PAFAH1B3 is a KLF9 target gene that promotes proliferation and metastasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Uncontrolled cell proliferation, invasion and migration of pancreatic cancer cells are the fundamental causes of death in PDAC patients. Our previous studies showed that KLF9 inhibits the proliferation, invasion and migration of pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In this study, we found that platelet-activating factor acetylhydrolase IB3 (PAFAH1B3) is highly expressed in pancreatic cancer tissues and cells. In vitro and in vivo studies showed that overexpression of PAFAH1B3 promoted the proliferation and invasion of pancreatic cancer cells, while downregulation of PAFAH1B3 inhibited these processes. We found that KLF9 expression is negatively correlated with PAFAH1B3 expression in pancreatic cancer tissues and cells. Western blotting revealed that KLF9 negatively regulates the expression of PAFAH1B3 in pancreatic cancer tissues and cells. Rescue experiments showed that overexpression of PAFAH1B3 could partially attenuate the suppression of pancreatic cancer cell proliferation, invasion and migration induced by KLF9 overexpression. Finally, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out, and the results showed that KLF9 directly binds to the promoter of PAFAH1B3 and inhibits its transcriptional activity. In conclusion, our study indicated that KLF9 can inhibit the proliferation, invasion, migration and metastasis of pancreatic cancer cells by inhibiting PAFAH1B3.

The effects of anastomoses between anterior and posterior circulation on postoperative prognosis of patients with moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) is a chronic ischemic cerebrovascular disease. Collateral circulation in MMD has emerged as a research focus. Our aims were to assess the impact of anastomoses between the anterior and posterior circulations on the prognosis of MMD patients. METHODS: We reviewed the preoperative digital subtraction angiography images of patients with MMD who underwent revascularization surgery at our hospital between March 2014 and May 2020 and divided the patients into two groups: those with anastomoses (PtoA group) and those without anastomoses (non-PtoA group). The differences in follow-up (more than 6 months) collateral vessel establishment (Matsushima grade) and the modified Rankin Scale (mRS) were compared between the two groups as well as between the patients with different degrees of anastomoses. The early complications following revascularization were also compared between the two groups. RESULTS: This study included 104 patients with MMD, of which 38 were non-PtoA and 66 were PtoA. There were no significant differences in Matsushima score (P = 0.252) and mRS score (P = 0.066) between the two groups. In addition, Matsushima score (P = 0.243) and mRS score (P = 0.360) did not differ significantly between patients with different degrees of anastomoses. However, the non-PtoA group had a significantly higher rate of cerebral hyperperfusion syndrome (CHS) than the PtoA group (34.2% vs 16.7%, P = 0.041). CONCLUSION: MMD patients without anastomoses between anterior and posterior circulations preoperatively should be vigilant of the occurrence of CHS in the early stages after revascularization.

Integrating single-cell and bulk RNA sequencing reveals CK19 + cancer stem cells and their specific SPP1 + tumor-associated macrophage niche in HBV-related hepatocellular carcinoma.

PURPOSE: Cytokeratin 19-positive cancer stem cells (CK19 + CSCs) and their tumor-associated macrophages (TAMs) have not been fully explored yet in the hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Single-cell RNA sequencing was performed on the viable cells obtained from 11 treatment-naïve HBV-associated HCC patients, including 8 CK19 + patients, to elucidate their transcriptomic landscape, CK19 + CSC heterogeneity, and immune microenvironment. Two in-house primary HCC cohorts (96 cases-related HBV and 89 cases with recurrence), TCGA external cohort, and in vitro and in vivo experiments were used to validate the results. RESULTS: A total of 64,581 single cells derived from the human HCC and adjacent normal tissues were sequenced, and 11 cell types were identified. The result showed that CK19 + CSCs were phenotypically and transcriptionally heterogeneous, co-expressed multiple hepatics CSC markers, and were positively correlated with worse prognosis. Moreover, the SPP1 + TAMs (TAM_SPP1) with strong M2-like features and worse prognosis were specifically enriched in the CK19 + HCC and promoted tumor invasion and metastasis by activating angiogenesis. Importantly, matrix metalloproteinase 9 (MMP9) derived from TAM_SPP1, as the hub gene of CK19 + HCC, was activated by the VEGFA signal. CONCLUSIONS: This study revealed the heterogeneity and stemness characteristics of CK19 + CSCs and specific immunosuppressive TAM_SPP1 in CK19 + HCC. The VEGFA signal can activate TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. This might provide novel insights into the clinical treatment of HCC patients.

White matter hyperintensities in cholinergic pathways correlates of cognitive impairment in moyamoya disease.

OBJECTIVE: To investigate the effect of cholinergic pathways damage caused by white matter hyperintensities (WMHs) on cognitive function in moyamoya disease (MMD). METHODS: We included 62 patients with MMD from a prospectively enrolled cohort. We evaluated the burden of cholinergic pathways damage caused by WMHs using the Cholinergic Pathways Hyperintensities Scale (CHIPS). Cognitive function was evaluated with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Cognitive impairment was determined according to the cut-off of MMSE and education. Multivariate linear and logistic regression models were used to analyze whether CHIPS was independently associated with cognition. Receiver operating characteristic curve analysis was performed to identify the ability of CHIPS in discriminating cognitive impairment and normal cognition. RESULTS: CHIPS was associated with both MMSE and MoCA (ß = - 0.601 and ß = - 0.672, both p < 0.001). After correcting age, sex, education, volumes of limbic areas, and other factors, CHIPS remained to be independently associated with both MMSE and MoCA (ß = - 0.388 and ß = - 0.334, both p < 0.001). In the logistic regression, only CHIPS was associated with cognitive impairment (odds ratio = 1.431, 95% confidence interval = 1.103 to 1.856, p = 0.007). The optimal cut-off of CHIPS score was 10, yielding a sensitivity of 87.5% and a specificity of 78.3% in identifying MMD patients with cognitive impairment. CONCLUSIONS: The damage of cholinergic pathways caused by WMHs plays an independent effect on cognition and CHIPS could be a useful method in identifying MMD patients likely to be cognitive impairment. CLINICAL RELEVANCE STATEMENT: This study shows that Cholinergic Pathways Hyperintensities Scale (CHIPS) could be a simple and reliable method in identifying cognitive impairment for patients with moyamoya disease. CHIPS could be helpful in clinical practice, such as guiding treatment decisions and predicting outcome. KEY POINTS: • Cholinergic Pathways Hyperintensities Scale was significantly associated with cognitive screening tests in patients with moyamoya disease. • Cholinergic Pathways Hyperintensities Scale plays an independent effect on cognitive impairment in patients with moyamoya disease. • Cholinergic Pathways Hyperintensities Scale shows higher accuracy than education, volumes of limbic areas, and sex in identifying cognitive impairment in moyamoya disease.

Predicting the Outcome of Patients with Aneurysmal Subarachnoid Hemorrhage: A Machine-Learning-Guided Scorecard.

Aneurysmal subarachnoid hemorrhage (aSAH) frequently causes long-term disability, but predicting outcomes remains challenging. Routine parameters such as demographics, admission status, CT findings, and blood tests can be used to predict aSAH outcomes. The aim of this study was to compare the performance of traditional logistic regression with several machine learning algorithms using readily available indicators and to generate a practical prognostic scorecard based on machine learning. Eighteen routinely available indicators were collected as outcome predictors for individuals with aSAH. Logistic regression (LR), random forest (RF), support vector machines (SVMs), and fully connected neural networks (FCNNs) were compared. A scorecard system was established based on predictor weights. The results show that machine learning models and a scorecard achieved 0.75~0.8 area under the curve (AUC) predicting aSAH outcomes (LR 0.739, RF 0.749, SVM 0.762~0.793, scorecard 0.794). FCNNs performed best (~0.95) but lacked interpretability. The scorecard model used only five factors, generating a clinically useful tool with a total cutoff score of ≥5, indicating poor prognosis. We developed and validated machine learning models proven to predict outcomes more accurately in individuals with aSAH. The parameters found to be the most strongly predictive of outcomes were NLR, lymphocyte count, monocyte count, hypertension status, and SEBES. The scorecard system provides a simplified means of applying predictive analytics at the bedside using a few key indicators.

Age- and time-of-day dependence of glymphatic function in the human brain measured via two diffusion MRI methods.

Advanced age, accompanied by impaired glymphatic function, is a key risk factor for many neurodegenerative diseases. To study age-related differences in the human glymphatic system, we measured the influx and efflux activities of the glymphatic system via two non-invasive diffusion magnetic resonance imaging (MRI) methods, ultra-long echo time and low-b diffusion tensor imaging (DTIlow-b) measuring the subarachnoid space (SAS) flow along the middle cerebral artery and DTI analysis along the perivascular space (DTI-ALPS) along medullary veins in 22 healthy volunteers (aged 21-75 years). We first evaluated the circadian rhythm dependence of the glymphatic activity by repeating the MRI measurements at five time points from 8:00 to 23:00 and found no time-of-day dependence in the awake state under the current sensitivity of MRI measurements. Further test-retest analysis demonstrated high repeatability of both diffusion MRI measurements, suggesting their reliability. Additionally, the influx rate of the glymphatic system was significantly higher in participants aged >45 years than in participants aged 21-38, while the efflux rate was significantly lower in those aged >45 years. The mismatched influx and efflux activities in the glymphatic system might be due to age-related changes in arterial pulsation and aquaporin-4 polarization.

Molecular subtype identification and signature construction based on Golgi apparatus-related genes for better prediction prognosis and immunotherapy response in hepatocellular carcinoma.

Introduction: The Golgi apparatus (GA) is the center of protein and lipid synthesis and modification in normal cells and is involved in regulating various cellular process as a signaling hub, the dysfunction of which can lead to the development of various pathological conditions, including tumors. Mutations in Golgi apparatus-related genes (GARGs) are prevalent in most tumors, and their mutations can make them pro-tumor metastatic. The aim of this study was to analyze the predictive role of GARGs in the prognosis and immunotherapeutic outcome of hepatocellular carcinoma. Methods: We used TCGA, GEO and ICGC databases to classify hepatocellular carcinoma samples into two molecular subtypes based on the expression of GARGs. Signature construction was then performed using GARGs, and signature genes were selected for expression validation and tumor phenotype experiments to determine the role of GARGs in the prognosis of hepatocellular carcinoma. Results: Using the TCGA, GEO and ICGC databases, two major subtypes of molecular heterogeneity among hepatocellular carcinoma tumors were identified based on the expression of GARGs, C1 as a high-risk subtype (low survival) and C2 as a low-risk subtype (high survival). The high-risk subtype had lower StromalScore, ImmuneScore, ESTIMATEScore and higher TumorPurity, indicating poorer treatment outcome for ICI. Meanwhile, we constructed a new risk assessment profile for hepatocellular carcinoma based on GARGs, and we found that the high-risk group had a worse prognosis, a higher risk of immune escape, and a higher TP53 mutation rate. Meanwhile, TME analysis showed higher tumor purity TumorPurity and lower ESTIMATEScore, ImmuneScore and StromalScore in the high-risk group. We also found that the high-risk group responded more strongly to a variety of anticancer drugs, which is useful for guiding clinical drug use. Meanwhile, the expression of BSG was experimentally found to be associated with poor prognosis of HCC. After interfering with the expression of BSG in HCC cells SMMC-7721, the proliferation and migration ability of HCC cells were significantly restricted. Discussion: The signature we constructed using GARGs can well predict the prognosis and immunotherapy effect of hepatocellular carcinoma, providing new ideas and strategies for the treatment of hepatocellular carcinoma.

Preoperative Brain Functional Connectivity Improve Predictive Accuracy of Outcomes After Revascularization in Moyamoya Disease.

BACKGROUND: In patients with moyamoya disease (MMD), focal impairments in cerebral hemodynamics are often inconsistent with patients' clinical prognoses. Evaluation of entire brain functional networks may enable predicting MMD outcomes after revascularization. OBJECTIVE: To investigate whether preoperative brain functional connectivity could predict outcomes after revascularization in MMD. METHODS: We included 34 patients with MMD who underwent preoperative MRI scanning and combined revascularization surgery. We used region of interest analyses to explore the differences in functional connectivity for 90 paired brain regions between patients who had favorable outcomes 1 year after surgery (no recurrent stroke, with improved preoperative symptoms, or modified Rankin Scale [mRS]) and those who had unimproved outcomes (recurrent stroke, persistent symptoms, or declined mRS). Variables, including age, body mass index, mRS at admission, Suzuki stage, posterior cerebral artery involvement, and functional connectivity with significant differences between the groups, were included in the discriminant function analysis to predict patient outcomes. RESULTS: Functional connectivity between posterior cingulate cortex and paracentral lobule within the right hemisphere, and interhemispheric connection between superior parietal gyrus and middle frontal gyrus, precuneus and middle cingulate cortex, cuneus and precuneus, differed significantly between the groups (P < .001, false discovery rate corrected) and had the greatest discriminant function in the prediction model. Although clinical characteristics of patients with MMD showed great accuracy in predicting outcomes (64.7%), adding information on functional connections improved accuracy to 91.2%. CONCLUSION: Preoperative functional connectivity derived from rs-fMRI may be an early hallmark for predicting patients' prognosis after revascularization surgery for MMD.

Bloody fluids located between the temporal muscle and targeted cerebral cortex affect the establishment of indirect collaterals in Moyamoya disease with surgical bypass: A case-control study.

Objective: Bypass yields favorable outcomes in the treatment of Moyamoya disease (MMD). Bloody fluids accumulate between the targeted cortex and the temporal muscle after surgical bypass. These fluids are handled empirically via subcutaneous tubes or conservative treatments. However, substances located in certain positions may adversely affect the establishment of indirect collaterals (ICs) from muscular grafts. Methods: Patients in our hospital from January 2014 to December 2019 were eligible for inclusion. Digital subtraction angiography (DSA) and radiological examinations were used during the perioperative and follow-up periods. Bloody fluid volumes were calculated using computed tomography- (CT-) based 3D Slicer software. The characteristics of bloody fluids, patient demographics, and clinical data were retrospectively analyzed. Results: In total, 110 patients underwent indirect or combined bypass with follow-up DSA. The mean age of the enrolled patients was 42.4 ± 11.8 years. Previous ischemia (p = 0.001), previous hemorrhage (p = 0.013), bloody fluid volume (p = 0.049), and the time of imaging (p = 0.081) were associated with indirect outcomes. Ordinal regression analysis confirmed that good indirect outcomes were associated with previous ischemia (p < 0.001) and a large bloody fluid volume (p = 0.013). Further subgroups based on fluid volume were significantly correlated with IC establishment (p = 0.030). Conclusions: A large bloody fluid volume and previous ischemic history were associated with good indirect outcomes. The presence of bloody fluids may reflect impaired degrees of muscular donors due to bipolar electrocoagulation, thus highlighting the importance of appropriate application of bipolar forceps.

Clonorchis sinensis infection contributes to hepatocellular carcinoma progression in rat.

Clonorchis sinensis (C. sinensis) infection is a risk factor for cholangiocarcinoma. Whether it also contributes to the development of hepatocellular carcinoma (HCC) is still unclear. This study explored the potential relationship between C. sinensis infection and HCC. A total of 110 Sprague-Dawley rats were divided into four treatment groups, the negative control group (NC) received intragastric (i.g.) administration of saline, while the clonorchiasis group (CS) received i.g. administration of 150 C. sinensis metacercariae. The diethylnitrosamine-induced group (DEN) received intraperitoneal (i.p.) administration of DEN. The clonorchiasis DEN-induced group (CSDEN) received i.g. administration of 150 C. sinensis metacercariae followed by i.p. administration of DEN. Hematoxylin and eosin staining, immunohistochemistry, and Masson's trichrome staining were performed for histopathological analysis of the isolated tissues. RNA-seq technology and RT-PCR were employed for gene expression. In the DEN group, 15 rats survived, of which 9 developed liver cirrhosis and 7 developed HCC. In the CSDEN group, all of the 17 surviving rats developed cirrhosis, and 15 showed development of HCC. The incidence of liver cirrhosis and HCC was significantly higher in the CSDEN group than in the DEN group. KEGG pathway analysis of the differentially expressed genes suggested significant upregulation in inflammation-associated pathways. Immunohistochemistry and RT-PCR results showed significant upregulation of hepatic progenitor cell markers (CK19, SOX9, EpCAM) in the CS group compared to the NC group, as well as in the CSDEN group compared to the DEN group. Our study suggests that C. sinensis infection increases risk of HCC in a rat model by stimulating proliferation of hepatic progenitor cells.

The Recipient Vessel Hemodynamic Features Affect the Occurrence of Cerebral Edema in Moyamoya Disease After Surgical Revascularization: A Single-Center Retrospective Study.

Objective: In moyamoya disease (MMD) with direct or combined revascularization, the initially hemodynamic recipient features are likely one of the main causes of acute hemodynamic disruption. Previous studies have explored the relationship between recipient diameter or flow velocity and postoperative complications, but there are still no optimal selection criteria with multiple potential recipient vessels. Cerebral edema is one of the most common radiological manifestations in the acute postoperative period. This study assessed the hemodynamic characteristics of cortex vessels related to postoperative cerebral edema. Methods: All patients who had undergone direct or combined revascularization with preoperative digital subtraction angiography (DSA) between 2019 and 2021 were eligible for inclusion in this study. The application of DSA was performed and regular radiological examinations were employed after surgery. DSA was analyzed with the hemodynamic features within chosen recipient vessels. Cerebral edema was identified as a low-density image on CT or high signaling in the MRI T2 phase. The recipient hemodynamic characteristics and demographic presentation, as well as clinical data, were retrospectively analyzed in this study. Results: A total of 103 patients underwent direct or combined revascularization with preoperative DSA. The mean age of this enrolled cohort was 44.31 ± 10.386 years, in which bilaterally involved MMD accounted for the main part. The preliminary correlation analysis found preoperative disease period (p = 0.078), recipients observed in angiography (p = 0.002), and surgery on the left (p = 0.097) may be associated with cerebral edema. The following regression analysis confirmed low occurrence of cerebral edema was accompanied by recipients observed in angiography (p = 0.003). After subdividing by flow direction and hemodynamic sources, the incidence rate of anterograde direction, anterior sources, and posterior sources were significantly lower than undetected recipients. Conclusions: Cerebral edema is a common radiological manifestation in MMDs after surgery. In this study, the observation in angiography reliably identifies a variety of physiological or pathological recipient detection, flow direction, and hemodynamic sources in patients with MMD after revascularization, which indicates the selection strategy of potential recipients and highlights the importance of recipient observability in DSA. Meanwhile, vascular conditions determined by recipient hemodynamics meditate the occurrence of postoperative cerebral edema.

Moyamoya Disease With Initial Ischemic or Hemorrhagic Attack Shows Different Brain Structural and Functional Features: A Pilot Study.

Objective: Cerebral ischemia and intracranial hemorrhage are the two main phenotypes of moyamoya disease (MMD). However, the pathophysiological processes of these two MMD phenotypes are still largely unknown. Here, we aimed to use multimodal neuroimaging techniques to explore the brain structural and functional differences between the two MMD subtypes. Methods: We included 12 patients with ischemic MMD, 10 patients with hemorrhagic MMD, and 10 healthy controls (HCs). Each patient underwent MRI scans and cognitive assessment. The cortical thickness of two MMD subtypes and HC group were compared. Arterial spin labeling (ASL) and diffusion tensor imaging (DTI) were used to inspect the cerebral blood flow (CBF) of cortical regions and the integrity of related white matter fibers, respectively. Correlation analyses were then performed among the MRI metrics and cognitive function scores. Results: We found that only the cortical thickness in the right middle temporal gyrus (MTG) of hemorrhagic MMD was significantly greater than both ischemic MMD and HC (p < 0.05). In addition, the right MTG showed higher ASL-CBF, and its associated fiber tract (arcuate fasciculus, AF) exhibited higher fractional anisotropy (FA) values in hemorrhagic MMD. Furthermore, the cortical thickness of the right MTG was positively correlated with its ASL-CBF values (r = 0.37, p = 0.046) and the FA values of right AF (r = 0.67, p < 0.001). At last, the FA values of right AF were found to be significantly correlated with cognitive performances within patients with MMD. Conclusions: Hemorrhagic MMD shows increased cortical thickness on the right MTG in comparison with ischemic MMD and HCs. The increased cortical thickness is associated with the higher CBF values and the increased integrity of the right AF. These findings are important to understand the clinical symptoms and pathophysiology of MMD and further applied to clinical practice.

Abnormal brain functional and structural connectivity between the left supplementary motor area and inferior frontal gyrus in moyamoya disease.

BACKGROUND: Disruption of brain functional connectivity has been detected after stroke, but whether it also occurs in moyamoya disease (MMD) is unknown. Impaired functional connectivity is always correlated with abnormal white matter fibers. Herein, we used multimodal imaging techniques to explore the changes in brain functional and structural connectivity in MMD patients. METHODS: We collected structural images, resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging for each subject. Cognitive functions of MMD patients were evaluated using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Trail Making Test parts A and B (TMT-A/-B). We calculated the functional connectivity for every paired region using 90 regions of interest from the Anatomical Automatic Labeling Atlas and then determined the differences between MMD patients and HCs. We extracted the functional connectivity of paired brain regions with significant differences between the two groups. Correlation analyses were then performed between the functional connectivity and variable cognitive functions. To explore whether the impaired functional connectivity and cognitive performances were attributed to the destruction of white matter fibers, we further analyzed fiber integrity using tractography between paired regions that were correlated with cognition. RESULTS: There was lower functional connectivity in MMD patients as compared to HCs between the bilateral inferior frontal gyrus, between the bilateral supramarginal gyrus, between the left supplementary motor area (SMA) and the left orbital part of the inferior frontal gyrus (IFGorb), and between the left SMA and the left middle temporal gyrus (P < 0.01, FDR corrected). The decreased functional connectivity between the left SMA and the left IFGorb was significantly correlated with the MMSE (r = 0.52, P = 0.024), MoCA (r = 0.60, P = 0.006), and TMT-B (r = -0.54, P = 0.048) in MMD patients. White matter fibers were also injured between the SMA and IFGorb in the left hemisphere and were positively correlated with reduced functional connectivity. CONCLUSIONS: Brain functional and structural connectivity between the supplementary motor area and inferior frontal gyrus in the left hemisphere are damaged in MMD. These findings could be useful in the evaluation of disease progression and prognosis of MMD.

Palmitoylethanolamide ameliorates neuroinflammation via modulating PPAR-α to promote the functional outcome after intracerebral hemorrhage.

Intracerebral hemorrhage is a type of acute cerebrovascular disease that remains one of the main causes of death and disability. After the onset of ICH, different types of severe pathophysiological changes can cause great damage to brain tissue, including neuroinflammation. Our study demonstrated the effect of PEA on modulating microglia phenotype and neuroinflammation, as well as the possible underlying mechanisms after ICH for the first time. The phenotypic transformation of microglia and simulation of neuroinflammation after ICH in vitro was induced by hemoglobin on BV2 cells. Additionally, the experiment in vivo model was induced by collagenase injection in mice. The role of PEA on hematoma clearance was also discussed. Western blot, ELISA and immunofluorescence staining were used to determine the phenotypic polarization of microglia and neuroinflammation. In order to evaluate the role of PPAR-α in the anti-inflammatory effect of PEA after ICH, the PPAR-α antagonist GW6471 was utilized. Behavior tests examined the effect of PEA on improving neuronal function. Our results showed that PEA can ameliorate neuroinflammation by inhibiting upregulation of NF-κB, IL-1ß and TNF-α, both in vivo and in vitro. Additionally, PEA can improve motor function in ICH mice and promotes hematoma clearance. At the same time, PEA can increase the levels of PPAR-α in the nucleus. Hence, PPAR-α antagonists can reverse the protective effects of PEA on neuroinflammation. These results suggest that PEA is involved in microglia polarization, attenuating the activation of neuroinflammation, as well as improving motor function after ICH. This, at least in part, may contribute to the involvement of PPAR-α modulation of NF-κB.

Late combination of transarterial chemoembolization with apatinib and camrelizumab for unresectable hepatocellular carcinoma is superior to early combination.

OBJECTIVE: The purpose of this study was to explore the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib and camrelizumab (TACE + AC) for unresectable hepatocellular carcinoma (HCC), and the impact of the timing of the combination on it. METHODS: In this single-arm retrospective study, consecutive data of patients with unresectable HCC treated to our hospital from March 2017 to September 2021 were collected. These patients were treated with TACE and started on camrelizumab and apatinib within one week of TACE. Camrelizumab 200 mg intravenously once every three weeks and apatinib 250 mg orally once daily. Repeat TACE treatment was available on an on-demand basis. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. The univariate and multivariate Cox regression analyses were used to assess the effect of early and late combination on OS and PFS. RESULTS: A total of 80 patients were enrolled in this study. The median OS was 22.1 months (95% confidence interval [CI]: 13.8-30.5 months) and the median PFS was 15.7 months (95% CI: 14.7-16.6 months). The ORR was 58.8% (95% CI: 47.2-69.6) and DCR reached 81.2% (95% CI: 71.0-89.1). Multivariable Cox proportional hazard regression analyses showed that TACE late combined with apatinib and camrelizumab provided better OS than early combination (HR = 0.175, 95% CI:0.060-0.509, P = 0.001), as did PFS (HR = 0.422, 95% CI:0.184-0.967, P = 0.041). All treatment-related adverse events were tolerable, and no serious adverse events were observed. CONCLUSION: TACE combined with apatinib plus camrelizumab for patients with unresectable HCC has promising antitumor activity and a manageable safety profile. For unresectable HCC with large tumor burden, late combination provides better OS and PFS compared to early combination.

Thalamic structure and anastomosis in different hemispheres of moyamoya disease.

Objective: The progression of the asymptomatic hemisphere of moyamoya disease (MMD) is largely unknown. In this study, we investigated the differences in subcortical gray matter structure and angiographic features between asymptomatic and symptomatic hemispheres in patients with MMD. Methods: We retrospectively reviewed patients with MMD in consecutive cases in our center. We compared subcortical gray matter volume and three types of collaterals (lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis) between symptomatic and asymptomatic hemispheres. Symptomatic hemispheres were classified as ischemic hemisphere (i-hemisphere) and hemorrhagic hemisphere (h-hemisphere). Asymptomatic hemispheres were classified as contralateral asymptomatic hemisphere of i-hemisphere (ai-hemisphere), contralateral asymptomatic hemisphere of h-hemisphere (ah-hemisphere), bilateral asymptomatic hemispheres in asymptomatic group (aa-hemisphere). Results: A total of 117 MMD patients were reviewed, and 49 of them met the inclusion criteria, with 98 hemispheres being analyzed. The thalamic volume was found to differ significantly between the i- and ai-hemispheres (P = 0.010), between the i- and ah-hemispheres (P = 0.004), as well as between the h- and ai-hemispheres (P = 0.002), between the h- and ah-hemispheres (P < 0.001). There was a higher incidence of thalamic anastomosis in the ai-hemispheres than i-hemispheres (31.3% vs. 6.3%, P = 0.070), and in the ah-hemispheres than h-hemispheres (29.6% vs. 11.1%, P = 0.088). Additionally, the hemispheres with thalamic anastomosis had a significantly greater volume than those without thalamic anastomosis (P = 0.024). Univariate and multivariate logistic regression analysis showed that thalamic volume was closely associated with thalamic anastomosis. Conclusion: The thalamic volume and the incidence of thalamic anastomosis increase in asymptomatic hemispheres and decrease in symptomatic hemispheres. Combining these two characteristics may be helpful in assessing the risk of stroke in the asymptomatic hemispheres of MMD as well as understanding the pathological evolution of the disease.

What Does Channel Say? Understanding How Social Media Social Capital Facilitates COVID-19-Related Information-Seeking and Opinion-Expression on Two Types of Platforms: User-oriented versus Content-oriented.

Social capital (i.e., resources obtained from social relationships) facilitates informational use of media, yet how in detail the mechanism functions in a multi-platform social media environment remains underexplored. Taking an affordance approach, this study aimed to investigate the differentiated effects of social media social capital on COVID-19-related information behaviors on user-oriented and content-oriented social media (USM&CSM). It was hypothesized that information exposure on USM mediates the relationship between social capital and information-seeking intention, whereas exposure on CSM was expected to mediate the relationship between social capital and opinion expression. Web-based survey data collected among Chinese social media users (N = 256) supported the hypotheses, and in-depth interviews (N = 15) further revealed how people explored the affordances of different platforms to enjoy the information resources. Implications were discussed.

AXL kinase-mediated astrocytic phagocytosis modulates outcomes of traumatic brain injury.

BACKGROUND: Complex changes in the brain microenvironment following traumatic brain injury (TBI) can cause neurological impairments for which there are few efficacious therapeutic interventions. The reactivity of astrocytes is one of the keys to microenvironmental changes, such as neuroinflammation, but its role and the molecular mechanisms that underpin it remain unclear. METHODS: Male C57BL/6J mice were subjected to the controlled cortical impact (CCI) to develop a TBI model. The specific ligand of AXL receptor tyrosine kinase (AXL), recombinant mouse growth arrest-specific 6 (rmGas6) was intracerebroventricularly administered, and selective AXL antagonist R428 was intraperitoneally applied at 30 min post-modeling separately. Post-TBI assessments included neurobehavioral assessments, transmission electron microscopy, immunohistochemistry, and western blotting. Real-time polymerase chain reaction (RT-PCR), siRNA transfection, and flow cytometry were performed for mechanism assessments in primary cultured astrocytes. RESULTS: AXL is upregulated mainly in astrocytes after TBI and promotes astrocytes switching to a phenotype that exhibits the capability of ingesting degenerated neurons or debris. As a result, this astrocytic transformation promotes the limitation of neuroinflammation and recovery of neurological dysfunction. Pharmacological inhibition of AXL in astrocytes significantly decreased astrocytic phagocytosis both in vivo and in primary astrocyte cultures, in contrast to the effect of treatment with the rmGas6. AXL activates the signal transducer and activator of the transcription 1 (STAT1) pathway thereby further upregulating ATP-binding cassette transporter 1 (ABCA1). Moreover, the supernatant from GAS6-depleted BV2 cells induced limited enhancement of astrocytic phagocytosis in vitro. CONCLUSION: Our work establishes the role of AXL in the transformation of astrocytes to a phagocytic phenotype via the AXL/STAT1/ABCA1 pathway which contributes to the separation of healthy brain tissue from injury-induced cell debris, further ameliorating neuroinflammation and neurological impairments after TBI. Collectively, our findings provide a potential therapeutic target for TBI.

CircPTK2-miR-181c-5p-HMGB1: a new regulatory pathway for microglia activation and hippocampal neuronal apoptosis induced by sepsis.

BACKGROUND: Circular RNA hsa_circ_0008305 (circPTK2), miR-181c-5p and High mobility group box-1 (HMGB1) had a targeted regulatory relationship through bioinformatics analysis. This study explained the effects of these genes in microglia and sepsis mice. METHODS: Lipopolysaccharide (LPS) or Cecal Ligation and Puncture (CLP) was used to induce inflammation cell model or sepsis mouse model, as needed. Gene levels were measured by enzyme linked immunosorbent assay (ELISA), quantitative real-time PCR or Western blot, as required. Apoptosis was detected by TUNEL assay, and RNase R was used to test the stability of circPTK2. Targeting relationships between genes were analyzed using bioinformatics analysis and dual luciferase assay. Morris water maze test and mitochondrial membrane potential (MMP) detection were conducted to analyze the effects of genes on cognitive dysfunction of mice. RESULTS: Lipopolysaccharide induction triggered the release of pro-inflammatory cytokines, the upregulation of HMGB1 and circPTK2, and the downregulation of miR-181c-5p in microglia. Overexpression of HMGB1 enhanced the effect of LPS, while silencing HMGB1 partially counteracted the effect of LPS. Moreover, miR-181c-5p was a target of circPTK2 and bound to HMGB1. MiR-181c-5p mimic partially reversed the functions of LPS and HMGB1 overexpression, reduced the levels of TNF-α, IL-1ß, and HMGB1, and inhibited apoptosis. CircPTK2 knockdown had the same effect as miR-181c-5p up-regulation. In vivo, sicircPTK2 improved cognitive function, restored MMP level, inhibited apoptosis, reduced the levels of inflammatory factors and apoptotic factors, and increased the survival rate of CLP-induced mice. CONCLUSION: Our research reveals that circPTK2 regulates microglia activation and hippocampal neuronal apoptosis induced by sepsis via miR-181c-5p-HMGB1 signaling.

Integrated Genomic and Transcriptomic Analysis reveals key genes for predicting dual-phenotype Hepatocellular Carcinoma Prognosis.

Dual-phenotype hepatocellular carcinoma (DPHCC) expresses both hepatocyte and cholangiocyte markers, and is characterized by high recurrence and low survival rates. The underlying molecular mechanisms of DPHCC pathogenesis are unclear. We performed whole exome sequencing and RNA sequencing of three subtypes of HCC (10 DPHCC, 10 CK19-positive HCC, and 14 CK19-negative HCC), followed by integrated bioinformatics analysis, including somatic mutation analysis, mutation signal analysis, differential gene expression analysis, and pathway enrichment analysis. Cox proportional hazard regression analyses were applied for exploring survival related characteristics. We found that mutated genes in DPHCC patients were associated with carcinogenesis and immunity, and the up-regulated genes were mainly enriched in transcription-related and cancer-related pathways, and the down-regulated genes were mainly enriched in immune-related pathways. CXCL9 was selected as the hub gene, which is associated with immune cells and survival prognosis. Our results showed that low CXCL9 expression was significantly associated with poor prognosis, and its expression was significantly reduced in DPHCC samples. In conclusion, we explored the molecular mechanisms governing DPHCC development and progression and identified CXCL9, which influences the immune microenvironment and prognosis of DPHCC and might be new clinically significant biomarkers for predicting prognosis.