Epithelial Ovarian Cancer Experimental Models

Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of cells and cellular aggregates into the peritoneal cavity, survival of matrix-detached cells in a complex ascites fluid phase, and subsequent adhesion to the mesothelium lining covering abdominal organs to establish secondary lesions containing host stromal and inflammatory components. Development of experimental models to recapitulate this unique mechanism of metastasis presents a remarkable scientific challenge and many approaches used to study other solid tumors (lung, colon, and breast, for example) are not transferable to OvCa research given the distinct metastasis pattern and unique tumor microenvironment. This review will discuss recent progress in the development and refinement of experimental models to study OvCa. Novel cellular, three-dimensional organotypic, and ex vivo models are considered and the current in vivo models summarized. The review critically evaluates currently available genetic mouse models of OvCa, the emergence of xenopatients, and the utility of the hen model to study OvCa prevention, tumorigenesis, metastasis, and chemoresistance. As these new approaches more accurately recapitulate the complex tumor microenvironment, it is predicted that new opportunities for enhanced understanding of disease progression, metastasis and therapeutic response will emerge

Diabetes in old male offspring of rat dams fed a reduced protein diet.

Restricted fetal growth is associated with increased risk for the future development of Type 2 diabetes in humans. The study aim was to assess the glucose tolerance of old (seventeen months) male rats, which were growth restricted in early life due to maternal protein restriction during gestation and lactation. Rat mothers were fed diets containing either 20% or 8% protein and all offspring weaned onto a standard rat diet. In old-age fasting plasma glucose concentrations were significantly higher in the low protein offspring: 8.4 (1.3) mmol/l v. 5.3 (1.3) mmol/l (p = 0.005). Areas under the curves were increased by 67% for glucose (p = 0.01) and 81% for insulin (p = 0.01) in these rats in intravenous glucose tolerance tests, suggesting (a degree of) insulin resistance. These results show that early growth retardation due to maternal protein restriction leads to the development of diabetes in old male rat offspring. The diabetes is predominantly associated with insulin resistance.Peer Reviewe

SuperCLASS - II. Photometric redshifts and characteristics of spatially resolved mu Jy radio sources

We present optical and near-infrared imaging covering a ∼1.53 deg2 region in the Super-Cluster Assisted Shear Survey (SuperCLASS) field, which aims to make the first robust weak lensing measurement at radio wavelengths. We derive photometric redshifts for ≈176 000 sources down to i′AB∼24 and present photometric redshifts for 1.4 GHz expanded Multi-Element Radio Linked Interferometer Network (e-MERLIN) and Karl G. Jansky Very Large Array (VLA) detected radio sources found in the central 0.26 deg2. We compile an initial catalogue of 149 radio sources brighter than S1.4 > 75 μJy and find their photometric redshifts span 0 7σ in the density map and we confirm the photometric redshifts are consistent with previously measured spectra from a few galaxies at the cluster centres

SuperCLASS - I. The super cluster assisted shear survey: Project overview and data release 1

The SuperCLuster Assisted Shear Survey (SuperCLASS) is a legacy programme using the e-MERLIN interferometric array. The aim is to observe the sky at L-band (1.4 GHz) to a r.m.s. of 7μJybeam−1 over an area of ∼1deg2 centred on the Abell 981 supercluster. The main scientific objectives of the project are: (i) to detect the effects of weak lensing in the radio in preparation for similar measurements with the Square Kilometre Array (SKA); (ii) an extinction free census of star formation and AGN activity out to z ∼ 1. In this paper we give an overview of the project including the science goals and multiwavelength coverage before presenting the first data release. We have analysed around 400 h of e-MERLIN data allowing us to create a Data Release 1 (DR1) mosaic of ∼0.26deg2 to the full depth. These observations have been supplemented with complementary radio observations from the Karl G. Jansky Very Large Array (VLA) and optical/near infrared observations taken with the Subaru, Canada-France-Hawaii, and Spitzer Telescopes. The main data product is a catalogue of 887 sources detected by the VLA, of which 395 are detected by e-MERLIN and 197 of these are resolved. We have investigated the size, flux, and spectral index properties of these sources finding them compatible with previous studies. Preliminary photometric redshifts, and an assessment of galaxy shapes measured in the radio data, combined with a radio-optical cross-correlation technique probing cosmic shear in a supercluster environment, are presented in companion papers

SuperCLASS - III. Weak lensing from radio and optical observations in Data Release 1

We describe the first results on weak gravitational lensing from the SuperCLASS survey: the first survey specifically designed to measure the weak lensing effect in radio-wavelength data, both alone and in cross-correlation with optical data. We analyse 1.53deg2 of optical data from the Subaru telescope and 0.26deg2 of radio data from the e-MERLIN and VLA telescopes (the DR1 data set). Using standard methodologies on the optical data only we make a significant (10σ) detection of the weak lensing signal (a shear power spectrum) due to the massive supercluster of galaxies in the targeted region. For the radio data we develop a new method to measure the shapes of galaxies from the interferometric data, and we construct a simulation pipeline to validate this method. We then apply this analysis to our radio observations, treating the e-MERLIN and VLA data independently. We achieve source densities of 0.5 arcmin−2 in the VLA data and 0.06 arcmin−2 in the e-MERLIN data, numbers which prove too small to allow a detection of a weak lensing signal in either the radio data alone or in cross-correlation with the optical data. Finally, we show preliminary results from a visibility-plane combination of the data from e-MERLIN and VLA which will be used for the forthcoming full SuperCLASS data release. This approach to data combination is expected to enhance both the number density of weak lensing sources available, and the fidelity with which their shapes can be measured

Flow cytometry based techniques to study testicular acidophilic granulocytes from the protandrous fish gilthead seabream (Sparus aurata L.)

The gilthead seabream is a protandrous seasonal breeding teleost that is an excellent model for studying the testicular regression process which occurs in both seasonal testicular involution and sex reversion. Little is known about the cell types and the molecular mechanisms involved in such processes, mainly because of the lack of appropriate methods for testis dissociation, and testicular cell isolation, culture and functional characterization. We have previously reported that gilthead seabream acidophilic granulocytes infiltrate the testis at post-spawning stage, settle close to the spermatogonia and accumulate intracellular interleukin-1β. In this paper, we report several flow cytometry based assays which allow to establish the role played by gilthead seabream testicular acidophilic granulocytes and permits their quantification

Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

First-Borns Carry a Higher Metabolic Risk in Early Adulthood: Evidence from a Prospective Cohort Study

Birth order has been associated with early growth variability and subsequent increased adiposity, but the consequent effects of increased fat mass on metabolic risk during adulthood have not been assessed. We aimed to quantify the metabolic risk in young adulthood of being first-born relative to those born second or subsequently.Body composition and metabolic risk were assessed in 2,249 men, aged 17-19 years, from a birth cohort in southern Brazil. Metabolic risk was assessed using a composite z-score integrating standardized measurements of blood pressure, total cholesterol, high density lipoprotein, triglycerides and fat mass. First-borns had lower birth weight z-score (Δ = -0.25, 95%CI -0.35, -0.15,p<0.001) but showed greater weight gain during infancy (change in weight z-score from birth to 20 months: Δ = 0.39, 95%CI 0.28-0.50, p<0.0001) and had greater mean height (Δ = 1.2 cm, 95%CI: 0.7-1.6, p<0.0001) and weight (Δ = 0.34 kg, 95%CI: 0.13-0.55, p<0.002) at 43 months. This greater weight and height tracked into early adulthood, with first-borns being significantly taller, heavier and with significantly higher fat mass than later-borns. The metabolic risk z-score was significantly higher in first-borns.First-born status is associated with significantly elevated adiposity and metabolic risk in young adult men in Brazil. Our results, linking cardiovascular risk with life history variables, suggest that metabolic risk may be associated with the worldwide trend to smaller family size and it may interact with changes in behavioural or environmental risk factors

Mitochondrial function is involved in regulation of cholesterol efflux to apolipoprotein (apo)A-I from murine RAW 264.7 macrophages

<p>Abstract</p> <p>Background</p> <p>Mitochondrial DNA damage, increased production of reactive oxygen species and progressive respiratory chain dysfunction, together with increased deposition of cholesterol and cholesteryl esters, are hallmarks of atherosclerosis. This study investigated the role of mitochondrial function in regulation of macrophage cholesterol efflux to apolipoprotein A-I, by the addition of established pharmacological modulators of mitochondrial function.</p> <p>Methods</p> <p>Murine RAW 264.7 macrophages were treated with a range of concentrations of resveratrol, antimycin, dinitrophenol, nigericin and oligomycin, and changes in viability, cytotoxicity, membrane potential and ATP, compared with efflux of [³H]cholesterol to apolipoprotein (apo) A-I. The effect of oligomycin treatment on expression of genes implicated in macrophage cholesterol homeostasis were determined by quantitative polymerase chain reaction, and immunoblotting, relative to the housekeeping enzyme, <it>Gapdh</it>, and combined with studies of this molecule on cholesterol esterification, <it>de novo</it> lipid biosynthesis, and induction of apoptosis. Significant differences were determined using analysis of variance, and Dunnett’s or Bonferroni post <it>t</it>-tests, as appropriate.</p> <p>Results</p> <p>The positive control, resveratrol (24 h), significantly enhanced cholesterol efflux to apoA-I at concentrations ≥30 μM. By contrast, cholesterol efflux to apoA-I was significantly inhibited by nigericin (45%; <it>p</it><0.01) and oligomycin (55%; <it>p</it><0.01), under conditions (10 μM, 3 h) which did not induce cellular toxicity or deplete total cellular ATP content. Levels of ATP binding cassette transporter A1 (ABCA1) protein were repressed by oligomycin under optimal efflux conditions, despite paradoxical increases in <it>Abca1</it> mRNA. Oligomycin treatment did not affect cholesterol biosynthesis, but significantly inhibited cholesterol esterification following exposure to acetylated LDL, and induced apoptosis at ≥30 μM. Finally, oligomycin induced the expression of genes implicated in both cholesterol efflux (<it>Abca1</it>, <it>Abcg4</it>, <it>Stard1</it>) and cholesterol biosynthesis (<it>Hmgr</it>, <it>Mvk</it>, <it>Scap</it>, <it>Srebf2</it>), indicating profound dysregulation of cholesterol homeostasis.</p> <p>Conclusions</p> <p>Acute loss of mitochondrial function, and in particular Δψ_m, reduces cholesterol efflux to apoA-I and dysregulates macrophage cholesterol homeostasis mechanisms. Bioavailable antioxidants, targeted to mitochondria and capable of sustaining effective mitochondrial function, may therefore prove effective in maintenance of arterial health.</p