Dynamic relocalization of NHERF1 mediates chemotactic migration of ovarian cancer cells toward lysophosphatidic acid stimulation

NHERF1/EBP50 (Na⁺/H⁺ exchanger regulating factor 1; Ezrin-binding phosphoprotein of 50 kDa) organizes stable protein complexes beneath the apical membrane of polar epithelial cells. By contrast, in cancer cells without any fixed polarity, NHERF1 often localizes in the cytoplasm. The regulation of cytoplasmic NHERF1 and its role in cancer progression remain unclear. In this study, we found that, upon lysophosphatidic acid (LPA) stimulation, cytoplasmic NHERF1 rapidly translocated to the plasma membrane, and subsequently to cortical protrusion structures, of ovarian cancer cells. This movement depended on direct binding of NHERF1 to C-terminally phosphorylated ERM proteins (cpERMs). Moreover, NHERF1 depletion downregulated cpERMs and further impaired cpERM-dependent remodeling of the cell cortex, suggesting reciprocal regulation between these proteins. The LPA-induced protein complex was highly enriched in migratory pseudopodia, whose formation was impaired by overexpression of NHERF1 truncation mutants. Consistent with this, NHERF1 depletion in various types of cancer cells abolished chemotactic cell migration toward a LPA gradient. Taken together, our findings suggest that the high dynamics of cytosolic NHERF1 provide cancer cells with a means of controlling chemotactic migration. This capacity is likely to be essential for ovarian cancer progression in tumor microenvironments containing LPA.

The enhanced expression of IL-17-secreting T cells during the early progression of atherosclerosis in ApoE-deficient mice fed on a western-type diet

Atherosclerosis is a chronic progressive inflammatory disorder and the leading cause of cardiovascular mortality. Here we assessed the dynamic changes of T-cell-derived cytokines, such as inteferon (IFN)-gamma, interleukin (IL)-17 and IL-4, during the progression of atherosclerosis in apolipoprotein E-null (ApoE(-/-)) mice, to understand the role of immune responses in different stages of atherosclerosis. Male ApoE(-/-) mice were fed a high-fat, western-type diet (WD: 21% lipid, 1.5% cholesterol) after 5 weeks of age and were compared with C57BL/6 wild-type control mice fed a standard chow diet. Atherosclerotic lesions appeared in the aortic sinus of ApoE(-/-) mice 4 weeks after WD and the lesions progressed and occupied >50% of the total sinus area 16 weeks after WD. Aortic IL-17 mRNA and protein expression started to increase in ApoE(-/-) mice after 4 weeks on the WD and peaked at around 8-12 weeks on the WD. In terms of systemic expression of T-cell-derived cytokines, IL-17 production from splenocytes after anti-CD3/CD28 stimuli increased from 4 weeks on the WD, peaked at 12 weeks and returned to control levels at 16 weeks. The production of IFN-gamma and IL-4 (Th1 and Th2 cytokines, respectively) from splenocytes was delayed compared with IL-17. Taken together, the present data indicate that Th17 cell response may be involved at an early stage in the development of atherosclerosis.

The enhanced expression of IL-17-secreting T cells during the early progression of atherosclerosis in ApoE-deficient mice fed on a western-type diet

Atherosclerosis is a chronic progressive inflammatory disorder and the leading cause of cardiovascular mortality. Here we assessed the dynamic changes of T-cell-derived cytokines, such as inteferon (IFN)-gamma, interleukin (IL)-17 and IL-4, during the progression of atherosclerosis in apolipoprotein E-null (ApoE(-/-)) mice, to understand the role of immune responses in different stages of atherosclerosis. Male ApoE(-/-) mice were fed a high-fat, western-type diet (WD: 21% lipid, 1.5% cholesterol) after 5 weeks of age and were compared with C57BL/6 wild-type control mice fed a standard chow diet. Atherosclerotic lesions appeared in the aortic sinus of ApoE(-/-) mice 4 weeks after WD and the lesions progressed and occupied >50% of the total sinus area 16 weeks after WD. Aortic IL-17 mRNA and protein expression started to increase in ApoE(-/-) mice after 4 weeks on the WD and peaked at around 8-12 weeks on the WD. In terms of systemic expression of T-cell-derived cytokines, IL-17 production from splenocytes after anti-CD3/CD28 stimuli increased from 4 weeks on the WD, peaked at 12 weeks and returned to control levels at 16 weeks. The production of IFN-gamma and IL-4 (Th1 and Th2 cytokines, respectively) from splenocytes was delayed compared with IL-17. Taken together, the present data indicate that Th17 cell response may be involved at an early stage in the development of atherosclerosis.

Clinical Implications and Risk Factors of Acute Pancreatitis after Cardiac Valve Surgery

PURPOSE: Acute pancreatitis is one of the potentially lethal complications that occurs after cardiac surgery. We tried to identify risk factors for and the prognosis of acute pancreatitis after cardiac valve surgery with cardiopulmonary bypass. MATERIALS AND METHODS: We retrospectively analyzed a database of consecutive patients who underwent cardiac valve surgery with cardiopulmonary bypass between January 2005 and April 2010 at our institution. Patients were classified as having acute pancreatitis based on serum lipase concentration and clinical symptoms (lipase > or =180 U/L or > or =60 U/L with relevant symptoms). RESULTS: Of the 986 patients who underwent cardiac valve surgery with cardiopulmonary bypass, 58 (5.9%) patients developed post-operative pancreatitis. Post-operative hospital stay was significantly longer (29.7+/-45.6 days vs. 12.4+/-10.7 days, p=0.005) and in-hospital mortality rate was higher (15.5% vs. 2.0%, p<0.001) in patients with post-operative pancreatitis than those without. Hypertension, chronic kidney disease, and peri-operative use of norepinephrine were identified as independent risk factors for developing pancreatitis after cardiac valve surgery. CONCLUSION: We found that acute pancreatitis after cardiac valve surgery requires longer hospitalization and increases the in-hospital mortality rate. Clinicians should be aware that patients could develop pancreatitis after cardiac valve surgery, especially in patients with hypertension and chronic kidney disease treated with norepinephrine.

The Clinical Utility of Positron Emission Tomography-computed Tomography in the Evaluation of Inflammatory Bowel Diseases

BACKGROUND/AIMS: Positron emission tomography-computed tomography (PET-CT) is a nuclear imaging technique that provides noninvasive, three dimensional, quantitative images. Recently, PET-CT has been shown to be valuable in assessing patients with inflammatory diseases; however, the clinical utility of PET-CT in the evaluation of inflammatory bowel disease (IBD) has not been defined. Thus, the aim of this study was to determine the clinical utility of PET-CT in the evaluation of IBD. METHODS: Between November 2006 and September 2010, clinical, endoscopic, and radiological data on 14 patients (6 males and 8 females: age range, 33-79 years) with suspected IBD were collected. The standard work-up method for a definite diagnosis of IBD included ileocolonoscopy. RESULTS: The 14 patients were divided into the following five groups: ulcerative colitis (n=4, 29%), intestinal Behcet's disease (n=3, 21%), intestinal tuberculosis (n=2, 14%), malignancy (n=2, 14%), and no abnormal findings with colonoscopy (n=3, 21%). A PET-CT based-diagnosis of IBD correlated with a colonoscopic diagnosis in nine cases (64.3%), but the matching ratio of the distribution of lesions between PET-CT findings and colonoscopic findings was only 18.1% (2/11). CONCLUSIONS: The utility of PET-CT in the diagnosis of IBD requires further evaluation.

The Early Diagnostic Accuracy for Gastrointestinal T-cell Lymphoma from a Perspective of Gastroenterologists

BACKGROUND/AIMS: Primary T-cell lymphoma of the gastrointestinal tract is a very difficult disease entity to diagnose, and has an extremely poor prognosis. The aim of this study was to determine the early diagnostic accuracy for gastrointestinal T-cell lymphoma by gastroenterologists. METHODS: Between January 2000 and October 2010, the clinical features of 15 patients with primary gastrointestinal T-cell lymphomas, including endoscopic findings, radiologic diagnosis, endoscopic biopsy findings, and final diagnosis, were retrospectively reviewed. RESULTS: The most common initial presenting symptoms of primary gastrointestinal T-cell lymphomas was abdominal pain (n=11, 73%). The anatomic location of the primary lesion the small bowel (n=8, 53%), colon (n=5, 33%), and stomach (n=3, 20%). There were no cases of T-cell lymphomas diagnosed based on clinical symptoms, radiologic findings, or endoscopic findings without biopsy alone. Pathologic confirmation of T-cell lymphomas by endoscopic examination was achieved in 7 cases (64%) and the remaining cases (n=8, 53%) were diagnosed with T-cell lymphomas based on pathologic examination after surgery. CONCLUSIONS: All of the patients with primary T-cell lymphomas of the gastrointestinal tract were diagnosed exclusively by endoscopic or surgical pathologic examainations, suggesting that gastroenterologists should scrutinize and suspect this disease with caution due to atypical gastrointestinal ulcers.

A case of community-acquired pneumonia and sepsis caused by Chryseobacterium meningosepticum / 대한내과학회지

Chryseobacterium meningosepticum is a ubiquitous Gram-negative rod widely distributed in natural and hospital environments. It mostly causes meningitis in premature and newborn infants. Few such cases have been reported in Korea, and no case of community-acquired pneumonia caused by Chryseobacterium meningosepticum. A 53-year-old man was brought to the emergency department because of severe pneumonia. We report a case of community-acquired pneumonia and sepsis caused by Chryseobacterium meningosepticum.

A case of imported Shigella sonnei infection complicated with acute appendicitis / 대한내과학회지

Shigellosis may mimic acute appendicitis clinically, but Shigella species rarely cause appendicitis. We experienced acute appendicitis with perforation caused by Shigella sonnei in a 24-year-old woman who had traveled abroad.

A Case of Esophagogastroduodenoscopy Associated Actinomycosis Presenting as Ulcers of Hard Palate

Actinomyces is a normal flora of the oral cavity but lesions localized to the oral mucosa are very rare. We herein present a rare case of actinomycosis presenting as ulcers of hard palate which developed after esophagogastroduodenoscopy.

A Case of Esophagogastroduodenoscopy Associated Actinomycosis Presenting as Ulcers of Hard Palate

Actinomyces is a normal flora of the oral cavity but lesions localized to the oral mucosa are very rare. We herein present a rare case of actinomycosis presenting as ulcers of hard palate which developed after esophagogastroduodenoscopy.

Adenocarcinoma and Tuberculous Lymphadenitis on the Same Site of the Sigmoid Colon: A Case Report and Literature Review / 대한소화기내시경학회지

Inflammatory bowel disease can progress to colon cancer. However, there is not much of a causal relationship between intestinal tuberculosis and colon cancer. There have been a few case reports of intestinal tuberculosis in association with colon cancer. We experienced a 59-year-old man who had the collision-like pathology of adenocarcinoma and tuberculous lymphadenitis on the sigmoid colon. He visitied our hospital because of abdominal pain and hematochezia. Colonoscopy showed a mass on the sigmoid colon that was causing luminal obstruction. Therefore, sigmoidectomy was performed and the resected specimen revealed a collision-like appearance; the mass was composed of adenocarcinoma invading the proper muscle layer and caseating granuloma in the serosa and lymph nodes. We report here on a case of collision-like pathology that was composed of adenocarcinoma and tuberculosis on the sigmoid colon, and we review the relevant literature.

Secretin induces neurite outgrowth of PC12 through cAMP-mitogen-activated protein kinase pathway

The gastrointestinal functions of secretin have been fairly well established. However, its function and mode of action within the nervous system remain largely unclear. To gain insight into this area, we have attempted to determine the effects of secretin on neuronal differentiation. Here, we report that secretin induces the generation of neurite outgrowth in pheochromocytoma PC12 cells. The expressions of Tau and beta-tubulin, neuronal differentiation markers, are increased upon secretin stimulation. In addition, secretin induces sustained mitogen-activated protein kinase (MAPK) activation and also stimulates the cAMP secretion. Moreover, the neurite outgrowth elicited by secretin is suppressed to a marked degree in the presence of either PD98059, a specific MAPK/ERK kinase (MEK) inhibitor, or H89, a specific protein kinase A (PKA) inhibitor. Taken together, these observations demonstrate that secretin induces neurite outgrowth of PC12 cells through cAMP-MAPK pathway, and provide a novel insight into the manner in which secretin participates in neuritogenesis.

Lysophosphatidylcholine suppresses apoptosis and induces neurite outgrowth in PC12 cells through activation of phospholipase D2

Lysophosphatidylcholine (LPC) is a bioactive lipid generated by phospholipase A2-mediated hydrolysis of phosphatidylcholine. In the present study, we demonstrate that LPC stimulates phospholipase D2 (PLD2) activity in rat pheochromocytoma PC12 cells. Serum deprivation induced cell death of PC12 cells, as demonstrated by decreased viability, DNA fragmentation, and increased sub-G1 fraction of cell cycle. LPC treatment protected PC12 cells partially from the cell death and induced neurite outgrowth of the cells. Overexpression of PLD2 drastically enhanced the LPC-induced inhibition of apoptosis and neuritogenesis. Pretreatment of the cells with 1-butanol, a PLD inhibitor, completely abrogated the LPC-induced inhibition of apoptosis and neurite outgrowth in PC12 cells overexpressing PLD2. These results indicate that LPC possesses the neurotrophic effects, such as anti-apoptosis and neurite outgrowth, through activation of PLD2.

Inositol 5'-phosphatase, SHIP1 interacts with phospholipase C-gamma1 and modulates EGF-induced PLC activity

Phospholipase C-gamma1, containing two SH2 and one SH3 domains which participate in the interaction between signaling molecules, plays a significant role in the growth factor-induced signal transduction. However, the role of the SH domains in the growth factor-induced PLC-gamma1 regulation is unclear. By peptide-mass fingerprinting analysis, we have identified SHIP1 as the binding protein for the SH3 domain of PLC-gamma1. SHIP1 was co-immunoprecipitated with PLC-gamma1 and potentiated EGF-induced PLC-gamma1 activation. However, inositol 5'-phosphatase activity of SHIP1 was not required for the potentiation of EGF-induced PLC-gamma1 activation. Taken together, these results suggest that SHIP1 may function as an adaptor protein which can potentiate EGF-induced PLC-gamma1 activation without regards to its inositol 5'-phosphatase activity.

A study on usefulness of the reference line in diagnosis of the facial asymmetry

PURPOSE: To assess the relationship between soft tissue reference line and hard tissue reference line using the standardized photographs and the posteroanterior cephalometric radiographs(P-A)in facial asymmetric patients and to compare the differences of angular measurement between normal group and asymmetry group. METHODS: Normal group consisted of 44 persons with normal occlusion and normal facial morphology. Asymmetry group consisted of 90 patients with facial asymmetry. Standardized facial photographs and P-A were taken in all subjects. The horizontal reference lines were bipupillary line in photographs and latero-orbitale line in P-A respectively. The vertical reference line were the line from the midpoint of horizontal reference line perpendicularly. Angular measurement of otobasion canting, lip canting, nose deviation, chin deviation, and maxillary deviation were compared and analyzed in photographs. And angular measurement of mastoid canting, mandibular canting, nose deviation, chin deviation, and maxillary deviation were compared and analyzed in P-A. RESULTS: 1. The variables of photographs and P-A were significantly related in the asymmetry group. 2. Significant differences between all variables except for PT2 and PA2 were shown in the asymmetry group and between PT1 and PA1, PT3 and PA3 in the normal group respectively. 3. Comparison measurement scores of angular difference between control group and experimental group concerning each variable showed significant difference except for PA1. CONCLUSIONS: Soft tissue components may not compensate for underlying skeletal imbalance in nose deviation and chin deviation. The horizontal reference lines in photographs were significant related with the P-A, but angular variables between the two studies show significant differences. Therefore, we do not recommend use photography in the assessment the facial asymmetry as complemented in the P-A.

Trp-Lys-Tyr-Met-Val-Met stimulates phagocytosis via phospho-lipase D-dependent signaling in mouse dendritic cells

Dendritic cells (DCs) play a key role in activating the immune response against invading pathogens as well as dying cells or tumors. Although the immune response can be initiated by the phagocytic activity by DCs, the molecular mechanism involved in this process has not been fully investigated. Trp-Lys-Tyr-Met-Val-Met-NH2 (WKYMVM) stimulates the activation of phospholipase D (PLD) via Ca2+ increase and protein kinase C activation in mouse DC cell line, DC2.4. WKYMVM stimulates the phagocytic activity, which is inhibited in the presence of N-butanol but not t-butanol in DC2.4 cells. Furthermore, the addition of phosphatidic acid, an enzymatic product of PLD activity, enhanced the phagocytic activity in DC2.4 cells. Since at least two of formyl peptide receptor (FPR) family (FPR1 and FPR2) are expressed in DC2.4 as well as in mouse bone marrow-derived dendritic cells, this study suggests that the activation of FPR family by WKYMVM stimulates the PLD activity resulting in phagocytic activity in DC2.4 cells.

Phosphorylation of phospholipase D1 and the modulation of its interaction with RhoA by cAMP-dependent protein kinase

Agents that elevate cellular cAMP are known to inhibit the activation of phospholipase D (PLD). We investigated whether PLD can be phosphorylated by cAMP-dependent protein kinase (PKA) and PKA-mediated phosphorylation affects the interaction between PLD and RhoA, a membrane regulator of PLD. PLD1, but not PLD2 was found to be phosphorylated in vivo by the treatment of dibutyryl cAMP (dbcAMP) and in vitro by PKA. PKA inhibitor (KT5720) abolished the dbcAMP-induced phosphorylation of PLD1, but dibutyryl cGMP (dbcGMP) failed to phosphorylate PLD1. The association between PLD1 and Val14RhoA in an immunoprecipitation assay was abolished by both dbcAMP and dbcGMP. Moreover, RhoA but not PLD1 was dissociated from the membrane to the cytosolic fraction in dbcAMP-treated cells. These results suggest that both PLD1 and RhoA are phosphorylated by PKA and the interaction between PLD1 and RhoA is inhibited by the phosphorylation of RhoA rather than by the phosphorylation of PLD1.

Neurosensory deficit after orthognathic surgery

AIMS:This study was designed to determine the incidence of altered sensation in patients undergoing orthognathic surgery. METHOD: Seventy two patients who underwent orthognathic surgery between January, 1999 and December, 1999 constituted the study group. Seven patients were excluded because of lack of follow up. Sixty five patients were followed using objective and subjective neurologic testing during the period immediately following operation, 1 month, 2 months, 6 months, and 1 year postoperatively. Age ranged from 17 to 38 years, with a mean of 24.5 years. Male patients were 21, female 44. Twenty eight bilateral sagittal splitting ramus osteotomy(BSSRO) of mandible were performed, 35 BSSRO with genioplasty, 2 genioplasties. Information on the degree of intraoperative nerve encounter was obtained from the surgical reports in 47 patients and was divided into the following three categories: (1) the nerve was not encountered in 23 patients; (2) the nerve was exposed in 11 patients; (3) the nerve was exposed and repositioned from the proximal segment in 13 patients. RESULTS: Four patients reported altered nerve sensation of lower lip and/or chin(6.2%) at final follow up. Two patients underwent BSSRO and the other two patients BSSRO with genioplasty. Three of the patients underwent nerve exposure during the operation. CONCLUSION: We suggest that the nerve exposure during the operation might be partly responsible for nerve dysfunction after orthognathic surgery.

Phototoxic effects of low level laser irradiation on human osteosarcoma cells

Photodynamic therapy(PDT) has advanced to clinical trials for the treatment of a variety of solid tumors and presents an alternative treatment option for tumors resistant to chemo-and/or radio-therapy. PDT is based on the combination of laser light of appropriate wavelength and energy to activate a systemically or locally applied photosensitizer that concentrates preferentially in malignant tissues. In this study, phototoxicity of laser EIT 21 was analysed in human osteosarcoma cell(HOS) and the second objective of this study was to determine the ability of laser EIT 21 to induce apoptosis. This study demonstrated that laser EIT 21 had a phototoxicity to HOS cells. In order to examinate whether cell death was induced by necrosis or apoptosis, variety of techniques which assess apoptosis were used. TUNEL assay showed only a few the positive reaction on condensed nuclei. It is hard to find condensed or fragmented nuclei on HOS cells irradiated with laser EIT 21 in Hemastat and AO/EB stain. By DNA electrophoresis, cells also did not show DNA degradation characteristic of apoptosis with a ladder pattern of DNA fragments. Apoptosis-related factors were analyzed by western blotting. The expression of p53 was constant and cells irradiated with laser did not show the caspase-3 and PARP degradation, therefore we suggest that p53 and caspase-3 are not involved in laserinduced cell death.

Predictive Factors of Prostatic Cancer Detection on Repeat Prostate Biopsy / 대한비뇨기과학회지

PURPOSE: To determine the demographic and tumor related predictors of repeat biopsy cancer detection in men diagnosed with benign prostatic tissue following an initial prostate biopsy. We evaluated the clinical parameters of prostate cancers detected on repeat biopsy. MATERIALS AND METHODS: Between May 1994 and 2001, 1,016 patients with suspected prostatic cancer underwent a transrectal ultrasound guided prostate biopsy. Of the 721 patients whose biopsy specimens were negative for prostate cancer, 53 had a repeat prostate biopsy for persistently, or abruptly elevated, prostate specific antigen (PSA) values. We examined their serum PSA, PSA density, free to total PSA value, annualized interbiopsy PSA change and biopsy core numbers, as well as their age, prostate size and the histological results of their initial, and repeated, biopsies, to determine if any predictor of the need for a repeat biopsy could be identified. RESULTS: From the repeat biopsies, 15 patients (28.3%) had prostate cancer. There were significant differences between the benign and malignant repeat biopsies, in relation to PSA density (p=0.001), free to total PSA value (p=0.002) and annualized interbiopsy PSA change (p=0.001). No patient with high-grade prostatic intraepithelial neoplasia was subsequently found to have cancer. CONCLUSIONS: The PSA density, free to total PSA value and annualized interbiopsy PSA change appear to aid in the prediction of cancer on a repeat biopsy.