BACKGROUND: Recent work has suggested a role for nuclear factor jB (NF-jB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-jB in ovarian cancer is unknown. The authors hypothesized that the NF-jB pathway is over activated in aggressive ovarian cancers. METHODS: The levels of 3 NF-jB transcription factors, the activating inhibitors of NF-jB (IjB) kinases, and the NF-jB target matrix metalloproteinase 9 (MMP9) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel, cisplatin, and cyclophosphamide. Associations were made between NF-jB pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. RESULTS: The presence of NF-jB proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with IjB kinase a, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-jB machinery suggested activity of NF-jB signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P ¼ .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P ¼ .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. CONCLUSIONS: The deregulation of NF-jB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-jB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity. Cancer 2010;116:3276-84.

Purpose: Ovarian/primary peritoneal serous carcinoma (OC/PPC) and diffuse peritoneal malignant mesothelioma (DMPM) are highly aggressive tumors that are closely related morphologically and histogenetically. It remains unclear whether both tumors are molecularly distinct neoplasms. The current study compared global gene expression patterns in OC/PPC and DMPM. Experimental Design: Ten OC/PPC and five DMPM effusions were analyzed for gene expression profiles using the Affymetrix U133 Plus 2 arrays and the dCHIP analysis program. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. Results: Unsupervised hierarchical clustering using all 54,675 genes in the array classified the samples into two groups: DMPM specimens versus OC/PPC specimens. A total of 189 genes that were differentially expressed in these two groups were selected based on statistical significance. Genes overexpressed in DMPM (n = 68) included calretinin, vitronectin, claudin 15, a 4 laminin, hyaluronan synthase 1, cadherin 11, RAB7, v-maf, and the epidermal growth factor^containing fibulin-like extracellular matrix protein 1. Genes overexpressed in OC/PPC (n = 121) included insulin-like growth factor II (IGF-II); IGF-II binding protein 3; cyclin E1; folate receptors 1 and 3; RAB25; MUC4; endothelin-1; CD24; kallikreins 6, 7, and 8; claudins 3, 4, and 6; Notch3; and MMP-7. Quantitative real-time PCR validated the differential expression of 13 genes, and immunohistochemistry confirmed the differences for four gene products. Conclusions: Expression profiling separates OC/PPC from DMPM and identifies a number of genes that are differentially expressed in these tumors. The molecular signatures unique to OC/PPC and DMPM should provide a molecular basis to study both tumors and new potential markers for facilitating their differential diagnosis.Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive cancer that originates from the native mesothelial cells of the peritoneal cavity. DMPM is less common than its pleural counterpart (9:1 ratio), differs in its gender predilection (roughly similar incidence in women and men), and has a weaker etiologic link to asbestos exposure (1, 2). The prognosis of DMPM patients has been extremely poor in earlier series, with median survival of 10 to 12 months (2). However, recent studies have shown improved survival (26-92 months) when DMPM patients are treated aggressively with combined debulking and preheated i.p. chemotherapy consisting of cisplatin, doxorubicin, and paclitaxel as major agents (2 -4). Recently, a response rate of 25% was achieved following pemetrexed treatment (5). The majority of DMPM are of the epithelioid type (6).Ovarian cancer (OC) is the most lethal gynecologic malignancy in the Western world and the fourth most frequent cause of cancer-related death in women (7). As DMPM, OC and the closely related and morphologically indistinguishable primary peritoneal carcinoma (PPC) are thought to develop from the peritoneal mesot...

Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod‐phosphate (fingolimod‐P), is a sphingosine 1‐phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod‐P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P1 S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti‐inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10× the approved 0.5mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies. Ann Neurol 2011;69:759–777

No abstract

No abstract

No abstract

The aim of the present study was to evaluate HLA-G expression in breast carcinoma and malignant mesothelioma (MM). Malignant breast carcinoma effusions (46) and corresponding solid tumors (39) and 104 MM (26 effusions, 78 solid tumors) were analyzed using immunohistochemistry (IHC). HLA-G protein and mRNA expression were further studied using immunoblotting (IB) and RT-PCR. HLA-ABC expression was analyzed using flow cytometry (FCM). IHC showed predominantly focal HLA-G expression in 12 of 46 (26%) breast carcinoma effusions and 16 of 39 (41%) solid lesions. In MM, 20 of 78 (26%) solid lesions and 14 of 26 (54%) effusions were focally HLA-G positive. Expression in MM was higher in effusions (p=0.008). IB showed more frequent HLA-G expression in MM compared with breast carcinoma effusions, while RT-PCR showed HLA-G mRNA expression in both tumors. FCM showed conserved HLA-ABC expression in 15 of 15 effusions. Breast cancer patients with HLA-G-positive tumor cells had shorter disease-free survival (mean 37 vs 85, median 25 vs 31 months), though not significantly (p=0.14). In conclusion, HLA-G is focally expressed in MM and breast carcinoma, while HLA-ABC expression is conserved. However, the up-regulated expression of HLA-G in MM effusions and its possible association with shorter disease-free survival in advanced stage of breast carcinoma suggest a possible role in immune response evasion in some tumors.

We analyzed the diagnostic role of claudins in effusion cytology in 325 effusions, including 218 ovarian, 49 breast, 15 cervical or endometrial, 10 gastrointestinal, and 8 lung adenocarcinomas and 25 malignant mesotheliomas (MMs). Specimens were analyzed for claudin-1 and claudin-3 expression using immunohistochemical analysis. Ovarian and breast adenocarcinoma were further analyzed for claudin-7 expression. Claudin-1 expression was most frequent in ovarian and cervical or endometrial adenocarcinoma compared with other adenocarcinomas and MMs (P < .001). Claudin-3 expression was comparable in adenocarcinomas of different origin but was absent in MMs (P < .001). Reactive mesothelial cells rarely expressed claudins. Claudin-7 expression was higher in ovarian than in breast adenocarcinoma (P < .001). Our data suggest that expression of claudin-3 or claudin-7 is specific for adenocarcinoma and rules out the diagnosis of cells as mesothelial and that absence of claudin-1 expression excludes ovarian carcinoma as the possible origin of metastatic adenocarcinoma. Claudins may, therefore, be of diagnostic value in effusion cytology.