Super-resolution reconstruction improves multishell diffusion: using radiomics to predict adult-type diffuse glioma IDH and grade.

Objectives: Multishell diffusion scanning is limited by low spatial resolution. We sought to improve the resolution of multishell diffusion images through deep learning-based super-resolution reconstruction (SR) and subsequently develop and validate a prediction model for adult-type diffuse glioma, isocitrate dehydrogenase status and grade 2/3 tumors. Materials and methods: A simple diffusion model (DTI) and three advanced diffusion models (DKI, MAP, and NODDI) were constructed based on multishell diffusion scanning. Migration was performed with a generative adversarial network based on deep residual channel attention networks, after which images with 2x and 4x resolution improvements were generated. Radiomic features were used as inputs, and diagnostic models were subsequently constructed via multiple pipelines. Results: This prospective study included 90 instances (median age, 54.5 years; 39 men) diagnosed with adult-type diffuse glioma. Images with both 2x- and 4x-improved resolution were visually superior to the original images, and the 2x-improved images allowed better predictions than did the 4x-improved images (P<.001). A comparison of the areas under the curve among the multiple pipeline-constructed models revealed that the advanced diffusion models did not have greater diagnostic performance than the simple diffusion model (P>.05). The NODDI model constructed with 2x-improved images had the best performance in predicting isocitrate dehydrogenase status (AUC_validation=0.877; Brier score=0.132). The MAP model constructed with the original images performed best in classifying grade 2 and grade 3 tumors (AUC_validation=0.806; Brier score=0.168). Conclusion: SR improves the resolution of multishell diffusion images and has different advantages in achieving different goals and creating different target diffusion models.

MARCH5 promotes hepatocellular carcinoma progression by inducing p53 ubiquitination degradation.

BACKGROUND: Human MARCH5 is a mitochondria-localized E3 ubiquitin-protein ligase that is essential for the regulation of mitochondrial dynamics. A large body of evidence suggests that imbalances in mitochondrial dynamics are strongly associated with cancer. However, the expression, biological function and prognostic significance of MARCH5 in hepatocellular carcinoma (HCC) have not been determined. MATERIALS AND METHODS: The mRNA and protein expression of MARCH5 in HCC cell lines and tumor tissues was assessed by real-time quantitative PCR, Western blot analysis and immunohistochemistry. The clinical prognostic significance of MARCH5 was evaluated in 135 HCC patients. Knockdown or overexpression of MARCH5 in HCC cells was determined by in vitro cell proliferation, migration and invasion assays, and in vivo tumor growth and metastasis assays. In addition, the intrinsic mechanisms by which MARCH5 regulates HCC cell growth and metastasis were explored. RESULTS: MARCH5 was significantly overexpressed in HCC cells and was closely associated with patients' poor postoperative prognosis. In vivo and in vitro experiments revealed that MARCH5 significantly promoted the increase and invasive and migratory ability of hepatocellular carcinoma cells, which was mainly due to the promotion of autophagy by MARCH5. Mechanistic studies revealed that MARCH5 promoted autophagy through ubiquitination degradation of p53 leading to malignant progression of hepatocellular carcinoma. CONCLUSION: Our findings suggest that MARCH5 plays a critical oncogenic role in HCC cells, which provides experimental evidence for the use of MARCH5 as a potential target for HCC therapy.

Structural changes in corticospinal tract profiling via multishell diffusion models and their relation to overall survival in glioblastoma.

PURPOSE: Advanced MR fiber tracking imaging reflects fiber bundle invasion by glioblastoma, particularly of the corticospinal tract (CST), which is more susceptible as the largest downstream fiber tracts. We aimed to investigate whether CST features can predict the overall survival of glioblastoma. METHODS: In this prospective secondary analysis, 40 participants (mean age, 58 years; 16 male) pathologically diagnosed with glioblastoma were enrolled. Diffusion spectrum MRI was used for CST reconstruction. Fifty morphological and diffusion indicators (DTI, DKI, NODDI, MAP and Q-space) were used to characterize the CST. Optimal parameters capturing fiber bundle damage were obtained through various grouping methods. Eventually, the correlation with overall survival was determined by the hazard ratios (HRs) from various Cox proportional hazard model combinations. RESULTS: Only intracellular volume fraction (ICVF) and non-Gaussianity (NG) values on the affected tumor level were significant in all four groups or stratified comparisons (all P < .05). During the median follow-up 698 days, only the ICVF on the affected tumor level was independently associated with overall survival, even after adjusting for all classic prognostic factors (HR [95 % CI]: 0.611 [0.403, 0.927], P = .021). Moreover, stratification by the ICVF on the affected tumor level successfully predicted risk (P < .01) and improved the C-index of the multivariate model (from 0.695 to 0.736). CONCLUSIONS: This study demonstrates a relationship between NODDI-derived CST features, ICVF on the affected tumor level, and overall survival in glioblastoma. Independent of classical prognostic factors for glioblastoma, a lower ICVF on the affected tumor level might predict a lower overall survival.

Heterogeneity matching and IDH prediction in adult-type diffuse gliomas: a DKI-based habitat analysis.

Objective: To explain adult-type diffuse gliomas heterogeneity through diffusion kurtosis imaging-based habitat characteristics and develop and validate a comprehensive model for predicting isocitrate dehydrogenase (IDH) status. Materials and methods: In this prospective secondary analysis, 103 participants (mean age, 52 years; range, 21-77; 54 [52%] male) pathologically diagnosed with adult-type diffuse gliomas were enrolled between June 2018 and February 2022. The Otsu method was used to generate habitat maps with mean diffusivity (MD) and mean kurtosis (MK) for a total of 4 subhabitats containing 16 habitat features. Habitat heatmaps were created based on the Pearson correlation coefficient. The Habitat imAging aNd clinicraD INtegrated prEdiction SyStem (HANDINESS) was created by combining clinical features, conventional MRI morphological features, and habitat image features. ROC, calibration curve, and decision curve analyses were used to select the optimal model after 32 pipelines for model training and validation. Results: In the restricted diffusion and high-density subhabitat, MK was highly correlated with MD (R2 = 0.999), volume (0.608) and percentage of volume (0.663), and this region had the highest MK value (P<.001). The unrestricted diffusion and low-density subhabitat had the highest MD value (P<.001). When MK was less than the Otsu threshold, there was still a difference between restricted diffusion and low-density and unrestricted diffusion and low-density subhabitats (P<.01). The HANDINESS enabled more accurate prediction of the IDH status in the training (AUC=0.951 [0.902-0.987]) and internal validation cohorts (0.938 [0.881-0.949]). AUC values for single-modality models and independent factors ranged from 0.593 to 0.916. Calibration and decision curve analyses showed that the HANDINESS demonstrated a high level of clinical applicability and predictive consistency. Conclusion: Diffusion kurtosis imaging-based habitat analysis provides additional important information on microscopic tumor spatial heterogeneity. The HANDINESS has higher diagnostic performance and robustness than single-modality models.

AARS2 as a novel biomarker for prognosis and its molecular characterization in pan-cancer.

INTRODUCTION: The mitochondrial alanyl-tRNA synthetase 2 (AARS2) as one of aminoacyl-tRNA synthases (ARSs) performs amino acid transportation and involves protein synthesis. However, its role in cancer remains largely unexplored. METHODS: In this study, more than 10,000 samples were enrolled to explore genomic alterations, biological function, prognosis, and clinical treatment based on AARS2 across pan-cancer. The molecular characterization of AARS2 was confirmed in hepatocellular carcinoma (HCC) using proteomics analysis, quantitative real-time PCR, western blotting, immunohistochemical staining, and cell experiments. RESULTS: For genomic landscape, the AARS2 was dramatically upregulated in multiple cancers, which might be mainly caused by copy number alteration rather than mutation and methylation. The abnormal expression of AARS2 was prominently associated with activity of cancer pathways and performed oncogenic roles in most cancers. Systematic experiments in vitro substantiated the elevated expression of AARS2, and the deficiency of it inhibited cell proliferation and cell migration in HCC. Meanwhile, our findings suggested that AARS2 could serve as a novel promising and stable biomarker for assessing prognosis and immunotherapy. Moreover, a variety of therapeutic drugs and targeted pathways were proposed for cancer treatment, which might enhance clinical efficacy. CONCLUSION: The AARS2 could serve as a new oncogenic gene that promotes cell proliferation and migration in HCC. The comprehensive investigations increased the understanding of AARS2 across human cancers and generated beginning insights of AARS2 in genomic landscape, molecular biological function, prognosis, and clinical treatment.

Model incorporating multiple diffusion MRI features: development and validation of a radiomics-based model to predict adult-type diffuse gliomas grade.

OBJECTIVES: To develop and validate a radiomics-based model (ADGGIP) for predicting adult-type diffuse gliomas (ADG) grade by combining multiple diffusion modalities and clinical and imaging morphologic features. METHODS: In this prospective study, we recruited 103 participants diagnosed with ADG and collected their preoperative conventional MRI and multiple diffusion imaging (diffusion tensor imaging, diffusion kurtosis imaging, neurite orientation dispersion and density imaging, and mean apparent propagator diffusion-MRI) data in our hospital, as well as clinical information. Radiomic features of the diffusion images and clinical information and morphological data from the radiological reports were extracted, and multiple pipelines were used to construct the optimal model. Model validation was performed through a time-independent validation cohort. ROC curves were used to evaluate model performance. The clinical benefit was determined by decision curve analysis. RESULTS: From June 2018 to May 2021, 72 participants were recruited for the training cohort. Between June 2021 and February 2022, 31 participants were enrolled in the prospective validation cohort. In the training cohort (AUC 0.958), internal validation cohort (0.942), and prospective validation cohort (0.880), ADGGIP had good accuracy in predicting ADG grade. ADGGIP was also significantly better than the single-modality prediction model (AUC 0.860) and clinical imaging morphology model (0.841) (all p < .01) in the prospective validation cohort. When the threshold probability was greater than 5%, ADGGIP provided the greatest net benefit. CONCLUSION: ADGGIP, which is based on advanced diffusion modalities, can predict the grade of ADG with high accuracy and robustness and can help improve clinical decision-making. CLINICAL RELEVANCE STATEMENT: Integrated multi-modal predictive modeling is beneficial for early detection and treatment planning of adult-type diffuse gliomas, as well as for investigating the genuine clinical significance of biomarkers. KEY POINTS: • Integrated model exhibits the highest performance and stability. • When the threshold is greater than 5%, the integrated model has the greatest net benefit. • The advanced diffusion models do not demonstrate better performance than the simple technology.

Applying MAP-MRI to Identify the WHO Grade and Main Genetic Features of Adult-type Diffuse Gliomas: A Comparison of Three Diffusion-weighted MRI Models.

RATIONALE AND OBJECTIVES: Currently, there is no noninvasive method to effectively judge the genotype of diffuse gliomas. We explored the association between mean apparent propagator-MRI (MAP-MRI) and WHO grade 2/3, IDH 1/2 mutations, and chromosome 1p/19q combined deletion genotypes in adult-type diffuse gliomas and compared it with the diagnostic efficiency of diffusion tensor imaging (DTI) and diffusional kurtosis imaging (DKI). MATERIALS AND METHODS: We prospectively recruited 67 participantshistopathologically diagnosed with adult-type diffuse gliomas. Routine MRI, DKI, and DSI were performed before surgery. The extreme and average partial diffusion indexes of solid tumors were measured. A comprehensive assessment of statistically significant diffusion parameters was performed after Bonferroni correction, including ROC curves, correct classification percentage (CCP), integrated discrimination improvement (IDI), net reclassification improvement (NRI), and k-fold cross validation. RESULTS: For differentiating WHO grade 2/3, q-space inverse variance (QIV), mean kurtosis (MK), non-Gaussianity (NG), and return to the origin probability (RTOP) were different (p' < .05), with the mean QIV exhibiting the best diagnostic efficacy and stability (AUC = 0.973, CCP = 0.906). We observed significant differences in mean diffusivity (MD), mean square displacement, QIV, MK, and RTOP between the IDH wild-type and IDH mutant groups (p' < .001) (AUC, 0.806-0.978) and MAP-MRI showed a higher IDI than DTI and DKI (0.094-0.435, NRI > 0, respectively). For the chromosome 1p/19q combined deletion, the minimum QIV was different between the overall (p' < .05) and no significant differences  in MD and MK was observed. CONCLUSION: MAP-MRI effectively predicts the WHO grade 2/3, IDH 1/2 mutations, and chromosome 1p/19q combined deletion in adult-type diffuse gliomas, and it may perform better than DTI and DKT.

Evaluation of diffuse glioma grade and proliferation activity by different diffusion-weighted-imaging models including diffusion kurtosis imaging (DKI) and mean apparent propagator (MAP) MRI.

PURPOSE: To evaluate two advanced diffusion models, diffusion kurtosis imaging and the newly proposed mean apparent propagation factor-magnetic resonance imaging, in the grading of gliomas and the assessing of their proliferative activity. METHODS: Fifty-nine patients with clinically diagnosed and pathologically proven gliomas were enrolled in this retrospective study. All patients underwent DKI and MAP-MRI scans. Manually outline the ROI of the tumour parenchyma. After delineation, the imaging parameters were extracted using only the data from within the ROI including mean diffusion kurtosis (MK), return-to-origin probability (RTOP), Q-space inverse variance (QIV) and non-Gaussian index (NG), and the differences in each parameter in the classification of glioma were compared. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of these parameters. RESULTS: MK, NG, RTOP and QIV were significantly different amongst the different grades of glioma. MK, NG and RTOP had excellent diagnostic value in differentiating high-grade from low-grade glioma, with largest areas under the curve (AUCs; 0.929, 0.933 and 0.819, respectively; P < 0.01). MK and NG had the largest AUCs (0.912 and 0.904) when differentiating grade II tumours from III tumours (P < 0.01) and large AUCs (0.791 and 0.786) when differentiating grade III from grade IV tumours. Correlation analysis of tumour proliferation activity showed that MK, NG and QIV were strongly correlated with the Ki-67 LI (P < 0.001). CONCLUSION: MK, RTOP and NG can effectively represent the microstructure of these altered tumours. Multimodal diffusion-weighted imaging is valuable for the preoperative evaluation of glioma grade and tumour proliferative activity.

Diagnostic performance of mono-exponential DWI versus diffusion kurtosis imaging in breast lesions: A meta-analysis.

BACKGROUND: This meta-analysis aimed to explore the diagnostic value of diffusion kurtosis imaging (DKI) compared to mono-exponential diffusion weighted imaging (DWI) in the diagnosis of breast cancer. METHODS: A systematic electronic literature search (up to September 2020) was conducted for published English-language studies comparing the diagnostic values of DKI and DWI for the detection of breast cancer. The data of mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) were extracted to construct 2 × 2 contingency tables. The pooled sensitivities, specificities, and areas under the receiver operating characteristic curve (AUCs) were compared between DKI and DWI in the diagnosis of breast cancer. RESULTS: Eight studies were finally included, with a total of 771 patients in the same population. Pooled sensitivities were 82.0% [95% confidence interval (95% CI), 78.2-85.3%] for ADC, 87.3% (95% CI, 83.9-90.1%) for MK, and 83.9% (95% CI, 80.2-87.1%) for MD. Pooled specificities were 81.1% (95% CI, 76.7-84.9%) for ADC, 85.1% (95% CI, 81.1-88.5%) for MK, and 83.2% (95% CI, 79.0-86.8%) for MD. According to the summary receiver operator characteristic curve analyses, the AUCwas 0.901 for ADC, 0.930 for MK, and 0.918 for MD (ADC vs MK, P = .353; ADC vs MD, P = .611). No notable publication bias was found, while significant heterogeneity was observed. CONCLUSIONS: Although DKI is feasible for identifying breast cancer, MD and MK offer similar diagnostic performance to ADC values. Thus, we recommend that DKI should not be included in the routine evaluation of breast lesions now.

A Dual-Responsive Magnetoactive and Electro-Ionic Soft Actuator Derived from a Nickel-Based Metal-Organic Framework.

There is growing demand for multiresponsive soft actuators for the realization of natural, safe, and complex motions in robotic interactions. In particular, soft actuators simultaneously stimulated by electrical and magnetic fields are always under development owing to their simple controllability and reliability during operation. Herein, magnetically and electrically driven dual-responsive soft actuators (MESAs) derived from novel nickel-based metal-organic frameworks (Ni-MOFs-700C), are reported. Nanoscale Ni-MOFs-700C has excellent electrochemical and magnetic properties that allow it to be used as a multifunctional material under both magnetoactive and electro-ionic actuations. The dual-responsive MESA exhibits a bending displacement of 30 mm and an ultrafast rising time of 1.5 s under a very low input voltage of 1 V and also exerts a bending deflection of 12.5 mm at 50 mT under a high excitation frequency of 5 Hz. By utilizing a dual-responsive MESA, the hovering motion of a hummingbird robot is demonstrated under magnetic and electrical stimuli.

ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14.

High aggressiveness is the main reason for the poor prognosis of hepatocellular carcinoma (HCC) patients. However, its molecular mechanisms still remain largely unexplored. ACADL, a mitochondrial enzyme that facilitates the primary regulated step in mitochondrial fatty acid oxidation, plays a role in HCC growth inhibition. However, the function of ACADL in tumor metastasis is not well elucidated. We found that the reduced expression of ACADL is closely associated with the loss of tumor encapsulation, extrahepatic metastasis, and poor prognosis in HCC patients. Upregulation of ACADL significantly inhibited HCC migration and invasion ability. Whereas knockdown of ACADL markedly enhanced cell invasive capability. Expression of matrix metalloproteinase-14 (MMP14) was negatively associated with the content of ACADL in HCC specimens. MMP14-positive patients with a low expression of ACADL showed worse outcome. Treatment with MMP14 agonist reversed the inhibitory effect of ACADL on HCC metastasis. In addition, ACADL negatively regulated MMP14 expression by inhibiting the STAT3 signaling pathway, as the sustained activation of STAT3 effectively restored the level of MMP14 in ACADL-overexpressed cells. Collectively, these findings disclose that ACADL represses HCC metastasis via STAT3-MMP14 pathway. This study may propose a promising strategy for the precise treatment of metastatic HCC patients.

Prognostic and Clinicopathological Correlations of Pretreatment Prognostic Nutritional Index in Renal Cell Carcinoma: A Meta-Analysis.

INTRODUCTION: Prognostic nutritional index (PNI) was indicted as a potential prognostic biomarker for cancer. However, the conclusion remains uncertain for renal cell carcinoma (RCC). This study was to confirm the association of PNI with prognosis and clinicopathological features in RCCs. METHODS: The PubMed, EMBASE, Cochrane Library, CNKI, and Wan Fang databases were searched to retrieve eligible studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled to assess the strength of the association. RESULTS: Fifteen studies were included. The results showed a low pretreatment PNI level was significantly associated with poor overall survival (HR = 1.67, 95% CI: 1.45-1.92), progression-free survival (HR = 1.72, 95% CI: 1.23-2.42), cancer-specific survival (HR = 1.17, 95% CI: 1.09-1.26), disease-free survival (HR = 1.28, 95% CI: 1.09-1.26), and recurrence-free survival (HR = 2.14, 95% CI: 1.38-3.31). This prognostic role of PNI was almost not changed by subgroup analysis based on study design, HR source, RCC type, sample size, cutoff, follow-up, treatment, and country. Furthermore, low PNI was correlated with old age, large tumor size and high T stage, Fuhrman grade, lymph node, and distant metastases. CONCLUSION: Pretreatment PNI might be a promising indicator to beforehand predict the progression and prognosis for RCC patients.

Pharmacological Activating Transcription Factor 6 Activation Is Beneficial for Liver Retrieval With ex vivo Normothermic Mechanical Perfusion From Cardiac Dead Donor Rats.

Background: Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Activating transcription factor 6 (ATF6) was recently shown to mitigate liver ischemia/reperfusion injury and confer protection. The aims of this study were to assess the implication of ATF6 in liver retrieval from DCD rat livers with NMP and explore the effect of pharmacologic ATF-6 activation on liver retrieval. Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Perfusates and livers were harvested to detect ATF6 expression, liver function, and inflammation. Results: DCD livers with NMP were associated with ATF6 overexpression and activation based on IHC and WB (P < 0.05). The ATF6 activator downregulated perfusate aminotransferases, decreased the Suzuki score, downregulated CD68 and MPO based on IHC, induced the expression of cytochrome c in mitochondria and inhibited the expression of cytochrome c in cytoplasm based on WB, reduced TNFα and IL-6 levels based on ELISA, decreased levels of MDA, GSSG and ATP, and increased SOD activity and GSH levels in the perfused livers (P < 0.05). Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model.

Primary application of mean apparent propagator-MRI diffusion model in the grading of diffuse glioma.

PURPOSE: To evaluate the diagnostic -->performance of mean apparent propagator-magnetic resonance imaging (MAP-MRI) in distinguishing the grades of diffuse gliomas. METHOD: Thirty-six patients with pathologically confirmed diffuse gliomas were enrolled in this study. MAP-MRI parameters were measured in the parenchymal area of the tumour: non-Gaussianity (NG), non-Gaussianity axial (NGAx), non-Gaussianity vertical (NGRad), Q-space inverse variance (QIV), return to the origin probability (RTOP), return to the axis probability (RTAP), return to the plane probability (RTPP), and mean square displacement (MSD). Differences in the parameters between any two grades were compared, the characteristics of the parameters for different diffuse glioma grades were analysed, and receiver operating characteristic (ROC) curves were plotted to analyse the diagnostic value of each parameter. RESULTS: Compared with grade III gliomas, grade II gliomas had lower NG, NGAx and NGRad values. NG, NGAx and NGRad had great area under the ROC curve (AUC) values (0.823, 0.835, and 0.838, P < 0.05). Compared with those of grade IV glioma, the NG, NGAx, NGRad, RTAP and RTOP values for grade II glioma were lower, the QIV values were higher (all P < 0.05). NG, NGAx, NGRad, RTAP, RTOP and QIV had great area under the ROC curve (AUC) values (0.923, 0.929, 0.923,0.793,0.822, and 0.769, P < 0.05). CONCLUSIONS: Quantitative MAP-MRI parameters can distinguish grade II and III and grade II and IV gliomas before surgery but not grade III and IV gliomas. Thus, these parameters have clinical guiding value in the noninvasive preoperative evaluation of tumour pathological grading.

Single nucleotide polymorphisms in interleukin-6 attenuates hepatocytes injury in hypoxia/re-oxygenation via STAT3 signal pathway mediated autophagy.

Ischemia-reperfusion injury (IRI) is inevitable during liver surgery, and it is an important factor affecting the prognosis of patients. IL-6 rs1800796 single nucleotide polymorphisms (SNPs) can promote synthesis and secretion of IL-6 and protect hepatocytes from IRI. In this study, we investigated the mechanisms by which IL-6 alleviates hepatic IRI. We transfected lentivirus which carries IL-6 rs1800796 to L02 cells and constructed the cell line (L02-IL6) with a high expression of IL-6. The biological function of IL-6 SNPs was explored through a cell model of hypoxia-reoxygenation (H/R). Cell viability was evaluated by CCK8 and Real-Time Cell Analysis (RTCA), and found that the viability of the L02-IL6 cells was higher than that of the control group (P < 0.01). Flow cytometry assay showed that the rate of apoptosis was significantly decreased in L02-IL6 cells. Furthermore, in comparison with the control group, the level of cleaved-caspase3, which is an important marker of apoptosis, was dramatically decreased. These differences showed that the sequence variants at rs1800796 of the IL-6 gene could improve the resistance against H/R. Moreover, the levels of autophagy-related proteins, such as LC3 and Beclin-1, were upregulated in L02-IL6 group on H/R injury, which means IL-6 could alleviate apoptosis via activating the autophagy pathway. And we also found that the STAT3 signal pathway was activated. Next, we investigated whether the exogenous treatment with IL-6 affect hepatocytes and thus play a protective role. We pre-treated the L02 cells with recombinant human IL-6 for 12 h and then made H/R treatment. We found the treatment with 100 ng/ml IL-6 alleviated the damage of L02 cells and inhibited the apoptosis. And the further study revealed the pre-treatment with IL-6 activated the STAT3 signaling pathway in the L02 cells and then caused the activation of autophagy and apoptosis inhibition. IL-6 might play a critical role in alleviating hepatic IRI, through its modulation of the STAT3 signaling pathway, and activation of autophagy. Recombinant human IL-6 might be a potential therapeutic target in hepatic IRI.

Tripartite Motif-Containing 27 Attenuates Liver Ischemia/Reperfusion Injury by Suppressing Transforming Growth Factor ß-Activated Kinase 1 (TAK1) by TAK1 Binding Protein 2/3 Degradation.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (I/R) injury, which mainly involves inflammatory responses and apoptosis, is a common cause of organ dysfunction in liver transplantation (LT). As a critical mediator of inflammation and apoptosis in various cell types, the role of tripartite motif-containing (TRIM) 27 in hepatic I/R injury remains worthy of study. APPROACH AND RESULTS: This study systemically evaluated the putative role of TRIM27/transforming growth factor ß-activated kinase 1 (TAK1)/JNK (c-Jun N-terminal kinase)/p38 signaling in hepatic I/R injury. TRIM27 expression was significantly down-regulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Subsequently, using global Trim27 knockout mice (Trim27-KO mice) and hepatocyte-specific Trim27 transgenic mice (Trim27-HTG mice), TRIM27 functions to ameliorate liver damage, reduce the inflammatory response, and prevent cell apoptosis. In parallel in vitro studies, activating TRIM27 also prevented H/R-induced hepatocyte inflammation and apoptosis. Mechanistically, TRIM27 constitutively interacted with the critical components, TAK1 and TAK1 binding protein 2/3 (TAB2/3), and promoted the degradation of TAB2/3, leading to inactivation of TAK1 and the subsequent suppression of downstream JNK/p38 signaling. CONCLUSIONS: TRIM27 is a key regulator of hepatic I/R injury by mediating the degradation of TAB2/3 and suppression of downstream TAK1-JNK/p38 signaling. TRIM27 may be a promising approach to protect the liver against I/R-mediated hepatocellular damage in transplant recipients.

Antinociceptive effects of oleuropein in experimental models of neuropathic pain in male rats.

BACKGROUND: The present investigation explored the therapeutic actions of oleuropein along with the possible signaling pathway involved in attenuating neuropathic pain in chronic constriction injury (CCI) and vincristine-induced neuropathic pain in male rats. METHODS: Four loose ligatures were placed around the sciatic nerve to induce CCI, and vincristine (50 µg/kg) was injected for 10 days to develop neuropathic pain. The development of cold allodynia, mechanical allodynia, and mechanical hyperalgesia was assessed using different pain-related behavioral tests. The levels of H2S, cystathionine-γ-lyase (CSE), cystathionine-ß-synthase (CBS), orexin, and nuclear factor erythroid-2-related factor 2 (Nrf2) were measured in the sciatic nerve. RESULTS: Treatment with oleuropein for 14 days led to significant amelioration of behavioral manifestations of neuropathic pain in two pain models. Moreover, oleuropein restored both CCI and vincristine-induced decreases in H2S, CSE, CBS, orexin, and Nrf2 levels. Co-administration of suvorexant, an orexin receptor antagonist, significantly counteracted the pain-attenuating actions of oleuropein and Nrf2 levels without modulating H2S, CSE and CBS. CONCLUSIONS: Oleuropein has therapeutic potential to attenuate the pain manifestations in CCI and vincristine-induced neuropathic pain, possibly by restoring the CSE, CBS, and H2S, which may subsequently increase the expression of orexin and Nrf2 to ameliorate behavioral manifestations of pain.

Dexmedetomidine as an adjuvant for patients undergoing breast cancer surgery: A meta-analysis.

BACKGROUND: The goal of this study was to comprehensively evaluate the analgesic and antiemetic effects of adjuvant dexmedetomidine (DEX) for breast cancer surgery using a meta-analysis. METHODS: Electronic databases were searched to collect the studies that performed randomized controlled trials. The effect size was estimated by odd ratio (OR) or standardized mean difference (SMD). Statistical analysis was performed using the STATA 13.0 software. RESULTS: Twelve published studies involving 396 DEX treatment patients and 395 patients with control treatment were included. Pooled analysis showed that the use of DEX significantly prolonged the time to first request of analgesia (SMD = 1.67), decreased the postoperative requirement for tramadol (SMD = -0.65) and morphine (total: SMD = -2.23; patient-controlled analgesia: SMD = -1.45) as well as intraoperative requirement for fentanyl (SMD = -1.60), and lower the pain score at 1 (SMD = -0.30), 2 (SMD = -1.45), 4 (SMD = -2.36), 6 (SMD = -0.63), 8 (SMD = -2.47), 12 (SMD = -0.81), 24 (SMD = -1.78), 36 (SMD = -0.92), and 48 (SMD = -0.80) hours postoperatively compared with the control group. Furthermore, the risks to develop postoperative nausea/vomiting (PONV) (OR = 0.38) and vomiting (OR = 0.54) were significantly decreased in the DEX group compared with the control group. The pain relief at early time point (2, 6, 12, 24 hours postoperatively) and the decrease in the incidence of PONV were especially obvious for the general anesthesia subgroup (P < .05) relative to local anesthesia subgroup (P >.05). CONCLUSION: DEX may be a favorable anesthetic adjuvant in breast cancer surgery, which could lower postoperative pain and the risk to develop PONV. DEX should be combined especially for the patients undergoing general anesthesia.

Synaptopodin-2 promotes hepatocellular carcinoma metastasis via calcineurin-induced nuclear-cytoplasmic translocation.

Hepatocellular carcinoma (HCC), a type of malignant liver tumor, has a grim prognosis. As a functional protein, synaptopodin-2 (SYNPO2) has been associated with malignancy; however, the expression profile and function of SYNPO2 in HCC remains unknown. Herein, we revealed that SYNPO2 was transcriptionally downregulated in HCC tissues from both The Cancer Genome Atlas cohort and our cohort, and was also decreased at the translational level as determined by western blotting and immunohistochemical staining. Furthermore, reduced SYNPO2 expression correlated significantly with short overall survival and recurrence free survival of HCC patients. Restoring SYNPO2 expression inhibited the proliferation and aggressiveness of hepatocarcinoma cells. Mechanistically, increasing the ratio of cytoplasmic SYNPO2 to nuclear SYNPO2 was positively associated with recurrence rate in HCC patients; calcineurin (CaN) activity positively correlated with cytoplasmic SYNPO2 levels in HCC tissues; and nuclear-cytoplasmic translocation of SYNPO2 was induced by CaN to facilitate metastasis of HCC through assembly of peripheral actin bundles. In short, our findings uncover a novel role of SYNPO2 in HCC metastasis via the CaN/SYNPO2/F-actin axis, and indicate that SYNPO2 may serve as a possible prognostic marker and novel therapeutic target.

A signature of 33 immune-related gene pairs predicts clinical outcome in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) has become the second most common tumor type that contributes to cancer-related death worldwide. The study aimed to establish a robust immune-related gene pair (IRGP) signature for predicting the prognosis of HCC patients. METHODS: Two RNA-seq datasets (The Cancer Genome Atlas Program and International Cancer Genome Consortium) and one microarray dataset (GSE14520) were included in this study. We used a series of immune-related genes from the ImmPort database to construct gene pairs. Lasso penalized Cox proportional hazards regression was employed to develop the best prognostic signature. We assigned patients into two groups with low immune risk and high immune risk. Then, the prognostic ability of the signature was evaluated by a log-rank test and a Cox proportional hazards regression model. RESULTS: After 1000 iterations, the 33-immune gene pair model obtained the highest frequency. As a result, we chose the 33 immune gene pairs to establish the immune-related prognostic signature. As we expected, the immune-related signature accurately predicted the prognosis of HCC patients, and high-risk groups showed poor prognosis in the training datasets and testing datasets as well as in the validation datasets. Furthermore, the immune-related gene pair (IRGP) signature also showed higher predictive accuracy than three existing prognostic signatures. CONCLUSION: Our prognostic signature, which reflects the link between the immune microenvironment and HCC patient outcome, is promising for prognosis prediction in HCC.