Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

BACKGROUND: Interleukin (IL) 11 is produced by human endometrium and endometrial cancer tissue. It has roles in endometrial epithelial cell adhesion and trophoblast cell invasion, two important processes in cancer progression. This study aimed to determine the levels of IL11 in uterine lavage fluid in women with endometrial cancer and postmenopausal women. It further aimed to determine the levels of IL11 protein and its signaling molecules in human endometrial cancer of varying grades, and endometrium from postmenopausal women and IL11 signalling mechanisms in endometrial cancer cell lines. METHODS: IL11 levels in uterine lavage were measured by ELISA. IL11, IL11 receptor(R) α, phosphorylated (p) STAT3 and SOCS3 were examined by immunohistochemistry in endometrial carcinomas and in control endometrium from postmenopausal women and normal cycling women. The effect of IL11 on pSTAT3/STAT3 and SOCS3 protein abundance in endometrial cancer cell lines and non-cancer endometrial epithelial cells was determined by Western blot. RESULTS: IL11 was present in uterine flushings and was significantly higher in women with Grade 1 carcinomas compared to postmenopausal women (p < 0.05). IL11 immunostaining was significantly elevated in the endometrial tumour epithelial cells from Grade 1 and 3 compared to endometrial epithelium from postmenopausal and cycling women. IL11Rα immunostaining intensity was increased in cancer epithelium in the Grades 1 and 2 tumours compared to epithelium from postmenopausal women. Both IL11 and IL11Rα localized to vascular endothelial and smooth muscle cells while IL11 also localized to subsets of leucocytes in the cancer tissues. pSTAT3 was found in both the tumour epithelial and stromal compartments but was maximal in the tumour epithelial cells, while SOCS3 was predominantly found in the tumour epithelial cells. pSTAT3 staining intensity was significantly higher in Grade 1 and 2 tumour epithelial cells compared to epithelial cells from cycling and postmenopausal women. SOCS3 staining intensity did not differ between between each tumour and postmenopausal endometrial epithelium but SOCS3 in cycling endometrium was significantly higher compared to postmonopausal and Tumour Grades 2 and 3. IL11 increased pSTAT3/STAT3 in all tumour cell lines, while SOCS3 abundance was increased only in one tumour cell line. CONCLUSIONS: The present study suggests that IL11 in uterine washings may be useful as a diagnostic marker for early stage endometrial cancer. It indicates that IL11, along with its specific receptor, IL11Rα, and downstream signalling molecules, STAT3 and SOCS3, are likely to play a role in the progression of endometrial carcinoma. The precise role of IL11 in endometrial cancer remains to be elucidated

The Molecular Origin and Taxonomy of Mucinous Ovarian Carcinoma

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases

Selection for improved stress tolerance in rainbow trout (Oncorhynchus mykiss) leads to reduced feed waste.

The magnitude of the cortisol response to a standardised stressor is a heritable trait in salmonid fishes, and selection for stress responsiveness induces differences in both behaviour and neuroendocrine function. For instance, in laboratory studies, fish with a high cortisol response show a greater propensity for stress induced anorexia. Some authors have, however, commented that controlled studies encompassing relatively small groups of fish hold little or no relevance to practical aquaculture. This notion may be flawed, since understanding the mechanisms behind the behaviour of individuals is a proviso to predict behaviour in groups even with the caveat that some behaviors may be modified by group size. As an example, optimal feeding regimes should be easier to predict in a population consisting of individuals whose appetite is relatively less affected by external stressors. In a fluctuating and potentially stressful environment, such a population should also generate less feed waste, if kept on fixed rations. In the present experiment, we tested this hypothesis by monitoring feed waste and feed onversion efficiency in lines of rainbow trout selected for a low (LR) or high (HR) cortisol response to stress. The study was carried out after fish had been transported between rearing sites in the United Kingdom and Norway. There was significantly more feed waste from rearing units containing HR fish, and these fish also showed lower feed efficiency (growth per unit feed consumed). The difference in feed waste became more apparent with increasing time after transport, as rations increased. Simultaneously, size was more variable and growth was slower in HR rearing units. These results suggest that there are several potential benefits of selection for low stress responsiveness in aquaculture

The utility of serum CA-125 in predicting extra-uterine disease in apparent early-stage endometrial cancer

Objectives: To evaluate the clinical value of pre-operative serum CA125 in predicting the presence of extra-uterine disease in patients with apparent early stage endometrial cancer. Methods: Between October 6, 2005 and June 17, 2010, 760 patients were enrolled in an international, multicentre, prospective randomized trial (LACE) comparing laparotomy with laparoscopy in the management of endometrial cancer apparently confined to the uterus. This study is based on data from 657 patients with endometrial adenocarcinoma who had a pre-operative serum CA125 value, and was undertaken to correlate pre-operative serum CA125 with final stage. Results: Using a pre-operative CA-125 cutpoint of 30U/ml was associated with the smallest misclassification error (14.5%) using a multiple cross-validation method. Median pre-operative serum CA-125 was 14U/ml, and using a cutpoint of 30U/ml, 14.9% of patients had elevated CA-125 levels. Of 98 patients with elevated CA-125 level, 36 (36.7%) had evidence of extra-uterine disease. Of the 116 patients (17.7%) with evidence of extra-uterine disease, 31.0% had elevated CA-125 level. In univariate and multivariate logistic regression analysis, only pre-operative CA-125 level was found to be associated with extra-uterine spread of disease. Utilising a cutpoint of 30U/ml achieved a sensitivity, specificity, positive predictive value and negative predictive value of 31.0%, 88.5%, 36.7% and 85.7% respectively. Overall, 326/657 (49.6%) of patients had full surgical staging involving lymph node dissection. When analysis was limited to patients that had undergone full surgical staging, the outcomes remained essentially unchanged. Conclusions: Elevated CA-125 above 30U/ml in patients with apparent early stage disease is associated with a sensitivity of 31.0% and specificity of 88.5% in detecting extra-uterine disease. Pre-operative identification of this risk factor may assist to triage patients to tertiary centres and comprehensive surgical staging

The stress response of three-spined sticklebacks is modified in proportion to effluent exposure downstream of wastewater treatment works

This study was conducted to investigate whether exposure to wastewater treatment works (WWTW) effluent affects the adaptive stress axis of fish resident within the receiving water. Three-spined sticklebacks (Gasterosteus aculeatus) were sampled from sites downstream of ten WWTWs in north-west England, selected to provide a range of population equivalents between 1,000 and 120,000. Following capture, indices of stress (whole-body cortisol and glucose concentrations) were measured both prior to, and following, a standardised stressor to establish both baseline and stress-induced cortisol and glucose concentrations. There was considerable between-site variation in size, and to a lesser extent condition, of the fish. Pre- and post-stress cortisol and glucose concentrations also exhibited significant between-site variation. A large proportion of the variation in both somatic characters and stress response was explained by variation in the proportion of effluent contributing to total river flow at the study sites. Mass (r2 = 0.35, P < 0.001) and length (r2 = 0.37, P < 0.001) of the fish, and cortisol (r2 = 0.26, P < 0.001) and glucose (r2 = 0.12, P < 0.01) concentrations in unstressed sticklebacks, were positively related to the concentration of effluent across the sample sites. However, in stressed fish cortisol (r2 = 0.32, P < 0.001) and glucose (r2 = 0.14, P < 0.001) concentrations exhibited a negative trend in relation to the effluent concentrations across sites. Individual variation in fish size did not account for the variation in either cortisol or glucose levels. These data are the first in which the activity and responsiveness of the stress axis has been compared across multiple populations of fish and provide the first indication that modulation of the stress axis in fish by anthropogenic factors might be a widespread phenomenon and therefore of greater significance than hitherto assumed

A patient derived xenograft model of cervical cancer and cervical dysplasia.

AIM:To develop a patient derived xenograft (PDX) model of cervical cancer and cervical dysplasia using the subrenal capsule. METHODS:Cervical cancer (12 Squamous Cell Carcinoma, 1 Adenocarcinoma, 1 Adenosquamous Carcinoma), 7 cervical dysplasia biopsy and normal cervical tissues were transplanted beneath the renal capsule of immunocompromised NOD/SCID/gamma mice. Resulting tumours were harvested and portions serially transplanted into new recipient mice for up to three in vivo passages. Parent and xenograft tumours were examined by immunohistochemistry for p16INK41, HPV, and CD-45. Single cell suspensions of mixed mouse and human, or human only cell populations were also transplanted. RESULTS:The overall engraftment rate for the primary cervical cancer PDX model was 71.4 ±12.5% (n = 14). Tumours maintained morphological, histoarchitecture and immunohistochemical features of the parent tumour, and demonstrated invasiveness into local tissues. Single cell suspensions did not produce tumour growth in this model. Mean length of time (32.4 +/- 3.5 weeks) for the transplanted tissue to generate a tumour in the animal was similar between successive transplantations. Three of four xenografted cervical dysplasia tissues generated microscopic cystic structures resembling dysplastic cervical tissue. Normal cervical tissue (4 of 5 xenografted) also developed microscopic cervical tissue grafts. CONCLUSION:The subrenal capsule can be used for a PDX model of human cervical cancer with a good engraftment rate and the ability to model in vivo characteristics of cervical cancer. For the first time we have demonstrated that cervical dysplasia and normal cervical tissue generated microscopic tissues in a PDX model