Simultaneous resection of pituitary adenoma and clipping of aneurysm through endoscopic endonasal approach: a case report.

Pituitary adenomas and intracranial aneurysms are prevalent neurosurgical conditions, but their simultaneous presence is uncommon, affecting only 0.5%-7.4% of those with pituitary adenomas. The strategy of treating aneurysms endovascularly before removing pituitary adenomas is widely adopted, yet reports on addressing both conditions at once through an endoscopic endonasal approach (EEA) are scarce. We present a case involving a pituitary adenoma coupled with an anterior communicating artery aneurysm. Utilizing the EEA, we excised the adenoma and clipped the aneurysm concurrently. The patient recovered well post-surgery, with follow-up assessments confirming the successful resolution of both the adenoma and aneurysm. We proved the feasibility of the EEA in the treatment of pituitary adenomas with anterior communicating artery aneurysms under specific anatomical relationships and close intraoperative monitoring.

Management of cavernous sinus meningiomas: Clinical features, treatment strategies, and long-term outcomes.

OBJECTIVES: The purpose of this research was to summarize the clinical and prognostic features of cavernous sinus meningiomas (CSM), evaluate the treatment strategies and long-term prognosis of CSM, and improve the management of CSM and the treatment effect for patients. METHODS: We retrospectively studied the data of 54 patients who received initial surgical resection and 45 patients who received initial gamma knife radiosurgery (GKRS) for CSM at West China Hospital of Sichuan University from 2009 to 2021. Progression-free survival (PFS), Karnofsky Performance Scale (KPS) scores and neurological function recovery were adopted to assess a comprehensive management strategy for CSM. RESULTS: Gross total resection (GTR) was performed in 51.9 % of cases with 3.7 % surgical mortality. The average follow-up time was 48.7 months, with a progression rate of 29.3 %. The overall improvement rate for cranial nerve function deficits was 50.0 %. By survival analysis, the extent of resection and the histological grade were significantly related to the prognosis. The role of postoperative GKRS is uncertain. For patients who received initial GKRS, the progression rate was 17.8 %, and the overall improvement rate for cranial nerve function deficits was 61.1 %. Primary treatment with GKRS showed better long-term tumor control in patients with CSM (P = 0.046). CONCLUSIONS: Maximum safe resection of CSM can improve the neurological function and quality of life of patients, but aggressive resection will cause high perioperative mortality and complication rates. For CSM patients who are suitable for initial gamma knife treatment, choosing GKRS can achieve better long-term tumor control and neurological outcomes.

Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Oxygen-Glucose Deprivation/Reperfusion-Induced Microglial Pyroptosis by Promoting FOXO3a-Dependent Mitophagy.

BACKGROUND: Mesenchymal stem cell-derived exosomes (MSC-exos) have been recognized as a promising therapeutic strategy for neonatal hypoxic-ischemic brain damage (HIBD). Recently, microglial pyroptosis was shown to play a vital role in the progression of neonatal HIBD. However, whether MSC-exos improve HIBD by regulating microglial pyroptosis remains unknown. METHODS: Exosomes were isolated from human umbilical cord mesenchymal stem cells (huMSCs) and identified by transmission electron microscopy (TEM), western blot, and nanoparticle tracking analysis (NTA). BV-2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce microglial ischemia/reperfusion (I/R) in vitro. CCK-8, ELISA, western blot, and Hoechst 33342/PI double staining were performed to detect the pyroptosis of BV-2 cells. Conditioned medium (CM) from BV-2 cells exposed to different treatments was used to investigate its effect on neuronal injury. Moreover, 3-methyladenine (3-MA) and mitochondrial division inhibitor-1 (mdi-1) were used to verify the involvement of mitophagy in the protection of MSC-exos against OGD/R-induced pyroptosis in BV-2 cells. Finally, FOXO3a siRNA was used to investigate the involvement of FOXO3a in MSC-exo-induced mitophagy and pyroptosis inhibition. RESULTS: Exosomes from huMSCs were successfully extracted. In OGD/R-exposed BV-2 cells, MSC-exos increased cell viability and decreased the expression of NLRP3, cleaved caspase-1, and GSDMD-N as well as the release of IL-1ß and IL-18. Compared with CM from OGD/R-exposed BV-2 cells treated with PBS, CM from OGD/R-exposed BV-2 cells treated with MSC-exos significantly increased the viability of SH-SY5Y cells and decreased LDH release. MSC-exos also increased the expression of TOM20 and COX IV in OGD/R-exposed BV-2 cells. Additionally, 3-MA and mdi-1 attenuated the inhibition of pyroptosis with MSC-exo treatment. Furthermore, FOXO3a siRNA partially abolished the neuroprotective effect of MSC-exos and attenuated mitophagy and pyroptosis inhibition induced by MSC-exo treatment. CONCLUSIONS: Our findings demonstrated that MSC-exos increased FOXO3a expression to enhance mitophagy, therefore protecting microglia from I/R-induced pyroptosis and alleviating subsequent neuronal injury.

TUDCA inhibits HSV-1 replication by the modulating unfolded protein response pathway.

Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, was used to protect liver function through antiapoptosis or reducing endoplasmic reticulum stress (ER stress). Previous studies showed that ER stress was modulated by herpes simplex virus types 1 (HSV-1) infection to facilitate viral replication. Here, we investigated the effect of TUDCA on HSV-1 infection of HEC-1-A cells and showed that both replication and multiplication of the virus were inhibited by TUDCA in a dose dependent manner. Unfolded protein response was induced to deliver stress signals from ER to nucleus. We found that TUDCA alleviated activating transcription factor 6 branch inhibition, partially enhanced protein kinase RNA-like ER kinase pathway activation, and repressed inositol-requiring protein 1α arm activation significantly in infected cells. The findings of this study suggest that TUDCA inhibits HSV-1 replication through ER stress pathway, which may provide a potential therapeutic strategy for HSV-1 infection.

FOXO3a-dependent up-regulation of Mxi1-0 promotes hypoxia-induced apoptosis in endothelial cells.

Endothelial cell apoptosis induced by hypoxia is implicated in the pathogenesis of vascular diseases. However, the underlying mechanism is not clearly elucidated. In this study, we found that hypoxia increased Mxi1-0 expression, and the Mxi1-0 siRNA could inhibit caspase-8 activation and apoptosis in HUVECs induced by hypoxia. In addition, hypoxia induced FOXO3 activation, while Mxi1-0 expression and apoptosis were inhibited by transfection with FOXO3 siRNA. Using ChIP assay, we confirmed that FOXO3a binds to the Mxi1-0 promoter region. Furthermore, hypoxia treatment leads to remarkable production of reactive oxygen species (ROS), while ROS scavenger N-acetyl-L-cysteine (NAC) inhibits hypoxia-induced ROS production, apoptosis and FOXO3a-mediated Mxi1-0 up-regulation. Finally, we found that the HIF-1α siRNA inhibited hypoxia-induced HIF-1α expression and ROS production, as well as FOXO3a/Mxi1-0 activation and apoptosis in HUVECs. Taken together, this study identifies a HIF-1α/FOXO3a/Mxi1-0/caspase-8 signaling pathway in hypoxia-induced endothelial cell apoptosis. These data also indicate that HIF-1α-dependent ROS production is required for FOXO3a-mediated Mxi1-0 up-regulation and apoptosis in hypoxic endothelial cells.

Mxi1-0 regulates the growth of human umbilical vein endothelial cells through extracellular signal-regulated kinase 1/2 (ERK1/2) and interleukin-8 (IL-8)-dependent pathways.

Mxi1 plays an important role in the regulation of cell proliferation. Mxi1-0, a Mxi1 isoform, has a different N-terminal amino acid sequence, intracellular location and expression profile from Mxi1. However, the precise role of Mxi1-0 in cell proliferation and the molecular mechanism underlying its function remain poorly understood. Here, we showed that Mxi1-0 suppression decreased the proliferation of human umbilical vein endothelial cells (HUVECs) along with cell accumulation in the G2/M phase. Mxi1-0 suppression also significantly decreased the expression and secretion of interleukin (IL-8). Neutralizing IL-8 in conditioned medium (CM) from Mxi1-0-overexpressed HUVECs significantly eliminated CM-induced proliferation of HUVECs. In addition, Mxi1-0 suppression significantly decreased the activity of MAP kinase ERK1/2. Treatment of HUVECs with U0126, an ERK1/2 signaling inhibitor, attenuated autocrine production of IL-8 induced by Mxi1-0 overexpression. On the other hand, Mxi1-0 overexpression-induced IL-8 increased the level of phosphorylated ERK1/2 in HUVECs, and such increasing was diminished in cells incubated with CM, which neutralized with anti-IL-8 antibody. Taken together, our results suggest that Mxi1-0 regulates the growth of HUVECs via the IL-8 and ERK1/2 pathways, which apparently reciprocally activate each other.

Mxd1 mediates hypoxia-induced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene.

Hypoxia-induced chemoresistance remains a major obstacle to treating osteosarcoma effectively. Mxd1, a member of the Myc/Max/Mxd family, was shown to be involved in the development of drug resistance under hypoxia. However, the effect of Mxd1 on hypoxia-induced cisplatin (CDDP) resistance and its mechanism in osteosarcoma have not been fully elucidated. In this study, we demonstrated that HIF-1α-induced Mxd1 contributed to CDDP resistance in hypoxic U-2OS and MG-63 cells. The knockdown of Mxd1 expression elevated PTEN expression at both protein and RNA levels in these hypoxic cells. Using Luciferase reporter and ChIP assays, we confirmed that Mxd1 directly bound to the E-box sites within the PTEN promoter region. We further demonstrated that PTEN knockdown decreased CDDP sensitivity in Mxd1 siRNA-transfected U-2OS and MG-63 cells under hypoxia. Our results also showed that Mxd1 deficiency in hypoxic U-2OS and MG-63 cells lead to inactivation of PI3K/AKT signaling, which is the downstream of PTEN. Furthermore, blockade of PI3K/AKT signal re-sensitized hypoxic U-2OS and MG-63 cells to CDDP. Taken together, these findings suggest that HIF-1α-induced Mxd1 up-regulation suppresses the expression of PTEN under hypoxia, which leads to the activation of PI3K/AKT antiapoptotic and survival pathway. As a result CDDP resistance in osteosarcoma cells is induced.

A positive feedback loop between ROS and Mxi1-0 promotes hypoxia-induced VEGF expression in human hepatocellular carcinoma cells.

VEGF expression induced by hypoxia plays a critical role in promoting tumor angiogenesis. However, the molecular mechanism that modulates VEGF expression under hypoxia is still poorly understood. In this study, we found that VEGF induction in hypoxic HepG2 cells is ROS-dependent. ROS mediates hypoxia-induced VEGF by upregulation of Mxi1-0. Furthermore, PI3K/AKT/HIF-1α signaling pathway is involved in ROS-mediated Mxi1-0 and VEGF expression in hypoxic HepG2 cells. Finally, Mxi1-0 could in turn regulate ROS generation in hypoxic HepG2 cells, creating a positive feedback loop. Taken together, this study demonstrate a positive regulatory feedback loop in which ROS mediates hypoxia-induced Mxi1-0 via activation of PI3K/AKT/HIF-1α pathway, events that in turn elevate ROS generation and promote hypoxia-induced VEGF expression. These findings could provide a rationale for designing new therapies based on inhibition of hepatocellular carcinoma (HCC) angiogenesis.

Polymorphisms of p53 and MDM2 genes are associated with severe toxicities in patients with non-small cell lung cancer.

Adverse events in platinum-based chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) are major challenges. In this study, we investigated the role of the p53 and MDM2 genes in predicting adverse events in NSCLC patients treated with platinum-based chemotherapy. Specifically, we examined the p53 p. Pro72Arg (rs1042522), MDM2 c.14 + 309T>G (rs2279744) and MDM2 c.- 461C > G (rs937282) polymorphisms using PCR-based restriction fragment length polymorphism (RFLP) in 444 NSCLC patients. We determine that MDM2 c.14 + 309T > G was significantly associated with severe hematologic and overall toxicities for advanced NSCLC patients treated with platinum-based chemotherapy, especially for patients aged 57 and younger. This was also true for patients with adenocarcinoma. Second, we determine that severe gastrointestinal toxicities in patients with heterozygous MDM2 c.-461C > G were significantly higher than in patients with the G/G genotype. Third, patients with the MDM2 c.-461C > G - c.14 + 309T > G CT haplotype show much higher toxicities than those of CG haplotype. Moreover, patients carrying the MDM2 c.-461 > G -c.14 + 309T > G CG/CT diplotype exhibited higher toxicities than those carrying CG/CG. Fourth, we found that the p53 p. Pro72Arg polymorphism interacts with both age and genotype. In addition, no significant associations were observed between the 3 SNPs and the response to first-line platinum-based chemotherapy in advanced NSCLC patients. In summary, we found that the p53 p. Pro72Arg, MDM2 c.14 + 309T > G and MDM2 c.-461C > G polymorphisms are associated with toxicity risks following platinum-based chemotherapy treatment in advanced NSCLC patients. We suggest that MDM2 c.14 + 309T > G may be used as a candidate biomarker to predict adverse events in advanced NSCLC patients who had platinum-based chemotherapy treatment.

Downregulation of galectin-3 causes a decrease in uPAR levels and inhibits the proliferation, migration and invasion of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. Galectin-3 (Gal-3), a multifunctional ß-galactoside-binding protein, is highly expressed and associated with the prognosis of HCC. However, the functions of Gal-3 in HCC cells are not fully understood. To address the function of Gal-3 in HCC cells, we used small interfering RNA (siRNA) to knock down Gal-3 expression in HepG2, an HCC cell line. We found that in vitro the silencing of Gal-3 decreased the proliferative activity, colony formation ability, migratory and invasive potential of HepG2 cells. The silencing of Gal-3 significantly decreased the mRNA and protein levels of urokinase-type plasminogen activator receptor (uPAR) as well as uPAR's downstream signaling transduction pathway, including phosphorylation of AKT. Furthermore, the downregulation of Gal-3 by siRNA resulted in significantly decreased activity of the MEK/ERK signaling pathway, and the treatment of HepG2 cells with MEK/ERK inhibitor U0126 significantly reduced the mRNA and protein levels of uPAR. Taken together, our results suggest that Gal-3 modulates uPAR expression via the MEK/ERK pathway, and that Gal-3 may be a potential therapeutic target for the treatment of HCC.

LPS induced miR-181a promotes pancreatic cancer cell migration via targeting PTEN and MAP2K4.

BACKGROUND: Pancreatic cancer is aggressive; 80-90 % of pancreatic cancer patients have already developed metastatic cancer at the time of diagnosis. Inflammation has been shown to facilitate pancreatic cancer migration. The toll-like receptors (TLRs) pathway is an important inflammatory signal transduction pathway. However, the mechanism of inflammation pathway to induce pancreatic cancer migration is unclear. AIMS: The purpose of this study was to investigate how inflammation affects pancreatic cancer migration. METHODS: RT-PCR was used to detect the TLRs expression files in pancreatic cancer cells and tissues. Pancreatic cancer cells migration was assessed after treatment with TLR4 agonist, lipopolysaccharide (LPS). Moreover, two tumor suppressors, PTEN and MAP2K4, were detected. Then we predicted and proved the miRNA which targeted PTEN and MAP2K4. RESULTS: We found that the expression of TLR4 was increased in pancreatic cancer cells and tissues. After treatment with LPS, the migration of pancreatic cancer cells was increased and the protein levels of two tumor suppressors, PTEN and MAP2K4, were inhibited. To investigate the possible mechanism, we checked the expression of miR-181a. The result showed that miR-181a was decreased by LPS. Furthermore, we predicted and confirmed that both PTEN and MAP2K4 were miR-181a targets. Pancreatic cancer tissues analysis showed that PTEN and MAP2K4 were all negatively correlated with miR-181a. CONCLUSIONS: These results suggest that the LPS-TLR4-miR-181a signaling pathway plays a significant role in pancreatic cancer invasion and progression.

Poly (4-styrenesulfonic acid-co-maleic acid) is an entry inhibitor against both HIV-1 and HSV infections - potential as a dual functional microbicide.

Genital herpes is one of the most prevalent sexually transmitted diseases (STD) caused by herpes simplex viruses type 1 and 2 (HSV-1 and -2). HSV is considered as a major risk factor in human immunodeficiency virus type-1 (HIV-1) infection and rapid progression to acquired immunodeficiency syndrome (AIDS). Here, we reported the finding of a polymer of styrenesulfonic acid and maleic acid (PSM) which exhibited antiviral activity with low cytotoxicity. PSM exhibited in vitro inhibitory activity against HIV-1 pseudovirus and HSV-1 and -2. In vivo efficacy of PSM against HSV-2 (G) was also investigated. We found that both 1% and 5% PSM gels protected mice from HSV-2 vaginal infection and disease progression significantly. Mechanistic analysis demonstrated that PSM was likely an entry inhibitor that disrupted viral attachment to the target cells. In particular, PSM disrupted gp120 binding to CD4 by interacting with the gp120 V3-loop and the CD4-binding site. The in vitro cytotoxicity studies showed that PSM did not stimulate NF-κB activation and up-regulation of proinflammatory cytokine IL-1ß and IL-8 in vaginal epithelial cells. In addition, PSM also showed low adverse effect on the growth of vaginal Lactobacillus strains. PSM is, therefore, a novel viral entry inhibitor and a potential microbicide candidate against both HIV-1 and HSV.

Downregulation of galectin-3 by EGF mediates the apoptosis of HepG2 cells.

Epidermal growth factor (EGF) in high concentrations induces apoptosis of the tumor cells which express high levels of epidermal growth factor receptor. However, the precise mechanism for this induction is not clear. Galectin-3 is the most probable candidate for mediating this effect, as it is known to induce anti-apoptotic activity in a variety of tumor cells exposed to diverse apoptotic stimuli. In this study, we determined whether galectin-3 plays a role in high concentrations of EGF-induced apoptosis of HepG2 cells. We found that EGF in high concentrations led to the growth inhibition of HepG2 cells, which were associated with promotion of cell death. High concentrations of EGF suppressed cytoplasmic expression of galectin-3. Moreover, we demonstrated overexpression of galectin-3 could reduce EGF-induced apoptosis in HepG2 cells. Our study demonstrated for the first time that downregulation of cytoplasmic galectin-3 was essential for high concentrations of EGF-induced apoptosis in HepG2 cells.

GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells.

BACKGROUND: Epidermal growth factor (EGF) signaling is implicated in the invasion and metastasis of hepatoma cells. However, the signaling pathways for EGF-induced motility of hepatoma cells remain undefined. METHODOLOGY/PRINCIPAL FINDINGS: We found that EGF dose-dependently stimulated the migration of human hepatoma cells HepG2, with the maximal effect at 10 ng/mL. Additionally, EGF increased Arf6 activity, and ectopic expression of Arf6 T27N, a dominant negative Arf6 mutant, largely abolish EGF-induced cell migration. Blocking GEP100 with GEP100 siRNA or GEP100-△PH, a pleckstrin homology (PH) domain deletion mutant of GEP100, blocked EGF-induced Arf6 activity and cell migration. EGF also increased ERK and Rac1 activity. Ectopic expression GEP100 siRNA, GEP100-△PH, or Arf6-T27N suppressed EGF-induced ERK and Rac1 activity. Furthermore, blocking ERK signaling with its inhibitor U0126 remarkably inhibited both EGF-induced Rac1 activation as well as cell migration, and ectopic expression of inactive mutant form of Rac1 (Rac1-T17N) also largely abolished EGF-induced cell migration. CONCLUSIONS/SIGNIFICANCE: Taken together, this study highlights the function of the PH domain of GEP100 and its regulated Arf6/ERK/Rac1 signaling cascade in EGF-induced hepatoma cell migration. These findings could provide a rationale for designing new therapy based on inhibition of hepatoma metastasis.

Abba promotes PDGF-mediated membrane ruffling through activation of the small GTPase Rac1.

Abba is a member of the I-BAR-domain protein family that is characterized by a convex-shaped membrane-binding motif. Overexpression of GFP-tagged Abba in murine fibroblasts potentiated PDGF-mediated formation of membrane ruffles and lamellipodia. Immunofluorescent microscopy and pull-down analysis revealed that GFP-Abba colocalized with an active form of Rac1 in the membrane ruffles and enhanced the Rac GTPase activity in response to PDGF stimulation. Further immunoprecipitation assays demonstrated that GFP-Abba bound to both wild-type and constitutively active Rac1 and that the binding to either of the Rac1 forms was significantly enhanced upon PDGF stimulation. On the other hand, an Abba mutant deficient in Rac1 binding failed to promote membrane ruffling and Rac1 activation in response to PDGF. However, the cells overexpressing a truncated mutant carrying the I-BAR domain alone displayed numerous filopodia-like microspikes in a manner independent of growth factors. Also, the Rac-binding activity of the mutant was not affected by PDGF treatment. Our data indicates that the interaction between full-length Abba and Rac1 is implicated in membrane deformation and subjected to a growth factor-mediated regulation through the C-terminal sequence.

Lysophosphatidic acid induces MDA-MB-231 breast cancer cells migration through activation of PI3K/PAK1/ERK signaling.

BACKGROUND: Enhanced motility of cancer cells is a critical step in promoting tumor metastasis. Lysophosphatidic acid (LPA), representing the major mitogenic activity in serum, stimulates migration in various types of cancer cells. However, the underlying signaling mechanisms for LPA-induced motility of cancer cells remain to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that LPA dose-dependently stimulated migration of MDA-MB-231 breast cancer cells, with 10 µM being the most effective. LPA also increased ERK activity and the MEK inhibitor U0126 could block LPA-induced ERK activity and cell migration. In addition, LPA induced PAK1 activation while ERK activation and cell migration were inhibited by ectopic expression of an inactive mutant form of PAK1 in MDA-MB-231 cells. Furthermore, LPA increased PI3K activity, and the PI3K inhibitor LY294002 inhibited both LPA-induced PAK1/ERK activation and cell migration. Moreover, in the breast cancer cell, LPA treatment resulted in remarkable production of reactive oxygen species (ROS), while LPA-induced ROS generation, PI3K/PAK1/ERK activation and cell migration could be inhibited by N-acetyl-L-Cysteine, a scavenger of ROS. CONCLUSIONS/SIGNIFICANCE: Taken together, this study identifies a PI3K/PAK1/ERK signaling pathway for LPA-stimulated breast cancer cell migration. These data also suggest that ROS generation plays an essential role in the activation of LPA-stimulated PI3K/PAK1/ERK signaling and breast cancer cell migration. These findings may provide a basis for designing future therapeutic strategy for blocking breast cancer metastasis.

Lung cancer risk associated with Thr495Pro polymorphism of GHR in Chinese population.

The incidence of lung cancer has been increasing over recent decades. Previous studies showed that polymorphisms of the genes involved in carcinogen-detoxication, DNA repair and cell cycle control comprise risk factors for lung cancer. Recent observations revealed that the growth hormone receptor (GHR) might play important roles in carcinogenesis and Rudd et al. found that the Thr495Pro polymorphism of GHR was strongly associated with lung cancer risk in Caucasians living in the UK (OR = 12.98, P = 0.0019, 95% CI: 1.77-infinity). To test whether this variant of GHR would modify the risk of lung cancer in Chinese population, we compared the polymorphism between 778 lung cancer patients and 781 healthy control subjects. Our results indicate that the frequency of 495Thr (2.8%) allele in cases was significantly higher than in controls (OR = 2.04, P = 0.006, 95% CI: 1.21-3.42) which indicated this allele might be a risk factor for lung cancer. Further analyses revealed Thr495Pro variant was associated with lung cancer in the subpopulation with higher risk for lung cancer: male subpopulation, still-smokers subpopulation and the subpopulation with familial history of cancer. In different histological types of lung cancer, Thr495Pro SNP was significantly associated with small cell and squamous cell lung cancer, but not with adenocarcinoma, which suggested a potential interaction between this polymorphism and metabolic pathways related to smoking. The potential gene-environment interaction on lung cancer risk was evaluated using MDR software. A significant redundant interaction between Thr495Pro polymorphism and smoking dose and familial history of cancer was identified and the combination of genetic factors and smoking status or familial history of cancer barely increased the cancer risk prediction accuracy. In conclusion, our results suggested that the Thr495Pro polymorphism of GHR was associated with the risk of lung cancer in a redundant interaction with smoking and familial history of cancer.

Mxi1-0, an alternatively transcribed Mxi1 isoform, is overexpressed in glioblastomas.

The c-Myc transcription factor regulates expression of genes related to cell growth, division, and apoptosis. Mxi1, a member of the Mad family, represses transcription of c-Myc-regulated genes by mediating chromatin condensation via histone deacetylase and the Sin3 corepressor. Mxi1 is a c-Myc antagonist and suppresses cell proliferation in vitro. Here, we describe the identification of Mxi1-0, a novel Mxi1 isoform that is alternatively transcribed from an upstream exon. Mxi1-0 and Mxi1 have different amino-terminal sequences, but share identical Max- and DNA-binding domains. Both isoforms are able to bind Max, to recognize E-box binding sites, and to interact with Sin3. Despite these similarities and in contrast to Mxi1, Mxi1-0 is predominantly localized to the cytoplasm and fails to repress c-Myc-dependent transcription. Although Mxi1-0 and Mxi1 are coexpressed in both human and mouse cells, the relative levels of Mxi1-0 are higher in primary glioblastoma tumors than in normal brain tissue. This variation in the levels of Mxi1-0 and Mxi1 suggests that Mxi1-0 may modulate the Myc-inhibitory activity of Mxi1. The identification of Mxi1-0 as an alternatively transcribed Mxi1 isoform has significant implications for the interpretation of previous Mxi1 studies, particularly those related to the phenotype of the mxi1 knockout mouse.