PURPOSE: To report the frequency and clinical features of sterile inflammation after intravitreal aflibercept injection in a Korean population. METHODS: A single-center, retrospective study was performed in patients who received intravitreal aflibercept from July 2013 through January 2015. RESULTS: A total of four cases of post-injection sterile inflammation were identified from 723 aflibercept injections in 233 patients. Patients presented 1 to 13 days after intravitreal aflibercept injection (mean, 5 days). The mean baseline visual acuity was 20 / 60, which decreased to 20 / 112 at diagnosis but ultimately recovered to 20 / 60. Three cases had inflammatory cells in the anterior chamber (mean, 2.25+; range, 0 to 4+), and all cases had vitritis (mean, 3+; range, 2+ to 4+). No patients had pain. Only one patient underwent anterior chamber sampling (culture negative) and injection of antibiotics. Three of four patients were treated with a topical steroid, and all experienced improvement in their symptoms and signs of inflammation. CONCLUSIONS: The overall incidence of sterile inflammation after intravitreal aflibercept injection in a Korean population was 4 of 723 injections (0.55%), or 4 of 233 patients (1.79%). Sterile inflammation after intravitreal aflibercept injection typically presents without pain, and the visual outcomes are generally favorable.
Aged ; Aged, 80 and over ; Female ; Follow-Up Studies ; Humans ; Incidence ; Intravitreal Injections ; Macular Edema/*drug therapy/epidemiology ; Male ; Middle Aged ; Receptors, Vascular Endothelial Growth Factor/*administration & dosage ; Recombinant Fusion Proteins/*administration & dosage ; Republic of Korea/epidemiology ; Retrospective Studies ; Treatment Outcome ; Vascular Endothelial Growth Factor A ; Visual Acuity

Impaired tumor necrosis factor receptor-1 (TNFR-1) signaling has been found in some malignant tumors with poor prognosis. However, the exact role of TNFR-1 signaling in fibrosarcoma remains unclear. Here, we explored the question by comparing the growth of TNFR-1 deficient (Tnfr1 (-)) and TNFR-1 competent (Tnfr1 (+)) fibrosarcoma FB61 cells (FB61-m and FB61-R1) in mice. TNFR-1 expression on fibrosarcoma cells delayed their growth in vivo but not in vitro. Moreover, reduced FB61-R1 tumor growth was also obtained in TNFR-1 knockout mice. The mechanism relies mainly on the TNFR-1-mediated downregulation of vascular endothelial growth factor (VEGF) production by tumor cells. Importantly, treatment of FB61-m tumors with melphalan resulted in a short delay of tumor growth, followed by a quick remission. However, when FB61-R1 tumors were treated with melphalan, tumor growth was similarly delayed at first and then completely rejected. Our results reveal evidence for TNFR-1 on tumor cells as a prerequisite in chemotherapy for fibrosarcoma, and provide novel insight into the therapeutic approach against some types of tumors using TNFR-1 angonist.
Animals ; Down-Regulation ; drug effects ; Fibrosarcoma ; drug therapy ; genetics ; pathology ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Melphalan ; administration & dosage ; Mice ; Molecular Targeted Therapy ; Receptors, Tumor Necrosis Factor, Type I ; genetics ; Signal Transduction ; drug effects ; Vascular Endothelial Growth Factor A ; biosynthesis

PURPOSE: To report the results of switching treatment to vascular endothelial growth factor (VEGF) Trap-Eye (aflibercept) in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) refractory to anti-VEGF (ranibizumab and bevacizumab). METHODS: This is a retrospective study involving 32 eyes from 29 patients; 18 were cases of neovascular AMD and 14 were cases of PCV. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of spectral-domain optical coherence tomography were evaluated. RESULTS: BCVA and CMT improved from 0.58 to 0.55 (p = 0.005) and from 404 to 321 microm (p < 0.001), respectively, after switching to aflibercept. The 14 eyes that received 6 or more aflibercept injections remained stable at 0.81 to 0.81 and 321 to 327 microm (p = 1.0, 0.29), respectively, after 3 aflibercept injections. The 10 eyes that received 3 or more bevacizumab injections after 3 or more aflibercept injections worsened, from 0.44 to 0.47 and from 332 to 346 microm (p = 0.06, 0.05), respectively. The results showed similar improvement of BCVA and CMT in neovascular AMD and PCV. CONCLUSIONS: Aflibercept seems to be effective for improvement and maintenance of BCVA and CMT for neovascular AMD and PCV refractory to anti-VEGF. Switching from aflibercept back to bevacizumab treatment may not be a proper strategy.
Angiogenesis Inhibitors/administration & dosage ; Bevacizumab/administration & dosage ; Choroid/*blood supply ; Choroid Diseases/complications/diagnosis/*drug therapy ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Humans ; Intravitreal Injections ; Male ; Ranibizumab/administration & dosage ; Receptors, Vascular Endothelial Growth Factor/*administration & dosage ; Recombinant Fusion Proteins/*administration & dosage ; Retinal Neovascularization/complications/diagnosis/*drug therapy ; Retrospective Studies ; Tomography, Optical Coherence ; Treatment Outcome ; Vascular Endothelial Growth Factor A/*antagonists & inhibitors ; *Visual Acuity ; Wet Macular Degeneration/diagnosis/*drug therapy/etiology

OBJECTIVEBronchopulmonary displasia (BPD) is characterized by decreased alveolar development resulting in large saccular airspaces that are thought to result from the superposition of injury on the developing lung. Inflammation and hyperoxia appear to be the common factors. Preterm delivery is frequently preceded by chorioamnionitis, resulting in exposure of the fetal lung to inflammation. Subsequently, resuscitation with positive-pressure ventilation or supplemental O2 can continue to injure the lungs. Although mechanisms that impair lung growth in BPD are poorly understood, recent studies have shown that disruption of vascular endothelial growth factor (VEGF) function plays a pivotal role in the pathogenesis of BPD. The purpose of this study was to investigate the expression of VEGF and its receptors in premature lungs of rats with intra-amniotic endotoxin priming and/or exposed to 60% O2 and to elucidate the relationship between intrauterine inflammatory/chronic high O2 exposure and the pathogenesis of BPD.

METHODSTimed pregnant Sprague Dawley (SD) rats were randomly divided into two groups: lipopolysaccharide (LPS) group and saline solution group. LPS or saline solution was intra-amniotically injected into the sacs on gestational age day 15 (70% of term). Six days after intra-amniotic injection, the preterm rats of each group were delivered and further randomized to put in 60% O2 exposure or in room air. On days 1, 7 and 14 after birth, the lungs of the rats from both groups were removed and dissected from the main bronchi for analysis. Left lungs of each group were used to assess lung histological changes after hematoxylin and eosin (HE) staining. Total RNA and protein were extracted from the right frozen lung tissues. Lung VEGF and its receptors mRNA and protein levels were measured by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and polypeptides analysis (Western blot).

RESULTS(1) Lung histology revealed striking differences in lung structure in the four experimental groups. Compared with control rat lungs, endotoxin and/or hyperoxia treated groups showed a histological pattern of alveolar simplification characterized by the presence of larger and fewer distal air spaces. To quantify the apparent decreases in alveolar number, radial alveolar counts (RAC) were measured in the four experimental groups: RAC increased along with the lung development from d 1 to d 14 in both control and endotoxin alone groups. However, in endotoxin alone group, RAC was significantly lower than that of controls from d 1 to d 14. In hyeroxia alone group, RAC began to decrease on day 7, and became significantly lower than that of the control group on day 14 (P < 0.05). In endotoxin plus hyperoxia groups, RAC significantly decreased as compared to controls on days 1 and 7, and became significantly lower than those of the other three groups on day 14. (2) Western blotting showed changes in protein content of VEGF164 and its receptor Flk-1 increased from day 1 to day 14 in both control group and endotoxin alone group. However, In endotoxin alone group, they were significantly lower than those of controls from d 1 to d 7 (P < 0.05). Conversely, they decreased from day 1 to day 14 in the other two groups, and were significantly lower than those of the control group on days 7 and 14 in both hyperoxia alone group and endotoxin plus hyperoxia groups. Importantly, the expression of VEGF and its receptor in endotoxin plus hyperoxia group was lower than those of both the hyperoxia alone group and the endotoxin alone group with significant difference. The levels of Flt-1 had obviously an age-dependent increase from day 1 to day 14 in the four experimental groups. (3) The changes of mRNA expression of VEGF and its receptors were basically consistent with the changes on protein expression.

CONCLUSIONSThese results suggest that the intra-amniotic endotoxin and/or hyperoxia can down-regulate expression of VEGF and Flk-1, which may contribute to the pathogenesis of BPD.

Amnion ; chemistry ; Animals ; Animals, Newborn ; Drug Administration Routes ; Endotoxins ; metabolism ; pharmacology ; Female ; Lung ; drug effects ; metabolism ; Oxygen ; metabolism ; Pregnancy ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Vascular Endothelial Growth Factor ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

Gastric cancer overexpressing the human epidermal growth factor 2 (HER2) protein has a poor outcome, although a combination of chemotherapy and the anti-HER2 antibody trastuzumab has been approved for the treatment of advanced gastric cancer. Vascular endothelial growth factor (VEGF) expression in gastric cancer is correlated with recurrence and poor prognosis; however, the anti-VEGF antibody bevacizumab has shown limited efficacy against gastric cancer in clinical trials. In this study, we evaluated the antitumor effects of trastuzumab; VEGF-Trap binding to VEGF-A, VEGF-B and placental growth factor (PlGF); and a combination of trastuzumab and VEGF-Trap in a gastric cancer xenograft model. Although trastuzumab and VEGF-Trap each moderately inhibited tumor growth, the combination of these agents exerted greater inhibition compared with either agent alone. Immunohistochemical analyses indicated that the reduction in tumor growth was associated with decreased proliferation and increased apoptosis of tumor cells and decreased tumor vascular density. The combined treatment resulted in fewer proliferating tumor cells, more apoptotic cells and reduced tumor vascular density compared with treatment with trastuzumab or VEGF-Trap alone, indicating that trastuzumab and VEGF-Trap had additive inhibitory effects on the tumor growth and angiogenesis of the gastric cancer xenografts. These data suggest that trastuzumab in combination with VEGF-Trap may represent an effective approach to treating HER2-overexpressing gastric cancer.
Animals ; Antibodies, Monoclonal, Humanized/administration & dosage/*therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Mice ; Mice, Inbred BALB C ; Neovascularization, Pathologic/drug therapy ; Receptor, erbB-2/*antagonists & inhibitors ; Receptors, Vascular Endothelial Growth Factor/administration & dosage/*therapeutic use ; Recombinant Fusion Proteins/administration & dosage/*therapeutic use ; Stomach Neoplasms/*drug therapy/pathology ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Xenograft Model Antitumor Assays

BACKGROUND: The main symptoms of allergic rhinitis (AR) are sneezing, rhinorrhea and nasal obstruction. It was reported that the nasal skin temperature after intranasal administration of histamine or grass pollen rose. In patients with AR, the levels of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) have increased in nasal fluids and mucosa. OBJECTIVE: The present study were to determine the temperature changes of the nose in rat allergic rhinitis model, and if olopatadine, an antiallergic agent with histamine H1 receptor antagonistic action, proved to be effective, were studied the productions of NGF and VEGF in nasal lavage fluids (NALF). In the present study, we used ovalbumin (OVA)-sensitized rats as an animal model of nasal allergy and examined the effects of olopatadine on the skin temperature of the nose area, and the productions of NGF and VEGF in NALF. METHODS: The temperature changes of the nose area were carried out with thermo tracer in rat passively sensitized with OVA antiserum. The numbers of sneezing episodes were counted and, NGF and VEGF levels in NALF were examined using the specific ELISA. RESULTS: In OVA-sensitized rats, the number of sneezing episodes increase and the nasal skin temperature rise were provoked after OVA challenge. The levels of NGF and VEGF in NALF also were increased. Olopatadine reduced the increased frequency of sneezing and the nasal skin temperature rise. It also inhibited the increased NGF and VEGF productions in NALF. CONCLUSION: The nasal skin temperature after OVA challenge rose even in OVA-sensitized rats. These results suggest that the suppression of the increased NGF and VEGF levels might partially be involved in the improvement of allergy-like behavior (sneezing and nasal skin temperature rise) by the treatment of olopatadine.
Administration, Intranasal ; Animals ; Enzyme-Linked Immunosorbent Assay ; Histamine ; Humans ; Hypersensitivity ; Models, Animal ; Mucous Membrane ; Nasal Lavage Fluid ; Nasal Obstruction ; Nerve Growth Factor ; Nose ; Olopatadine Hydrochloride ; Ovalbumin ; Ovum ; Poaceae ; Pollen ; Rats ; Receptors, Histamine H1 ; Rhinitis ; Rhinitis, Allergic ; Skin Temperature ; Sneezing ; Thermography ; Vascular Endothelial Growth Factor A

AIM: To investigate the anticancer activity of DT-13 under normoxia and determine the underlying mechanisms of action. METHODS: MDA-MB-435 cell proliferation, migration, and adhesion were performed to assess the anticancer activity of DT-13, a saponin from Ophiopogon japonicus, in vitro. In addition, the effects of DT-13 on tumor growth and metastasis in vivo were evaluated by orthotopic implantation of MDA-MB-435 cells into nude mice; mRNA levels of vascular endothelial growth factor (VEGF), C-C chemokine receptor type 5 (CCR5) and hypoxia-inducible factor 1α (HIF-1α) were evaluated by real-time quantitative PCR; and CCR5 protein levels were detected by Western blot assay. RESULTS: At 0.01 to 1 μmol·L(-1), DT-13 inhibited MDA-MB-435 cell proliferation, migration, and adhesion significantly in vitro. DT-13 reduced VEGF and CCR5 mRNAs, and decreased CCR5 protein expression by down-regulating HIF-1α. In addition, DT-13 inhibited MDA-MB-435 cell lung metastasis, and restricted tumor growth slightly in vivo. CONCLUSION DT-13 inhibited MDA-MB-435 cell proliferation, adhesion, and migration in vitro, and lung metastasis in vivo by reducing VEGF, CCR5, and HIF-1α expression.
Animals ; Antineoplastic Agents, Phytogenic ; administration & dosage ; Breast Neoplasms ; drug therapy ; genetics ; metabolism ; physiopathology ; CCR5 Receptor Antagonists ; Cell Adhesion ; drug effects ; Cell Line, Tumor ; Cell Movement ; drug effects ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Liriope Plant ; chemistry ; Mice ; Mice, Nude ; Plant Tubers ; chemistry ; Receptors, CCR5 ; genetics ; metabolism ; Saponins ; administration & dosage ; Vascular Endothelial Growth Factor A ; antagonists & inhibitors ; genetics ; metabolism

OBJECTIVETo assess the effect of endostatin on growth and neoplastic angiogenesis in transplanted human lung adenocarcinoma Calu-6 tumor in nude mice.

METHODSTo treat Calu-6 tumor-bearing mice with endostatin at different doses, and to record the changes of the tumor size. The expressions of survivin, VEGF, COX-2 and MVD in tumor tissue were examined by immunohistochemistry staining, circulating endothelial cells (CECs) by flow cytometry and mRNA of CD146 and CD105 by RT-PCR and real-time PCR.

RESULTSAfter endostatin treatment, the tumor size was conspicuously shrunk, and the expressions of survivin, COX-2 and VEGF protein and MVD in tumor tissue decreased concomitantly with the significant difference between each of trial groups and control group (all P < 0.05). Both CECs and mRNA of CD146 and CD105 diminished remarkably. A positive correlation between both exhibition and change of amount of activated CECs and survivin, VEGF expression and MVD count in tumor tissue was found.

CONCLUSIONEndostatin can decrease the expression of survivin, COX-2, VEGF and MVD, and to inhibit the growth of transplanted tumor. Activated CECs may probably serve as an ideal marker to predict the efficacy and prognosis of anti-angiogenesis therapy.

Adenocarcinoma ; pathology ; Angiogenesis Inhibitors ; administration & dosage ; pharmacology ; Animals ; Antigens, CD ; metabolism ; Antineoplastic Agents ; administration & dosage ; pharmacology ; CD146 Antigen ; metabolism ; Cell Line, Tumor ; Cyclooxygenase 2 ; metabolism ; Dose-Response Relationship, Drug ; Endoglin ; Endostatins ; administration & dosage ; pharmacology ; Endothelial Cells ; pathology ; Female ; Humans ; Inhibitor of Apoptosis Proteins ; Lung Neoplasms ; metabolism ; pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microtubule-Associated Proteins ; metabolism ; Microvessels ; pathology ; Neoplasm Transplantation ; RNA, Messenger ; metabolism ; Random Allocation ; Receptors, Cell Surface ; metabolism ; Tumor Burden ; drug effects ; Vascular Endothelial Growth Factor A ; metabolism

Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in several pathological processes of cardiovascular diseases. In this study, the effects of XCT790, a potent and selective inverse agonist of estrogen-related receptor alpha (ERRalpha), on rat VSMCs proliferation and related signal pathways were investigated. The proliferative activity of VSMCs was determined by CCK-8 assay. The mRNA levels of ERRalpha, PGC-1alpha, OPN and MCAD were assayed by RT-PCR. The protein levels of ERRalpha, ERK2 and p-ERK1/2 were evaluated by Western blotting. ELISA was used to assess the protein expression of VEGF. The results showed that XCT790 (5-20 micromol x L(-1)) inhibited rat VSMCs proliferation, and the expression of ERRalpha and its target genes, as well as p-ERK1/2, were also inhibited. XCT790 inhibited VSMCs proliferation in a dose-dependent manner at the dose range from 5 to 20 micromol x L(-1) and in a time-dependent manner at the dose range from 10 to 20 micromol x L(-1). These findings demonstrate that XCT790 inhibits rat VSMCs proliferation by down-regulating the gene level of ERRalpha and thus inhibiting the ERK signal pathway, suggesting that ERRalpha may be a novel potential target for therapeutic approaches to inhibit VSMCs proliferation, which plays an important role in several cardiovascular diseases.
Animals ; Cadherins ; genetics ; metabolism ; Cell Proliferation ; drug effects ; Cells, Cultured ; Cytoskeletal Proteins ; genetics ; metabolism ; Dose-Response Relationship, Drug ; GTPase-Activating Proteins ; genetics ; metabolism ; MAP Kinase Signaling System ; Male ; Muscle, Smooth, Vascular ; cytology ; Myocytes, Smooth Muscle ; cytology ; drug effects ; metabolism ; Nitriles ; administration & dosage ; pharmacology ; Nuclear Proteins ; genetics ; metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Phosphorylation ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Estrogen ; genetics ; metabolism ; Thiazoles ; administration & dosage ; pharmacology ; Transcription Factors ; genetics ; metabolism ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

OBJECTIVETo investigate the effects of SOM230, a new somatostatin analogue, on the proliferation of hepatocellular carcinoma (HCC) cell line HepG2 in vitro and in vivo, and explore the mechanism underline the necrosis of tumors.

METHODSMTT, TdT-mediated dUTP nick end labeling assay (TUNEL) and flow cytometric assay were used to measure the effects of SOM230 on the proliferation and apoptosis of HCC HepG2 cells. Nude mice bearing HCC xenografts of the HepG2 cell line were treated with SOM230 (100 microg/kg/d subcutaneously injection) and saline as a control for eight weeks. The mass and percentage of necrotic volume of the HCC xenografts in nude mice were determined. Western blot was used to detect SSTR2 in HCC xenografts. Immunohistochemical method was used to detect the expression sites of SSTR2 and VEGF in HCC xenografts. ELISA was used to detect the levels of TNFalpha.

RESULTSNo proliferation and apoptosis of HepG2 cells were induced by SOM230 in vitro (F = 0.16, P more than 0.05). The percentage of necrotic volume in SOM230 were significantly higher than that of control group (73.4%+/-7.0% vs 30.2%+/-14.0%, t = -8.02, P more than 0.01). SSTR2 was expressed in blood sinus of HCC xenografts in nude mice. There was no significance difference in the level of SSTR2 expression between SOM230 group and saline treated group. VEGF expression in xenografts was down-regulated by SOM230 treatment. SOM230 treatment did not affect the level of TNFalpha in HCC xenografts (t = -0.24, P more than 0.05).

CONCLUSIONSSOM230 can induce massive necrosis of HCC xenografts only after the blockage of blood flow through down-regulation of VEGF mediated by SSTR2.

Animals ; Antineoplastic Agents ; administration & dosage ; pharmacology ; Carcinoma, Hepatocellular ; blood supply ; metabolism ; pathology ; Cell Proliferation ; drug effects ; Disease Models, Animal ; Flow Cytometry ; Gene Expression Regulation, Neoplastic ; Hep G2 Cells ; Humans ; Immunohistochemistry ; Injections, Subcutaneous ; Liver Neoplasms ; blood supply ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Random Allocation ; Receptors, Somatostatin ; metabolism ; Somatostatin ; administration & dosage ; analogs & derivatives ; pharmacology ; Vascular Endothelial Growth Factor A ; metabolism ; Xenograft Model Antitumor Assays