Neutralization of IL-18 by IL-18 binding protein ameliorates bleomycin-induced pulmonary fibrosis via inhibition of epithelial-mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a fatal parenchymal lung disease with limited effective therapies. Interleukin (IL)-18 belongs to a rather large IL-1 gene family and is a proinflammatory cytokine, which acts in both acquired and innate immunity. We have previously reported that IL-18 play an important role in lipopolysaccharide-induced acute lung injury in mice. Persistent inflammation often drives fibrotic progression in the bleomycin (BLM) injury model. However, the role of IL-18 in pulmonary fibrosis (PF) is still unknown. IL-18 binding protein (IL-18BP) is able to neutralize IL-18 biological activity and has a protective effect against renal fibrosis. The aim of this study was to investigate the effects of IL-18BP on BLM-induced PF. In the present study, we found that IL-18 was upregulated in lungs of BLM-injured mice. Neutralization of IL-18 by IL-18BP improved the survival rate and ameliorated BLM-induced PF in mice, which was associated with attenuated pathological changes, reduced collagen deposition, and decreased content of transforming growth factor-ß1 (TGF-ß1). We further demonstrated that IL-18BP treatment suppressed the BLM-induced epithelial mesenchymal transition (EMT), characterized by decreased α-smooth muscle actin (α-SMA) and increased E-cadherin (E-cad) in vivo. In addition, we provided in vitro evidence demonstrating that IL-18 promoted EMT through upregulation of Snail-1 in A549 cells. In conclusion, our findings raise the possibility that the increase of IL-18 is involved in the development of BLM-induced PF through modulating EMT in a Snail-1-dependent manner. IL-18BP may be a worthwhile candidate option for PF therapy.

Interleukin-18 binding protein attenuates lipopolysaccharide-induced acute lung injury in mice via suppression NF-κB and activation Nrf2 pathway.

Interleukin (IL)-18 belongs to a rather large IL-1 gene family and is a proinflammatory cytokine. IL-18 plays important roles in lung injury. IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, binds IL-18 with high affinity. IL-18BP is able to neutralize IL-18 biological activity and has a protective effect against renal fibrosis. The aim of this study was to evaluate the potential protective effect of IL-18BP on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms. Results indicated that pretreatment with IL-18BP significantly attenuated LPS-induced pulmonary pathological injury. Meanwhile, IL-18BP pretreatment markedly inhibited infiltration of inflammatory cell and release of inflammatory factor in ALI mice in vivo and in primary macrophages after LPS insult in vitro. IL-18BP treatment dramatically reduced oxidative stress through increasing superoxide dismutase (SOD) and glutathione (GSH) contents, and decreasing the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in LPS-induced ALI mice and primary macrophages. Additionally, IL-18BP was also observed to markedly decreased the activation of nuclear factor-kappa B (NF-κB) and upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, IL-18BP possessed protective effect against LPS-induced ALI, which might be associated with its regulation of NF-κB and Nrf2 activities. The results rendered IL-18BP worthy of further development into a pharmaceutical drug for the treatment of ALI.

BMP9 inhibits the bone metastasis of breast cancer cells by downregulating CCN2 (connective tissue growth factor, CTGF) expression.

Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-ß superfamily, regulate a wide range of cellular responses including cell proliferation, differentiation, adhesion, migration, and apoptosis. BMP9, the latest BMP to be discovered, is reportedly expressed in a variety of human carcinoma cell lines, but the role of BMP9 in breast cancer has not been fully clarified. In a previous study, BMP9 was found to inhibit the growth, migration, and invasiveness of MDA-MB-231 breast cancer cells. In the current study, the effect of BMP9 on the bone metastasis of breast cancer cells was investigated. After absent or low expression of BMP9 was detected in the MDA-MB-231 breast cancer cells and breast non-tumor adjacent tissues using Western blot and immunohistochemistry, In our previous study, BMP9 could inhibit the proliferation and invasiveness of breast cancer cells MDA-MB-231 in vitro and in vivo. This paper shows that BMP9 inhibit the bone metastasis of breast cancer cells by activating the BMP/Smad signaling pathway and downregulating connective tissue growth factor (CTGF); however, when CTGF expression was maintained, the inhibitory effect of BMP9 on the MDA-MB-231 cells was abolished. Together, these observations indicate that BMP9 is an important mediator of breast cancer bone metastasis and a potential therapeutic target for treating this deadly disease.

[Clinical analysis of 42 cases of chronic expanding intracerebral hematoma].

OBJECTIVE: To summarize our own experiences of managing chronic expanding intracerebral hematoma (CEICH) and discuss its diagnosis and treatment. METHODS: The courses of CEICH, clinical and imaging features, intraoperative findings, pathological examinations and follow-up outcomes were reviewed retrospectively. The relevant literatures were reviewed simultaneously. RESULTS: The course of CEICHs ranged from 22 days to 10 years. Twenty-three cases (54.8%) were misdiagnosed as cystic gliomas, cystic gliomas, brain cysticercoses, brain abscesses and tumor strokes, etc. The misdiagnostic rate had decreased to 19.0% since June 1997. Thirty-eight patients underwent surgical operations and 4 had puncture drainage of hematoma. There was no operative death. Thirty-three cases achieved an excellent recovery and 9 cases had varying degrees of nervous dysfunctions. The follow-up period was 1-21 years. One patient had recurrence after 10 years. Among the cases of multiple CEICH, two lesions underwent no surgical treatment. One increased obviously after 7 years and another disappeared. CONCLUSION: The following five points may be used as the diagnostic criteria of CEICH: (1) intracerebral cystic space-occupying lesions on brain images; (2) circular or circle-like enhancement around lesions; (3) a mixed signal of concentric circular lamellar structures on MRI T1WI; (4) abnormal vascular lesions on CTA, MRA or DSA; (5) clinical signs and symptoms of slow progress of intracranial pressure. CEICHs with clinical symptoms of local mass effect shall be obliterated surgically. The abnormal tissues in cyst wall of hematoma should be resected. Small hematomas (< 2 cm) may be followed up.

[Rapid pore cranial drilling and ventricular drainage in the treatment of ventricular hemorrhage caused by thalamic hemorrhage: an analysis of 401 cases].

OBJECTIVE: To summarize the clinical efficacies and experiences of using rapid pore cranial drilling and external ventricular drainage (EVD) in the treatment of ventricular hemorrhage caused by thalamic hemorrhage. METHODS: Retrospective analysis was conducted for 401 patients at 5 hospitals from May 1983 to December 2010. They underwent EVD with an infusion of urokinase for intraventricular hemorrhage caused by thalamic hemorrhage. There were 212 males and 189 females with an age range of 19 - 78 years. RESULTS: After a 1-month therapy, the outcomes were cure 147/401 (36.7%), improvement 192/401 (47.9%) and others (death and against-advice discharge) 62/401 (15.4%). After 1-3-month treatment, their prognoses were evaluated by activity of daily living (ADL): ADLI 147/401, ADLII 82/401, ADLIII 76/401, ADLIV 19/401, ADLV 15/401, death 43/401 and against-advice discharge 19/401. During a follow-up period of 1 - 3 years, 274 patients showed the following outcomes: ADLI 122/243, ADLII 63/243, ADLIII 58/243 while 31 patients died from pulmonary infection. CONCLUSION: The procedure of EVD (including an infusion of urokinase) with rapid pore cranial drilling is preferred treatment for ventricular hemorrhage caused by thalamic hemorrhage.

[Clinical experiences of normal saline pressed injection via lumbar puncture in the treatment of apnea due to acute tonsillar hernia].

OBJECTIVE: To summarize the clinical experiences of normal saline pressed injection via lumbar puncture in the treatment of acute tonsillar hernia induced apnea. This procedure was routinely carried out after external ventricular drainage and/or lesion removal via open craniotomy. METHODS: During the period of 1969 to 2005, a total of 43 patients failed to regain respiratory after external ventricular drainage using rapid small hole cranio-puncture apparatus or lesion removal via open craniotomy. They underwent lumbar puncture and normal saline was pressed injected via a lumbar puncture needle. The patient data were retrospectively analyzed. RESULTS: Eleven of 43 patients had spontaneous respiration and fully recovered (25.6%), 16 patients regained respiration but died eventually (37.2%) and 16 patients failed to regain respiration (37.2%). The effective rate was 62.8%. CONCLUSION: For the patients failing to regain respiration after external ventricular drainage or supratentorial lesion removal via open craniotomy, the conservative treatment should not be the first choice. The pressed injection of normal saline via lumbar puncture may rescue some patients.

Maternal oral contraceptive pill use and the risk of atopic diseases in the offspring: A systematic review and meta-analysis.

Studies of maternal oral contraceptive pill (OCP) exposure and the offspring's risk of atopic diseases are of current interest due to concerns about widespread use of OCP before or during pregnancy.We evaluated whether maternal OCP exposure is associated with an increased risk of atopic diseases by reviewing the literature and performing a meta-analysis. The PubMed and Embase databases were searched to identify potential studies for inclusion. Three common atopic outcomes were included: asthma, eczema, and rhinitis.We found 693 titles, abstracts, and citations, and 6 studies were included in this analysis. A meta-analysis revealed that maternal OCP exposure was associated with higher odds of asthma (odds ratio [OR] 1.1; 95% confidence interval [CI] 1.02-1.19; P = .014), rhinitis (OR 1.34; 95% CI 1.07-1.68; P = .011) during childhood, whereas there was no association with eczema (OR 1.17; 95% CI 0.81-1.68; P = .383). This analysis was limited by the small number of studies included and the limited adjustments for the possible confounders in the studies.Current evidence suggests that maternal OCP exposure increases the risk for respiratory allergic diseases (asthma and rhinitis) in the offspring, but not for eczema. Given the few studies included, future larger, prospective studies that control for important confounders are needed to verify our findings.

Interleukin-18 promotes fibroblast senescence in pulmonary fibrosis through down-regulating Klotho expression.

Idiopathic pulmonary fibrosis (IPF) is a lethal disease of unknown aetiology that largely presents in the elderly. The mechanisms related to aging such as fibroblast senescence have been strongly implicated in pathology of IPF. We have previously demonstrated the protective effects of IL-18 binding protein (IL-18BP) against bleomycin (BLM)-induced pulmonary fibrosis (PF) via inhibition of epithelial-to-mesenchymal transition. However, the role of IL-18 in fibroblast senescence in PF is still unknown. The aim of this study was to investigate the effects of IL-18 on fibroblast senescence in the development of PF. We found that SA-ß-gal positive cells, the proportion of cells in G1 phase, and expressions of p21 and p53 were increased in primary lung fibroblasts isolated from BLM-challenged mice, while the fibroblasts from IL-18BP-treated mice showed decreased senescence propensity. We further demonstrated that IL-18 was sufficient to trigger senescence of primary lung fibroblasts. The senescence-associated secretory phenotype (SASP) of fibroblasts treated with IL-18 robustly stimulated a fibrotic phenotype in pulmonary fibroblasts. Moreover, the expression of Klotho, an anti-senescence protein, was down-regulated after IL-18 treatment in primary lung fibroblasts. Overexpression of Klotho reversed the senescence and SASP induced by IL-18 in lung fibroblasts. In summary, we reported for the first time that IL-18 promoted the lung fibroblast senescence and SASP in PF through blocking Klotho pathway. Neutralize IL-18 by IL-18BP exhibited antifibrotic effects partly by suppressing lung fibroblast senescence in PF. It contributes to the growing evidence that IL-18 could be a therapeutic target for PF.

Human Exposure to Ferret Badger Rabies in Taiwan.

On 17 July 2013, Taiwan confirmed multiple cases of the rabies virus (RABV) in the wild Taiwan Ferret badger (TFB) (Melogale moschata) member of the family Mustelidae. This study aims at investigating the risk factors for human exposure to rabid TFBs. Statistical inference based on Pearson correlation showed that there was a strong positive correlation between the total number of positive TFB rabies cases and the number of rabid TFBs involved with human activities in 81 enzootic townships (r = 0.91; p < 0.001). A logistic regression analysis indicated that the risk probability of a human being bitten by rabid TFBs was significantly higher when there were no dogs around (35.55% versus 6.17% (indoors, n = 171, p = 0.0001), and 52.00% versus 5.26% (outdoors, n = 44, p = 0.021)), and whether or not there was a dog around was the only crucial covariate that was statistically significantly related to the risk of a human being bitten. In conclusion, this study showed the value of having vaccinated pets as a deterrent to TFB encounters and as a buffer to prevent human exposure to rabid TFBs. The presence of unvaccinated pets could become a significant risk factor in the longer term if rabies isn’t controlled in TFBs because of the spillover between the sylvatic and urban cycles of rabies. Consequently, raising dogs, as well as keeping rabies vaccinations up-to-date for them, can be considered an effective preventive strategy to reduce the risk for human exposure to rabid TFBs.

DNALK2 inhibits the proliferation and invasiveness of breast cancer MDA-MB-231 cells through the Smad-dependent pathway.

Breast cancer is one of the most common malignant neoplasms diagnosed in females worldwide. Bone morphogenetic proteins (BMPs), which belong to the TGF-ß superfamily, regulate a wide range of cellular responses including cell proliferation, differentiation, adhesion, migration and apoptosis in breast cancer. BMPs can bind to type I and II serine/threonine kinase receptors to regulate cell proliferation, invasion, migration, and apoptosis. Type I receptors are expressed in various breast cancer cell lines and primary tumor samples. Activin­like kinase 2 (ALK2) is generally expressed in breast cancer cells (MDA-MB-231, MCF7, SK-BR-3 and MDA-MB­468); however, the effect of ALK2 on the proliferation and metastasis of breast cancer cells remains unknown. We used a dominant-negative mutant of ALK2 to research the function of ALK2. We aimed to ascertain whether dominant-negative mutant ALK2 adenovirus vector (DNALK2) receptors can compete with wild-type ALK2 receptors. The present study showed that DNALK2 inhibited the growth, migration and metastasis of breast cancer cells by inhibiting the SMAD-dependent pathway and downregulating connective tissue growth factor and inhibitor of differentiation 1 expression, in vivo and in vitro. These observations indicate that ALK2 is a potential therapeutic agent for the treatment of breast cancer.

Cranioplasty with autogenous bone flaps cryopreserved in povidone iodine: a long-term follow-up study.

OBJECTIVE The aim of this study was to investigate the long-term therapeutic efficacy of cranioplasty with autogenous bone flaps cryopreserved in povidone iodine and explore the risk factors for bone resorption. METHODS Clinical data and follow-up results of 188 patients (with 211 bone flaps) who underwent cranioplasty with autogenous bone flaps cryopreserved in povidone-iodine were retrospectively analyzed. Bone flap resorption was classified into 3 types according to CT features, including bone flap thinning (Type I), reduced bone density (Type II), and osteolysis within the flaps (Type III). The extent of bone flap resorption was graded as mild, moderate, or severe. RESULTS Short-term postoperative complications included subcutaneous or extradural seroma collection in 19 flaps (9.0%), epidural hematoma in 16 flaps (7.6%), and infection in 8 flaps (3.8%). Eight patients whose flaps became infected and had to be removed and 2 patients who died within 2 years were excluded from the follow-up analysis. For the remaining 178 patients and 201 flaps, the follow-up duration was 24-122 months (mean 63.1 months). In 93 (46.3%) of these 201 flaps, CT demonstrated bone resorption, which was classified as Type I in 55 flaps (59.1%), Type II in 11 (11.8%), and Type III in 27 (29.0%). The severity of bone resorption was graded as follows: no bone resorption in 108 (53.7%) of 201 flaps, mild resorption in 66 (32.8%), moderate resorption in 15 (7.5%), and severe resorption in 12 (6.0%). The incidence of moderate or severe resorption was higher in Type III than in Type I (p = 0.0008). The grading of bone flap resorption was associated with the locations of bone flaps (p = 0.0210) and fragmentation (flaps broken into 2 or 3 fragments) (p = 0.0009). The incidence of bone flap collapse due to bone resorption was higher in patients who underwent ventriculoperitoneal (VP) shunt implantation than in those who did not (p = 0.0091). CONCLUSIONS Because of the low incidence rates of infection and severe bone resorption, the authors conclude that cranioplasty with autogenous bone flaps cryopreserved in povidone-iodine solution is safe and effective. The changes characteristic of bone flap resorption became visible on CT scans about 2 months after cranioplasty and tended to stabilize at about 18 months postoperatively. The bone resorption of autogenous bone flap may be classified into 3 types. The rates of moderate and severe resorption were much higher in Type III than in Type I. The grade of bone flap resorption was associated with bone flap locations. Fragmented bone flaps or those implanted in patients treated with VP shunts may have a higher incidence of bone flap collapse due to bone resorption.

Application of contrast-enhanced T1-weighted MRI-based 3D reconstruction of the dural tail sign in meningioma resection.

OBJECT The goal of this study was to investigate the significance of contrast-enhanced T1-weighted (T1W) MRI-based 3D reconstruction of dural tail sign (DTS) in meningioma resection. METHODS Between May 2013 and August 2014, 18 cases of convexity and parasagittal meningiomas showing DTS on contrast-enhanced T1W MRI were selected. Contrast-enhanced T1W MRI-based 3D reconstruction of DTS was conducted before surgical treatment. The vertical and anteroposterior diameters of DTS on the contrast-enhanced T1W MR images and 3D reconstruction images were measured and compared. Surgical incisions were designed by referring to the 3D reconstruction and MR images, and then the efficiency of the 2 methods was evaluated with assistance of neuronavigation. RESULTS Three-dimensional reconstruction of DTS can reveal its overall picture. In most cases, the DTS around the tumor is uneven, whereas the DTS around the dural vessels presents longer extensions. There was no significant difference (p > 0.05) between the vertical and anteroposterior diameters of DTS measured on the contrast-enhanced T1W MR and 3D reconstruction images. The 3D images of DTS were more intuitive, and the overall picture of DTS could be revealed in 1 image, which made it easier to design the incision than by using the MR images. Meanwhile, assessment showed that the incisions designed using 3D images were more accurate than those designed using MR images (ridit analysis by SAS, F = 7.95; p = 0.008). Pathological examination showed that 34 dural specimens (except 2 specimens from 1 tumor) displayed tumor invasion. The distance of tumor cell invasion was 1.0-21.6 mm (5.4 ± 4.41 mm [mean ± SD]). Tumor cell invasion was not observed at the dural resection margin in all 36 specimens. CONCLUSIONS Contrast-enhanced T1W MRI-based 3D reconstruction can intuitively and accurately reveal the size and shape of DTS, and thus provides guidance for designing meningioma incisions.

[Effect of Recombinant Adenovirus AdE-SH2-Caspase 8 on the Apoptosis of Imatinib-resistant K562/G01 Cell Line].

OBJECTIVE: To investigate the effect of SH2-Caspase 8 fusion protein expressed by recombinant adenovirus AdE-SH2-Caspase8-HA-GFP (SC) on the apoptosis of K562/G01 cell line, which is a BCR/ABL positive chronic myeloid leukemia cell line and resistant to imatinib. METHODS: The K562/G01 cell line was infected with AdE-SH2-Caspase 8-HA-GFP adenovirus (SC), then the cells were divided into 3 groups: AdE-SH2m-Caspase 8-HA-GFP (SmC) group, AdE-GFP (CMV) group and PBS group as control. The infection efficiency was observed under fluorescent microscopy and by flow cytometry. The expression of fusion protein SH2-Caspase 8-HA was measured by Western blot. The morphology of the cells detected by Wright's staining. The apoptosis of the cells were detected by flow cytometry and DNA ladder. The expression of Caspase 3 and PARP were detected by Western blot. RESULT: The infection efficiency of SC on K562/G01 cells was high which was confirmed by fluorescent microscopy and FCM. SH2-Caspase 8-HA fusion protein were expressed correctly in K562/G01 cells. After treatment with SC the apoptosis of K562/G01 cells could be observed by microscopy. The result of FCM showed that early apoptosis of K562/G01 cells increased significantly as compared with control groups (P < 0.05). DNA ladder showed that the classic DNA ladders appeared in K562/G01 cells after treatment with SC. The wester blot detection showed that the expression level of apoptosis-related protein Caspase 3 and PARP increased. CONCLUSION: The recombinant adenovirus SC expressing SH2-Caspase 8 fusion protein can induces the apoptosis of K562/G01 cells.

Rapid Pore Cranial Drilling With External Ventricular Drainage for Treatment of Intraventricular Hemorrhage: A 36-Year Case Series.

This study aimed to describe the technique details of rapid pore cranial drilling with external ventricular drainage and document its clinical outcomes by highlighting the advantages over the traditional and modified cranial drilling technique. Intraventricular hemorrhage is one of the most severe subtypes of hemorrhagic stroke with high mortality. The amount of blood in the ventricles is associated with severity of outcomes, and fast removal of the blood clot is the key to a good prognosis. Between 1977 and 2013, 3773 patients admitted for intraventricular hemorrhage underwent rapid pore cranial drilling drainage. The therapeutic effects and clinical outcomes were retrospectively analyzed. Of these patients, 1049 (27.8%) experienced complete remission, 1788 (47.4%) had improved condition, and 936 (24.8%) died. A total of 3229 (85.6%) patients gained immediate remission. One typical case was illustrated to demonstrate the efficacy of the rapid pore drilling technique. Rapid pore cranial drilling drainage in patients with intraventricular hemorrhage is fast, effective, and provides immediate relief in patients with severe conditions. It could be a better alternative to the conventional drilling approach for treatment of intraventricular hemorrhage. A randomized controlled trial for direct comparison between the rapid pore cranial drilling drainage and conventional drilling technique is in urgent need.

Normal saline injection via lumbar puncture for the treatment of acute tonsillar herniation: a report of 45 cases.

OBJECTIVE: Current treatment of apnea attributable to acute tonsillar herniation often is inadequate. This study was undertaken to verify the clinical usefulness of normal saline injection via lumbar puncture for the treatment of apnea secondary to acute tonsillar herniation. METHODS: Between 1969 and 2009, 45 patients who had not regained spontaneous respiratory function after external ventricular drainage or removal of a supratentorial lesion via open craniotomy received an injection of normal saline via lumbar puncture. Patient data were retrospectively analyzed. RESULTS: Eleven of the 45 patients regained spontaneous breathing and recovered fully (24.4%). Sixteen patients regained spontaneous breathing but died later (35.6%), and 18 patients did not regain spontaneous respiration (40.0%). The overall rate of effectiveness of injected normal saline was therefore 60.0%. CONCLUSION: For patients with tonsillar hernia who did not regain spontaneous respiration after external ventricular drainage or removal of a supratentorial lesion, an aggressive approach may be considered. Injection of normal saline via lumbar puncture could improve outcome in some of these patients.

BMP9 regulates cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells.

PURPOSE: Breast cancer cells frequently metastasize to distant organs, including bone. Interactions between breast cancer cells and the bone microenvironment are known to enhance tumor growth and osteolytic damage. Here we investigated whether BMP9 (a secretary protein) may change the bone microenvironment and, by doing so, regulate the cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells. METHODS: After establishing a co-culture system composed of MDA-MB-231 breast cancer cells and HS-5 bone marrow-derived mesenchymal stem cells, and exposure of this system to BMP9 conditioned media, we assessed putative changes in migration and invasion capacities of MDA-MB-231 cells and concomitant changes in osteogenic marker expression in HS-5 cells and metastases-related genes in MDA-MB-231 cells. RESULTS: We found that BMP9 can inhibit the migration and invasion of MDA-MB-231 cells, and promote osteogenesis and proliferation of HS-5 cells, in the co-culture system. We also found that the BMP9-induced inhibition of migration and invasion of MDA-MB-231 cells may be caused by a decreased RANK ligand (RANKL) secretion by HS-5 cells, leading to a block in the AKT signaling pathway. CONCLUSIONS: From our data we conclude that BMP9 inhibits the migration and invasion of breast cancer cells, and promotes the osteoblastic differentiation and proliferation of bone marrow-derived mesenchymal stem cells by regulating cross-talk between these two types of cells through the RANK/RANKL signaling axis.

BMP9 inhibits proliferation and metastasis of HER2-positive SK-BR-3 breast cancer cells through ERK1/2 and PI3K/AKT pathways.

Bone morphogenetic protein 9 (BMP9), a member of TGF-ß superfamily, is reported to inhibit the growth and migration of prostate cancer, osteosarcoma and triple-negative MDA-MB-231 breast cancer cells. However, little is known about the effect of on the biological behaviors of HER2-positive SK-BR-3 breast cancer cells and the underlying mechanisms. This study aimed to investigate the effects of BMP9 on the proliferation and metastasis of SK-BR-3 cells with BMP9 over-expression or BMP9 down-regulated expression. Results indicated that exogenously expressed BMP9 inhibited the proliferation and metastasis of SK-BR-3 cells while decreased endogenous BMP9 expression in SK-BR-3 cells promoted the proliferation and migration of breast cancer cells in vitro and in vivo. In SK-BR-3 cells with BMP9 over-expression, the phosphorylation of HER2, ERK1/2 and AKT was markedly suppressed and the HER2 expression decreased at both mRNA and protein levels, while opposite results were observed in SK-BR-3 cells with BMP9 knock down. When the phosphorylation of ERK1/2 and PI3K/AKT was inhibited by PD98059 and LY294002, respectively, the decreased proliferation and invasion induced by BMP9 knock down were eliminated. These findings suggest that BMP9 can inhibit the proliferation and metastasis of SK-BR-3 cells via inactivating ERK1/2 and PI3K/AKT signaling pathways. Thus, BMP9 may serve as a useful agent in the treatment of HER-2 positive breast cancer.

The values of thin sections and three-dimensional reconstruction in the sellar region.

OBJECTIVE: The computerized freezing milling technique is derived from the virtual human project. It has been widely used in three-dimensional (3D) reconstruction of the human body and organs. With this technique, the study was undertaken to explore the 3D features and adjacent anatomic relationships of the sellar region for skull base surgery. METHODS: Continuous thin sections on the coronary plane were performed with the computerized freezing milling technique using a human head specimen. The related structures were described in six sections. After segmenting, labeling, and extracting in serial sections, the 3D reconstruction of the sellar region was finished with Amira 4.1 software. RESULTS: A total of 390 thin coronary sections were obtained. In six sections, the anatomic relationships of the pituitary gland, carotid artery, sphenoid sinus, and nerves are displayed. Three-dimensional images of the sellar region are video films that continuously and dynamically display anatomic structures in 3D space at different velocities. It can show that the cavernous segment of the internal carotid artery is located anterolateral to the sphenoid sinus and lateral to the pituitary gland. The optic nerve protrudes into the superolateral portion of the sphenoid sinus. CONCLUSIONS: The combination of coronary sectional anatomy and 3D reconstruction can display the anatomic characteristics of the sellar region. The 3D models are video films that continuously and dynamically display anatomic structures in 3D space at different velocities.