Machine learning models reveal the critical role of nighttime systolic blood pressure in predicting functional outcome for acute ischemic stroke after endovascular thrombectomy.

Background: Blood pressure (BP) is a key factor for the clinical outcomes of acute ischemic stroke (AIS) receiving endovascular thrombectomy (EVT). However, the effect of the circadian pattern of BP on functional outcome is unclear. Methods: This multicenter, retrospective, observational study was conducted from 2016 to 2023 at three hospitals in China (ChiCTR2300077202). A total of 407 patients who underwent endovascular thrombectomy (EVT) and continuous 24-h BP monitoring were included. Two hundred forty-one cases from Beijing Hospital were allocated to the development group, while 166 cases from Peking University Shenzhen Hospital and Hainan General Hospital were used for external validation. Postoperative systolic BP (SBP) included daytime SBP, nighttime SBP, and 24-h average SBP. Least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), Boruta were used to screen for potential features associated with functional dependence defined as 3-month modified Rankin scale (mRS) score ≥ 3. Nine algorithms were applied for model construction and evaluated using area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Results: Three hundred twenty-eight of 407 (80.6%) patients achieved successful recanalization and 182 patients (44.7%) were functional independent. NIHSS at onset, modified cerebral infarction thrombolysis grade, atrial fibrillation, coronary atherosclerotic heart disease, hypertension were identified as prognostic factors by the intersection of three algorithms to construct the baseline model. Compared to daytime SBP and 24-h SBP models, the AUC of baseline + nighttime SBP showed the highest AUC in all algorithms. The XGboost model performed the best among all the algorithms. ROC results showed an AUC of 0.841 in the development set and an AUC of 0.752 in the validation set for the baseline plus nighttime SBP model, with a brier score of 0.198. Conclusion: This study firstly explored the association between circadian BP patterns with functional outcome for AIS. Nighttime SBP may provide more clinical information regarding the prognosis of patients with AIS after EVT.

Multiomics and blood-based biomarkers of moyamoya disease: protocol of Moyamoya Omics Atlas (MOYAOMICS).

BACKGROUND: Moyamoya disease (MMD) is a rare and complex cerebrovascular disorder characterized by the progressive narrowing of the internal carotid arteries and the formation of compensatory collateral vessels. The etiology of MMD remains enigmatic, making diagnosis and management challenging. The MOYAOMICS project was initiated to investigate the molecular underpinnings of MMD and explore potential diagnostic and therapeutic strategies. METHODS: The MOYAOMICS project employs a multidisciplinary approach, integrating various omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, to comprehensively examine the molecular signatures associated with MMD pathogenesis. Additionally, we will investigate the potential influence of gut microbiota and brain-gut peptides on MMD development, assessing their suitability as targets for therapeutic strategies and dietary interventions. Radiomics, a specialized field in medical imaging, is utilized to analyze neuroimaging data for early detection and characterization of MMD-related brain changes. Deep learning algorithms are employed to differentiate MMD from other conditions, automating the diagnostic process. We also employ single-cellomics and mass cytometry to precisely study cellular heterogeneity in peripheral blood samples from MMD patients. CONCLUSIONS: The MOYAOMICS project represents a significant step toward comprehending MMD's molecular underpinnings. This multidisciplinary approach has the potential to revolutionize early diagnosis, patient stratification, and the development of targeted therapies for MMD. The identification of blood-based biomarkers and the integration of multiple omics data are critical for improving the clinical management of MMD and enhancing patient outcomes for this complex disease.

CRP­1 promotes the malignant behavior of hepatocellular carcinoma cells via activating epithelial­mesenchymal transition and Wnt/ß­catenin signaling.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. It has been reported that cysteine rich protein 1 (CRP-1) is dysregulated in several types of human cancer; however, its role in HCC is poorly understood. Therefore, the current study aimed to investigate the role of CRP-1 in HCC. Western blotting and reverse transcription-quantitative PCR results showed that CRP-1 was upregulated in HCC cell lines. Furthermore, for in vitro experiments, CRP-1 was knocked down and overexpressed in the HCC cell lines Hep 3B2.1-7 and BEL-7405, respectively. c-Myc and proliferating cell nuclear antigen upregulation, and cleaved caspase 3 and poly(ADP-ribose) polymerase downregulation suggested that CRP-1 silencing could inhibit the proliferation and colony-forming ability of HCC cells, and induce apoptosis. In addition, CRP-1 overexpression promoted the malignant behavior of HCC cells and induced epithelial-mesenchymal transition (EMT), as verified by E-cadherin downregulation, and N-cadherin and vimentin upregulation. Additionally, CRP-1 overexpression promoted the nuclear translocation of ß-catenin, and activated the expression of cyclin D1 and matrix metalloproteinase-7. Furthermore, inhibition of Wnt/ß-catenin signaling, following cell treatment with XAV-939, an inhibitor of the Wnt/ß-catenin signaling pathway, abrogated the effects of CRP-1 on enhancing the proliferation and migration of HCC cells. These findings indicated that the regulatory effect of CRP-1 on HCC cells could be mediated by the Wnt/ß-catenin signaling pathway. Overall, CRP-1 could promote the proliferation and migration of HCC cell lines, partially via promoting EMT and activating the Wnt/ß-catenin signaling pathway.

Exploring the prognostic differences in patients of Chiari malformation type I with syringomyelia undergoing different surgical methods.

Background: The best surgical treatment of Chiari malformation patients with syringomyelia remains controversial, and whether cerebellar tonsillectomy should be performed has not been decided. Objective: To evaluate the efficacy of posterior fossa decompression with duraplasty (PFDD) and Posterior fossa decompression with resection of tonsils (PFDRT) in patients of Chiari malformation type I (CM-I) with syringomyelia and explore relevant factors affecting prognosis. Patients and methods: We retrospectively analyzed 182 adult patients of CM-I with syringomyelia who underwent PFDD or PFDRT over a 6-year period, and analyzed their clinical manifestations, imaging features, and follow-up data. Clinical outcomes were assessed using the Chicago Chiari Outcome Scale (CCOS), and imaging outcomes were assessed using the syrinx remission rate. Difference comparisons were performed to compare the differences between different surgical groups. Influencing factors associated with outcome were investigated using bivariate analysis and multiple linear regression analysis. Results: There were statistically significant differences in CCOS score (p = 0.034) and syrinx remission rates (p = 0.046) between the PFDRT group and the PFDD group after surgery. Regression analysis showed that preoperative motor dysfunction, cerebellar-related symptoms and different surgical methods may have influenced the CCOS score and that brainstem-related symptoms and age may have influenced the syrinx remission rates in the total patient group (p < 0.05). Regression analysis showed that the duration of symptoms, cerebellar-related symptoms and preoperative syrinx diameter may have influenced the CCOS score and that the preoperative cerebellar tonsillar hernia distance may have influenced the postoperative syrinx remission rate in the PFDRT group (p < 0.05). Age and length of hospital stay may have influenced the CCOS score, and brainstem-related symptoms and age may have influenced the syrinx remission rates in the PFDD group (p < 0.05). Conclusion: This study showed that the CCOS score in the PFDRT group was better than that in the PFDD group. Preoperative motor dysfunction, cerebellar-related symptoms, and different surgical methods in patients of CM-I with syringomyelia affected postoperative CCOS score. Both the duration of symptoms and the age of the patients should be actively considered as factors influencing prognosis. Symptomatic CM-I patients with syringomyelia should undergo surgical treatment as early as possible.

miR-145-5p Modulates Gefitinib Resistance by Targeting NRAS and MEST in Non-Small Cell Lung Cancer.

OBJECTIVE: microRNAs may play essential roles in the development and drug resistance of non-small cell lung cancer (NSCLC). However, their functions and mechanisms are not fully understood. Our goal was to define the role of miR-145-5p in the gefitinib resistance of NSCLC. MATERIALS AND METHODS: An A549 gefitinib-resistant cell line and xenograft nude mice were used in this study. The expression of miR-145-5p and its targets, NRAS and MEST, were detected and measured by qPCR, Western blot, RNA-FISH, or immunofluorescence analysis. RESULTS: miR-145-5p was downregulated in gefitinib-resistant A549 cells (A549/Gef R). Overexpression of miR-145-5p enhanced the sensitivity to gefitinib and inhibited cell proliferation and invasion in A549/Gef R. miR-145-5p was also significantly reduced in LUAD and LUSC clinical samples and closely associated with a favorable prognosis, according to the UALCAN and TCGA databases. Moreover, NRAS and MEST were found to be downstream target genes of miR-145-5p and to function as oncogenes in NSCLC samples, and gefitinib resistance could be improved following the interference of these two molecules. CONCLUSION: miR-145-5p improves the sensitivity of acquired gefitinib-resistant cells to gefitinib via inhibiting NRAS and MEST expression. The miR 145-5p-NRAS/MEST axis in NSCLC provides insights for the development of a NRAS/MEST targeting therapeutic approach to overcome gefitinib resistance in NSCLC patients.

Development and Validation of Predicting Nomograms for Craniopharyngioma: A Retrospective, Multiple-Center, Cohort Study.

Craniopharyngiomas (CPs) are benign tumors arising from the sellar region. However, little is known about their clinical features and long-term recurrence due to low morbidity and the lack of large cohort studies. Thus, we aimed to develop nomograms to accurately predict the extent of resection and tumor recurrence using clinical parameters. A total of 545 patients diagnosed with CP between 2009 and 2019 were examined: 381 in the development cohort and 164 in the validation cohort. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were performed to establish two nomograms. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA) and Kaplan-Meier (KM) curves were used to evaluate their predictive performance and discriminative power, respectively, in the two cohorts. In addition, the EORTC QLQ-BN20 questionnaire was used to assess neuropsychological status in the follow-up. In the development cohort, the area under the curve (AUC) and C-index were 0.760 and 0.758, respectively, for predicting the extent of resection and 0.78 and 0.75, respectively, for predicting 3-year progression-free survival (PFS) and 5-year PFS. Additionally, the model had a predictive accuracy of 0.785. Both nomograms showed acceptable discrimination in the two cohorts. Moreover, DCA demonstrated excellent clinical benefits from the two nomograms. Finally, participants were classified into two distinct risk groups according to the risk score, and an online calculator was created for convenient clinical use. During long term follow-up, hypothyroidism (77.61%) and hypocortisolism (76.70%) were the most common endocrine dysfunction after surgery and significant deficits were observed concerning visual disorder, motor dysfunction and seizures in the recurrent groups. In particular, better quality of life was associated with gross total resection (GTR), postoperative radiation, anterior interhemispheric (AI) approach and transsphenoidal approach. To our knowledge, these are the first nomograms based on a very large cohort of patients with CP that show potential benefits for guiding treatment decisions and long-term surveillance. The current study demonstrated the online calculator serve as the practical tool for individual strategies based on the patient's baseline characteristics to achieve a better prognosis.

Sulforaphane exerts anticancer effects on human liver cancer cells via induction of apoptosis and inhibition of migration and invasion by targeting MAPK7 signalling pathway.

Retraction of: 'Sulforaphane exerts anticancer effects on human liver cancer cells via induction of apoptosis and inhibition of migration and invasion by targeting MAPK7 signalling pathway', by Bo Huang, Shixiong Lei, Dong Wang, Yibo Sun, Jikai Yin JBUON 2019;25(2):959-964; PMID:32521892. Following the publication of the above article, readers drew to our attention that part of the data was unreliable. The authors were requested to provide the raw data to prove the originality, but were unable to do so. After an investigation, the Editors of JBUON decided to retract this article. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

Sphingosine-1-phosphate receptor 3 is implicated in BBB injury via the CCL2-CCR2 axis following acute intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a catastrophic cerebrovascular disease with high morbidity and mortality. Evidence demonstrated that sphingosine-1-phosphate receptor (S1PR) plays a vital role in inflammatory damage via the upregulation of CCL2 expression. However, whether S1PR3 is involved in blood-brain barrier (BBB) breakdown via CCL2 activation after ICH has not been described. METHODS: We investigated the expression profiles of all S1PRs using high-throughput RNA-seq analysis and RT-PCR. The potential role of S1PR3 and interaction between S1PR3 and CCL2 were evaluated via Western blotting, immunofluorescence, and flow cytometry. BBB disruption was examined via magnetic resonance imaging, transmission electron microscopy, and Evans blue extravasation. Microglial activation, proliferation, and polarization were assessed via histopathological analysis. The expression levels of CCL2, p-p38 MAPK, ICAM-1, and ZO-1 were examined in vitro and in vivo. RESULTS: The present results showed that the levels of S1PR3 and its ligand, sphingosine 1-phosphate (S1P), were dramatically increased following ICH, which regulated the expression of CCL2 and p38MAPK. Moreover, reductions in brain edema volume, amelioration of BBB integrity, and improvements in behavioral deficits were achieved after the administration of CAY10444, an S1PR3 antagonist, to rats. Remarkably increased CCL2, p-p38MAPK, and ICAM-1 expression and decreased ZO-1 expression were observed in cocultured human astrocytes (HAs) and hCMEC/D3 cells after S1P stimulation. However, the expression levels of CCL2, p-p38 MAPK, and ICAM-1 were decreased and ZO-1 expression was increased after S1PR3 inhibition. In addition, microglial proliferation and M1 polarization were attenuated after CAY10444 administration. CONCLUSION: To the best of our knowledge, this is the first demonstration of the neuroprotective role of S1PR3 modulation in maintaining BBB integrity by inhibiting the S1PR3-CCL2 axis after ICH, providing a novel treatment for ICH by targeting S1PR3.

Identification and Characterization of TF-lncRNA Regulatory Networks Involved in the Tumorigenesis and Development of Adamantinomatous Craniopharyngioma.

Craniopharyngiomas (CPs) are rare tumors arising from the sellar region. Although the best outcome for patients with one subtype, adamantinomatous craniopharyngioma (ACP), is obtained by gross total resection, little is known about the roles of long noncoding RNAs (lncRNAs) and transcription factors (TFs) in ACP tumorigenesis. In total, 12 human ACP and 5 control samples were subjected to transcriptome-level sequencing. We built an integrated algorithm for identifying lncRNAs and TFs regulating the CP-related pathway. Furthermore, ChIP-Seq datasets with binding domain information were used to further verify and identify TF-lncRNA correlations. RT-PCR and immunohistochemistry staining were performed to validate the potential targets. Five pathways associated with ACP were identified and defined by an extensive literature search. Based on the specific pathways and the whole gene expression profile, 266 ACP-related lncRNAs and 39 TFs were identified by our integrating algorithm. Comprehensive analysis of the ChIP-Seq datasets revealed that 29 TFs were targeted by 12000 lncRNAs in a wide range of tissues, including 161 ACP-related lncRNAs that were identified by the computational method. These 29 TFs and 161 lncRNAs, constituting 1004 TF-lncRNA pairs, were shown to potentially regulate different ACP-related pathways. A total of 232 TF-lncRNA networks were consequently established based on differential gene expression. Validation by RT-PCR and immunohistochemistry staining revealed positive expression of the ACP-related TFs E2F2 and KLF5 in ACP. Moreover, the expression of the lncRNA RP11-360P21.2 was shown to be upregulated in ACP tissues. In this study, we introduced an integrated algorithm for identifying lncRNAs and TFs regulating the ACP-related pathway. This is the first comprehensive study to systematically investigate the potential TF and lncRNA regulatory network in ACP. The resulting data serve as a valuable resource for understanding the mechanisms underlying ACP-related lncRNAs and TFs.

Sulforaphane exerts anticancer effects on human liver cancer cells via induction of apoptosis and inhibition of migration and invasion by targeting MAPK7 signalling pathway.

PURPOSE: This study was undertaken to investigate the anticancer effects of Sulforaphane against liver cancer and to elucidate the underlying molecular mechanisms. METHODS: WST-1 assay was used to monitor the proliferation rate. DAPI and annexin V/propidium iodide (PI) staining was used for apoptosis. Flow cytometry was used for cell cycle analysis. Wound heal and transwell assays were used to monitor cell migration and invasion. The protein expression was determined by western blot analysis. RESULTS: It was found that Sulforaphane decreased the viability of the liver cancer HepG2 cells and exhibited an IC50 of 9 µM. Nonetheless, Sulforaphane (µM) exerted very low toxic effects on the normal AML12 hepatocytes and exhibited an IC50 of 100 µM. Flow cytometery analysis showed that Sulforaphane triggered G2/M arrest of the liver HepG2 cancer cells. DAPI staining revealed that Sulforaphane triggered the apoptotic cell death of HepG2 cells which was accompanied with activation of caspases 3 and 9, upregulation of Bax and downregulation of Bcl-2. Transwell assays showed that Sulforaphane inhibited the migration and invasion of the HepG2 liver cancer cells in a dose dependent manner. The effects of Sulforaphane were also investigated on the MAPK7 signalling pathway and it was found that Sulforaphane could block this pathway in HepG2 cells. CONCLUSION: Taken together, Sulforaphane may prove essential in the development of chemotherapy for liver cancers.

The diagnostic value of the combination of Golgi protein 73, glypican-3 and alpha-fetoprotein in hepatocellular carcinoma: a diagnostic meta-analysis.

BACKGROUND: Alpha-fetoprotein (AFP) has been extensively applied in clinical practice to detect and predict postoperative outcomes of patients with hepatocellular carcinoma (HCC). However, due to its low sensitivity and specificity, its efficacy has been questioned. Recently, novel serum biomarkers including Golgi protein 73 (GP73) and glypican-3 (GPC-3) have shown a better discriminatory ability than AFP in detecting early HCC. The results of the combined use of GP73, GPC-3 and AFP in the diagnosis of HCC remain inconclusive. This investigation aimed to evaluate the discriminatory ability of GP73, GPC-3 and AFP to jointly identify HCC using the statistical methods of meta-analysis. METHODS: Comprehensive database searches of, Web of Science, the Cochrane Library, Embase, the Chinese Biomedical Literature Database, and the China National Knowledge Infrastructure were performed for literature dated up to 1 November, 2019. Studies relating to the diagnostic accuracy of the combination of GP73, GPC-3 and AFP in the identification of HCC were included. A random-effects model was used to pool sensitivity, specificity, the positive and negative likelihood ratios [positive likelihood ratio (PLR) and negative likelihood ratio (NLR), respectively], and the diagnostic odds ratio (DOR). We applied the Fagan nomogram to assess the clinical utility of joint detection. The overall detection accuracy was determined using summary receiver operating characteristic curve (SROC) analysis. Meta-regression analysis of heterogeneity publication bias was analyzed with Stata (version 12.0). RESULTS: Our meta-analysis focused on 12 studies involving 919 patients with HCC and 1,549 non-HCC patients. Sensitivity, specificity, PLR, NLR and DOR for joint detection, were 0.91 (95% CI: 0.87-0.94), 0.84 (95% CI: 0.77-0.89), 5.83 (95% CI: 4.05-8.40), 0.10 (95% CI: 0.07-0.15), 57.51 (95% CI: 35.92-92.08), respectively, when pooled, and the area under the SROC curve was 0.95. CONCLUSIONS: Current evidence indicates that GP73, GPC-3 and AFP exhibit much better accuracy for the diagnosis of HCC when used in combination rather than alone or in pairs.

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) remains a devastating type of stroke that lacks an effective treatment. Recent evidence has demonstrated that CCL2 is involved in the blood-brain barrier (BBB) disruption and propagermanium (PG) as a CCL2 receptor inhibitor is neuroprotective in ischemic stroke. However, whether PG therapy exert effective role in acute ICH still unclear. In this study, our goal was to investigate the potential role of CCL2 and the effects of PG in ICH. Differentially expressed RNAs including CCL2 were detected in human ICH. CCL2 and the activation of p-p38 MAPK and AQP4 expression were analyzed in rats after ICH. Brain water content and BBB integrity as well as neurological function were also examined after PG administration. In addition, the mechanism by which CCL2-mediated BBB injury was further investigated by cell coculture. Our findings showed that PG could effectively reduce brain edema and improve neurobehavioral functions. p-p38 MAPK and AQP4 expression were significantly inhibited by PG in vivo and in vitro. To the best of our knowledge, this is the first demonstration of PG in neuroprotecting the BBB integrity by inhibition of CCL2-CCR2-p38 MAPK pathway following ICH, targeting CCL2 could be developed as a novel treatment for hemorrhagic stroke.

Risk factors associated with postoperative recurrence in atypical intracranial meningioma: analysis of 263 cases at a single neurosurgical centre.

OBJECTIVE: Atypical meningioma (AM) has a high rate of local recurrence after surgery, and the role of adjuvant radiotherapy in AM remains controversial. We analysed progression-free survival (PFS) and identified the factors associated with postoperative recurrence in AM patients. METHODS: Data were obtained from 263 AM patients who underwent surgery at our institution between October 2009 and September 2018. Analyses included factors such as the extent of surgical resection, MIB-1 labelling index, brain invasion and therapy modality. Univariate and multivariate analyses were used to assess recurrence-related prognostic factors. RESULT: The median follow-up duration was 41 months, and the median PFS was 28 months. Gross total resection (GTR) was achieved in 213 (81.0%) patients, and 86 (32.7%) patients received postoperative radiation therapy (RT). During follow-up, there were 61 (23.2%) tumour recurrences. In a Cox multivariate analysis, MIB-1 labelling index (hazard ratio = 2.637; p < 0.001), secondary tumour (hazard ratio = 3.541; p < 0.001), tumour size (hazard ratio = 1.818; p = 0.032) and extent of resection (hazard ratio = 2.861; p < 0.001) were independent significant predictors of tumour recurrence. RT was associated with reduced tumour recurrence in subtotal resection (STR) (p = 0.023) but not GTR (p = 0.923). An analysis of 6 meningioma patients who underwent more than 3 operations suggested that the recurrence time became shorter and the MIB-1 labelling index increased as the number of recurrences increased. CONCLUSIONS: MIB-1 labelling index, secondary tumour, tumour size and extent of resection were powerful predictors of recurrence in AM patients. Postoperative RT did not decrease the risk of recurrence in GTR patients.

Multiple Distinctive Demyelinating Lesions Caused by Eosinophilic Granulomatosis With Polyangiitis: Case Report and Literature Review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an extremely rare rheumatic immune disease characterized by vasculitis of small- and medium-sized blood vessels. Central nervous system (CNS) involvement frequently consists of cerebrovascular disease; a manifestation with multiple demyelinating lesions has never been reported in detail. This report describes a 38-year-old man, who presented with progressive memory deterioration and underwent microsurgery; EGPA was subsequently confirmed. Unique clinical and radiological features as well as immunohistological outcomes and DNA sequencing revealed a potential disease-associated human leukocyte antigen (HLA) type, and single-nucleotide polymorphisms (SNPs) are described for this uncommon case. Although EGPA rarely involves the CNS, this differential diagnosis should be considered when patients present with a history of nasosinusitis, elevated eosinophil percentage, clinical pulmonitis, and neurological manifestations. Microsurgery is necessary for precise diagnosis and effective treatment.

MiR-101 targets USP22 to inhibit the tumorigenesis of papillary thyroid carcinoma.

Increasing evidence suggests that microRNA-101 (miR-101) is involved in the progression of various human cancers, including papillary thyroid carcinoma (PTC). However, the biological functions of miR-101 and underlying molecular mechanisms in PTC remain largely unknown. In this study, we demonstrated that miR-101 underexpression in PTC tissue was associated with lymph node metastasis and poor prognosis of PTC patients. MiR-101 reduced PTC cell proliferation, apoptosis resistance, and invasion. Ubiquitin-specific protease 22 (USP22) was confirmed as a direct target of miR-101. USP22 restoration attenuated the inhibitory effects of miR-101 on PTC malignant traits in vitro. In vivo, miR-101 overexpression or USP22 depletion reduced the tumorigenesis of PTC. Overall, our findings provide new insight into the mechanism of PTC inhibition by miR-101, suggesting the potential of miR-101 as a therapeutic target in PTC patients.

FLIP(L) is critical for aerobic glycolysis in hepatocellular carcinoma.

BACKGROUND: Tumor cells use aerobic glycolysis to rapidly generate ATP and growth substrate which expenses a large amount of glucose. However, how tumor cells take in enough glucose from the tumor microenvironment of insufficient blood supply remains poorly understood. The cellular FLICE-like inhibitory protein (FLIP), a cell apoptosis inhibiting molecule, is highly expressed in hepatocellular carcinoma (HCC) and is implicated in HCC development. METHODS: The effects of FLIPL (the long form of FLIP) on aerobic glycolysis and glucose uptake were assessed in HCC cells and xenograft tumors. The correlations between FLIPL expression and sodium/glucose cotransporter 1 (SGLT1) expression in clinical HCC tissues were analyzed. The consequences of FLIPL-induced regulation of SGLT1 at the transcription and translation levels and the interaction between FLIPL and SGLT1 were examined. FLIPL-mediated tolerance upon glucose limitation and its mechanism were detected. RESULTS: We report a novel role for FLIPL in promoting the aerobic glycolysis of HCC cells. FLIPL overexpression induced a significant increase in cell aerobic glycolysis indexes including glucose uptake, glucose consumption, and lactate production. FLIPL co-localized and interacted with SGLT1, a major active glucose transporter in HCC cells. FLIPL increased the stability of SGLT1 protein by inhibiting its ubiquitination and degradation. The expression level of FLIPL was positively correlated with the expression level of SGLT1 in 79 HCC tissues from surgical operation. Furthermore, FLIPL increased cell tolerance ability and decreased cell apoptosis to low glucose by regulating SGLT1. CONCLUSIONS: Our results indicate that FLIPL plays an essential role in HCC aerobic glycolysis and that SGLT1 is required for FLIPL-modulated tumor proliferation under low glucose conditions. Targeting the actions of FLIPL in cell glucose-dependent aerobic glycolysis may provide an attractive strategy for therapeutic intervention in HCC.

N-myc downstream-regulated gene 2 expression is associated with glucose transport and correlated with prognosis in breast carcinoma.

INTRODUCTION: N-myc downstream-regulated gene 2 (NDRG2), a novel tumour suppressor and cell stress-related gene, is involved in many cell metabolic processes, such as hormone, ion and fluid metabolism. We investigated whether NDRG2 is involved in any glucose-dependent energy metabolism, as well as the nature of its correlation with breast carcinoma. METHODS: The correlations between NDRG2 expression and glucose transporter 1 (GLUT1) expression in clinical breast carcinoma tissues were analysed. The effects of NDRG2 on glucose uptake were assessed in breast cancer cells and xenograft tumours. The consequences of NDRG2-induced regulation of GLUT1 at the transcription and translation levels and the interaction between NDRG2 and GLUT1 were examined. RESULTS: Data derived from clinical breast carcinoma specimens revealed that (1) patients with high NDRG2 expression had better disease-free survival and overall survival than those with low NDRG2 expression and (2) NDRG2 expression was negatively correlated with GLUT1 expression in these breast carcinoma tissues. NDRG2 inhibited glucose uptake by promoting GLUT1 protein degradation without affecting GLUT1 transcription in both breast cancer cells and xenograft tumours. In addition, NDRG2 protein interacted and partly colocalised with GLUT1 protein in cell cytoplasm areas. CONCLUSIONS: The results of our study support the notion that NDRG2 plays an important role in tumour glucose metabolism, in which GLUT1 is a likely candidate contributor to glucose uptake suppression and tumour growth. Targeting the actions of NDRG2 in cell glucose-dependent energy delivery may provide an attractive strategy for therapeutic intervention in human breast carcinoma.