercorrelated. In conclusion, the cue-reactivity paradigms significantly activated the dynamic neural activations in the prefrontal system. It is suggested that the dynamic response patterns in the PFC system characterize the impaired brain control functions in heroin-dependent subjects.

[Treatment of acquired arteriovenous fistulas with interventional minimally invasive techniques].

OBJECTIVE: To evaluate the efficacy and safety of the interventional techniques for treatment of acquired arteriovenous fistulas (AVF). METHODS: Ten patients with acquired AVFs, including 4 with renal AVF, 3 with iliac AVF, and 3 with subclavian AVF, were treated with interventional procedures. The etiological factors of the AVFs were penetrating trauma in 5 cases, iatrogenic injury in 3, malignancy in 1, and intestine Crohn's disease in 1. The patients presented with peripheral venous hypertension (n = 6), local bruit (n = 10), cardiac overload (n = 10), the right cardiac failure (n = 2), and hematuria (n = 4). Three patients underwent transcatheter super-selective coils embolization and 7 underwent stent-graft placement in the involved arteries. RESULTS: The technical success was achieved in all cases. Completion angiography documented complete exclusion of the fistulas. Minor complications occurred in 3 patients, but without significant consequences. The patients experienced immediate relief of the limb swelling, peripheral venous hyperemia, and tachycardia. The local bruit was disappeared. The cardiac overload conditions were improved significantly, which was confirmed by ultrasound scan. Renal function tests in patients with renal AVF were stable. Radioactive isotopic scan revealed that the function was preserved in the treated kidney in two patients using stent-graft placement in the renal arteries. Follow-up time ranged from 6 months to 6 years. Three patients respectively died of unrelated AVF diseases in 6, 9, and 14 months after the treatment. Re-intervention with an another stent-graft placement was performed on 2 patients with recurrence of the AVF respectively at 3 weeks and two months after the procedures. The minor stenosis was found in stent-graft 2 of patients on the follow-up angiography respectively at 6 and 8 months after the treatment. Seven patients are still alive and in good condition without further intervention. CONCLUSIONS: Minimally invasive interventional procedures, including super-selective embolization and stent-graft exclusion, are safe and effective in the treatment of acquired arteriovenous fistulas.

Endotoxins enhance hepatocarcinogenesis induced by oral intake of thioacetamide in rats.

AIM:To clarify whether endotoxin is of pathogenic importance for hepatocarcinogenesis,or the increased cancer risk results solely from the cirrhotic process.METHODS:The rat model of hepatoma was treated by the intake of 0.03% thioacetamide in drinking water for six months. During induction of hepatoma, rats were additionally treated with splenectomy and/or lipopolysaccharide administration.The liver nuclear DNA index and proliferation index were quantitatively analyzed by flow cytometry. Hepatic histology was examined with light and electron microscopes. Plasmic endotoxin concentration and gamma-glutamyl transpeptidase activity were measured, and hepatoma incidence was recorded.RESULTS: Thioacetamide induced cirrhosis and hepatoma in Wistar rats with histology or regenerative nodule, fibrosis and neoplastic foci were quite similar to the pathogenic process of human cirrhosis leading to hepatoma. In comparison with TAA controls (DNA index: 1.15 plus minus 0.21), exo-endotoxin increased the DNA index by 7.8% (1.24 plus minus0.25, P < 0.02) and hepatoma rate by 16.7. Splenectomy-induced enteric endotoxemia increased the DNA index by 25% (1.44plus minus0.15, P < 0.01) and hepatoma rate by 33%. A summation of the effects of these two factors increased the DNA index by 36% (P < 0.01)and hepatoma incidence by 50%, moreover, the level of endotoxemia showed a close relation with DNA index (r = 0.96, P < 0.01), as well as with the occurrence rate of hepatoma (r = 0.00, P < 0.01). Histological findings further verified such alterations.CONCLUSION:Lipopolysaccharide administration and/or splenectomy-induced enterogenic endotoxemia may enhance rat hepatocarcinogenesis induced by oral intake of thioacetamide.