EMMPRIN expression is associated with metastatic progression in osteosarcoma.

BACKGROUND: Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell-surface glycoprotein, is overexpressed in several cancer types. EMMPRIN induces a metastatic phenotype by triggering the production of matrix metalloproteinase proteins (MMPs) such as MMP1 and MMP2, and vascular endothelial growth factor (VEGF) in cancer cells and the surrounding stromal cells. The purpose of this study was to investigate the expression and role of EMMPRIN in osteosarcoma. METHODS: The level of EMMPRIN expression was evaluated using reverse transcriptase polymerase chain reaction (RT-PCR) in 6 tumor-derived osteosarcoma cell lines and compared with that in normal osteoblasts. To study the prognostic significance of EMMPRIN expression, immunohistochemistry was carried out in prechemotherapy biopsies of 54 patients. siRNA knockdown of EMMPRIN in SaOS-2 cells was conducted to explore the role of EMMPRIN. To study the role of EMMPRIN in tumor-stromal interaction in MMP production and invasion, co-culture of SaOS-2 cells with osteoblasts and fibroblasts was performed. Osteosarcoma 143B cells were injected into the tail vein of BALB/c mice and lung metastasis was analyzed. RESULTS: EMMRIN mRNA expression was significantly higher in 5 of 6 (83%) tumor-derived cells than in MG63 cells. 90% of specimens (50/54) stained positive for EMMPRIN by immunohistochemistry, and higher expression of EMMPRIN was associated with shorter metastasis-free survival (p = 0.023). Co-culture of SaOS-2 with osteoblasts resulted in increased production of pro-MMP2 and VEGF expression, which was inhibited by EMMPRIN-targeting siRNA. siRNA knockdown of EMMPRIN resulted in decreased invasion. EMMPRIN shRNA-transfected 143B cells showed decreased lung metastasis in vivo. CONCLUSIONS: Our data suggest that EMMPRIN acts as a mediator of osteosarcoma metastasis by regulating MMP and VEGF production in cancer cells as well as stromal cells. EMMPRIN could serve as a therapeutic target in osteosarcoma.

Anti-cancer effect of dung beetle glycosaminoglycans on melanoma.

BACKGROUND: Dung beetle glycosaminoglycan is known to possess anti-aging activities. However, its anti-cancer mechanisms are not fully elucidated yet. The objective of this study was to evaluate the anti-cancer effect of insect-derived polymer dung beetle glycosaminoglycan (GAG) after intraperitoneally injecting it to melanoma mice induced by B16F10 cells. METHODS: To determine molecular mechanism involved in the anti-cancer effect of dung beetle GAG, its origin N-glycan under 3KD Dalton was assayed for melanoma cell cytotoxicity. Quantitative comparisons of adhesive molecule on extracellular matrix and activities of tissue inhibitor of metalloprotease 2 (TIMP-2) were also investigated. In vivo anti-cancer effect of dung beetle GAG on solid tumor size, survival time and gene-expression profiles was also assayed using B10F10 melanoma mice model. Mice with induced melanoma were then treated with Catharsius molossus (dung beetle) GAG (CaG) at 5 mg/kg for 8 weeks to investigate its anti-cancer effects compared to bumblebee (Bombus ignitus) queen glycosaminoglycan (IQG) and Huechys sanguinea glycosaminoglycan (HEG). RESULTS: These N-glycans derived from these GAG were composed of many linear heparinoid polysaccharides, polymers with hexose and N-acetylhexose. Adminstration with these GAGs increased survival time and decreased melanoma sizes in mice, in accordance with their inhibitory effects on cell growth ratio of melanoma B16F10. In addition, treatment with N-glycans derived from theses glycosaminoglycan increased activities of TIMP-2 in HMVEC cells pretreated with TNF-alpha and in melanoma cells, suggesting that they had anti-inflammatory and anticancer activities. In DNA microarray results, compared to control, CaG treated mouse group showed upregulation of 192 genes including collagen,typeI,alpha1 (Col1a1), consistent with the highly increased in vitro extracellular matrix (ECM) adhesion on collagen 1 and up-regulation of heparanase (Hpse). After treatment with CaG, a total of 152 genes were down-regulated, including nuclear RNA export factor (Nxf3) and hyaluronan proteoglycan link protein1 (Hapln1). CONCLUSIONS: Glycosaminoglycan, CaG can strengthen ECM by increasing activity of TIMP-2 and adhesion activity on collagen known to inhibit changes of ECM, leading to tumor cell invasion and progression.

Progranulin Controls Sepsis via C/EBPα-Regulated Il10 Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation.

Progranulin (PGRN) is a widely expressed, pleiotropic protein that is involved in diverse biological processes, including cellular proliferation, neuron development, and wound healing. However, the role of PGRN in the regulation of pathogen-induced systemic inflammation and the mechanisms involved have not been established. In this study, we show that PGRN-deficient mice display heightened mortality in models of polymicrobial sepsis and endotoxinemia, with increased tissue levels of inflammatory cytokines and reduced IL-10 production. Conversely, administration of rPGRN decreases the susceptibility of PGRN-deficient mice to LPS-induced endotoxemic shock and augments IL-10 production by LPS-activated macrophages in a TNFR-dependent manner. Molecular analysis reveals a direct role of the transcription factor C/EBPα in PGRN-regulated IL-10 expression. C/EBPα-deficient macrophages produce less IL-10 in response to LPS. Furthermore, mice deficient in C/EBPα in hematopoietic cells are highly vulnerable to LPS-induced septic shock. Lastly, the defective IL-10 production by PGRN-deficient cells is primarily due to reduced C/EBPα protein stability via the E3 ubiquitin-conjugating enzyme E6AP and proteasome-mediated degradation. To our knowledge, this study provides the first evidence that PGRN is a nonredundant regulator of systemic inflammation via modulating the levels and activity of C/EBPα, IL-10, and the ubiquitin-proteasome proteolysis pathway. The results bear strong and profound implications for PGRN insufficiency and its mutation-associated systemic and organ-specific inflammatory human diseases.

A targeted ferritin-microplasmin based thrombolytic nanocage selectively dissolves blood clots.

The use of thrombolytic therapies is limited by an increased risk of systemic hemorrhage due to lysis of hemostatic clots. We sought to develop a plasmin-based thrombolytic nanocage that efficiently dissolves the clot without causing systemic fibrinolysis or disrupting hemostatic clots. Here, we generated a double chambered short-length ferritin (sFt) construct that has an N-terminal region fused to multivalent clot targeting peptides (CLT: CNAGESSKNC) and a C-terminal end fused to a microplasmin (µPn); CLT recognizes fibrin-fibronectin complexes in clots, µPn efficiently dissolves clots, and the assembly of double chambered sFt (CLT-sFt-µPn) into nanocage structure protects the activated-µPn from its circulating inhibitors. Importantly, activated CLT-sFt-µPn thrombolytic nanocage showed a prolonged circulatory life over activated-µPn and efficiently lysed the preexisting clots in both arterial and venous thromboses models. Thus, CLT-sFt-µPn thrombolytic nanocage platform represents the prototype of a targeted clot-busting agent with high efficacy and safety over existing thrombolytic therapies.

Identification of Downstream Genes of the mTOR Pathway that Predict Recurrence and Progression in Non-Muscle Invasive High-Grade Urothelial Carcinoma of the Bladder.

Microarray analysis was used to investigate the lack of identified mammalian target of rapamycin (mTOR) pathway downstream genes to overcome cross-talk at non-muscle invasive high-grade (HG)-urothelial carcinoma (UC) of the bladder, gene expression patterns, gene ontology, and gene clustering by triple (p70S6K, S6K, and eIF4E) small interfering RNAs (siRNAs) or rapamycin in 5637 and T24 cell lines. We selected mTOR pathway downstream genes that were suppressed by siRNAs more than 2-fold, or were up-regulated or down-regulated by rapamycin more than 2-fold. We validated mTOR downstream genes with immunohistochemistry using a tissue microarray (TMA) of 125 non-muscle invasive HG-UC patients and knockout study to evaluate the synergistic effect with rapamycin. The microarray analysis selected mTOR pathway downstream genes consisting of 4 rapamycin up-regulated genes (FABP4, H19, ANXA10, and UPK3A) and 4 rapamycin down-regulated genes (FOXD3, ATP7A, plexin D1, and ADAMTS5). In the TMA, FABP4, and ATP7A were more expressed at T1 and FOXD3 was at Ta. ANXA10 and ADAMTS5 were more expressed in tumors ≤ 3 cm in diameter. In a multivariate Cox regression model, ANXA10 was a significant predictor of recurrence and ATP7A was a significant predictor of progression in non-muscle invasive HG-UC of the bladder. In an ATP7A knock-out model, rapamycin treatment synergistically inhibited cell viability, wound healing, and invasion ability compared to rapamycin only. Activity of the ANXA10 and ATP7A mTOR pathway downstream genes might predict recurrence and progression in non-muscle invasive HG-UC of the bladder. ATP7A knockout overcomes rapamycin cross-talk.

Anti-Obesity Effect of Bombus ignitus Queen Glycosaminoglycans in Rats on a High-Fat Diet.

The mechanism of functional insect glycosaminoglycan (GAG) on obesity caused a high fat diet has not yet been elucidated. Therefore, insect glycosaminoglycans derived from Isaria sinclairii, Bombus ignitus (a type of bumblebee) queen, and Gryllus bimaculatus were purified and investigated as a potential functional food. 14-week old male Wistar rats were fed a high-fat diet (HFD) for 6 weeks. There were five groups that received daily intraperitoneal administration of phosphate buffered saline (PBS, control), GbG (GAG from Gryllus bimaculatus) 10 mg/kg, ISG (GAG from Isaria sinclairii) 10 mg/kg, IQG (GAG from Bombus ignites) 10 mg/kg, or Pravastatin (2 mg/kg). All treatments were performed for one month. IQG produced a potential anti-inflammatory effect with the inhibition of c-reactive protein and sero-biochemical parameters of phospholipids and free fatty acids indicative of an anti-hyperlipidemic effect. Abdominal and epididymidal fat weight were reduced in conjunction with a mild increase in body weight. The level of laminin in HMVEC-C cells or fibronectin in HFD rat hepatocytes was significantly affected by these GAG treatments, which regulated adipogenesis and adipocyte function. Compared to the control rats, IQG-treated rats displayed up-regulation of 87 genes (test:control ratio >2.0) including fatty acid synthase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase, with the down-regulation of 47 genes including the uridine diphosphate (UDP) glycosyltransferase 2 families, polypeptidase B, and insulin-like growth factor binding protein 1. The data suggest that IQG could potentially prevent or treat fatty liver or hyperlipidemia.

Role of Nucleotide-binding and Oligomerization Domain 2 Protein (NOD2) in the Development of Atherosclerosis.

NOD2 (nucleotide-binding and oligomerization domain 2) was initially reported as a susceptibility gene for Crohn's disease, with several studies focused on elucidating its molecular mechanism in the progression of Crohn's disease. We now know that NOD2 is an intracellular bacterial sensing receptor, and that MDP-mediated NOD2 activation drives inflammatory signaling. Various mutations in NOD2 have been reported, with NOD2 loss of function being associated with the development of Crohn's disease and other autoimmune diseases. These results suggest that NOD2 not only has an immune stimulatory function, but also an immune regulatory function. Atherosclerosis is a chronic inflammatory disease of the arterial wall; its pathologic progression is highly dependent on the immune balance. This immune balance is regulated by infiltrating monocytes and macrophages, both of which express NOD2. These findings indicate a potential role of NOD2 in atherosclerosis. The purpose of this review is to outline the known roles of NOD2 signaling in the pathogenesis of atherosclerosis.

Safety and efficacy of aprepitant, ramosetron, and dexamethasone for chemotherapy-induced nausea and vomiting in patients with ovarian cancer treated with paclitaxel/carboplatin.

PURPOSE: Women with ovarian carcinoma that are treated with paclitaxel/carboplatin are particularly susceptible to chemotherapy-induced nausea and vomiting (CINV). The current study evaluated the new combination (aprepitant/ramosetron/dexamethasone, 20 mg) in ovarian cancer patients receiving multiple cycles of paclitaxel/carboplatin. METHODS: This is a prospective non-randomized single site study. Patients received the following regimen for the prevention of CINV-day 1, 125 mg aprepitant, 0.6 mg ramosetron, and 20 mg dexamethasone before chemotherapy; and days 2-3, 80 mg aprepitant each day. The primary end point was the proportion of patients with complete response (CR) during the 120 h following the first chemotherapy cycle. Toxicity assessments were conducted using the NCI-CTC investigator guide (version 3.0). RESULTS: Of the 89 patients enrolled, 85 patients were evaluable for efficacy and toxicity, and 68 (80 %) completed all 6 cycles. In cycle 1, the percentage of patients who achieved CR in the acute, delayed, and overall phases was 98.8 %, 89.4 %, and 89.4 %, respectively. Of the 460 cycles, adverse events, drug-related adverse events, and serious adverse events occurred in 179 (38.9 %), 35 (7.6 %), and 10 cycles (2.2 %), respectively. The most common adverse event was constipation (12.4 %) and headache (11.1 %). None of the patients discontinued the study because of adverse events. CONCLUSIONS: The combination of aprepitant, ramosetron, and high-dose dexamethasone demonstrated efficacy for CINV prevention in ovarian cancer patients receiving paclitaxel and carboplatin.

Prognostic factors influencing decisions about surgical treatment of villoglandular adenocarcinoma of the uterine cervix.

OBJECTIVE: The objectives of this study were to analyze the clinicopathologic features of villoglandular adenocarcinoma (VGA) of the uterine cervix, a variant of cervical adenocarcinoma with good prognosis, and to discuss the association of human papillomavirus (HPV) infection with VGA. METHODS: A retrospective review of medical records was performed to identify the patients with VGA between 1999 and 2007 at the Samsung Medical Center. RESULTS: Fifteen patients were identified among 171 women diagnosed with adenocarcinoma of the cervix. The median age was 40 years (range, 32-72 years). Four patients were treated by cone biopsy and 10 patients by hysterectomy with or without pelvic lymphadenectomy. Five patients had invasion of more than half of the depth of tumor in the cervix. Lymphovascular space invasion was present in 2 patients, one of whom also had lymph node metastases. Three recurrences were identified during the median follow-up of 64 months (range, 9-149 months). An HPV test was positive in 6 of 7 patients. Of the 6 patients with HPV infection, 2 were positive for HPV type 18, one for HPV type 6, and the remaining 3 were positive for 1 or more types of high-risk HPV. CONCLUSIONS: Although VGA has been reported to have a favorable prognosis, we observed recurrences in those patients with close margins by the tumor, lymph node metastasis, or advanced stage. Human papillomavirus DNA, mostly HPV types 16 and 18, was associated with VGA. Further studies are warranted on prognostic factors and the pathogenetic role of HPV infections.

Stabilin-2 mediated apoptotic cell phagocytosis induces interleukin-10 expression by p38 and Pbx1 signaling.

Apoptotic cell death occurs under normal physiological conditions, such as development, tissue remodeling, and inflammation. Appropriate removal of apoptotic cells by phagocytes and the secretion of anti-inflammatory cytokines such as IL-10 are important mechanisms for maintaining tissue homeostasis. Apoptotic cell phagocytosis is mediated by several phosphatidylserine recognition receptors on non-professional or professional phagocytes, such as neighboring epithelial cells or macrophages. Stabilin-2 is reported as a phosphatidylserine recognition receptor for apoptotic cell phagocytosis, and its downstream signaling pathway for cytoskeletal rearrangement for phagocytosis is well known. However, the mechanisms for stabilin-2-mediated IL-10 production has not yet been reported. In this study, we aimed to investigate stabilin-2 receptor-mediated IL-10 transcription regulation signaling pathway.

Contributing factors for bone metastasis in uterine cervical cancer.

OBJECTIVE: The purpose of this study was to describe the clinical characteristics and to assess the contributing factors in patients developing bone metastasis in uterine cervical cancer. METHODS: Two thousand thirteen patients had a diagnosis of uterine cervical cancer at Samsung Medical Center between June 1994 and December 2011. During the study period, 105 patients with bone metastasis were identified, and their clinicopathologic data were investigated retrospectively. RESULTS: Among 105 patients with bone metastasis, 14 patients were excluded and 91 patients were evaluable. The median bone metastasis-free survival was 27 months (range, 0-279 months).The time to bone metastasis was significantly shorter in patients with adenocarcinoma than in patients with squamous cell carcinoma (median duration, 12 vs 29 months; P = 0.016). In addition, it was shorter in patients with stage IIB to stage IV disease than in those with stage I to stage IIA disease (15 vs 22 months; P = 0.02). The median survival after bone metastasis was 10 months, longer in the patients who received radiotherapy (± chemotherapy) than in the patients who received chemotherapy alone as a salvage therapy (12 vs 7 months; P = 0.01). Initial stage, number of bone metastases, location of involved bone, and coexisting metastatic lesion were not associated with the overall survival of the patients. CONCLUSIONS: Our study demonstrates that adenocarcinoma, advanced stage (IIB-IV) and initial multiple bone metastases contribute to earlier bone metastasis. Once bone metastasis was recognized, the survival of these patients was poor and no factors were identified to predict survival of those patients.

TGFBI remodels adipose metabolism by regulating the Notch-1 signaling pathway.

Extracellular matrix proteins are associated with metabolically healthy adipose tissue and regulate inflammation, fibrosis, angiogenesis, and subsequent metabolic deterioration. In this study, we demonstrated that transforming growth factor-beta (TGFBI), an extracellular matrix (ECM) component, plays an important role in adipose metabolism and browning during high-fat diet-induced obesity. TGFBI KO mice were resistant to adipose tissue hypertrophy, liver steatosis, and insulin resistance. Furthermore, adipose tissue from TGFBI KO mice contained a large population of CD11b+ and CD206+ M2 macrophages, which possibly control adipokine secretion through paracrine mechanisms. Mechanistically, we showed that inhibiting TGFBI-stimulated release of adipsin by Notch-1-dependent signaling resulted in adipocyte browning. TGFBI was physiologically bound to Notch-1 and stimulated its activation in adipocytes. Our findings revealed a novel protective effect of TGFBI deficiency in obesity that is realized via the activation of the Notch-1 signaling pathway.

CyTOF analysis for differential immune cellular profiling between latent tuberculosis infection and active tuberculosis.

Limited data exist about the comparative immune cell population profile determined by cytometry by time-of-flight (CyTOF) analysis between active tuberculosis (TB) and latent TB infection (LTBI). In this study, we performed CyTOF analysis using peripheral blood mononuclear cells (PBMCs) to compare the differential immune cellular profile between active TB and LTBI. A total of 51 subjects (active TB [n = 34] and LTBI [n = 17]) were included. CyTOF analysis of 16 subjects (active TB [n = 8] and LTBI [n = 8]) identified a significantly higher Th17-like cell population in active TB than in LTBI. This finding was validated in the remaining 35 subjects (active TB [n = 26] and LTBI [n = 9]) using flow cytometry analysis, which consistently reveals a higher percentage of Th17 cell population in active TB (p = 0.032). The Th1/Th17 ratio represented good ability to discriminate between active TB and LTBI (AUC = 0.812). Among patients with active TB, the Th17 cell percentage was found to be lower in more advanced forms of the disease. Additionally, Th17 cell percentage positively correlated with the levels of IL-6 and neutrophil-lymphocyte ratio, respectively. In conclusion, CyTOF analysis of PBMCs showed a significantly higher percentage of Th17 cells in active TB although fairly similar immune cell populations between active TB and LTBI were observed.

Comparison of laparoscopic-assisted radical vaginal hysterectomy and laparoscopic radical hysterectomy in the treatment of cervical cancer.

BACKGROUND: The aim of this study was to compare the surgical and oncologic outcomes of laparoscopic-assisted radical vaginal hysterectomy (LARVH) with that of laparoscopic radical hysterectomy (LRH) for early-stage cervical cancer. METHODS: Patients affected by invasive cervical cancer (FIGO stage I-IIA) who had received LARVH (n = 89) in our institute between September 2004 and December 2010 were compared with patients treated by LRH (n = 105) during the same period. All patient information, surgical and pathological data, and oncological results were prospectively collected. Patients undergoing abdominal radical hysterectomy (ARH) were included for comparison of safety, morbidity, and recurrence rate. RESULTS: The mean estimated blood loss (EBL) and return of bowel activity were significantly reduced in the LRH group compared with the LARVH group (p = .011 and p = .002, respectively). Intraoperative complications occurred in 10 patients (11.2 %) in the LARVH group, 6 (5.7 %) in the LRH group, and 3 (3.0 %) in the ARH group. Forest plot analyses of the previous studies showed higher incidence of intraoperative complication in the LARVH group than in LRH group (p = .02). Despite the similar overall recurrence rate, stump recurrence seems to be high in the LRH group in the forest plot analysis of previous studies (p = 0.08). CONCLUSIONS: Both LARVH and LRH are safe and effective therapeutic procedures for the management of early-stage cervical cancer, although LRH is characterized by less blood loss and shorter bowel recovery time. Possible higher stump recurrence in the LRH should be further evaluated.

Prognostic value of pre-treatment circulating monocyte count in patients with cervical cancer: comparison with SCC-Ag level.

OBJECTIVE: Higher level of circulating monocyte has been reported to be related with higher cancer incidence and mortality. We investigated the role of pre-treatment circulating monocyte count for cancer specific survival in cervical squamous cell carcinoma patients comparing with pre-treatment squamous cell carcinoma-related antigen (SCC-Ag) level. METHODS: We retrospectively enrolled patients with squamous cell carcinoma of the cervix (FIGO stage IB to IVA) who had complete blood cell counts with differential cell count and serum SCC-Ag level within 2 weeks before starting initial treatment and were treated at Samsung Medical Center, Seoul, Korea, from 1996 to 2007. RESULTS: The 788 patients in our study group had a median follow-up of 53.4 months and a five-year survival rate of 87.8%. The median value for pre-treatment circulating monocyte count was 349/µl (21-1463), and the median concentration of SCC-Ag was 1.6 ng/ml (0.1-362.0). In multivariable analysis, the pre-treatment circulating monocyte count was an independent prognostic factor for progression-free survival and overall survival in locally advanced disease (P=0.007 and P=0.038) but not in case of SCC-Ag for overall survival. The combined index of monocyte count and SCC-Ag level could enhance the prognostic value of SCC-Ag alone in patients with locally advanced cervical squamous cell carcinoma. CONCLUSIONS: A higher pre-treatment circulating monocyte count is independently associated with poor prognosis in patients with locally advanced cervical squamous cell carcinoma. The pre-treatment circulating monocyte count may be considered as an adjunctive biomarker with SCC-Ag.

Clinical significance of changes in peripheral lymphocyte count after surgery in early cervical cancer.

OBJECTIVE: Immune competence is an important prognostic factor in cancer patients. Surgical management of cancer can cause a variety of immunological disturbances, the clinical consequences of which are still unclear. MATERIALS AND METHODS: Patients with clinically staged cervical carcinoma (IB to IIA) who were treated at Samsung Medical Center, Seoul, Korea from 1994 to 2007 were retrospectively enrolled. We compared peri-operative peripheral lymphocyte counts, tumor-infiltrating lymphocyte scores, and survival in patients with early cervical cancer treated by abdominal type III radical hysterectomy. RESULTS: The sample included 756 patients. The median follow-up was 58 months with a range of 3-181 months. There was a positive correlation between pre-operative peripheral lymphocyte counts and tumor infiltrating lymphocyte score. Pre-operative peripheral lymphocyte counts decreased significantly after surgery. In multivariate analyses for recurrence, higher pre-operative peripheral lymphocyte counts and recovery of lymphocyte counts (more than 100/µL from the pre-operative level) on post-operative day 3 were independent positive prognostic factors and LN metastasis was negatively associated with post-operative recovery of peripheral lymphocyte counts. CONCLUSION: Peripheral lymphocyte counts after cervical cancer surgery are important prognostic factors, and management aimed at minimizing immune disturbances after surgery should be assessed, especially in patients with LN metastasis.

The septic shock-associated IL-10 -1082 A > G polymorphism mediates allele-specific transcription via poly(ADP-Ribose) polymerase 1 in macrophages engulfing apoptotic cells.

The biallelic IL-10 single nucleotide polymorphism at -1082 of the promoter region linked to individual variation in cytokine inducibility has been strongly implicated in several pathological conditions including the development of, and outcomes in, septic shock during pneumococcal infection, acute respiratory distress syndrome, and cardiac dysfunction. However, the molecular basis of the single nucleotide polymorphism-mediated variable IL-10 production levels has not been explored. In this study, we report that the -1082G > A alleles in the promoter region of the human IL-10 gene physically interact with a nuclear protein in an allele-specific manner that results in different levels of IL-10 transcription. This protein has been identified as poly(ADP-ribose) polymerase 1 (PARP-1). We show that PARP-1 acts as a transcription repressor, and its DNA-binding activity is strongly regulated in macrophages that engulf apoptotic cells but not stimulated with LPS. These findings unveil a novel role of PARP-1 in the regulation of IL-10 production in an allele-dependent way, which determines individual susceptibility to sepsis-induced inflammatory pathology and the immunological sequelae in a physiological process in which clearance of infection-induced apoptotic cells by professional phagocytes triggers the cytokine synthesis.

Patterns of recurrence in endometrial cancer patients at risk of lymph node metastasis or recurrence according to extent of lymphadenectomy.

OBJECTIVE: The purpose of this study was to compare the patterns of recurrence in patients with risk of lymph node (LN) metastasis or recurrence according to the extent of lymphadenectomy (LND). METHODS: We selected 257 patients with risk of LN metastasis or recurrence who underwent definitive surgery as the first treatment between 1995 and 2009. These patients underwent hysterectomy, bilateral salpingo-oophorectomy, and systematic pelvic lymphadenectomy (PLND) with or without para-aortic lymphadenectomy (PALND). We identified patients with recurrence and evaluated the patterns of recurrence according to the type of LND. RESULTS: Among the 257 patients, 164 patients had systematic PLND only, and 93 patients had PLND with PALND. Regarding LN metastasis in PLND+PALND group, approximately 9.7% patients had involvement of para-aortic nodes. Thirty-six (14%) of the 257 patients showed recurrence. The rate of extrapelvic recurrence was significantly higher in the PLND group compared with the PLND+PALND group (96.0% vs 36.4%, respectively; P < 0.001). Using multivariate analysis, extent of LND was significantly related to extrapelvic recurrence (P = 0.004). CONCLUSIONS: The incidence of extrapelvic recurrence was significantly higher in the PLND group than in the PLND+PALND group, which suggests that PALND decreases the risk of extrapelvic recurrence.

Transforming growth factor-beta-induced protein (TGFBIp/beta ig-h3) activates platelets and promotes thrombogenesis.

Transforming growth factor-beta-induced protein (TGFBIp)/beta ig-h3 is a 68-kDa extracellular matrix protein that is functionally associated with the adhesion, migration, proliferation, and differentiation of various cells. The presence of TGFBIp in platelets led us to study the role of this protein in the regulation of platelet functions. Upon activation, platelet TGFBIp was released and associated with the platelets. TGFBIp mediates not only the adhesion and spread of platelets but also activates them, resulting in phosphatidylserine exposure, alpha-granule secretion, and increased integrin affinity. The fasciclin 1 domains of TGFBIp are mainly responsible for the activation of platelets. TGFBIp promotes thrombus formation on type I fibrillar collagen under flow conditions in vitro and induces pulmonary embolism in mice. Moreover, transgenic mice, which have approximately a 1.7-fold greater blood TGFBIp concentration, are significantly more susceptible to collagen- and epinephrine-induced pulmonary embolism than wild-type mice. These results suggest that TGFBIp, a human platelet protein, plays important roles in platelet activation and thrombus formation. Our findings will increase our understanding of the novel mechanism of platelet activation, contributing to a better understanding of thrombotic pathways and the development of new antithrombotic therapies.

Prognosis of ovarian clear cell carcinoma compared to other histological subtypes: a meta-analysis.

OBJECTIVE: To compare the survival outcome between clear cell carcinoma (CCC) and other histological subtypes in epithelial ovarian carcinoma (EOC). METHODS: From January 1974 to February 2011, we identified a total of 31,800 (CCC; 2152, non-CCC; 29648) patients from 12 studies meeting the inclusion criteria. RESULTS: Heterogeneity tests demonstrated significant between-study variation (I(2)=92.1%) with no significant difference in hazard ratio (HR) for death between CCC and non-CCC (HR; 1.16, 95% CI; 0.85-1.57, random-effects model). Comparing the HR based on stage I+II, and stage III+IV, between CCC and non-CCC, showed that CCC patients had a higher hazard rate for death than those with non-CCC of the ovary (stage I+II; HR; 1.17, 95% CI; 1.01-1.36, stage III+IV; HR; 1.65, 95% CI; 1.52-1.79). In a comparison of CCC and serous EOC, advanced stage (III and IV) CCC only showed a poorer hazard rate for death than serous EOC (HR; 1.71, 95% CI; 1.57-1.86). CONCLUSION: This analysis suggests that ovarian CCC patients had poorer prognosis than those with other histological subtypes of EOC, especially in advanced EOC stages. Different treatment strategies may be needed for patients with ovarian CCC.