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Post-exposure prophylaxis (PEP) is highly effective in preventing disease progression of rabies when used in timely and appropriate manner. The key treatment for PEP is infiltration of rabies immune globulin (RIG) into lesion site after bite exposure, besides wound care and vaccination. Unfortunately, however, RIG is expensive and its supply is limited. Currently, several anti-rabies virus monoclonal antibody (mAb) products are under development as alternatives to RIG, and two recently received regulatory approval in India. In this study, fully human mAbs that recognize different rabies virus glycoprotein conformational antigenic site (II and III) were created from peripheral blood mononuclear cells of heathy vaccinated subjects. These mAbs neutralized a diverse range of lyssavirus types. As at least two anti-rabies virus mAbs are recommended for use in human PEP to ensure broad coverage against diverse lyssaviruses and to minimize possible escape variants, two most potent mAbs, NP-19-9 and 11B6, were selected to be used as cocktail treatment. These two mAbs were broadly reactive to different types of lyssaviruses isolates, and were shown to have no interference with each other. These results suggest that NP-19-9 and 11B6 are potent candidates to be used for PEP, suggesting further studies involving clinical studies in human.

Robusta beans cultivated with Monascus ruber (RMR) were successively fermented with Leuconostoc mesenteroides (LM) and the antiobesity effects were examined. To produce an obese mouse model to investigate the hypolipidemic effects, ICR mice were fed the same high-fat diet for 6 weeks. Treatment groups were given 10 or 20% RMR-LM. Body weight changes in the 20% RMR-LM group were lower compared with those in the control group. Visceral adipose tissue weight and adipose size were significantly lower in the 20% RMR-LM group compared with those in the control group. Significant improvement in glucose tolerance was observed in the 10 and 20% RMR-LM groups compared with the control group. The 20% RMR-LM group exhibited a significant reduction in serum glucose concentration. Hepatic mRNA levels of sterol regulatory element-binding protein 1, fas cell surface death receptor, and peroxisome proliferator-activated receptor γ, which are associated with lipid, and fatty acid metabolism, in the 20% RMR-LM group were significantly lower compared with those in the control group. The results of the present study demonstrated that 20% RMR-LM may be used to prevent obesity, and ameliorate diabetes and lipid metabolism imbalances.

Purpose: To evaluate the relationship between lens density using the Scheimpflug system and phacodynamics in nuclear cataracts as related to patient age. Methods: In 262 eyes with nuclear cataracts, the objective lens density was determined by Pentacam Nucleus Staging (PNS) software while subjective grading was achieved using the Lens Opacities Classification System III (LOCS III). Results: Overall, cumulated dissipated energy (CDE) had a positive correlation with Scheimpflug lens density and LOCS III nuclear scores. When analysis was done by patient age, LOCS III nuclear scores and Scheimpflug lens density had a positive correlation with CDE for patients in all age groups. Of interest, patients >70 years old showed a higher correlation coefficient (r) with Scheimpflug lens density than with LOCS III nuclear score. Conclusions: Scheimpflug lens densitometry may be more useful for predicting phacodynamics than LOCS III scores in nuclear cataract patients, especially in old age (>70 years).

The protective effect of Phellinus linteus (ethanol extract) against osteoporosis was investigated using the Saos-2 human osteoblast-like cell line and osteoclasts. A nontoxic concentration of Ph. linteus (10-2 to 10-8 mg mL-1) increased alkaline phosphatase (ALP) (EC 3.1.3.1) activity to a larger extent than soy did. Ph. linteus also attenuated the number and the activity of tartrate-resistant acid phosphatase-positive multinucleated osteoclasts. These results indicate that Ph. linteus likely regulated both osteoblasts and osteoclasts, contributing to the protection against osteoporosis. The protective effect of Ph. linteus was examined in ovariectomized (OVX) rats. Histological analysis indicates that Ph. linteus improved trabecular bone mass and reduced osteoclast frequency without affecting lipid droplet accumulation in the femur of OVX rats. A Ph. linteus supplementation for 12 weeks also significantly increased serum ALP activity and reduced urinary deoxypyridinoline level in OVX rats. Ultimately, we found that 12-week Ph. linteus supplementation increased the bone accumulation of minerals, including calcium, magnesium, and phosphorus. Collectively, Ph. linteus protected against osteoporosis by balancing the number of osteoblasts and osteoclasts, which was particularly associated with increased ALP activity in vitro and in vivo and mineral accumulation in bone.

Chronic obstructive pulmonary disease (COPD) is highly heterogeneous and not well understood. Hyperpolarized xenon-129 (Xe129) magnetic resonance imaging (MRI) provides a unique way to assess important lung functions such as gas uptake. In this pilot study, we exploited multiple imaging modalities, including computed tomography (CT), gadolinium-enhanced perfusion MRI, and Xe129 MRI, to perform a detailed investigation of changes in lung morphology and functions in COPD. Utility and strengths of Xe129 MRI in assessing COPD were also evaluated against the other imaging modalities.Four COPD patients and four age-matched normal subjects participated in this study. Lung tissue density measured by CT, perfusion measures from gadolinium-enhanced MRI, and ventilation and gas uptake measures from Xe129 MRI were calculated for individual lung lobes to assess regional changes in lung morphology and function, and to investigate correlations among the different imaging modalities.No significant differences were found for all measures among the five lobes in either the COPD or age-matched normal group. Strong correlations (R0.5 or-0.5, p0.001) were found between ventilation and perfusion measures. Also gas uptake by blood as measured by Xe129 MRI showed strong correlations with CT tissue density and ventilation measures (R0.5 or-0.5, p0.001) and moderate to strong correlations with perfusion measures (R0.4 or-0.5, p0.01). Four distinctive patterns of functional abnormalities were found in patients with COPD.Xe129 MRI has high potential to uniquely identify multiple changes in lung physiology in COPD using a single breath-hold acquisition.

The importance of PPARγ (peroxisome proliferator-activated receptor γ) in gastric cancer (GC) is unclear. We investigated the role of PPARγ in GC cell lines and an animal model, and its prognostic significance of PPARγ in GC patients. We controlled PPARγ and galectin-9 expression by using siRNAs and lentiviral constructs. Interaction between PPARγ and galectin-9 was evaluated using luciferase and chromatin immunoprecipitation assays. PPARγ expression in GCs was determined by immunohistochemical staining of tissue microarrays and survival analysis was done. Overexpression of PPARγ was accompanied by increased galectin-9. Enhanced PPARγ or galectin-9 expression increased E-cadherin expression; decreased expression of N-cadherin, fibronectin, snail, twist and slug and reduced cell invasion and migration. PPARγ bound to the galectin-9 promoter region. Galectin-9 activity increased in PPARγ-overexpressing cells but decreased in PPARγ siRNA-treated cells. In a zebrafish xenograft model, the number of migrated cancer cells and number of fish with AGS cells in the tail vein were reduced in PPARγ-overexpressing GC cells. PPARγ was expressed in 462 of the 688 patients (69.2%) with GC. In 306 patients with intestinal-type GC, those with PPARγ-positive tumors had lower overall and cancer-specific mortalities than those with PPARγ-negative tumors. PPARγ expression was an independent prognostic factor for overall and GC-specific mortality in patients with intestinal-type GC (adjusted hazard ratio, 0.42; 95% CI, 0.22-0.81). PPARγ inhibits cell invasion, migration and epithelial-mesenchymal transition through upregulation of galectin-9 in vitro and in vivo.

Severe adenovirus pneumonia that causes acute respiratory failure can occur in infants, children, and immunocompromised patients. However, severe adenovirus pneumonia is rare in adults with a normal immune system. Adenovirus pneumonia may progress to acute respiratory failure in a few hours or a few days, and its clinical course cannot be predicted. In addition, the mortality rate is very high (range, 50% to 66%). However, the optimal treatment of adenovirus pneumonia has not been established. Herein, we report the successful treatment of acute respiratory failure due to adenovirus pneumonia with extracorporeal membrane oxygenation.

Obesity is the leading metabolic disease in industrialized countries and is closely associated with coronary heart disease, hypertension, diabetes, and cancer. The objective of this study was to evaluate the anti-adipogenic effects of two roasted coffee beans, Vietnam robusta (VR) and Ethiopia Mocha Sidamo G2 (ES), as well as fermented coffee beans with Monascus ruber (MR) mycelium on differentiation of 3T3-L1 preadipocytes. Treatments with 1,000 μg/mL of hot water extract from coffee beans significantly reduced intracellular lipid accumulation. In addition, VR more effectively inhibited transcription factors such as PPARγ, C/EBPα, FAS, and aP2 compared to ES. Further, ES fermented with MR showed more effective anti-adipogenic activity than non-fermented ES. These results suggest that VR and ES inhibit adipocyte differentiation which may contribute to their anti-adipogenic properties.

Background: Idiopathic interstitial pneumonia is characterized by fibroblast proliferation and extracellular matrix (ECM) accumulation. Matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) have been shown to regulate remodeling of the ECM, which indicates that they are important factors in the process of lung fibrosis. Therefore, we evaluated the expression of MMPs and TIMPs in tissues obtained from patients with idiopathic interstitial pneumonia and control tissues. Methods: Thirty-seven patients who were diagnosed with IIP (22: IPF, 13: NSIP, 2: COP) and 5 controls were enrolled in this study. The MMP-2 and -9 activity in lung tissue obtained from these patients was analyzed using gelatin zymography and the levels of TIMP-1 and -2 were measured by western blotting. We also evaluated the expression of MMP-2 and -9, as well as that of TIMP-1 and -2 in lung tissue using immunohistochemistry. Results: The levels of MMP-2 and MMP-9 were significantly increased in patients with IPF compared to those with NSIP and COP. The activities of TIMP-1 and -2 were also higher in patients with IPF than NSIP/COP patients and control subjects. There were no significant differences observed in the activities of MMPs and TIMPs obtained from patients with NSIP/COP and control subjects. The immunohistochemical analysis showed that TIMP-2 and MMP-2 were strongly stained at the fibroblasts of the fibroblastic foci in patients with IPF. Conclusions: These results suggest that over-expression of gelatinases and TIMPs in patients with IPF are important factors in the irreversible fibrosis that is associated with lung parenchyma.

Achievement of long-term survival of patients with lung cancer treated with conventional chemotherapy is still difficult for treatment of metastatic and advanced tumors. Despite recent progress in investigational therapies, survival rates are still disappointingly low and novel adjuvant and systemic therapies are urgently needed. A recently elucidated secretory pathway is attracting considerable interest as a promising anticancer target. The cis-Golgi matrix protein, GOLGA2/GM130, plays an important role in glycosylation and transport of protein in the secretory pathway. In this study, the effects of short hairpin RNA (shRNA) constructs targeting GOLGA2/GM130 (shGOLGA2) on autophagy and lung cancer growth were evaluated in vitro and in vivo. Downregulation of GOLGA2/GM130 led to induction of autophagy and inhibition of glycosylation in A549 cells and in the lungs of K-ras(LA1) mice. Furthermore, downregulation of GOLGA2/GM130 decreased angiogenesis and cancer cell invasion in vitro and suppressed tumorigenesis in lung cancer mice model. The tumor specificity of sequence targeting GOLGA2/GM130 was also demonstrated. Taken together, these results suggest that induction of autophagy by shGOLGA2 may induce cell death rather than cell survival. Therefore, downregulation of GOLGA2/GM130 may be a potential therapeutic option for lung cancer.

Osteopontin (OPN) is a secreted glycophosphoprotein that has been implicated in the regulation of cancer development. The function of OPN is primarily regulated through post-translational modification such as glycosylation. As yet, however, the relationship between OPN glycosylation and lung cancer development has not been investigated. In this study, we addressed this issue by studying the effect of a triple mutant (TM) of OPN, which is mutated at three O-glycosylation sites, on lung cancer development in K-ras (LA1) mice, a murine model for human non-small cell lung cancer.Aerosolized lentivirus-based OPN TM was delivered into the lungs of K-ras (LA1) mice using a nose-only-inhalation chamber 3 times/wk for 4 wks. Subsequently, the effects of repeated delivery of OPN TM on lung tumorigenesis and its concomitant OPN-mediated signaling pathways were investigated.Aerosol-delivered OPN TM inhibited lung tumorigenesis. In addition, the OPN-mediated Akt signaling pathway was inhibited. OPN TM also decreased NF-κB activity and the phosphorylation of 4E-BP1, while facilitating apoptosis in the lungs of K-ras (LA1) mice.Our results show that aerosol delivery of OPN TM successfully suppresses lung cancer development in the K-ras (LA1) mouse model and, therefore, warrant its further investigation as a possible therapeutic strategy for non-small cell lung cancer.

Radiotherapy alone has several limitations for treating lung cancer. Inhalation, a non-invasive approach for direct delivery of therapeutic agents to the lung, may help to enhance the therapeutic efficacy of radiation. Up-regulating beclin1, known as a tumor suppressor gene that plays a major role in autophagy, may sensitize tumors and lead to tumor regression in lungs of K-ras(LA1) lung cancer model mice. To minimize the side-effects of radiotherapy, fractionated exposures (five times, 24-h interval) with low dose (2 Gy) of radiation to the restricted area (thorax, 2 cm) were conducted. After sensitizing the lungs with radiation, beclin1, complexed with a nano-sized biodegradable poly(ester amine), was prepared and delivered into the murine lung via aerosol three times/week for four weeks. In a histopathological analysis, animals treated with beclin1 and radiation showed highly significant tumor regression and low progression to adenocarcinoma. An increase in the number of autophagic vacuoles and secondary lysosomes was detected. Dissociation of beclin1-bcl2 stimulated autophagy activation and showed a synergistic anti-tumor effect by inhibiting the Akt-mTOR pathway, cell proliferation and angiogenesis. The combination of radiation with non-invasive aerosol delivery of beclin1 may provide a prospect for developing novel therapy regimens applicable in clinics.

Seong-Ho Hong1,*, Ji-Eun Kim1,6,*, You-Kyoung Kim2, Arash Minai-Tehrani1, Ji-Young Shin1, Bitna Kang1, Hye-Joon Kim1, Chong-Su Cho2, Chanhee Chae3, Hu-Lin Jiang1, Myung-Haing Cho1,4–71Laboratory of Toxicology, 2Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, 3Laboratory of Pathology, College of Veterinary Medicine, 4Graduate Group of Tumor Biology, 5Center for Food and Toxicology, Seoul National University, Seoul, Korea; 6Department of Nano Fusion Technology, Graduate School of Convergence Science and Technology, 7Advanced Institute of Convergence Technology, Seoul National University, Suwon, Korea*These authors contributed equally to this workBackground: Polyethylenimine (PEI)-based nonviral gene-delivery systems are commonly employed because of their high transfection efficiency. However, the toxic nature of PEI is a significant obstacle in clinical gene therapy. In this study, we developed biocompatible glycerol triacrylate–spermine (GT–SPE) polyspermine as a nanosized gene carrier for potential lung cancer gene therapy.Methods: The GT–SPE was synthesized using the Michael addition reaction between GT and SPE. The molecular weight was characterized using gel permeability chromatography multiangle laser light scattering and the composition of the polymer was analyzed using proton nuclear magnetic resonance.Results: The GT–SPE successfully protected the DNA from nucleases. The average particle size of the GT–SPE was 121 nm with a zeta potential of +23.45 mV. The GT–SPE was found to be less toxic than PEI for various cell lines, as well as for a murine model. Finally, our results showed that the GT–SPE/small hairpin Akt1 (shAkt1) complex suppressed lung tumorigenesis in a K-rasLA1 lung cancer mice model by inducing apoptosis through the Akt signaling pathway and cell cycle arrest. Aerosol delivered GT–SPE/shAkt1, which reduced matrix metalloproteinase-9 activity and suppressed the expression levels of proliferating cell nuclear antigen, as well as vascular endothelial growth factors and CD31, which are known proliferation and angiogenesis markers, respectively.Conclusion: Our data suggest that GT–SPE may be a candidate for short hairpin-shaped RNA-based aerosol lung cancer gene therapy.Keywords: lung cancer, gene therapy, aerosol delivery, spermineCorrigendum has been published for this paper.

MicroRNAs, small non-coding RNAs, are key regulators of tumorigenesis and cancer metastasis through inhibition of gene expression. Therefore, there is increasing interest in developing anti-cancer therapies using microRNAs. In this study, we determined the therapeutic potency of microRNA-145(miR-145) against breast cancer. We found a reverse-correlation between the expression of miR-145 and its target genes, such as fascin-1, c-myc, SMAD2/3 and IGF-1R in breast cancer cell lines and breast cancer patient tissues. Transfected miR-145 mimicking double-stranded oligonucleotides was directly reduced cell proliferation and motility via interaction with 3'UTR of target gene and also indirectly regulates Wnt signaling. An inhibitor of miR-145 nullified this decreasing effect of miR-145 on cell proliferation and motility. We prepared an adenoviral constructed miR-145(Ad-miR-145) and subjected it to breast cancer cells in vitro and orthotopic breast cancer mice in vivo. Ad-miR-145 suppressed cell growth and motility in both the in vitro and in vivo systems. Furthermore, a treatment combining Ad-miR-145 with 5-FU significantly showed anti-tumor effects, compared to treating alone. In conclusion, this study demonstrated that miR-145 suppresses tumor growth by inhibition of multiple tumor survival effectors, and more we suppose that miR-145 is potentially useful in the therapy of breast cancers.

Rationale: Phosphate (Pi) is an essential nutrient to living organisms. Recent surveys indicate that the intake of Pi has increased steadily. Our previous studies have indicated that elevated Pi activates the Akt signaling pathway. An increased knowledge of the response of lung cancer tissue to high dietary Pi may provide an important link between diet and lung tumorigenesis. Objectives: The current study was performed to elucidate the potential effects of high dietary Pi on lung cancer development. Methods: Experiments were performed on 5-week-old male K-rasLA1 lung cancer model mice and 6-week-old male urethane-induced lung cancer model mice. Mice were fed a diet containing 0.5% Pi (normal Pi) and 1.0% Pi (high Pi) for 4 weeks. At the end of the experiment, all mice were killed. Lung cancer development was evaluated by diverse methods. Measurement and Main Results: A diet high in Pi increased lung tumor progression and growth compared with normal diet. High dietary Pi increased the sodium-dependent inorganic phosphate transporter-2b protein levels in the lungs. High dietary consumption of Pi stimulated pulmonary Akt activity while suppressing the protein levels of tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 as well as Akt binding partner carboxyl-terminal modulator protein, resulting in facilitated cap-dependent protein translation. In addition, high dietary Pi significantly stimulated cell proliferation in the lungs of K-rasLA1 mice. Conclusions: Our results showed that high dietary Pi promoted tumorigenesis and altered Akt signaling, thus suggesting that careful regulation of dietary Pi may be critical for lung cancer prevention as well as treatment.

Henoch-Schonlein purpura (HSP) frequently occurs in children under 15 years of age but is quite rare in adults. Most children who develop HSP nephritis completely recover from the illness, whereas up to 40% of adults have persistent hematuria and 10% develop chronic renal failure. Plasma exchange alone has been shown to be beneficial in children who have HSP nephritis. Adults have been treated using immunosuppressive drugs such as cyclophosphamide but effects are not certain. Here, we present a case of a 59-year-old white male who developed HSP nephritis while undergoing treatment with steroids. The patient developed acute renal failure with proteinuria and hematuria ∼2 weeks after being initially diagnosed with HSP by skin biopsy. Renal biopsy showed proliferative, exudative glomerulonephritis involving all 20 glomeruli; some with early crescent formation. Immunofluorescence staining showed 3+ IgA deposits in mesangium suggesting HSP-induced GN. The patient's serum creatinine rose to 2.5 mg/dl with ∼5 g of proteinuria by dipstick. Steroids were continued and the patient received plasma exchange treatments. Due to a very low leukocyte count, immunosuppressive agents were not given. Subsequently, renal function improved and the creatinine level came down to 1.3 mg/dl and proteinuria to

Introduction Automatic fire suppression systems use hydrofluorocarbons (HF) to extinguish fires chemically. At high temperatures, HF can release hydrofluoric acid (HFA), a toxic, potentially lethal gas. Case report A 52-year-old male visited our Pulmonary Division with dyspnea of 8-months duration. He had been working at a facility that manufactured fire extinguishers. Bronchoscopy was performed and a transbronchial lung biopsy was taken from the right lower lobe. After the patient was diagnosed with pulmonary alveolar proteinosis (PAP), whole-lung lavage was performed. In this case, fire extinguisher gas induced pulmonary alveolar proteinosis. This material should be used with care and investigated further. Discussion HFA is corrosive and penetrates organic materials, including body tissues. Depending on the mode of exposure, skin ulceration, pulmonary injury, or even systemic shock can result. This report describes PAP that developed after chronic, repeated exposure to fire extinguisher spray. Hydrofluoric acid can induce pulmonary disorders such as PAP.

Objectives/Hypothesis: Although there are numerous reports on otoconial morphology using field-emission scanning electron microscopy (FESEM), there are few reports regarding the changes of otoconial morphology with aging. The aim of the current study was to investigate changes in otoconial morphology in rats according to age, using FESEM. Study Design: Laboratory study using experimental animals. Methods: We investigated age-related changes in otoconial morphology using FESEM in three groups of rats: young (1 wk old), middle-aged (6 mo old), and aged (23 mo old). Results: There was great size variation in utricular otoconia in the young and aged rats, but we found no clear regional separation of saccular otoconia in all groups based on size. In the oldest rats, the bodies of many otoconia in both maculae were pitted, fissured, penetrated, and eventually broken into several fragments. However, the terminal facets were smooth and the lines of intersection of facets were sharp, despite the degenerated bodies of the otoconia in this group. Giant otoconia were discovered frequently on the outer margin of the utricular maculae in aged rats. We directly observed weakened or broken linking filaments and otoconial fragments in the aged group. Conclusion: The oldest rats showed the most degeneration of otoconia and linking filaments with otoconial fragments. This study of age-related morphologic changes in otoconia might help us understand the origin of idiopathic benign paroxysmal positional vertigo.

Quercetin, one of the most abundant flavonoids in human diet has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of quercetin on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant decrease in body and liver weight. Oral administration of quercetin (10 mg kg−1 daily for 4 weeks) remarkably prevented this DMN-induced loss in body and liver weight and inhibited the elevation of serum alanine transaminase, aspartate transaminase and bilirubin levels. Quercetin also increased serum albumin and hepatic glutathione levels and reduced the hepatic level of malondialdehyde. Furthermore, DMN-induced elevation of hydroxyproline content was reduced in the quercetin treated rats, the result of which was consistent with a reduction in type I collagen mRNA production and histological analysis of liver tissue stained with Sirius red. A reduction in hepatic stellate cell activation, as assessed by α-smooth muscle actin staining, was associated with quercetin treatment as well as a reduction in transforming growth factor-β1 expression. In conclusion, these results demonstrate that quercetin exhibited in-vivo hepatoprotective and anti-fibrogenic effects against DMN-induced liver injury and suggest that quercetin may be useful in the preventing the development of hepatic fibrosis.

Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG) have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC). Two kinds of chimeric human antibodies (chimeric #7 and #17) were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

MicroRNAs (miRNAs) play a critical role in gastric cancer progression and metastasis. This study investigated the role of miRNA-135a in early gastric cancer (EGC) including lymph node (LN) metastasis. We examined the correlation between miRNA-135a expression and clinical outcomes in 59 patients who underwent surgery for EGC. Using gastric cancer cell lines, we performed functional and target gene analyses. miRNA-135a expression was down-regulated in 33.9% of patients. These patients showed a significantly more advanced stage (TNM stage ≥ IB, 35.0% vs. 12.8%, p = 0.045) and higher rate of LN metastasis (30.0% vs. 5.1%, p = 0.014) than those with up-regulation of miRNA-135a expression. In a multivariate analysis, down-regulation of miRNA-135a was an independent risk factor for LN metastasis (adjusted odds ratio, 8.04; 95% confidence interval, 1.08-59.81; p = 0.042). Functional analyses using gastric cancer cell lines showed that miRNA-135a suppressed cell viability, epithelial-mesenchymal transition, cell invasion, and migration. ROCK1 was a target of miRNA-135a and its expression was inversely correlated to that of miRNA-135a. ROCK1 expression was significantly increased in EGC patients with LN metastasis than in those without LN metastasis. Our results confirm the tumor-suppressive role of miRNA-135a, and demonstrate its role in LN metastasis in EGC. miRNA-135a and its target gene ROCK1 may be novel therapeutic and prognostic targets for EGC.

Most cervical cancers are caused by 15 high-risk (HR) and three probable high-risk (pHR) oncogenic types of human papillomavirus (HPV). However, current commercial HR HPV screening test products do not include pHR HPV genotypes. Recently, PapilloScreen has been developed to detect the 15 HR and three pHR HPV types. In this study, we evaluated the concordance levels and clinical performance of Hybrid Capture 2 (HC2), PapilloScreen, and a PCR sequencing assay in detecting HR and pHR HPV. The PapilloScreen (96.8 %) and PCR sequencing assay (96.8 %) demonstrated higher sensitivity than HC2 (80.7 %) for detecting HR and pHR HPV. The three assays showed similar specificities and positive or negative predictive values. The concordance levels were 86.5 % (κ = 0.68) and 86.5 % (κ = 0.67) between HC2 and PapilloScreen and between HC2 and PCR sequencing, respectively. A near-perfect concordance was observed between PapilloScreen and PCR sequencing (97.8 %, κ = 0.95). Overall, the agreement between the three assays suggests that the results obtained by the HC2 assay are more often discordant (12.6 %) than the PCR-based tests. In conclusion, PapilloScreen is highly sensitive for detecting high-grade CIN or cervical cancer. The PapilloScreen assay should be considered an accurate and sensitive method for detecting HR and pHR HPV infections and an epidemiological tool for prevalence studies as well as early diagnosis and intervention in HR and pHR HPV infections.

As hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, development of novel therapeutic approaches for HCC is urgently needed. Two different genes, LETM1 and CTMP, which target mitochondrial functions, were chosen and linked using 2A-peptide sequence. Successful self-cleavage of 2A-peptide induced synergistic antitumor effect in the liver of H-ras12V, the HCC model mice, by simultaneous activation of LETM1 (Leucine zipper/EF hand-containing transmembrane-1) and CTMP (carboxyl-terminal modulator protein). Overexpression of LETM1 and CTMP significantly reduced the incidence of tumorigenesis, which were confirmed by gross and microscopic observations. Morphological changes in mitochondria, such as swelling and loss of cristae, were significant, and the prolonged activation of defects in mitochondrial function led to mitochondria-mediated apoptosis. Furthermore, with CTMP as a direct binding partner of Akt1, and LETM1 as a binding partner of CTMP, LETM1-2A-CTMP downregulated the Akt1 pathway at both Ser473 and Thr308 sites of phosphorylation. Proliferation and angiogenesis, which are important in cancer prognosis, were reduced in tumor sites after introduction of LETM1-2A-CTMP. Taken together, the results indicate that introduction of the mitochondria-targeting genes, LETM1 and CTMP, and self-processing capacity of 2A-peptide sequence exerts an antitumor effect in liver of H-ras12V mice, suggesting its potential as a tool for gene therapy.

Beclin1, as a key molecule in controlling autophagy pathway, can activate both cell survival and cell death pathway. As a role of autophagy in cancer progression remains controversial, introduction of beclin1 to the lungs of K-ras(LA1) mice was performed via inhalation. Prolonged autophagy activation was induced by repeated exposure of lentivirus-beclin1, total of 8 times (2 times/week, 4 weeks). By the time of sacrifice, lungs were collected and analyzed for the therapeutic efficacy. Total numbers of tumors on the surface and histopathological tumor progression were reduced in the lungs of K-ras(LA1) mice. Successful delivery of beclin1 induced autophagy and apoptosis in the target organ, which were confirmed by following features; increased autophagic vacuoles in the cytosol, increased number of mitochondria with decreased mitochondrial 12S RNA, and increased protein levels of mitochondria-related apoptosis. Markers for cell proliferation and angiogenesis, PCNA and VEGF, which used for prediction of cancer prognosis, were significantly reduced after introduction of beclin1. Taken together, the results indicate that autophagy regulating gene, beclin1, can be a potential target for lung cancer gene therapy.

Background The need for accurate genotyping of human papillomavirus (HPV) infections is becoming increasingly important as HPV is the primary cause of cervical cancer worldwide. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry-based restriction fragment mass polymorphism (RFMP) assay provides accurate, broad-spectrum, high-throughput genotyping of HPV. Objectives We evaluated the clinical performance of the RFMP assay compared to a commercially available Roche linear array HPV genotyping test (LA) for detecting and genotyping of HPV. Study design The RFMP assay and the LA were compared for detecting and genotyping HPV among a cohort of 244 liquid-based cytology samples. Results Overall, 216 specimens (93.1%, κ = 0.86) generated concordant results for the presence or absence of high-risk HPV (HR-HPV) by the two assays. The RFMP assay and the LA assay generated concordant, compatible, and discordant genotyping results for 79.3, 9.9, and 10.8%, respectively. The diagnostic sensitivity and specificity of RFMP and LA for the cervical lesions of squamous cell carcinoma (SCC) were similar, at 92.9 and 85.0% (RFMP) and 92.9 and 83.8% (LA), respectively. In addition, the odds ratio for SCC with HR-HPV positivity estimated by the RFMP assay (73.7, 95% CI: 8.9–3173.3) was higher than the LA assay (67.0, 95% CI: 8.2–2887.0). Conclusions The RFMP and the LA assays were highly comparable with regard to detection and genotyping analysis of HPV. The sensitivity and specificity of RFMP assay for the detection of HR-HPV in various levels of cervical lesions seems to be valuable in the monitoring of HPV-associated cervical cancer.

Osteopontin (OPN) serves as an indicator of resistance to radiotherapy. However, the role of OPN in the development of acquired radioresistance in human lung cancer cells has not yet been fully elucidated. Therefore, the potential importance of OPN as a marker of lung cancer with a potential significant role in the development of radioresistance against repeated radiotherapy has prompted us to define the pathways by which OPN regulates lung cancer cell growth. In addition, autophagy has been reported to play a key role in the radiosensitization of cancer cells. Here, we report that increased OPN expression through induction of nuclear p53 following irradiation was inhibited by exogenous beclin-1 (BECN1). Our results clearly show that BECN1 gene expression led to induction of autophagy and inhibition of cancer cell growth and angiogenesis. Our results suggest that the induction of autophagy abrogated the radioresistance of the cancer cells. Interestingly, we showed that knockdown of OPN by lentivirus-mediated shRNA induced the autophagy of human lung cancer cell. Taken together, these results suggest that OPN and BECN1 can be molecular targets for overcoming radioresistance by controlling autophagy.

To assess the usefulness of (18)F-fluorodeoxyglucose PET/CT in the detection of bone marrow (BM) involvement of high-grade non-Hodgkin's lymphoma (NHL).One hundred twenty patients with newly diagnosed diffuse large B-cell lymphoma or peripheral T-cell lymphoma between January 2007 and June 2011, who received BM trephine biopsy and (18)F-FDG PET/CT before chemotherapy, were included in this retrospective study. We reviewed their (18)F-FDG PET/CT images and bone marrow biopsy (BMB) results. After reviewing the images, we reviewed the medical records and radiological findings of interesting patients.There were 23 (18)F-FDG PET/CT scans in which the marrow was considered to be abnormal (either positive or equivocal), and 97 (18)F-FDG PET/CT scans were regarded as having negative FDG uptake. Of 120 patients, 100 (83.3 %) had a concordant result of BM interpretation between (18)F-FDG PET/CT and BMB, and the remaining 20 patients had discordant results. Among 23 patients with either positive or equivocal (18)F-FDG PET/CT scans, 1 of 12 patients with 'positive' (18)F-FDG PET/CT had a lymphomatous involvement on BMB. In contrast, 10 of 11 patients with 'equivocal' BM hypermetabolism were reported as having positive involvement by BMB. Patients with abnormal (18)F-FDG PET/CT had significantly higher mSUVhighest than those with normal FDG-PET/CT.(18)F-FDG PET/CT and BMB are complementary techniques in assessing the presence of BM involvement in patients with high-grade NHL. The increasing availability of (18)F-FDG PET/CT will raise the need for additional biopsy for FDG-avid lesions, especially in patients with negative standard BMBs. (18)F-FDG PET/CT can be useful as a decision-making tool for determining whether to perform a standard BMB or targeted biopsy to the FDG-avid lesion as an initial staging procedure. A direct bone biopsy for FDGpositive bone lesions should be included in staging guidelines in future. In (18)F-FDG PET/CT-negative cases, BMB is still a powerful procedure, but BMB alone is insufficient for full evaluation of BM.

The analysis using quantitative immunohistochemistry (IHC) with diagnostic and prognostic biomarkers is a powerful tool for scientific and clinical research in colon cancer at early stages. The potential utility of distinct protein expression depending on the stages of colon cancer has generated interest in diagnostic and prognostic biomarkers of colon cancer. Colon cancer secreted protein-2 (CCSP-2) has been reported as a novel protein expressed in colon adenomas and cancers but not in normal colon tissue. Thus, this protein has emerged as a potential prognostic marker at early stages. In addition, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been useful as a diagnostic or prognostic marker for colon cancer. To clarify the assessment parameters for CCSP-2 and 15-PGDH in colon cancer, we evaluated its clinical, molecular and survival associations in colon cancer, according to stages of colon cancer and the tumor microenvironment, such as immune cells, by multiplex immunohistochemistry. Formalin fixed paraffin embedded (FFPE) samples of patients' primary tumor were obtained and stained for markers include CD3, CD8, Cytokeratin, Ki-67, CCSP-2 and 15-PGDH by using PerkinElmer Opal system. Digital imaging and analysis were done using PerkinElmer Nuance and Inform software system. Density plot analysis revealed distributions of CCSP-2 and 15-PGDH in colon cancer tissues. The expression of CCSP-2 and 15-PGDH correlated with stages of colon cancer. Thus, CCSP-2 and 15-PGDH, as proteins that distinctly expressed in colon adenomas and adenocarcinomas, may be useful diagnostic and prognostic markers for detection of colorectal tumors. Citation Format: GyeongMin Park, Charles Jungje Cho, Ji-Young Shin, Eun-Ju Do, Yeon-Mi Ryu, Gil-Je Lee, Sang-Yeob Kim, Youngkuk Yun, Seung-Jae Myung. Digital quantitative immunohistochemistry for analysis of CCSP-2 and 15-PGDH expression in colon cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A83.

BACKGROUND: Galectin-3 is known to regulate cancer metastasis. However, the underlying mechanism has not been defined. Through the DNA microarray studies after galectin-3 silencing, we demonstrated here that galectin-3 plays a key role in up-regulating the expressions of protease-activated receptor-1 (PAR-1) and matrix metalloproteinase-1 (MMP-1) PAR-1 thereby promoting gastric cancer metastasis. METHODOLOGY/PRINCIPAL FINDINGS: We examined the expression levels of Galectin-3, PAR-1, and MMP-1 in gastric cancer patient tissues and also the effects of silencing these proteins with specific siRNAs and of over-expressing them using specific lenti-viral constructs. We also employed zebrafish embryo model for analysis of in vivo gastric cancer cell invasion. These studies demonstrated that: a) galectin-3 silencing decreases the expression of PAR-1. b) galectin-3 over-expression increases cell migration and invasion and this increase can be reversed by PAR-1 silencing, indicating that galectin-3 increases cell migration and invasion via PAR-1 up-regulation. c) galectin-3 directly interacts with AP-1 transcriptional factor, and this complex binds to PAR-1 promoter and drives PAR-1 transcription. d) galectin-3 also amplifies phospho-paxillin, a PAR-1 downstream target, by increasing MMP-1 expression. MMP-1 silencing blocks phospho-paxillin amplification and cell invasion caused by galectin-3 over-expression. e) Silencing of either galectin-3, PAR-1 or MMP-1 significantly reduced cell migration into the vessels in zebrafish embryo model. f) Galectin-3, PAR-1, and MMP-1 are highly expressed and co-localized in malignant tissues from gastric cancer patients. CONCLUSIONS/SIGNIFICANCE: Galectin-3 plays the key role of activating cell surface receptor through production of protease and boosts gastric cancer metastasis. Galectin-3 has the potential to serve as a useful pharmacological target for prevention of gastric cancer metastasis.

Background Metastasis to the lung may be the final step in the breast cancer-related morbidity. Conventional therapies such as chemotherapy and surgery are somewhat successful, however, metastasis-related breast cancer morbidity remains high. Thus, a novel approach to prevent breast tumor metastasis is needed. Methodology/Principal Finding Aerosol of lentivirus-based small hairpin osteopontin was delivered into mice with breast cancer twice a week for 1 or 2 months using a nose-only inhalation system. The effects of small hairpin osteopontin on breast cancer metastasis to the lung were evaluated using near infrared imaging as well as diverse molecular techniques. Aerosol-delivered small hairpin osteopontin significantly decreased the expression level of osteopontin and altered the expression of several important metastasis-related proteins in our murine breast cancer model. Conclusion/Significance Aerosol-delivered small hairpin osteopontin blocked breast cancer metastasis. Our results showed that noninvasive targeting of pulmonary osteopontin or other specific genes responsible for cancer metastasis could be used as an effective therapeutic regimen for the treatment of metastatic epithelial tumors.

Mutation of galectin-3 at position 191 (rs4644) substituting proline to histidine (gal-3H(64)) resulted in the acquisition of resistance to drug-induced apoptosis by breast cancer cells. This study employed gastric cancer cells and patient tissues in attempts to elucidate how and why this mutation in galectin-3 (gal-3H(64)) enhances cancer progression, compared to wild type galectin-3 (gal-3P(64)). First, we prepared lenti-virus constructs containing gal-3P(64), gal-3H(64) and LacZ, and used them to infect galectin-3 null SNU-638 cells. We found that gal-3H(64) over-expression increases gastric cancer cell growth more than gal-3P(64) or LacZ over-expression. Also, gal-3H(64) over-expression conferred more resistance to cisplatin or 5-FU induced cytotoxicity than gal-3P(64). Gal-3H(64) also enhanced nuclear accumulation of β-catenin as well as increased expression of TCF-4 target genes, such as fascin-1 and c-Myc through the augmented promoter binding activity of TCF-4, than gal-3P(64). We also demonstrated stronger staining of β-catenin and galectin-3 in malignant tissues from gastric cancer patients with mutated galectin-3 at position 191 (gal-3 191) (A/A) (H(64)) and greater localization in the nucleus than in gal-3 191 A/C (P(64)) cancer patients. Taken together, we elucidated in this study that germline variant of gal-3H(64) increases nuclear accumulation of β-catenin and promotes TCF transcriptional activity and enhances more the galectin-3's role in gastric cancer progression.

Carbon nanotubes (CNT) are known to have widespread industrial applications; however, several reports indicated that these compounds may be associated with adverse effects in humans. In this study, multiwalled carbon nanotubes were administered to murine lungs intratracheally to determine whether acute and chronic pulmonary toxicity occurred. In particular, pristine multiwalled carbon nanotubes (PMWCNT) and acid-treated multiwalled carbon nanotubes (TMWCNT) were used in this study. In broncheoalveolar lavage fluid (BALF) cell analysis, PMWCNT induced more severe acute inflammatory cell recruitment than TMWCNT. Histopathologically, both PMWCNT and TMWCNT induced multifocal inflammatory granulomas in a dose-dependent manner. The observed granulomas were reversible, with TMWCNT-induced granulomas diminishing faster than PMWCNT-induced granulomas. Although the area of granuloma reduced with time, hyperplasia and dysplastic characteristics such as mitotic figures, anisokaryosis, and anisocytosis were still observed. These findings demonstrate that MWCNT induces granulomatous inflammation, and the duration and pattern of inflammation seem to vary depending upon the types of MWCNT to which mice are exposed. Therefore, toxicity studies on various types of CNT are needed as the responsiveness to these compounds differs.

Galectin-3 is known to modulate cell proliferation and apoptosis and is highly expressed in human cancers, but its function in gastric cancer is still controversial. Here, we examined the role of galectin-3 in gastric cancer cells by silencing it with synthetic double-stranded siRNA. After silencing of galectin-3, cell numbers decreased and cell shape changed. Galectin-3 siRNA treatment also induced G1 arrest. DNA microarray analysis was used to assess changes in gene expression following galectin-3 silencing. We found that silencing of galectin-3 caused changes in gene expression. RT-PCR and real-time PCR were utilized for validation of the changes found in microarray studies. Western blot analysis confirmed changes in the expression of proteins of interest: cyclin D1, survivin, XIAP, XAF, PUMA, and GADD45α. Generally, it tended to increase the expression of several pro-apoptotic genes, and to decrease the expression of cell cycle progressive genes. We also confirmed that changes in the expression of these genes were caused by galectin-3 overexpression. Finally, we demonstrated that silencing of galectin-3 enhanced apoptosis induction with chemotherapeutic agents by further reducing the expression of anti-apoptotic and/or cell survival molecules such as survivin, cyclin D1, and XIAP, and increasing the expression of pro-apoptotic XAF-1. We conclude that galectin-3 is involved in cancer progression and malignancy by modulating the expression of several relevant genes, and inhibition of galectin-3 may be an approach to improve chemotherapy of gastric cancers. (Cancer Sci 2009)

Rationale: The low efficiency of conventional therapies in achieving long-term survival of patients with lung cancer calls for the development of novel therapeutic options. Recent advances in aerosol-mediated gene delivery have provided the possibility of an alternative for the safe and effective treatment of lung cancer. Objectives: To demonstrate the feasibility and emphasize the importance of noninvasive aerosol delivery of Akt1 small interfering RNA (siRNA) as an effective and selective option for lung cancer treatment. Methods:Nanosizedpoly(esteramine)polymerwassynthesizedand used as a gene carrier. An aerosol of poly(ester amine)/Akt1 siRNA complex was delivered into K-ras LA1 and urethane-induced lung cancer models through a nose-only inhalation system. The effects of Akt1 siRNA on lung cancer progression and Akt-related signals were evaluated. Measurements and Main Results: The aerosol-delivered Akt1 siRNA suppressed lung tumor progression significantly through inhibiting Akt-related signals and cell cycle. Conclusions: The use of poly(ester amine) serves as an effective carrier, and aerosol delivery of Akt1 siRNA may be a promising approach for lung cancer treatment and prevention.

Corynebacterium minutissimum is a non-spore forming, gram-positive, aerobic or facultative anaerobic bacillus. It is the causative organism of erythrasma, a common superficial infection of skin, which typically presents as reddish-brown macular patches. To date, it has rarely been found to cause invasive disease, although other non-diphtheria corynebacteria are becoming increasingly common as opportunistic pathogens. We report on a rare case of abdominal infection due to C. minutissimum in an immunocompetent adult who was successfully treated with intravenous amoxicillin/sulbactam.

Purpose: To report a case of corneal ulcer caused by Paecilomyces lilacinus after penetrating keratoplasty. Case summary: A 67-year-old male with a history of penetrating keratoplasty in the left eye 7 years prior and re-penetrating keratoplasty in the left eye due to graft failure in June 2013, visited our clinic for ocular pain and conjunctival injection in the left eye 3 days in duration. Corneal scrapings were performed for Gram and fungal stains and cultures. The patient was admitted to the hospital for hourly topical fortified ceftazidime and amphotericin B. Despite intensive topical therapy, no improvement was observed. Three days later, fungal culture confirmed Paecilomyces lilacinus and topical voriconazole was prepared from the intravenous formulation and was administered topically and intravenously. Despite medical therapy with voriconazole, perforation occurred requiring a tectonic keratoplasty. Conclusions: Keratitis caused by Paecilomyces lilacinus is difficult to eradicate and refractory to amphotericin B. We suggest early use of topical eyedrops, intracameral, and intravitreal injections of voriconazole may be an appropriate treatment for patients with Paecilomyces lilacinus keratitis. J Korean Ophthalmol Soc 2014;55(9):1384-1387

Introduction C-C chemokine receptor type 7 (CCR7) plays an important role in chemotactic and metastatic responses in various cancers, including breast cancer. In the present study, the authors demonstrated that microRNA (miRNA) let-7a downregulates CCR7 expression and directly influences the migration and invasion of breast cancer cells. Methods The expression of CCR7, its ligand CCL21, and let-7a was detected in breast cancer cell lines and in breast cancer patient tissues. Synthetic let-7a and an inhibitor of let-7a were transfected into MDA-MB-231 and MCF-7 breast cancer cells, respectively, and cell proliferation, cell migration, and invasion assays were performed. To confirm the fact that 3'UTR of CCR7 is a direct target of let-7a, a luciferase assay for the reporter gene expressing the let-7a binding sites of CCR7 3'UTR was used. An in vivo invasion animal model system using transparent zebrafish embryos was also established to determine the let-7a effect on breast cancer cell invasion. Results First, a higher expression of both CCR7 and CCL21 in malignant tissues than in their normal counterparts from breast cancer patients was observed. In addition, a reverse correlation in the expression of CCR7 and let-7a in breast cancer cell lines and breast cancer patient tissues was detected. Synthetic let-7a decreased breast cancer cell proliferation, migration, and invasion, as well as CCR7 protein expression in MDA-MB-231 cells. The let-7a inhibitor reversed the let-7a effects on the MCF-7 cells. The 3'UTR of CCR7 was confirmed as a direct target of let-7a by using the luciferase assay for the reporter gene expressing let-7a CCR7 3'UTR binding sites. Notably, when analyzing in vivo invasion, MDA-MB 231 cells after synthetic let-7a transfection were unable to invade the vessels in zebrafish embryos. Conclusions The results from the present study suggest that targeting of CCL21-CCR7 signaling is a valid approach for breast cancer therapy and that let-7a directly binds to the 3'UTR of CCR7 and blocks its protein expression, thereby suppressing migration and invasion of human breast cancer cells. Furthermore, the present study underscores the therapeutic potential of let-7a as an antitumor and antimetastatic manager in breast cancer patients.

As incidence and mortality due to lung cancer increase, great effort has been put into developing feasible therapeutics in medical field. Radiation, together with surgery and chemotherapy, is the must in treating lung cancer, however, side effects have to be taken into consideration. To minimize the side effect of radiotherapy, repeated exposures (5 times, 24 hours interval) with low dose (2Gy) of radiation to restricted area (thorax, 2cm) were attempted. After sensitizing lungs of K-rasLA1 mice with radiation, beclin1, known to be a tumor suppressor, involved in autophagy, complexed with nano-sized biodegradable poly(ester amine), was prepared and delivered into K-rasLA1 mice via aerosol 3 times for 4 weeks. Seventeen weeks old K-rasLA1 lung cancer model mice (n=20, 5 mice/group) were sacrificed and collected samples were analysed. K-rasLA1 mice treated with beclin1 and radiation showed significant tumor regression with low progression to adenocarcinoma and increment in number of autophagic vacuoles. Precedent event of beclin1-bcl2 dissociation stimulated synergistic anti-tumor effect via inhibition of protein translation and angiogenesis. Taken together, non-invasive treatment, radiation with PEA-beclin1 aerosol delivery, can be a feasible candidate for developing novel therapeutics in lung cancer treatment. This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (MEST) (NRF-2010-0000784). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5083. doi:10.1158/1538-7445.AM2011-5083

Surgery is the most effective therapy for early gastric cancers. In advanced gastric cancer (AGC), achievement of loco-regional control after tumor resection is less successful because of frequent recurrences after surgical and medical therapies. Combinations of 5-fluorouracil (5-FU) and platinum analogues or cytotoxic agents, such as capecitabine, cisplastin, oxaliplatin and S-1, are currently widely accepted as standard treatment for AGC. However, survival of AGC patients following sedative chemotherapy is poor. Therefore, the development of novel therapies has been needed, and some clinical studies already have been performed using novel molecular targeting agents have shown hopeful activity, particularly in combination with cytotoxic agents. Recently, the importance of Notch signal pathway has been reported in gastric cancer. Gamma-secretase inhibitors (GSI), a notch proteolytic activation blocker, can be considered as a novel target agent for gastric cancer. In this study, the anti-proliferation effects of GSI combined with 5-FU on gastric cancer cells in vitro and in vivo were studied. GSI combined with 5-FU was treated on gastric cancer cells, and then cell-proliferation by MTT assay, apoptosis by annexin V and expressions of protein level were determined by western blotting. Effects of GSI combined with 5-FU on tumor growth in vivo was assessed in an experimental model with orthotopically grown tumors. In gastric cancer cells, GSI combined with 5FU significantly inhibited cell proliferation and induced apoptosis. It was confirmed by expression changes of apoptosis related protein, such as caspase-3, caspase-8, caspase-9, PARP, BCL2, BID and BAX. GSI is also known to regulate PI3K/PTEN/AKT signaling pathway. After treatment with GSI plus 5-FU, this pathway was significantly down-regulated, and more, over-expression of constitutively activated AKT could prevent the apoptosis induction by combination treatment. This is suggested that the combination treatment with GSI plus 5-FU decreases the gastric cancer cell growth through inhibition of PI3K/PTEN/AKT signaling pathway. Moreover, administration of GSI in combination with 5-FU drastically reduced gastric tumor burdens in orthografted mice without prominent gastrointestinal toxicity. In conclusion, we present here that the combination treatment with GSI plus 5-FU has a potential for therapeutic activity in advanced gastric cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3506. doi:10.1158/1538-7445.AM2011-3506

Pulmonary sequestration is a rare anomaly, in which a local area of a lung is supplied separately by an anomalous artery that arises from the aorta or one of its branches. Infection, mainly bacterial, is a major complication of sequestration. We report the case of a 17-year-old male patient, who presented with cough and fever. The contrast-enhanced chest computer tomomgraphy (CT) scans revealed an aberrant artery that originated from the descending thoracic aorta. He underwent a left-lower lobectomy. Macroscopically, the abnormal segment presented as multiple heterogenous cystic and solid lesions, and the cysts were filled with mucoid and pus-like material. Histology showed that the pulmonary parenchyma had been replaced by caseating epitheloid granulomas. The mycobacterial culture of his sputum was positive. On the basis of these results, the diagnosis of tuberculosis was established. The patient was treated with anti-tuberculous medication for 6 months, and 1 year later, his clinical status remained excellent.

Gastric cancer is one of the most common cancers with mortal malignancy. Most patients with advanced gastric cancer have been treated with anti-cancer chemotherapies such as fluorouracil (5-FU), cisplatin and anthracycline which block mitotic cell division and induce consequent apoptotic cell death. However, there are needed novel gastric therapies and/or develop the new agents to overwhelm the resistance for traditional chemotherapeutic agents. Recent studies have reported that the Notch signaling pathway is associated with human gastric cancer and other cancers. Notch receptors are transmembrane proteins which are cleaved by protelolytic emzymes (gamma-secretase) and release their intracellular domain (ICD) upon activation status by ligand binding. In previous reports, notch intracellular domain (NICD) turns on target genes which are related with tumorigenesis such as COX-2, c-Myc and Snail in cancers, including gastric cancer cells. Thus we speculated that the blockage of notch signal would be useful strategy for chemotherapy of gastric cancers. We initially showed that Notch receptors and ligands are expressed in various gastric cancer cells through RT-PCR and western blotting. We also confirmed that Notch signals are activated in gastric cancer cells by Notch reporter gene analysis. Furthermore, GSI treatment reduced cell survival rate in gastric cancer cells, including AGS, SNU1, SNU601, and SNU638 cells. We observed G2/M mitotic arrest and subG1 arrest by GSI treatment in gastric cancer cells, accompanying with the increase of mitotic gene cyclin B1, cdc2, p21, and apototic caspase-3 activation. To demonstrate the effect of p21 increasing by GSI treatment, cell proliferation and G2/M cell cycle arrest was inhibited by GSI treatment in Myr-AKT lentivirus infection cell. Also, p21 and cyclinB1 protein levels were not increased after rapamycin treatment in Myr-AKT lentivirus infection cell. Collectively, these results suggest that GSI, which block Notch signal, would be a potential therapeutic drug in gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2488.

Results: There was no difference in the prevalence of typical symptoms between the younger and the elderly group. Dypsnea was the only symptom that occurred more frequently in the elderly group (16.8% vs 5.5%, p=0.008). On radiological study, pneumonic infiltration type was more common in the elderly group (28.6% vs 16.8%, p=0.035). Sputum Acid fast bacilli smear positivity rate was si milar between the 2 groups. Elderly patients with anti-tuberculosis medication had more frequent adverse drug reactions; however, there was no significant difference between the 2 groups in the number of patients required to stop medication due to an adverse drug reaction. There were more patients lost to follow-up in the elderly group (22/112, 19.6% vs 11/113, 9.7%, p=0.036). Conclusion: The majority of elderly patients did not complete the treatment, resulting in a poorer outcome. Therefore, we need to make an effort to support the continued screening of elderly patients by making this economically feasible.

Erdheim-Chester disease (ECD) is a proliferative non-Langerhans cell histiocytosis of multiple organs. This is a rare disease of unknown etiology with a high mortality. We present the case report of a 26-year-old man diagnosed with ECD. He was referred to our hospital with elevated levels of aminotransferases. Although the diagnosis was uncertain, the patient was lost to follow up at that time. One year later, the patient returned to the hospital with generalized edema. Although a specific bone lesion was not found, the patient was experiencing the following: glomerulonephritis, aplastic anemia, hepatitis, and lung involvement. A lung biopsy was performed: the immunohistochemical stain were positive for CD68 and negative for S-100 protein and CD1a. We diagnosed as the patient as havinf ECD. Approximately 50% of ECD cases present with extraskeletal involvement. ECD should be considered as part of the differential diagnosis when multiple organs are involved.

Antiretroviral therapy (ART) has increased the life expectancy of human immunodeficiency virus (HIV) infected patients. However, the incidence of kidney diseases in HIV-infected patients has increased. Before the ART era, HIV-associated nephropathy (HIVAN) was the most common type of glomerulonephritis in HIV-related kidney diseases, but after the advent of ART, many other types of glomerulonephritis, besides HIVAN, such as mesangial proliferative glomerulonephritis, immunoglobulin A (IgA) nephropathy, and immune-complex glomerulonephritis have been reported (1). In Korea, only 1 case of HIV-related membranous glomerulonephritis has been reported (2) and lupus-like glomerulonephritis has not been reported thus far. Therefore, we report a case of a patient with HIV-related lupus-like glomerulonephritis who showed good response to treatment with ART and steroids.

Background: Acute respiratory distress syndrome (ARDS) is ultimately an inflammatory state. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are inflammatory markers. The aim of this study was to evaluate the value of the ESR, CRP and APACHE II score as prognostic factors for patient with ARDS. Methods: We retrospectively analyzed the medical records of 87 ARDS patients. The predictors (APACHE II score, ESR and CRP) and outcomes (mortality and length of the total hospital stay, the ICU stay and mechanical ventilator care) were obtained from the patients' records. The patients were grouped according to survival as the Survivor and Non survivor groups. We compared the APACHE II score, the ESR and the CRP level between the survivor group and the nonsurvivor group. We evaluated the correlation between the predictors and the outcomes. The initial ESR, CRP level and APACHE II score were checked at the time of ICU admission and the second ESR and CRP level were checked days after ICU admission. Results: Thirty-eight (43.7%) patients remained alive and 49 (56.3%) patients died. The APACHE II score was significantly lower for the survivor group than that for the non survivor group ( vs , respectively, p=0.006). The initial ESR and CRP level were not different between the survivor and non-survivor groups (ESR vs , respectively, p=0.93, CRP vs , respectively, p=0.68). The decrement of the CRP level for the survivor group was greater than that for the non survivor group ( vs , respectively, p=0.003). Correlation analysis revealed the initial ESR was positively correlated with the length of the total hospital stay and the ICU stay (correlation coefficient of the total hospital days: R=0.43, p=0.001, correlation coefficient of the ICU stay: R=0.39, p=0.014). Conclusion: The initial APACHE II score can predict the mortality of ARDS patients, and the degree of the early CRP change can be a predictor of mortality for ARDS patients. The initial ESR has positive correlation with the ARDS patients' duration of the total hospital stay and the ICU stay.

Background: Surgical lung biopsy is required to establish the etiology and stage of interstitial lung disease(ILD). and this procedure can be safe and meaningful for making clinical decisions. We wanted to determine the safety of surgical lung biopsy(SLB) in patients with interstitial lung disease(ILD). Methods: We conducted a retrospective review of 40 patients with suspected ILD and they underwent surgical lung biopsy from January 2001 to June 2006 at Chungnam University Hospital. We analyzed retrospectively according to their age, gender, pulmonary function, chest tube duration, the arterial blood gases, the procedural technique, and the requirement for supplemental oxygen and mechanical ventilation(MV) at the time of SLB. Results: The mean age of the patients was 56.416.13 years(range: 21 to 77 years). Overall, the 30-day and 90-day mortality rates were 15% and 20%, respectively. The predictors of perioperative mortality were either the need for mechanical ventilation(MV) at the time of SLB or the need for supplemental oxygen prior to undergoing SLB. Among the 32 patients who were 90-day survivors, the proportion of those patients using the oxygen supplement was 28.1% (n=9). All 8 patients who were 90-day non-survivors used oxygen supplement (p=0.000). The use of the MV was 12.5% (n=4) in the 90-day survivors (n=32) and 62.5% (n=5) in the 90-day non-survivors (n=8); there was a significant difference between the 90-day survivors and non-survivors (p=0.000). Conclusion: Patients who require MV and supplemental oxygen are associated with an increased risk for death following SLB.