POLD2 and KSP37 (FGFBP2) Correlate Strongly with Histology, Stage and Outcome in Ovarian Carcinomas

BACKGROUND:Epithelial ovarian cancer (EOC) constitutes more than 90% of ovarian cancers and is associated with high mortality. EOC comprises a heterogeneous group of tumours, and the causes and molecular pathology are essentially unknown. Improved insight into the molecular characteristics of the different subgroups of EOC is urgently needed, and should eventually lead to earlier diagnosis as well as more individualized and effective treatments. Previously, we reported a limited number of mRNAs strongly upregulated in human osteosarcomas and other malignancies, and six were selected to be tested for a possible association with three subgroups of ovarian carcinomas and clinical parameters. METHODOLOGY/PRINCIPAL FINDINGS:The six selected mRNAs were quantified by RT-qPCR in biopsies from eleven poorly differentiated serous carcinomas (PDSC, stage III-IV), twelve moderately differentiated serous carcinomas (MDSC, stage III-IV) and eight clear cell carcinomas (CCC, stage I-IV) of the ovary. Superficial scrapings from six normal ovaries (SNO), as well as biopsies from three normal ovaries (BNO) and three benign ovarian cysts (BBOC) were analyzed for comparison. The gene expression level was related to the histological and clinical parameters of human ovarian carcinoma samples. One of the mRNAs, DNA polymerase delta 2 small subunit (POLD2), was increased in average 2.5- to almost 20-fold in MDSC and PDSC, respectively, paralleling the degree of dedifferentiation and concordant with a poor prognosis. Except for POLD2, the serous carcinomas showed a similar transcription profile, being clearly different from CCC. Another mRNA, Killer-specific secretory protein of 37 kDa (KSP37) showed six- to eight-fold higher levels in CCC stage I compared with the more advanced staged carcinomas, and correlated positively with an improved clinical outcome. CONCLUSIONS/SIGNIFICANCE:We have identified two biomarkers which are markedly upregulated in two subgroups of ovarian carcinomas and are also associated with stage and outcome. The results suggest that POLD2 and KSP37 might be potential prognostic biomarkers

The thick left ventricular wall of the giraffe heart normalises wall tension, but limits stroke volume and cardiac output

Giraffes – the tallest extant animals on Earth – are renowned for their high central arterial blood pressure, which is necessary to secure brain perfusion. The pressure which may exceed 300 mmHg has historically been attributed to an exceptionally large heart. Recently, this has been refuted by several studies demonstrating that the mass of giraffe heart is similar to that of other mammals when expressed relative to body mass. It remains enigmatic, however, how the normal-sized giraffe heart generates such massive arterial pressures. We hypothesized that giraffe hearts have a small intraventricular cavity and a relatively thick ventricular wall, allowing for generation of high arterial pressures at normal left ventricular wall tension. In nine anaesthetized giraffes (495±38 kg), we determined in vivo ventricular dimensions using echocardiography along with intraventricular and aortic pressures to calculate left ventricular wall stress. Cardiac output was also determined by inert gas rebreathing to provide an additional and independent estimate of stroke volume. Echocardiography and inert gas-rebreathing yielded similar cardiac outputs of 16.1±2.5 and 16.4±1.4 l min−1, respectively. End-diastolic and end-systolic volumes were 521±61 ml and 228±42 ml, yielding an ejection fraction of 56±4%, and a stroke volume of 0.59 ml kg−1. Left ventricular circumferential wall stress was 7.83±1.76 kPa. We conclude that, relative to body mass, a small left ventricular cavity and a low stroke volume characterizes the giraffe heart. The adaptations result in typical mammalian left ventricular wall tensions, but results in lowered cardiac output.</jats:p

Macroscopic digestive tract anatomy of two small antelopes, the blackbuck (Antilope cervicapra) and the Arabian sand gazelle (Gazella subgutturosa marica)

The digestive tract anatomy of 14 blackbucks (Antilope cervicapra) and seven Arabian sand gazelles (Gazella subgutturosa marica) was quantified by dimensions, area and weight. Data from the two small-sized antilopinae were evaluated against a larger comparative data set from other ruminants classified as having either a ‘cattle-type’ or ‘moose-type’ digestive system. The digestive anatomy of the blackbuck resembled that of ‘cattle-type’ ruminants, which corresponds to their feeding ecology and previous studies of solute and particle retention time; however, a surprising exception was the remarkably small omasum in this species, which makes the blackbuck stand out from the general rule of a relatively large omasum in grazing ruminants. Sand gazelles had morphological features that corresponded more to the ‘moose type’ or an intermediate position, although previous studies of solute and particle retention time had led to the expectation of a more ‘cattle-type’ anatomy. The results show that outliers to general morphological trends exist, that findings on physiology and anatomy do not always match completely and that differences in the digestive morphology among ruminant species are more difficult to demonstrate at the lower end of the body mass range

Physical characteristics of forestomach contents from two nondomestic small ruminants, the blackbuck (Antilope cervicapra) and the Arabian sand gazelle (Gazella subgutturosa marica)

Rumen content stratification and the degree of dissociation of particle and fluid retention in the reticulorumen differ between ‘moose-type’ and ‘cattle-type’ ruminant species. These differences are not strictly linked to diet, except for a seeming limitation of ‘moose-type’ ruminants to a browsing niche. Nevertheless, these differences can be plausibly linked to other observed differences in ruminants, such as the intraruminal papillation pattern, or the size of the omasum. However, many of the corresponding measures are still only available for a restricted number of species. Here, we investigated the dry matter (i.e., the inverse of the moisture) concentration in forestomach contents of 10 blackbuck (Antilope cervicapra) and 7 Arabian sand gazelle (Gazella subgutturosa marica), and quantified the rumen papillation pattern. The blackbucks had distinct rumen contents stratification, with more moisture in ventral than in dorsal contents (difference 3.6% units, P < 0.001), whereas this difference was much less pronounced in the sand gazelles (0.6% units, P = 0.227). While reticulum contents were particularly moist in both species, omasum contents were particularly dry in sand gazelles, but did not differ in moisture from rumen contents in the blackbuck. This species is an outlier among ruminants due to its extremely small omasum. The intraruminal papillation pattern did not differ between blackbucks and sand gazelles and showed a surface enlargement factor (SEF) in the dorsal rumen of 27–28% of the SEF in the Atrium ruminis. Compared to data on digesta retention in the same species, the findings are in line with the overall concept of a high fluid throughput causing a distinct stratification of rumen contents and intraruminal papillation, and necessitating a large omasum for fluid re-absorption. However, the data also show that individual species may not correspond to all the assumptions of the concept, suggesting taxon-specific differences between species. Reasons for these differences cannot be linked to a dietary grass-browse spectrum, but may lie in evolutionary contingency

<em>ZNF385B</em> and <em>VEGFA</em> Are Strongly Differentially Expressed in Serous Ovarian Carcinomas and Correlate with Survival

<div><h3>Background</h3><p>The oncogenesis of ovarian cancer is poorly understood. The aim of this study was to identify mRNAs differentially expressed between moderately and poorly differentiated (MD/PD) serous ovarian carcinomas (SC), serous ovarian borderline tumours (SBOT) and superficial scrapings from normal ovaries (SNO), and to correlate these mRNAs with clinical parameters including survival.</p> <h3>Methods</h3><p>Differences in mRNA expression between MD/PD SC, SBOT and SNO were analyzed by global gene expression profiling (n = 23), validated by RT-qPCR (n = 41) and correlated with clinical parameters.</p> <h3>Results</h3><p>Thirty mRNAs differentially expressed between MD/PD SC, SBOT and SNO were selected from the global gene expression analyses, and 21 were verified (p<0.01) by RT-qPCR. Of these, 13 mRNAs were differentially expressed in MD/PD SC compared with SNO (p<0.01) and were correlated with clinical parameters. ZNF385B was downregulated (FC = −130.5, p = 1.2×10⁻⁷) and correlated with overall survival (p = 0.03). VEGFA was upregulated (FC = 6.1, p = 6.0×10⁻⁶) and correlated with progression-free survival (p = 0.037). Increased levels of TPX2 and FOXM1 mRNAs (FC = 28.5, p = 2.7×10⁻¹⁰ and FC = 46.2, p = 5.6×10⁻⁴, respectively) correlated with normalization of CA125 (p = 0.03 and p = 0.044, respectively). Furthermore, we present a molecular pathway for MD/PD SC, including VEGFA, FOXM1, TPX2, BIRC5 and TOP2A, all significantly upregulated and directly interacting with TP53.</p> <h3>Conclusions</h3><p>We have identified 21 mRNAs differentially expressed (p<0.01) between MD/PD SC, SBOT and SNO. Thirteen were differentially expressed in MD/PD SC, including ZNF385B and VEGFA correlating with survival, and FOXM1 and TPX2 with normalization of CA125. We also present a molecular pathway for MD/PD SC.</p> </div