Jung Min Ha

Synergistic induction of cancer cell migration regulated by Gβγ and phosphatidylinositol 3-kinase

Phosphatidylinositol 3-kinase (PI3K) is essential for both G protein-coupled receptor (GPCR)- and receptor tyrosine kinase (RTK)-mediated cancer cell migration. Here, we have shown that maximum migration is achieved by full activation of phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) in the presence of Gβγ and PI3K signaling pathways. Lysophosphatidic acid (LPA)-induced migration was higher than that of epidermal growth factor (EGF)-induced migration; however, LPA-induced activation of Akt was lower than that stimulated by EGF. LPA-induced migration was partially blocked by either Gβγ or RTK inhibitor and completely blocked by both inhibitors. LPA-induced migration was synergistically increased in the presence of EGF and vice versa. In correlation with these results, sphingosine-1-phosphate (S1P)-induced migration was also synergistically induced in the presence of insulin-like growth factor-1 (IGF-1). Finally, silencing of P-Rex1 abolished the synergism in migration as well as in Rac activation. Moreover, synergistic activation of MMP-2 and cancer cell invasion was attenuated by silencing of P-Rex1. Given these results, we suggest that P-Rex1 requires both Gβγ and PI3K signaling pathways for synergistic activation of Rac, thereby inducing maximum cancer cell migration and invasion.

Acute Myocardial Infarction after Radiofrequency Catheter Ablation of Typical Atrial Flutter

A 53-yr-old man underwent radiofrequency ablation to treat persistent atrial flutter. After the procedure, the chest pain was getting worse, and the electrocardiogram showed ST-segment elevation in inferior leads with reciprocal changes. Immediate coronary angiography showed total occlusion with thrombi at the distal portion of the right coronary artery, which was very close to the ablation site. Intervention with thrombus aspiration and balloon dilatation was successful, and the patient recovered without any kind of sequelae. Although the exact mechanism is obscure, the most likely explanation is a thermal injury to the vascular wall that ruptured into the lumen and formed thrombus. Vasospasm and thromboembolism can also be other possibilities. This case raise the alarm to cardiologists who perform radiofrequency ablation to treat various kinds of cardiac arrhythmias, in that myocardial infarction has been rarely considered one of the complications. Graphical Abstract

Immunoglobulin G4 Non-Related Sclerosing Disease with Intracardiac Mass Mimicking Mitral Stenosis: Case Report

The cardiovascular system may be one of the target organs of both immunoglobulin G4 related and non-related systemic multifocal fibrosclerosis. We present a case of IgG4 non-related systemic multifocal fibrosclerosis mimicking mitral stenosis on echocardiography. For a more detailed differential diagnosis, we used multimodal imaging techniques. After surgical biopsy around the abdominal aortic area in the retroperitoneum, histological examination revealed IgG4 non-related systemic multifocal fibrosclerosis. We describe the multimodal imaging used to diagnose IgG4 non-related systemic multifocal fibrosclerosis and a positive response to steroid treatment. There have been no previous case reports of IgG4 non-related systemic multifocal fibrosclerosis with intracardiac involvement. Here, we report a case of IgG4 non-related systemic multifocal fibrosclerosis mimicking mitral stenosis.

Antifactor Xa Levels in Critically Ill Korean Patients Receiving Enoxaparin for Thromboprophylaxis: A Prospective Observational Study

The aim of this study was to investigate antifactor Xa (aFXa) levels after once daily dose of 40 mg of enoxaparin and to evaluate factors influencing aFXa levels among Korean intensive care unit (ICU) patients. This prospective observational study was conducted between August and December 2011 in medical ICUs at Samsung Medical Center. AFXa levels between 0.1 and 0.3 U/mL were considered to be effective for antithrombotic activity. Fifty-five patients were included. The median aFXa levels were 0.22 (IQR 0.17-0.26) at 4 hr, 0.06 (IQR 0.02-0.1) at 12 hr, and 0 U/mL (IQR 0-0.03) at 24 hr. The numbers of patients showing effective antithrombotic aFXa levels were 48 (87.3%), 18 (32.7%), and 0 (0%) at 4, 12 and 24 hr, respectively. At 12 hr, higher sequential organ failure assessment (SOFA) scores and hyperbilirubinemia were significantly associated with low aFXa levels (OR, 0.58; 95% CI, 0.36-0.93; P = 0.02 and 0.06; 0.003-0.87; 0.04, respectively). Once daily dose of 40 mg of enoxaparin is inadequate for maintaining effective antithrombotic aFXa levels, and the inadequacy is more salient for patients with high SOFA scores and hyperbilirubinemia.

Regulation of retinal angiogenesis by phospholipase C-β3 signaling pathway

Angiogenesis has an essential role in many pathophysiologies. Here, we show that phospholipase C-β3 (PLC-β3) isoform regulates endothelial cell function and retinal angiogenesis. Silencing of PLC-β3 in human umbilical vein endothelial cells (HUVECs) significantly delayed proliferation, migration and capillary-like tube formation. In addition, mice lacking PLC-β3 showed impaired retinal angiogenesis with delayed endothelial proliferation, reduced endothelial cell activation, abnormal vessel formation and hemorrhage. Finally, tumor formation was significantly reduced in mice lacking PLC-β3 and showed irregular size and shape of blood vessels. These results suggest that regulation of endothelial function by PLC-β3 may contribute to angiogenesis.

Unusual Manifestation of Intravascular Large B-Cell Lymphoma: Severe Hypercalcemia with Parathyroid Hormone-Related Protein

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. It usually presents with nonspecific symptoms, such as fever, rather than with overt lymphadenopathy. Reports of hypercalcemia, as the initial presentation of IVLBCL, are limited in the literature, despite it being a well-known complication of various solid cancers. We present a 68-year-old male with severe hypercalcemia and increased levels of serum parathyroid hormone-related protein. He was diagnosed with IVLBCL, involving the bone marrow and spleen, and was successfully treated with rituximab-containing chemotherapy. A few previous case reports have shown hypercalcemia in patients with IVLBCL. Much like our case, previous cases with hypercalcemia had advanced diseases, including bone marrow invasion. Although it was an extremely rare manifestation of IVLBCL, we suggest that IVLBCL should be a part of the differential diagnosis in patients with unexplained hypercalcemia. Therefore, an active work-up might be recommended, including positron emission tomography/ computed tomography scan and bone marrow examination, which may be useful for early diagnosis.

Regulation of Skeletal Muscle Differentiation by Akt

Akt plays an important role in a variety of cellular physiologies such as growth, proliferation, and differentiation. In skeletal muscle, Akt has been implicated in regulating regeneration, hypertrophy, and atrophy. In this study, the role of Akt has been examined during skeletal muscle differentiation. Culturing C2C12 myoblasts under low serum (1% horse serum) and high density converted cell morphology from a round shape to an elongated and multi-nucleated shape. Morphological changes were initiated from day 2 of differentiation. In addition, the expression of both myogenin G and myogenin D was elevated from day 2 of differentiation. Skeletal muscle differentiation was abolished by silencing Akt1 or Akt2, but was significantly enhanced by the over-expression of either Akt1 or Akt2. The activation of Akt was observed from day 2 of differentiation and disappeared after day 7. The expression of kruppel-like factor 4 was observed from day 6 of differentiation. Moreover, this expression was blocked in cells silencing either Akt1 or Akt2. In addition, the promoter activity of kruppel-like factor 4 was significantly reduced in cells silencing Akt1 or Akt2. These results suggest that Akt regulates skeletal muscle differentiation through the regulation of kruppel-like factor 4 expression.

Inhibition of Cancer Cell Migration by Compounds from Garlic Extracts

Cell migration plays a fundamental role in cancer cell invasion and metastasis as well as in many physiological responses. Here, we screened four different sources of garlic - water extract of normal and black garlic, as well as dried normal and black garlic - for the identification of anti-invasive and anti-metastatic activity on cancer cells. Inhibition of cancer cell migration was observed in the hexane extract of dried-garlic. Inhibitory activity was further purified to near homogeneity by thin layer chromatography and named inhibitor of cancer metastasis from garlic #27 (ICMG-27). ICMG-27 completely blocked insulin-like growth factor-1 (IGF-1)-induced OVCAR-3 cell migration at 6 ㎍/㎖. ICMG-27 completely blocked IGF-1-induced OVCAR-3 and NIH-3T3 cell migration whereas IGF-1-induced mouse embryonic fibroblast (MEF) cell migration was not affected byICMG-27. ICMG-27 inhibited all the tested IGF-1-induced cancer cell migration such as OVCAR-3, SKOV-3, and MDA-MB-231 cells. Finally, ICMG-27 could inhibit IGF-1-, lysophosphatidic acid (LPA)-, sphingosine-1-phosphate (S1P)-, leukotriene B4 (LTB4)-, and angiotensin Ⅱ (AngⅡ)-induced OVCAR-3 cell migration. These results indicate that ICMG-27 inhibits cancer cell migration by blocking essential steps in many agonists-induced cancer cell migrations. Unveiling an anti-invasive mechanism of ICMG-27 on cancer cells will provide a basis for cancer therapy.

Community-Acquired Necrotizing Pneumonia Caused by ST72-SCCmec Type IV-Methicillin- Resistant Staphylococcus aureus in Korea

Methcillin-resistant Staphylococcus aureus (MRSA) has emerged as an important cause of community-acquired infections, which has been recently designated as community-associated (CA) MRSA. Panton-Valentine leukocidin (PVL)-negative multilocus sequence type 72 (ST72)-staphylococcal cassette chromosome mec (SCCmec) type IV has been reported as the predominat CA-MRSA strain in Korea and is commonly associated with skin and soft tissue infections in addition to healthcare-associated pneumonia. However, community-acquired pneumonia (CAP) for this strain has not yet been reported. We hereby report two cases of CAP caused by PVL-negative ST72-SCCmec type IV strain in patients who had no risk factors for MRSA acquisition. While CA-MRSA infections are not yet prevalent in Korea, our cases suggest that CA-MRSA should be considered in cases of severe CAP, especially for cases associated with necrotizing pneumonia.

Oncogenic Role of BOLL in Colorectal Cancer.

BackgroundBoule-like RNA-binding protein (BOLL protein) is the progenitor of the Deleted in Azoospermia (DAZ) gene family. To date, previous studies have focused on the reproductive function of BOLL. While we were identifying new DNA methylation biomarkers for colorectal cancer (CRC), we found that BOLL protein was overexpressed in CRC.AimThe aim of this study was to determine the role of BOLL in CRC by epigenetic and functional studies in vivo and in vitro.MethodsBOLL promoter methylation and expression were determined by MethyLight, RT-PCR, Western blot, and immunohistochemistry. The functional role of BOLL in CRC was evaluated by cell proliferation, colony formation, migration and invasion, cell cycle status, and tumor growth in a xenograft model.ResultsBOLL promoter methylation was enhanced in CRC tissues compared with normal colorectal tissues [97/124 (78xa0%) vs. 2/124 (2xa0%)]. However, the mean immunoreactivity score of CRC tissues and paired adjacent normal tissues was 8.15xa0±xa00.18 (SD) and 3.35xa0±xa00.19 (SD), respectively (pxa0<xa00.01). No significant association was observed between immunoreactivity score and clinicopathological parameters, including age, gender, tumor size, tumor differentiation, and tumor node metastasis stage. Expression of BOLL in CRC cell lines significantly enhanced cell proliferation (pxa0<xa00.01), colony formation (pxa0<xa00.01), and migration (pxa0<xa00.01). In BOLL-expressing cells, the percentage of cells in S-phase of the cell cycle was significantly increased. Tumor volume in BOLL xenografted mice was significantly enhanced after subcutaneous implantation (pxa0<xa00.01).ConclusionsOur study demonstrated an oncogenic role of BOLL in CRC despite tumor-specific promoter hypermethylation.