CXCL5 promotes tumorigenesis and angiogenesis of glioblastoma via JAK-STAT/NF-κb signaling pathways.

BACKGROUND: The tumor microenvironment contains chemokines that play a crucial role in various processes, such as tumorigenesis, inflammation, and therapy resistance, in different types of cancer. CXCL5 is a significant chemokine that has been shown to promote tumor proliferation, invasion, angiogenesis, and therapy resistance when overexpressed in various types of cancer. This research aims to investigate the impact of CXCL5 on the biological functions of glioblastoma (GBM). METHODS: The TCGA GBM and GEO databases were utilized to perform transcriptome microarray analysis and oncogenic signaling pathway analysis of CXCL5 in GBM. Validation of CXCL5 expression was performed using RT-qPCR and Western Blot. The impact of CXCL5 on cell proliferation, tumorigenesis, and angiogenesis in GBM was assessed through various methods, including cell proliferation assay, cloning assay, intracranial xenograft tumor models, and tube formation assay. Clinical prognosis was evaluated in 59 samples of gliomas with varying degrees of malignancy (grades 2, 3, and 4) and the TCGA GBM database, based on CXCL5 expression levels. The activities of the JAK-STAT and NF-κB signaling pathways were detected using Western Blot. RESULTS: The expression of CXCL5 was highly enriched in GBM. Moreover, the inhibition of CXCL5 showed a significant efficacy in suppressing cellular proliferation and angiogenesis, resulting in extended survival rates in xenograft mouse models in comparison to the control group. Notably, pretreatment with dapsone exhibited a reversal of the impact of CXCL5 on the formation of colonies and tubes in GBM cells. Elevated expression of CXCL5 was correlated with poor outcomes in GBM patients. Furthermore, the overexpression of CXCL5 has been associated with the activation of JAK-STAT and NF-κB signaling pathways. CONCLUSIONS: CXCL5 plays an important role in tumorigenesis and angiogenesis, indicating the potential for novel therapies targeting CXCL5 in GBM.

LncRNA MYMLR promotes pituitary adenoma development by upregulating carbonyl reductase 1 via sponging miR-197-3p.

Long noncoding RNAs (lncRNAs) have been demonstrated to participate in various biological processes and play key roles in tumorigenesis and metastasis. Pituitary adenoma (PA) is one of the most common malignancies in central nervous system. Recently, multiple lncRNAs have been identified to regulate PA initiation, progression and metastasis. we aimed to elucidate the expression pattern and function of lncRNA MYMLR in PA development. The expression of lncRNA MYMLR in PA tissues and cells was examined by real-time quantitative PCR. Knockdown of MYMLR expression was achieved by using shRNA. The function of MYMLR and regulatory network were analyzed using CCK-8 assay, wound-healing assay, migration assay and Annexin V/PI staining. Xenograft tumor model was used to explore the function of MYMLR in vivo . Bioinformatics analysis and luciferase reporter assay were conducted to investigate the interaction between MYMLR and its regulatory network. LncRNA MYMLR was highly expressed in PA tissues compared with that in normal tissues. Knockdown of MYMLR suppressed cell proliferation, migration and invasion, while promoting PA cell apoptosis. Mechanistically, MYMLR functioned as a competing endogenous RNA (ceRNA) sponging microRNA miR-197-3p. Furthermore, miR-197-3p exerted its tumor inhibitory role via negatively regulating carbonyl reductase 1 (CBR1). Overexpression of CBR1 antagonized the inhibitory effect of lncRNA MYMLR knockdown or miR-197-3p overexpression. In addition, xenograft tumor model revealed that knockdown of lncRNA MYMLR suppressed PA tumor development in vivo via regulating CBR1. Our findings suggest a regulatory network of lncRNA MYMLR/miR-197-3p/CBR1, which benefits the understanding of PA development and provides a promising lncRNA-direct therapeutic strategy against PA.

circKIF4A promotes tumorogenesis of glioma by targeting miR-139-3p to activate Wnt5a signaling.

BACKGROUND: Glioma has the characteristics of high incidence and mortality, and is a common malignant tumor of the central nervous system. Circular RNAs (circRNAs) have been reported to play vital roles in progression of cancer including glioma, and circKIF4A is up-regulated in glioma tissues. However, its role and mechanisms in gliomas are unclear. METHODS: circKIF4A and miR-139-3p were determined by qRT-PCR. Transwell assay, wound-healing assay, cell colony formation and flow cytometry were performed to measure cell invasion, migration, proliferation and apoptosis. Western blotting was used to evaluate Wnt/ß-catenin pathway-related protein. Luciferase reporter assays confirmed the relationship among circKIF4A, miR-139-3p and Wnt5a. Sphere formation was performed to measure the ability of glioma-initiating cells (GICs) spheroid formation. A nude mouse xenograft model was established and immunohistochemical staining was used to detect Ki-67 and Wnt5a levels. RESULTS: circKIF4A and Wnt5a were up-regulated and miR-139-3p was down-regulated in both glioma cells and tissues. circKIF4A promoted Wnt5a expression by sponging miR-139-3p. Knockdown of circKIF4A inhibited the colony formation ability, migration and invasion, and promoted the apoptosis of glioma cells by regulating miR-139-3p. Knockdown of circKIF4A inhibited Wnt/ß-catenin signaling pathway and proliferation-related signal via miR-139-3p. Furthermore, knockdown of circKIF4A or overexpression of miR-139 suppressed the ability of sphere formation of GICs and inhibitd Wnt/ß-catenin signaling pathway and proliferation-related signal in GICs. Additionally, depletion of circKIF4A decreased the expression level of Wnt5a and Ki-67, inhibited tumorigenesis in xenograft modes. CONCLUSION: circKIF4A was overexpressed in glioma, and knockdown of circKIF4A suppressed glioma progression via miR-139-3p/Wnt5a axis. The results indicated that circKIF4A may be a potential target for clinical treatment of glioma.

Trephination mini-craniectomy for traumatic posterior fossa epidural hematomas in selected pediatric patients.

PURPOSE: Posterior fossa epidural hematomas (PFEDH) are uncommon in children but usually require timely surgical intervention due to the risk of life-threatening brainstem compression. We attempt to make the surgical procedure less invasive by treating selected pediatric patients with trephination mini-craniectomy. METHODS: We retrospectively reviewed the clinical courses, radiological findings, surgical procedures, and prognoses of the pediatric patients who were treated in our departments for traumatic PFEDH from January 2010 to January 2015. RESULTS: During this period, a total of 17 patients were surgically treated for PFEDH and 7 were managed with trephination mini-craniectomy for hematoma evacuation. The outcomes were good in all 7 patients as evaluated with Glasgow Outcome Score. There was no mortality in this series. The on average 30-month clinical follow-up showed that patients experienced satisfactory recoveries without complications. CONCLUSION: Our results suggest that trephination mini-craniectomy is a safe surgical technique for selected PFEDH patients with moderate hematoma volume and stabilized neurological functions. However, standard craniectomy is recommend when there are rapid deteriorations in patients' neurological functions or the hematomas are large and exerted severe mass effects.

Delayed surgical repair of cranial burst fracture without strict dura closure: a prudent choice in selected patients?

OBJECTIVES: Surgical management of cranial burst fracture (CBF) usually involves craniotomy to remove the devitalized brain tissues, followed by watertight repair of dural tears. However, there were times when the dural tear was so extensive that a substantially large bone flap would have to be removed in order to expose the retracted dural margins before it could be repaired. In such cases, strict dural repair would incur a significantly higher risk of damages to the surrounding neural tissues and severe bleeding, especially when the fracture was in the vicinity of eloquent cortical areas and sinus. Basing on our own clinical experiences, we suggest strict dural closure is not mandatory for these selected patients. METHODS: A retrospective review of patients who underwent cranial surgery for CBF at our hospital was performed. Computed tomography (CT) and magnetic resonance imaging (MRI) scans were performed to evaluate the extent of dural and brain laceration and the existence of extra-cranial cerebral tissues. Routine craniotomy was delivered to remove the lacerated brain tissues and evacuate the hematoma. The dural defect was only partially fixed with patient's own tissues or artificial dura patch. Then the fractured bone flaps were restored using titanium micro plates and screws. Data including preoperative neurological status, surgery related complications, postoperative cranial fracture healing, and clinical outcomes were obtained through clinical and radiological examinations. RESULTS: From October 2004 to March 2013, a total of four patients diagnosed with CBF were treated by this dural closure sparing technique. Their average age was 18.4 months old and the average area of the skull defects was 91 cm(2), with an average interval between primary injury and surgery of 13 days. The diagnosis of CBF was confirmed by intraoperative findings like extrusion of cerebral tissues out of the lacerated dura mater and skull defects. The postoperative courses were uneventful and all patients' neurological functions improved after surgery. Postoperative three dimensional CT reconstruction of the cranial vault showed the skull fractures healed properly in all patients. No patient developed posttraumatic cerebrospinal fluid leak or epilepsy during the on average 24-month follow-up period. CONCLUSIONS: In those selected cases of CBF in whom an extraordinary large craniotomy would be required to expose the entire retracted dura margins, given satisfactory evacuation of devitalized brain tissues and restoration of the bone flaps were achieved, we suggest strict dura closure is not compulsory.

Magnesium sulfate for acute traumatic brain injury.

BACKGROUND: The purpose of this systematic review was to evaluate the effect of magnesium sulfate in the treatment of acute traumatic brain injury. MATERIALS AND METHODS: A systematic search of ClinicalTrials.gov, the Cochrane Library database, EMBASE, MEDLINE, Web of Science, and the World Health Organization trial registry, plus manual searches of gray literature, was undertaken in April 2013. Two reviewers independently extracted the data with a predefined data extraction form. RevMan 5 software was used to synthesize data and calculate the risk ratio for mortality with the 95% confidence interval. For the Glasgow Outcome Scale and posttreatment Glasgow Coma Scale data, the weighted mean difference was calculated with the 95% confidence interval. RESULTS: A total of 8 randomized controlled trials with a total of 786 patients were included. Meta-analysis showed that there was no significant difference between the groups for mortality. The Glasgow Outcome Scale of the treatment group was higher than that of the control group, although the significance was borderline. The Glasgow Coma Scale score change posttreatment was significantly higher than that of the control. CONCLUSIONS: The present meta-analysis of existing randomized controlled trials does not identify a significant beneficial effect in the mortality of traumatic brain injury patients; however, it suggests that magnesium sulfate shows a tendency to improve the Glasgow Outcome Scale and Glasgow Coma Scale scores, which is a promising result for traumatic brain injury therapy. Further effort is necessary to explore which subgroup of traumatic brain injury patients could benefit from magnesium sulfate.

A novel reference coordinate system to locate the inferomedial point of the transverse-sigmoid sinus junction.

BACKGROUND: A coordinate system was previously developed to identify landmarks on the skull surface to help locate the transverse-sigmoid sinus junction in order to reduce surgical morbidity in retrosigmoid craniotomy; however, in practice we found that this system has important flaws. OBJECTIVE: To develop and evaluate a novel reference coordinate system to precisely locate the inferomedial point of the transverse-sigmoid sinus junction (IMTS) and evaluate the effect of gender and skull side (left or right). METHODS: Forty-two adult skulls (84 sides) were obtained for analyses. The X-axis was defined by point A (where the upper edge of the zygomatic arch joins with the frontal process of the zygomatic bone) and point B (where the upper edge of the zygomatic arch blends posterosuperiorly into the supramastoid crest). The Y-axis was defined by the line perpendicular to the X-axis and extending across the tip of the mastoid. The x and y coordinates of IMTS (IMTS-x and IMTS-y) were measured in this coordinate system. RESULTS: There were 20 male skulls and 22 female skulls. The mean IMTS-x measurements were significantly higher on the right side compared with the left side in both males and females. For the left skull side, the mean IMTS-y measurements were significantly lower in females compared with males. CONCLUSION: This novel reference coordinate system may be a reliable and practical method for identifying the IMTS during retrosigmoid craniotomy. There are significant differences in location of the axes with regard to gender and skull side.

A rare remote epidural hematoma secondary to decompressive craniectomy.

Remote epidural hematoma (REDH) is an uncommon complication of decompressive craniectomy. Remote epidural hematomas of the parietal occiput region have been reported only rarely. We report a unique case of delayed-onset bilateral extensive straddle postsagittal sinus and bilateral lateral sinus parietal occiput REDH after decompressive craniectomy, of which volume was approximately 130 mL, with left deviating midline structures. The patient was immediately taken back to the operating room for evacuation of the REDH via bilateral parietal and occiput craniectomy. Postoperatively, serial computed tomographic scans performed 3 days later showed that the REDH had been completely evacuated. Two months later, the patient regained full consciousness and obtained a near-complete recovery except for right facial paralysis.

Early pressure dressing for the prevention of subdural effusion secondary to decompressive craniectomy in patients with severe traumatic brain injury.

This study was performed to investigate the effect of early pressure dressing on the prevention of postoperative subdural effusion secondary to decompressive craniectomy (DC) in patients with severe traumatic brain injury (STBI). Patients with STBI who had undergone DC for refractory increased intracranial pressure between January 2008 and December 2011 (n = 169) were randomly divided into early pressure dressing (n = 82) and control (n = 87) groups. Early pressure dressing with an elastic bandage or general wrapping (control treatment) was applied 7 to 10 days after DC. Patients' age, sex, preoperative Glasgow Coma Scale score, incidence rate of subdural effusion, hospitalization time, and postoperative Glasgow Outcome Scale score were compared between groups. Intracranial pressure was measured immediately before and on the day after pressure dressing. No significant difference in age, sex, preoperative Glasgow Coma Scale score, or postoperative Glasgow Outcome Scale score was observed between groups (P > 0.05). Subdural effusion incidence rates were significantly lower in the early pressure dressing group than those in the control group (χ² = 5.449, P = 0.021), and a larger proportion of patients in the early pressure dressing group was hospitalized for 30 days or less (χ² = 5.245, P = 0.027). Early pressure dressing 7 to 10 days after DC, which is a noninvasive, simple procedure, reduced the incidence rate of subdural effusion and shortened hospitalization time after DC for STBI.

CCNA2 and NEK2 regulate glioblastoma progression by targeting the cell cycle.

Glioblastoma (GBM) is characterized by significant heterogeneity, leading to poor survival outcomes for patients, despite the implementation of comprehensive treatment strategies. The roles of cyclin A2 (CCNA2) and NIMA related kinase 2 (NEK2) have been extensively studied in numerous cancers, but their specific functions in GBM remain to be elucidated. The present study aimed to investigate the potential molecular mechanisms of CCNA2 and NEK2 in GBM. CCNA2 and NEK2 expression and prognosis in glioma were evaluated by bioinformatics methods. In addition, the distribution of CCNA2 and NEK2 expression in GBM subsets was determined using pseudo-time analysis and tricycle position of single-cell sequencing. Gene Expression Omnibus and Kyoto Encyclopedia of Genes and Genome databases were employed and enrichment analyses were conducted to investigate potential signaling pathways in GBM subsets and a nomogram was established to predict 1-, 2- and 3-year overall survival probability in GBM. CCNA2 and NEK2 expression levels were further validated by western blot analysis and immunohistochemical staining in GBM samples. High expression of CCNA2 and NEK2 in glioma indicates poor clinical outcomes. Single-cell sequencing of GBM revealed that these genes were upregulated in a subset of positive neural progenitor cells (P-NPCs), which showed significant proliferation and progression properties and may activate G2M checkpoint pathways. A comprehensive nomogram predicts 1-, 2- and 3-year overall survival probability in GBM by considering P-NPCs, age, chemotherapy and radiotherapy scores. CCNA2 and NEK2 regulate glioblastoma progression by targeting the cell cycle, thus indicating the potential of novel therapy directed to CCNA2 and NEK2 in GBM.

Modified external ventricular drainage in pediatric tuberculous meningitis: is it possible to avoid ventriculoperitoneal shunt placement?

OBJECTIVE: Ventriculoperitoneal shunting is the current mainstay of treatment for children with tuberculous meningitis with hydrocephalus. However, ventriculoperitoneal shunting is highly associated with complications, and more importantly, long-term, indwelling shunt devices may adversely affect children's spirits and psychological health. Therefore, there is clearly a need to explore methods of CSF diversion to avoid ventriculoperitoneal shunting. METHODS: We studied 6 cases of children with tuberculous meningitis with hydrocephalus in whom external drainage from the ventricle to the subcutaneous abdomen was adopted. Outcomes were assessed over a 6- to 9-month follow-up period based on improvements in radiological features, such as ventricular morphology, as well as the need for ventriculoperitoneal shunting and any complications. RESULTS: The drainage tubes were removed in 4 cases 4-6 months after the modified external ventricular drainage surgery, and 2 patients went on to receive a ventriculoperitoneal shunt. All patients' CSF protein and cell counts returned to normal, and imaging showed improved ventricular morphology and no intracranial secondary infection. CONCLUSION: In our preliminary study, the modified ventricular drainage device can produce satisfactory outcomes and relatively safe effects and may help some patients to avoid ventriculoperitoneal shunt placement.

Risk factors analysis on traumatic brain injury prognosis.

OBJECTIVE: To investigate the independent risk factors of traumatic brain injury (TBI) prognosis. METHODS: A retrospective analysis was performed in 885 hospitalized TBI patients from January 1, 2003 to January 1,2010 in the First Affiliated Hospital of Medical College of Xi'an Jiaotong University .Single-factor and logisticregression analysis were conducted to evaluate the association of different variables with TBI outcome. RESULTS: The single-factor analysis revealed significant association between several variables and TBI outcome, including age ( P=0.044 for the age group 40-60, Pü0.001 for the age group ≥60), complications ( P<0.001), cerebrospinal fluid leakage( P<0.001), Glasgow Coma Scale(GCS) ( P<0.001), pupillary light reflex ( P<0.001), shock ( P<0.001), associated extra-craniallesions ( P=0.01), subdural hematoma ( P<0.001), cerebral contusion ( P<0.001), diffuse axonal injury ( P<0.001), and subarachnoid hemorrhage( P<0.001), suggesting theinfluence of those factors on the prognosis of TBI. Furthermore, logistic regression analysis identified age, GCS score, pupillary light reflex, subdural hematoma,and subarachnoid hemorrhage as independent risk factors of TBI prognosis. CONCLUSION: Age, GCS score, papillary lightreflex, subdural hematoma, and subarachnoid hemorrhage may be risk factors influencing the prognosis of TBI. Paying attention to those factors might improve the outcome of TBI in clinical treatment.

[Role of modified external ventricular drainage in the management of children with tuberculous meningitis hydrocephalus].

OBJECTIVE: To explore the role of modified external ventricular drainage (mEVD) in the treatment of tuberculous meningitis obstructive hydrocephalus in children. METHODS: The records were retrospectively reviewed for 30 pediatric patients of tuberculous meningitis with hydrocephalus (TBMH) undergoing surgery between January 2007 and December 2010. The procedures included ventricular abdomen subcutaneous drainage (mEVD) (n = 6), Ommaya reservoir (n = 9) and ventriculoperitoneal shunt (VPS) (n = 15). White cell count and protein content of cerebrospinal fluid were measured repeatedly. And their clinical outcomes were assessed at 6 months post-operation. RESULTS: External drainage was extracted for 4 of 6 TBMH patients after 4 - 6 months of mEVD. Neither intracranial infections nor serious postoperative complications occurred. Two of 6 TBMH received VPS substituting for mEVD. No statistically significant difference in white cell count, protein content of cerebrospinal fluid and outcome was found between the mEVD and VPS groups. CONCLUSION: Ventricular abdomen subcutaneous drainage is both safe and efficacious in the management of children with tuberculous meningitis hydrocephalus. This approach may avoid possible complications and long-term indwelling shunt so that it is worthy of further clinical application.

Valproate reverses stress-induced somatic hyperalgesia and visceral hypersensitivity by up-regulating spinal 5-HT2C receptor expression in female rats.

Sodium valproate (VPA) has analgesic effects in clinical and experimental studies, but the mechanisms are still unclear. The present study examined the effects of VPA on stress-induced somatic hyperalgesia and visceral hypersensitivity and the role of 5-HT2C receptors in the spinal cord. Repeated 3 day forced swim (FS) significantly reduced the thermal withdrawal latency and mechanical withdrawal threshold, and increased the magnitude of the visceromotor response to colorectal distention compared to the baseline values in rats. The somatic hyperalgesia and visceral hypersensitivity were accompanied by significant down-regulation of 5-HT2C receptor expression in the L4-L5 and L6-S1 dorsal spinal cord. Intraperitoneal administration of VPA (300 mg/kg) before each FS and 1 day post FS prevented the development of somatic hyperalgesia and visceral hypersensitivity induced by FS stress, as well as down-regulation of 5-HT2C receptors in the spinal cord. The reversal of somatic hyperalgesia and visceral hypersensitivity by VPA in FS rats was blocked by intrathecal administration of the selective 5-HT2C receptor antagonist RS-102221 (30 µg/10 µL) 30 min after each VPA injection. The results suggest that VPA attenuates FS-induced somatic hyperalgesia and visceral hypersensitivity by restoring down-regulated function of 5-HT2C receptors in the spinal cord.

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is the most lethal primary malignant brain tumor in adults with poor survival due to acquired therapeutic resistance and rapid recurrence. Currently, the standard clinical strategy for glioma includes maximum surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy; however, the median survival of patients with GBM remains poor despite these comprehensive therapies. Therefore, the identification of new prognostic biomarkers is urgently needed to evaluate the malignancy and long-term outcome of glioma. AIMS: To further investigate prognostic biomarkers and potential therapeutic targets for GBM. RESULTS: In this study, we identified tribbles pseudokinase 2 (TRIB2) as one of the genes that is most correlated with pathological classification, radioresistance, and TMZ resistance in glioma. Additionally, the expression of mitogen-activated protein kinase kinase kinase 1 (MAP3K1) showed a strong correlation with TRIB2. Moreover, a combined increase in TRIB2 and MAP3K1 was observed in GBM and indicated a poor prognosis of patients with glioma. Finally, enriched TRIB2 expression and MAP3K1 expression were shown to be associated with resistance to TMZ and radiotherapy. CONCLUSION: Combined elevation of TRIB2 and MAP3K1 could be novel prognostic biomarkers and potential therapeutic targets to evaluate the malignancy and long-term outcomes of GBM.

PDZ-Binding Kinase-Dependent Transcriptional Regulation of CCNB2 Promotes Tumorigenesis and Radio-Resistance in Glioblastoma.

Increasing evidence has indicated that PDZ binding kinase (PBK) promotes proliferation, invasion, and therapeutic resistance in a variety of cancer types. However, the physiological function and therapy-resistant role of PBK in GBM remain underexplored. In this study, PBK was identified as one of the most therapy-resistant genes with significantly elevated expression level in GBM. Moreover, the high expression level of PBK was essential for GBM tumorigenesis and radio-resistance both in vitro and in vivo. Clinically, aberrant activation of PBK was correlated with poor clinical prognosis. In addition, inhibition of PBK dramatically enhanced the efficacy of radiation therapy in GBM cells. Mechanically, PBK-dependent transcriptional regulation of CCNB2 was critical for tumorigenesis and radio-resistance in GBM cells. Collectively, PBK promotes tumorigenesis and radio-resistance in GBM and may serve as a novel therapeutic target for GBM treatment.

Retraction: Receptor tyrosine kinase AXL is correlated with poor prognosis and induces temozolomide resistance in glioblastoma.

Retraction: Receptor tyrosine kinase AXL is correlated with poor prognosis and induces temozolomide resistance in glioblastoma, CNS Neuroscience & Therapeutics 2019, (https://doi.org/10.1111/cns.13227). The above article published online on 02 October 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief Jun Chen, and John Wiley & Sons Ltd. The retraction has been agreed due to unreliable data and consequently its misleading results and conclusions.

Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation.

BACKGROUND: Vascular maturity and functionality are closely associated with tumor progression and chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit tumor angiogenesis in metastatic breast cancer models. However, it remains unclear if or how metformin remodels the abnormal vasculature of metastatic breast cancer, while inhibiting angiogenesis. METHODS: Metastatic breast cancer models were constructed to compare microvessel density (MVD), vascular maturity and function, lung metastasis and chemosensitivity in metformin-treated or untreated mice. Protein array assay and transcriptome sequencing were performed for genetic screening. Lentiviral shRNA-PDGF-B transfection was used for observing the contribution of PDGF-B knockdown to metformin's vascular effects. RESULTS: Metastatic breast cancers were characterized by an excessively angiogenic, immature and morphologically abnormal vasculature. Compared to control, metformin significantly reduced MVD, leakage and hypoxia, and increased vascular mural cells coverage and perfusion, namely, "vessel normalization". Metformin at human blood concentrations had no direct effect on the migration and proliferation of cancer cells. Based on that, reduced lung metastasis of the primary tumor and improved chemosensitization by metformin were assumed to be mediated via metformin's vascular effects. Further results of genetic screening and in vivo experiments showed that the downregulation of platelet-derived growth factor B (PDGF-B) greatly contributed to the metformin-induced vessel normalization. CONCLUSIONS: These findings provide pre-clinical evidences for the vascular mechanism of metformin-induced metastasis inhibition and the chemosensitization of metastatic breast cancers.

Salvianolic acid B renders glioma cells more sensitive to radiation via Fis-1-mediated mitochondrial dysfunction.

Glioma remains the leading cause of brain tumor-related death worldwide, and radiation is a standard adjuvant therapy with proven efficacy. Salvianolic acid B (SalB), a bioactive compound isolated from Radix Salviae, has been shown to exert anti-cancer effects in many cancer cell lines, including glioma. This study aimed to investigate whether SalB could affect response to radiation in human glioma cells. We found that SalB decreased cell viability of U87 cells in a-dose-dependent manner. A subthreshold dose of SalB at 0.5 µM, which had no effect on cell viability and apoptosis, significantly increased radiation sensitivity of U87 cells in a dose- and time-dependent manner, but had no effect on sensitivity to temozolomide (TMZ). Similar results were also observed in human glioma U373 cells. In addition, SalB aggravated the radiation-induced apoptosis and mitochondrial dysfunction, as measured by mitochondrial Ca2+ buffering capacity and mitochondrial swelling. SalB treatment markedly promoted mitochondrial fission and differently regulated the expression of fission proteins. Furthermore, downregulation of the fission protein Fis-1 using siRNA was found to partially reversed the SalB-induced effects on cell viability, apoptosis and mitochondrial fission in U87 cells. In conclusion, our results suggest that a subthreshold dose of SalB renders glioma cells more sensitive to radiation via Fis-1-mediated mitochondrial dysfunction, and radiotherapy combined with SalB might be a novel treatment for glioma patients.