Explore the vast range of titles available.

Differential diagnosis of elevated high sensitive Troponin T (hsTnT) in acute ischemic stroke includes myocardial infarction (MI) and neurogenic stunned myocardium (NSM). The aim of this study was to identify factors associated with baseline hsTnT levels and MI or NSM in acute ischemic stroke. We studied 204 consecutive patients of the prospective acquired Bern Stroke Database with acute ischemic stroke diagnosed by brain MR. All patient histories and cardiac examinations were reviewed retrospectively. Volumetry of lesions on diffusion and perfusion weighted brain imaging (circular singular value decomposition, Tmax >6sec) was performed. Voxel based analysis was performed to identify brain areas associated with hsTnT elevation. Linear regression analysis was used to identify predictors of baseline hsTnT levels and myocardial infarction. Elevated hsTnT was observed in 58 of the 204 patients (28.4%). The mean age was 68.3 years in the normal hsTnT group and 69.7 years in the elevated hsTnT group. Creatinine (p<0.001, OR 6.735, 95% CI 58.734-107.423), baseline NIHSS score (p = 0.029, OR 2.207, 95% CI 0.675-12.096), ST segment depression (p = 0.025, OR 2.259, 95% CI 2.419-35.838), and negative T waves in baseline ECG (p = 0.002, OR 3.209, 95% CI 13.007-54.564) were associated with hsTnT elevation, while infarct location and size were not. Coronary angiography was performed in 30 of the 204 patients (14.7%) and myocardial infarction was diagnosed in 7 of them (23.3%). Predictive factors for myocardial infarction could not be identified. Elevated baseline baseline hsTnT was associated with NIHSS, creatinine, ST segment depression and inverted T waves, but not with stroke location or size. None of the factors was helpful to differentiate MI and NSM. Therefore, ancillary investigations such as coronary angiography, cardiac MRI or both may be needed to solve the differential diagnosis.

N eural precursor cell e xpressed, d evelopmentally d ownregulated 9 (NEDD9) supports oncogenic signaling in a number of solid and hematologic tumors. Little is known about the role of NEDD9 in ovarian carcinoma (OC), but available data suggest elevated mRNA and protein expression in advanced stage high-grade cancers. We used a transgenic MISIIR-TAg mouse OC model combined with genetic ablation of Nedd9 to investigate its action in the development and progression of OC. A Nedd9 −/− genotype delayed tumor growth rate, reduced incidence of ascites, and reduced expression and activation of signaling proteins including SRC, STAT3, E-cadherin, and AURKA. Cell lines established from MISIIR-TAg;Nedd9 −/− and MISIIR-TAg;Nedd9 +/+ mice exhibited altered migration and invasion. Growth of these cells in a syngeneic allograft model indicated that systemic Nedd9 loss in the microenvironment had little impact on tumor allograft growth, but in a Nedd9 wild-type background Nedd9 −/− allografts exhibited significantly reduced growth, dissemination, and oncogenic signaling compared to Nedd9 +/+ allografts. Gene expression analysis revealed that Nedd9 +/+ tumors exhibited more mesenchymal “stem-like” transcriptional program, including increased expression of Aldh1a1 and Aldh1a2 . Conversely, loss of Nedd9 resulted in increased expression of differentiation genes, including fallopian tube markers Foxj1 , Ovgp1 , and Pax8 . Collectively, these data suggest that tumor cell-intrinsic Nedd9 expression promotes OC development and progression by broad induction of oncogenic protein signaling and stem/mesenchymal gene expression.

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression.

Background Most cases of ovarian cancer are epithelial in origin and diagnosed at advanced stage when the cancer is widely disseminated in the peritoneal cavity. The objective of this study was to establish an immunocompetent syngeneic mouse model of disseminated epithelial ovarian cancer (EOC) to facilitate laboratory-based studies of ovarian tumor biology and preclinical therapeutic strategies. Methods Individual lines of Tg MISIIR-TAg transgenic mice were phenotypically characterized and backcrossed to inbred C57BL/6 mice. In addition to a previously described line of EOC-prone mice, two lines (Tg MISIIR-TAg-Low ) were isolated that express the oncogenic transgene, but have little or no susceptibility to tumor development. Independent murine ovarian carcinoma (MOVCAR) cell lines were established from the ascites of tumor-bearing C57BL/6 Tg MISIIR-TAg transgenic mice, characterized and tested for engraftment in the following recipient mice: 1) severe immunocompromised immunodeficient (SCID), 2) wild type C57BL/6, 3) oophorectomized tumor-prone C57BL/6 Tg MISIIR-TAg transgenic and 4) non-tumor prone C57BL/6 Tg MISIIR-TAg-Low transgenic. Lastly, MOVCAR cells transduced with a luciferase reporter were implanted in Tg MISIIR-TAg-Low mice and in vivo tumor growth monitored by non-invasive optical imaging. Results Engraftment of MOVCAR cells by i.p. injection resulted in the development of disseminated peritoneal carcinomatosis in SCID, but not wild type C57BL/6 mice. Oophorectomized tumor-prone Tg MISIIR-TAg mice developed peritoneal carcinomas with high frequency, rendering them unsuitable as allograft recipients. Orthotopic or pseudo-orthotopic implantation of MOVCAR cells in Tg MISIIR-TAg-Low mice resulted in the development of disseminated peritoneal tumors, frequently accompanied by the production of malignant ascites. Tumors arising in the engrafted mice bore histopathological resemblance to human high-grade serous EOC and exhibited a similar pattern of peritoneal disease spread. Conclusions A syngeneic mouse model of human EOC was created by pseudo-orthotopic and orthotopic implantation of MOVCAR cells in a susceptible inbred transgenic host. This immunocompetent syngeneic mouse model presents a flexible system that can be used to study the consequences of altered gene expression (e.g., by ectopic expression or RNA interference strategies) in an established MOVCAR tumor cell line within the ovarian tumor microenvironment and for the development and analysis of preclinical therapeutic agents including EOC vaccines and immunotherapeutic agents.

Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacological or RNA interference-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRC Y416 ). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared with either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression.

Behavioral economic studies of nicotine product consumption have traditionally examined substitution between two products and rarely examined substitution with more products. Increasing numbers of tobacco products available for commercial sale leads to more possible cross-product interactions, indicating a need to examine substitution in more complex arrangements that closely mirror the tobacco marketplace. The experimental tobacco marketplace (ETM) is an experimental online store that displays pictures, information, and prices for several tobacco products. Smokers were endowed with an account balance based on their weekly tobacco purchases. Participants then made potentially real purchases for seven (Experiment 1) or six (Experiment 2) tobacco/nicotine products under four price conditions for conventional cigarettes while prices for other products remained constant. Smokers returned 1 week later to report tobacco/nicotine use and return unused products for a refund. In Experiment 1 (n = 22), cigarette purchasing decreased as a function of price. Substitution was greatest for electronic cigarettes and cigarillos and significant for electronic cigarettes. Experiment 2 (n = 34) was a replication of Experiment 1, but with cigarillos unavailable in the ETM. In Experiment 2, cigarette purchases decreased as a function of price. Substitution was robust and significant for electronic cigarettes and Camel Snus. The ETM is a novel, practical assay that mimics the real-world marketplace, and functions as a simple research tool for both researchers and participants. Across the two experiments the product mix in the ETM altered which products functioned as substitutes suggesting complex interactions between purchasing and product availability. This article adds a novel method of collecting purchasing data that mimics real world purchasing to the existing literature. The ETM is a practical avenue by which to study both hypothetical and potentially real purchasing.