Long-Term Effects of Neonatal Exposure to Hydroxylated Polychlorinated Biphenyls in the BALB/cCrgl Mouse

The neonatal mouse model has been a valuable tool in determining the long-term effects of early exposure to estrogenic agents in mammals. Using this model, we compared the effects of 2′,4′,6′-trichloro-4-biphenylol (OH-PCB-30) and 2′,3′,4′,5′-tetrachloro-4-biphenylol (OH-PCB-61) as prototype estrogenic hydroxylated PCBs (OH-PCBs) because they are reported to exhibit relatively high estrogenic activity both in vivo and in vitro. The purpose of this study was to examine the relationship between estrogenicity and carcinogenicity of OH-PCB congeners. The OH-PCBs were tested individually and in combination to determine whether effects of combined OH-PCBs differed from those of these OH-PCBs alone. We evaluated the long-term effects of neonatal exposure to OH-PCBs with treatment doses that were based on the reported binding affinity of specific OH-PCB congeners to estrogen receptor α. BALB/cCrgl female mice were treated within 16 hr after birth by subcutaneous injections every 24 hr, for 5 days. The mice treated with OH-PCB-30 (200 μg/day) or 17β-estradiol (5 μg/day) showed similar increased incidences of cervicovaginal (CV) tract carcinomas (43% and 47%, respectively). In addition, when mice were treated with OH-PCBs as a mixture, a change in the type of CV tract tumor was observed, shifting from predominantly squamous cell carcinomas to adenosquamous cell carcinoma. From our results, we conclude that the individual OH-PCBs tested were estrogenic and tumorigenic in mice when exposed during development of the reproductive tract. These data support the hypothesis that mixtures may act differently and unexpectedly than do individual compounds

Endoglin (CD105) expression in ovarian serous carcinoma effusions is related to chemotherapy status

Endoglin (CD105), a cell surface co-receptor for transforming growth factor-β, is expressed in proliferating endothelial cells, as well as in cancer cells. We studied endoglin expression and its clinical relevance in effusions, primary tumors, and solid metastatic lesions from women with advanced-stage ovarian serous carcinoma. Endoglin expression was analyzed by immunohistochemistry in effusions (n = 211; 174 peritoneal, 37 pleural). Cellular endoglin staining was analyzed for association with the concentration of soluble endoglin (previously determined by ELISA) in 95 corresponding effusions and analyzed for correlation with clinicopathologic parameters, including survival. Endoglin expression was additionally studied in 34 patient-matched primary tumors and solid metastases. Carcinoma and mesothelial cells expressed endoglin in 95/211 (45%) and 133/211 (63%) effusions, respectively. Carcinoma cell endoglin expression was more frequent in effusions from patients aged ≤60 years (p = 0.048) and in post- compared to prechemotherapy effusions (p = 0.014), whereas mesothelial cell endoglin expression was higher in prechemotherapy effusions (p = 0.021). No association was found between cellular endoglin expression and its soluble effusion concentration. Endoglin was expressed in 17/34 (50%) primary tumors and 19/34 (56%) metastases, with significantly higher percentage of immunostained cells in solid metastases compared to effusions (p = 0.036). Endoglin expression did not correlate with survival. Tumor cell endoglin expression is higher in post- vs. prechemotherapy effusions, whereas the opposite is seen in mesothelial cells. Together with its upregulation in solid metastases, this suggests that the expression and biological role of endoglin may differ between cell populations and change along tumor progression in ovarian carcinoma

MED12 Alterations in Both Human Benign and Malignant Uterine Soft Tissue Tumors

The relationship between benign uterine leiomyomas and their malignant counterparts, i.e. leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), is still poorly understood. The idea that a leiomyosarcoma could derive from a leiomyoma is still controversial. Recently MED12 mutations have been reported in uterine leiomyomas. In this study we asked whether such mutations could also be involved in leiomyosarcomas and STUMP oncogenesis. For this purpose we examined 33 uterine mesenchymal tumors by sequencing the hot-spot mutation region of MED12. We determined that MED12 is altered in 66.6% of typical leiomyomas as previously reported but also in 11% of STUMP and 20% of leiomyosarcomas. The mutated allele is predominantly expressed in leiomyomas and STUMP. Interestingly all classical leiomyomas exhibit MED12 protein expression while 40% of atypical leiomyomas, 50% of STUMP and 80% of leiomyosarcomas (among them the two mutated ones) do not express MED12. All these tumors without protein expression exhibit complex genomic profiles. No mutations and no expression loss were identified in an additional series of 38 non-uterine leiomyosarcomas. MED12 mutations are not exclusive to leiomyomas but seem to be specific to uterine malignancies. A previous study has suggested that MED12 mutations in leiomyomas could lead to Wnt/β-catenin pathway activation however our immunohistochemistry results show that there is no association between MED12 status and β-catenin nuclear/cytoplasmic localization. Collectively, our results show that subgroups of benign and malignant tumors share a common genetics. We propose here that MED12 alterations could be implicated in the development of smooth muscle tumor and that its expression could be inhibited in malignant tumors

Systemic versus localized coagulation activation contributing to organ failure in critically ill patients

In the pathogenesis of sepsis, inflammation and coagulation play a pivotal role. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation not only leads to activation of coagulation but coagulation also considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may not only be relevant for vascular atherothrombotic disease in general but has in certain clinical settings considerable consequences, for example in the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Pro-inflammatory cytokines and other mediators are capable of activating the coagulation system and downregulating important physiological anticoagulant pathways. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by physiological anticoagulant mechanisms and endogenous fibrinolysis. Interestingly, apart from the overall systemic responses, a differential local response in various vascular beds related to specific organs may occur