Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins alphanubeta3, alpha4, beta1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1alpha to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.
Angiogenesis Inducing Agents ; Animals ; Blood Vessels ; Brain ; Brain Injuries* ; Brain Ischemia ; Capillaries ; Cartilage Oligomeric Matrix Protein ; Cell Membrane ; Cell- and Tissue-Based Therapy ; Fetal Blood ; Human Umbilical Vein Endothelial Cells ; Humans ; Integrins ; Ischemia ; Morphogenesis ; Rats ; Salvage Therapy ; Stem Cells ; Wounds and Injuries

Intrathyroidal thymic tissue is rare and may be confused with a malignant thyroid nodule because of hyperechoic dots mimicking calcifications. We report the case of a thyroid nodule with malignant ultrasonographic findings in a 4-year-old child, which was confirmed cytologically as ectopic thymic tissue. The sonographic findings of ectopic thymus were similar to those of the thymus; therefore, clinicians should be familiar with ultrasonography findings of normal thymic tissue.
Child* ; Child, Preschool* ; Humans ; Pediatrics ; Thymus Gland ; Thyroid Gland* ; Thyroid Nodule* ; Ultrasonography

OBJECTIVE: Although metastasis of hepatocellular carcinoma to the brain is uncommon, it is associated with a very high mortality rate and most patients usually expire within 1 year after brain metastasis. The aim of this study is to identify the effectiveness of the active interventions such as gamma knife radiosurgery or surgical intervention for these patients. METHODS: We retrospectively reviewed the medical records and imaging data of 59 patients with metastatic brain tumors from hepatocellular carcinoma from May 2004 to September 2012. The study included patients with available clinical and radiological data who had been diagnosed with metastatic hepatocellular carcinoma of the brain, confirmed by magnetic resonance imaging. The overall survival time was analyzed and compared according to each risk factor. RESULTS: The mean age at diagnosis of metastatic brain tumor was 52.2 years (14-77). The mean follow-up duration was 13.3 weeks (0.1-117.6). Overall median survival was 4.3 weeks (95% confidence interval, 2.2-6.4). The results from an analysis of clinical factors related to survival revealed that treatment modalities were significantly related to the patient's survival (log rank, p=0.006). Twenty patients (32.8%) experienced tumor bleeding, and the survival time of the patients with tumor bleeding tended to be shorter, although the result was not statistically significant (log rank, p=0.058). Hepatic reserve, by Child-Pugh classification, was grade A in 38 patients (64.4%), grade B in 16 patients (27.1%), and grade C in 5 patients (8.5%), and was significantly related to the patient's survival (log rank, p=0.000). CONCLUSION: Although patients with metastatic brain tumors from hepatocellular carcinoma showed poor survival, active intervention including surgical resection or gamma knife radiosurgery may result in better survival, especially if patients have preserved liver function.
Brain Neoplasms* ; Brain* ; Carcinoma, Hepatocellular* ; Classification ; Diagnosis ; Follow-Up Studies ; Hemorrhage ; Humans ; Liver ; Magnetic Resonance Imaging ; Medical Records ; Mortality ; Neoplasm Metastasis ; Radiosurgery* ; Retrospective Studies ; Risk Factors

OBJECTIVE: Angiopoietin-1 (Ang1) is a potent angiogenic factor that can increase synovial angiogenesis and also enhance osteoblast maturation and bone formation. However, its role in rheumatoid arthritis (RA) has not been well documented. Thus, we investigated roles of Ang1 in collagen-induced arthritis (CIA). METHODS: A recombinant adenovirus carrying the gene that encodes either cartilage oligomeric matrix protein (AdCOMP)-Ang1 (a modified form of Ang1) or LacZ (AdLacZ) was injected intravenously into CIA mice. Clinical, radiological, histopathological, and immunofluorescent analyses were performed. Serum levels of receptor activators of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) and expression of osteoblast maturation genes were analyzed. RESULTS: AdCOMP-Ang1-injected mice developed more severe inflammation than the AdLacZ-injected mice. However, there were no significant differences in cartilage damage and bone erosion. More PECAM-1-positive blood vessels were seen in the synovium of the AdCOMP-Ang1-injected mice than in those injected with AdLacZ. Interestingly, a lower number of TRAP-positive osteoclasts were observed in AdCOMP-Ang1-injected CIA mice than in the AdLacZ group when comparing sections obtained from joints showing similar synovial proliferation. The serum OPG/RANKL ratio and expression of osteoblast maturation genes, such as runt-related transcription factor 2, bone sialoprotein, type 1 collagen, osteopontin, and osterix, were significantly upregulated in the AdCOMP-Ang1 group. CONCLUSION: COMP-Ang1 facilitates arthritis onset and increases synovial inflammation, but enhances osteoblast maturation, which in turn inhibits osteoclastogenesis by increasing the OPG/RANKL ratio in CIA. Our results suggest that careful investigation is necessary to delineate the possible therapeutic use of COMP-Ang1 as an adjunctive agent, in combination with anti-inflammatory therapies, for the prevention of bone destruction in RA.
Adenoviridae ; Angiogenesis Inducing Agents ; Angiopoietin-1 ; Animals ; Arthritis ; Arthritis, Experimental ; Arthritis, Rheumatoid ; Blood Vessels ; Cartilage ; Collagen Type I ; Extracellular Matrix Proteins ; Glycoproteins ; Inflammation ; Integrin-Binding Sialoprotein ; Joints ; Lifting ; Mice ; Osteoblasts ; Osteoclasts ; Osteogenesis ; Osteopontin ; Osteoprotegerin ; Synovial Membrane ; Transcription Factors

Mycobacterium szulgai is a rare nontuberculous mycobacterium found in Korea. It is an opportunistic pathogen and is usually isolated from patients with a history of alcoholism, chronic pulmonary disease, or an immunocompromising condition. We present here a case of M. szulgai isolated from a patient with a history of pulmonary tuberculosis. A 54-year-old man was admitted with dyspnea and febrile sensation. He had a history of pulmonary tuberculosis which occurred 30 years earlier and treatment with anti-tuberculosis medication. His chest computed tomography scan showed cavitary consolidation in both upper lungs. A sputum acid-fast bacilli (AFB) smear was positive and anti-tuberculous medication was started. However, a polymerase chain reaction for mycobacterium tuberculosis was negative and anti-tuberculous medication was stopped. M. szulgai was isolated on 3 separate sputum and bronchial wash fluid AFB cultures. He was treated with clarithromycin, rifampicin, and ethambutol. After 1 month, a sputum AFB smear and culture became negative and no additional M. szulgai were isolated during a 16-month treatment.
Alcoholism ; Clarithromycin ; Dyspnea ; Ethambutol ; Humans ; Invasive Pulmonary Aspergillosis ; Korea ; Lung ; Lung Diseases ; Middle Aged ; Mycobacterium ; Mycobacterium tuberculosis ; Nontuberculous Mycobacteria ; Polymerase Chain Reaction ; Rifampin ; Sensation ; Sputum ; Thorax ; Tuberculosis ; Tuberculosis, Pulmonary

A leukemoid reaction is defined as reactive leukocytosis exceeding 50,000/mm3, with a significant increase in early neutrophil precursors, and can be a paraneoplastic manifestation of various malignant tumors. A 71-year-old male patient complained of decreased appetite, fatigue, and abdominal fullness. He had a palpable, firm liver, and laboratory investigations suggested leukemoid reaction. Liver dynamic computed tomography revealed a hypervascular mass, and an ultrasound-guided fine-needle aspiration of the mass confirmed hepatocellular carcinoma (HCC) with a sarcomatoid component. The leukocyte count of the patient had increased to 147,800/mm3, and he died 10 days after admission. This is a rare case of leukemoid reaction in a patient with sarcomatous HCC.
Aged ; Biopsy, Fine-Needle ; Carcinoma, Hepatocellular/*pathology ; Humans ; Leukemoid Reaction/*diagnosis ; Leukocyte Count ; Liver Neoplasms/*pathology ; Male ; Tomography, X-Ray Computed

BACKGROUND: Scar tissue formation is the major cause of failure in peripheral nerve surgery. Use of a hyaluronic acid-carboxymethylcellulose (HA-CMC) membrane (Seprafilm) as a solid anti-adhesion barrier agent is one of the therapeutic approaches to reduce postoperative scar tissue formation. However, a solid membrane may not be suitable for repair of a weak peripheral nerve site. This study examined the effect of HA-CMC solution on perineural scar formation after peripheral nerve repair in rats. METHODS: The sciatic nerves of 40 rats were transected and then immediately repaired using 10-0 nylon. The nerves were divided randomly into two groups. Saline and HA-CMC solution were applied topically to the nerve repair sites in the control and experimental groups, respectively. Reoperation was performed at 3, 6, 9, and 12 weeks to assess scar tissue formation. The assessment included the quality of wound healing, presence of perinueral adhesion, cellular components of the scar tissue, thickness of the scar tissue and histomorphological organization of the repair site. RESULTS: Topical application of the HA-CMC solution significantly decreased the macroscopic nerve adherence score and the numbers of the cellular components such as fibroblasts and inflammatory cells (p < 0.05, Mann-Whitney U-test). The scar tissue formation index was significantly lower in the experimental group at 12 weeks than that in the control group (p < 0.05, Mann-Whitney U-test). The grading scores of the histomorphological axonal organization at the repair site were significantly higher in the experimental group than those in the control group at 12 weeks (p < 0.05, Mann-Whitney U-test). No evidence of wound dehiscence or inflammatory reactions against the HA-CMC solution was noted. CONCLUSIONS: Topical application of a HA-CMC solution is effective in reducing the perineural scar formation and adhesion after sciatic nerve repair in rats, and is effective in promoting peripheral nerve regeneration at the repair site.
Animals ; Carboxymethylcellulose Sodium/therapeutic use ; Cicatrix/*prevention & control ; Drug Combinations ; Hyaluronic Acid/*therapeutic use ; *Membranes, Artificial ; Postoperative Complications/*prevention & control ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve/*surgery ; Solutions

Rectal metastasis of colon cancer without peritoneal carcinomatosis is a rare condition whose initial clinical presentation may mimic inflammation. To the best of our knowledge, there was no report on such cases. A 45-year-old man with a history of left hemicolectomy and adjuvant chemotherapy for primary signet ring cell carcinoma (SRCC) of the descending colon, admitted to have constipation and abdominal pain for 3 weeks. His colonoscopic findings did not show local tumor recurrence at the anastomsis site, however, a hard, concentric luminal narrowing of the lower rectum was encountered. Endoscopic biopsies revealed chronic inflammations, and positron emission tomography with 18F-fluorodeoxyglucose revealed diffuse mildly hypermetabolic lesion in the rectum, suggesting inflammation. Magnetic resonance image showed submucosal wall thickening with multiple perirectal lymph nodes. Rectal metastasis of colon cancer was highly suspected clinically and a surgical biopsy confirmed SRCC which was surgically removed thereafter.
Abdominal Pain ; Biopsy ; Carcinoma ; Carcinoma, Signet Ring Cell ; Chemotherapy, Adjuvant ; Colon ; Colon, Descending ; Colonic Neoplasms ; Constipation ; Humans ; Hydrazines ; Inflammation ; Lymph Nodes ; Magnetic Resonance Spectroscopy ; Middle Aged ; Neoplasm Metastasis ; Phenobarbital ; Positron-Emission Tomography ; Rectum ; Recurrence

BACKGROUND: Epithelial tumor cells with a CD44(+)/CD24(-/low) immunoprofile may have the ability to cause breast cancer. We studied these cells and their clinicopathological significance. METHODS: The clinicopathologic findings of 100 invasive ductal carcinoma (IDC) cases and 45 ductal carcinoma in situ (DCIS) cases were reviewed. CD44(+)/CD24(-/low) tumor cells were identified by immunohistochemistry, and their clinicopathological implications in IDC and DCIS were analyzed. RESULTS: IDC with a high prevalence of CD44(+)/CD24(-/low) tumor cells was significantly associated with larger mass, higher grade, estrogen receptor (ER) negativity, and tumor cells with a higher frequency of metastasis. The proportion of CD44(+)/CD24(-/low) tumor cells in IDC, and its DCIS components was not significantly different, whereas the proportion of CD44(+)/CD24(-/low) tumor cells was higher in DCIS than in the DCIS component of IDC (p < 0.001). CONCLUSIONS: IDC with a high prevalence of CD44(+)/CD24(-/low) tumor cells might correlate with aggressive features, such as ER and higher grades. Moreover, the proportion of CD44(+)/CD24(-/low) tumor cells in the DCIS components of IDC and DCIS might harbor different biology, which may lead to differences in cancer progression and early carcinogenesis.
Antigens, CD24 ; Antigens, CD44 ; Biology ; Breast ; Breast Neoplasms ; Carcinoma, Ductal ; Carcinoma, Intraductal, Noninfiltrating ; Estrogens ; Immunohistochemistry ; Neoplasm Metastasis ; Neoplastic Stem Cells ; Prevalence

BACKGROUND AND OBJECTIVES: Angiopoietin-1 (Ang1) is a regulator of blood vessel growth and maturation, and prevents radiation-induced or serum deprivation-induced apoptosis. Phosphatase and tensin homologue deleted from chromosome ten (PTEN), a well-known tumor suppressor, regulates cell cycle arrest and apoptosis. Hypoxia induces apoptosis by increasing the expression of PTEN. We hypothesized that Ang1 may regulate PTEN expression and, thus, reduce endothelial apoptosis under hypoxia in vitro and in vivo. Materials and METHODS: In vitro, human umbilical vein endothelial cells (HUVECs) were treated with Ang1, and signaling pathways were investigated. In vivo, eight-week-old C57BL/6 mice were used for a hind limb ischemia model. Ang1 or normal saline was intramusculary injected. Blood flow was evaluated by a laser Doppler perfusion analyzer and tissue histology. RESULTS: The expression of PTEN was markedly upregulated in HUVECs after hypoxic stimulation, whereas Ang1 suppressed PTEN expression. Tie2-Fc, a soluble form of Tie2 (sTie2) that blocks Ang1, reversed the Ang1 effect on PTEN reduction under hypoxia. Ang1 inhibited the nuclear translocation of nuclear transcription factor-kB (NF-kB), a binding factor for the PTEN promoter and Foxo1. Hypoxia-induced p27 expression and apoptosis were also suppressed by Ang1. In the mouse hind limb ischemia model, we observed a high capillary density, numerous proliferating cells and diminished cell death in skeletal muscle tissue in the Ang1 injected group. CONCLUSION: Ang1 enhanced endothelial cell survival by reducing apoptosis via PTEN down-regulation in HUVECs under hypoxia. Local injection of Ang1 significantly reduced apoptotic cells in vivo, and prevented limb loss for ischemic hind limb mice. Thus, Ang1 may be an effective therapeutic for protection from ischemic-endothelial cell injury.
Angiopoietin-1 ; Animals ; Anoxia ; Apoptosis ; Blood Vessels ; Capillaries ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Death ; Down-Regulation ; Endothelial Cells ; Extremities ; Glycosaminoglycans ; Human Umbilical Vein Endothelial Cells ; Ischemia ; Mice ; Microfilament Proteins ; Muscle, Skeletal ; Perfusion