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.

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.

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.

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.

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.

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.

Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies.

Ischemic stroke (IS) remains one of the major causes of death and disability due to the limited ability of central nervous system cells to regenerate and differentiate. Although several advances have been made in stroke therapies in the last decades, there are only a few approaches available to improve IS outcome. In the acute phase of IS, mechanical thrombectomy and the administration of tissue plasminogen activator have been widely used, while aspirin or clopidogrel represents the main therapy used in the subacute or chronic phase. However, in most cases, stroke patients fail to achieve satisfactory functional recovery under the treatments mentioned above. Recently, cell therapy, especially stem cell therapy, has been considered as a novel and potential therapeutic strategy to improve stroke outcome through mechanisms, including cell differentiation, cell replacement, immunomodulation, neural circuit reconstruction, and protective factor release. Different stem cell types, such as mesenchymal stem cells, marrow mononuclear cells, and neural stem cells, have also been considered for stroke therapy. In recent years, many clinical and preclinical studies on cell therapy have been carried out, and numerous results have shown that cell therapy has bright prospects in the treatment of stroke. However, some cell therapy issues are not yet fully understood, such as its optimal parameters including cell type choice, cell doses, and injection routes; therefore, a closer relationship between basic and clinical research is needed. In this review, the role of cell therapy in stroke treatment and its mechanisms was summarized, as well as the function of different stem cell types in stroke treatment and the clinical trials using stem cell therapy to cure stroke, to reveal future insights on stroke-related cell therapy, and to guide further studies.

Circulating Tumor Cells Undergoing the Epithelial-Mesenchymal Transition: Influence on Prognosis in Cytokeratin 19-Positive Hepatocellular Carcinoma.

PURPOSE: The purpose of this study was to elucidate the relationship between cytokeratin 19 (CK19) expression and levels of circulating tumor cells (CTCs) in preoperative peripheral blood of patients with hepatocellular carcinoma (HCC), and the potential influence of that relationship on prognosis. PATIENTS AND METHODS: CanPatrol™ CTC-enrichment technique and in situ hybridization (ISH) were used to enrich and classify CTCs undergoing the epithelial-mesenchymal transition (EMT) from blood samples of 105 HCC patients. CK19 immunohistochemistry staining was performed on HCC tissues and compared with demographic and clinical data. RESULTS: In total, 27 of 105 (25.7%) HCC patients were CK19-positive. CK19-positive patients had significantly lower median tumor-free survival (TFS) than CK19-negative patients (5 vs 10 months, P = 0.047). In total, 98 (93.3%) patients showed pre-surgery peripheral blood CTCs (range: 0-76, median: 6), and 57 of 105 (54.3%) patients displayed CTC counts ≥6. Furthermore, CK19-positive patients with CTC count ≥6 showed significantly higher percentage than CK19-negative ones (77.8% vs 46.2%, P = 0.004). CK19-positive patients showed a significantly higher proportion of mesenchymal CTCs among CTCs undergoing EMT than CK19-negative patients (mean rank: 62.28 vs 49.79, P = 0.046). We also found that CK19-positive patients with high CTC count showed significantly shorter median tumor-free survival than CK19-negative patients with low CTC count (5 vs 16 months, P = 0.039). CONCLUSION: High CTC count and high percentage of mesenchymal CTCs are closely related to the expression of CK19, which is associated with poor prognosis in HCC patients.

Recent insight into the role of RING-finger E3 ligases in glioma.

The ubiquitin proteasome system (UPS) serves as the major posttranslational modification system for the maintenance of protein homeostasis. The ubiquitin ligases (E3s) are responsible for the recognition and recruitment of specific substrate proteins for polyubiquitination. Really interesting new gene (RING) finger E3s account for the majority of E3s. The human genome encodes more than 600 RING E3s, which are divided into three subclasses: single polypeptide E3s, cullin-RING ligases (CRLs) and other multisubunit E3s. The abnormal regulation of RING E3s has been reported to disrupt normal biological processes and induce the occurrence of many human malignancies. Glioma is the most common type of malignant primary brain tumor. In the last few decades, patient prognosis has improved as novel targeted therapeutic agents have developed. In this review, we will summarize the current knowledge about the dysregulation of RING E3s and the altered stability of their substrates in glioma. We will further introduce and discuss the current status and future perspectives of the application of small inhibitors and proteolysis-targeting chimeric molecules (PROTACs) interfering with RING E3s as potential anticancer agents for glioma.

Rare asymptomatic giant cerebral cavernous malformation in adults: two case reports and a literature review.

Cavernous malformations are benign vascular malformations. Giant cavernous malformations are very rare. All reported cases have been symptomatic because of the large size and compression of the surrounding brain tissue. We report two asymptomatic cases of giant cavernous malformation that were both misdiagnosed as neoplasms because of their atypical presentations. The first case was a 54-year-old man whose computed tomography and magnetic resonance imaging scans revealed an inhomogeneous lesion of 6 cm diameter and mild enhancement in the left frontal lobe. A left lateral supraorbital and transcortical approach was applied and the lesion was completely removed. The second case was a 36-year-old man with an irregular large mass in the parasellar region. Craniopharyngioma was suspected and gross total resection was performed. Post-surgical pathological analyses confirmed the diagnoses as cavernous malformations. Both patients recovered uneventfully. The rare asymptomatic giant cavernous malformations reported here in adults had benign behavior for this specific disease entity. The different clinical characteristics of ordinary cavernous malformation and adult and pediatric giant cavernous malformation imply complex and distinct genetic backgrounds. Concerns should be raised when considering giant cavernous malformation as a differential diagnosis for atypical large lesions. Surgical resection is recommended as the primary treatment option.

Novel combination of celecoxib and metformin improves the antitumor effect by inhibiting the growth of Hepatocellular Carcinoma.

Objective: To explore the effect of COX-2 inhibitor celecoxib in combination with metformin on the prevention of Hepatocellular carcinoma (HCC) and the mechanisms involved. Methods: HCC cell lines and an HCC rat model were treated with celecoxib, metformin or a combination of both. Cell viability and tumor formation were measured. Results: In vitro and in vivo studies showed that treatment with a combination of celecoxib and metformin inhibited proliferation of HCC to a greater extent than either treatment alone, by reducing the phosphorylation of MTOR. Conclusion: The study suggested that celecoxib combined with metformin would be more effective for the preventing occurrence of HCC than either treatment alone and this combination of therapy is worthy of further study.

Intranasal wnt-3a alleviates neuronal apoptosis in early brain injury post subarachnoid hemorrhage via the regulation of wnt target PPAN mediated by the moonlighting role of aldolase C.

Neuronal apoptosis is one of the main pathophysiological events in the early brain injury (EBI) post subarachnoid hemorrhage (SAH). Wnt-3a, one of the endogenous wnt ligands crucial in neurogenesis, has been proven to be efficacious in neuroprotection in traumatic brain injury and ischemic stroke. The glycolytic enzyme aldolase C and ribosome biogenesis protein PPAN were revealed to be linked to wnt signaling pathway. The aim of the study was to explore the antiapoptotic effects of intranasal wnt-3a through Frizzled-1 (Frz-1)/aldolase C/PPAN pathway in SAH. Approaches for assessment included SAH grade, Garcia test, brain water content evaluation, rotarod test, Morris water maze test, Western blot, immunofluorescence and transmission electron microscopy. The results showed that wnt-3a improved the neurological scores, brain water content and long-term neurobehavioral functions after SAH. Wnt-3a increased the level of Frz-1, aldolase C, ß-catenin, PPAN and the Bcl-2/Bax ratio; and decreased the level of axin and cleaved caspase-3 (CC-3). The anti-apoptotic effect of wnt-3a was further evidenced by TUNEL staining and subcellular structure imaging. Frz-1 siRNA and aldolase C siRNA offset the effects of wnt-3a; and restoration of aldolase C by aldolase C CRISPR in Frz-1 siRNA preconditioned SAH rats salvaged the level of Frz-1, aldolase C, PPAN and reduced axin and CC-3. In summary, intranasal administration of wnt-3a alleviates neuronal apoptosis through Frz-1/aldolase C/PPAN pathway in the EBI of SAH rats. The feasible intranasal route and the long-lasting neuroprotective property of wnt-3a is of great clinical relevance.

IFITM3 upregulates c-myc expression to promote hepatocellular carcinoma proliferation via the ERK1/2 signalling pathway.

Interferon-induced transmembrane protein 3 (IFITM3) is associated with cancer development. Proto-oncogene c-myc can promote tumor proliferation. However, collections of IFITM3 and c-myc in hepatocellular carcinoma (HCC) and the potential role and mechanisms of IFITM3 in c-myc-mediated tumor proliferation remain unclear. In this study, we investigated a positive correlation between the expression of IFITM3 and c-myc in HCC. The down-regulation of IFITM3 significantly reduced c-myc expression and inhibited the proliferation of HCC in vitro and in vivo. In addition, upregulated c-myc expression restored the decrease in cell proliferation caused by the downregulation of IFITM3, while downregulation of c-myc reduced the proliferation of HCC enhanced by IFITM3. Mechanistically, IFITM3 regulates c-myc expression via the ERK1/2 signalling pathway. In conclusion, a novel path of IFITM3-ERK1/2-c-myc regulatory circuitry was identified, and its dysfunction may lead to HCC tumorigenesis.

CSN5 promotes the invasion and metastasis of pancreatic cancer by stabilization of FOXM1.

COP9 signalosome subunit 5 (CSN5) has been involved in the progression of diverse human cancers. MMP2 plays an important role in the metastasis of cancer cells. However, the roles and relationship of in pancreatic cancer (PC) is still unknown. Here, our data shown that both CSN5 and MMP2 were significantly upregulated in PC compared with the corresponding adjacent tissues, where a positive correlation in their expression and associated malignant characteristics were found. Further, silencing of CSN5 expression markedly inhibited PC invasion and metastasis in vitro and in vivo, accompanied by decreased MMP2 expression. Moreover, the anti-metastasis role of CSN5 silence was reversed by MMP2 overexpression, whereas knockdown of MMP2 decreased PC metastasis driven by upregulation of CSN5. Further investigation revealed that CSN5 regulated MMP2 expression via activation of FOXM1 in PC cells. Mechanistically, CSN5 directly bound FOXM1 and decreased its ubiquitination to enhance the protein stability of FOXM1. Taken together, the results indicate that CSN5 can contribute to PC invasion and metastasis through activation of FOXM1/MMP2 axis.

Intracerebral hematoma after endoscopic fenestration of an arachnoid cyst: A case report.

RATIONALE: An intracranial arachnoid cyst is a relatively common congenital benign lesion. A small number of patients present with neurological symptoms. Endoscopic fenestration has become a common treatment for arachnoid cysts in recent years, but intracerebral hematoma after surgery is rarely reported. PATIENT CONCERNS: A 60-year-old woman with an arachnoid cyst in the left parietal and occipital lobes showed obvious progressive neurological deficits. She had weakness in her right limbs for 2 years and a sudden convulsion in her left limbs. DIAGNOSIS: An arachnoid cyst in the left parietal and occipital lobes was detected on magnetic resonance imaging. INTERVENTION: Endoscopic fenestration was performed for the cyst. However, she developed an intracerebral hematoma after surgery, which was detected by computed tomography. Due to the exacerbation of the patient's condition in the early stage after surgery, reoperation was performed to remove the hematoma. OUTCOMES: The patient was finally cured with no serious neurological deficits. LESSONS: The rare complication of intracerebral hematoma after surgery for an arachnoid cyst can lead to a rapid deterioration in the patient's condition. More-adequate preoperative examination and neuronavigation should be conducted during surgery. Appropriate enlargement of the bone hole may help protect against this complication. Moreover, prompt reoperation for the intracerebral hematoma may improve the prognosis.

SPAG5 promotes hepatocellular carcinoma progression by downregulating SCARA5 through modifying ß-catenin degradation.

BACKGROUND: The sperm-associated antigen 5 (SPAG5) plays a key role in controlling various cellular phenomena, including cell cycle progression and proliferation. However, the role of SPAG5 in hepatocellular carcinoma (HCC) remains unknown. METHODS: This study investigated the function and clinical significance of SPAG5 protein expression in hepatocellular carcinoma. We analyzed SPAG5 expression in surgical specimens from 136 HCC patients. The correlation between the clinical characteristics and prognosis was also determined. Furthermore, the SPAG5 was overexpressed in HCC cell and silenced with shRNA in HCC cells. Moreover, cell proliferation and apoptosis were measured using Edu assay and flow cytometry and a molecular mechanism of SPAG5 promotes HCC progression was explored. RESULTS: Herein, our study showed that upregulation of SPAG5 was detected frequently in primary HCC tissues, and was associated with significantly worse survival among the HCC patients. Multivariate analyses revealed that high SPAG5 expression was an independent predictive marker for the poor prognosis of HCC. SPAG5 silence effectively abolished the proliferation abilities of SPAG5 in vivo and in vitro, while induced apoptosis in HCC cells. Furthermore, our results indicate that SPAG5 promoted cell progression by decreasing SCARA5 expression, which has been reported to control the progression of HCC, and our data demonstrated that SCARA5 is crucial for SPAG5-mediated HCC cell progression in vitro and in vivo. Moreover, we found that the expression of SPAG5 and SCARA5 are inversely correlated in HCC tissues. In addition, we demonstrated that SPAG5 promoted progression in HCC via downregulating SCARA5 depended on the ß-catenin/TCF4 signaling pathway. Interestingly, the underlying mechanism is which SPAG5 regulates SCARA5 expression by modulating ß-catenin degradation. CONCLUSIONS: Taken together, our data provide a novel evidence for the biological and clinical significance of SPAG5 as a potential biomarker, and we demonstrate that SPAG5-ß-catenin-SCARA5 might be a novel pathway involved in HCC progression.