Recent studies have detailed the genomic landscape of primary endometrial cancers, but their evolution into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors, and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites.

Platelet-derived growth factor (PDGF) isoforms lead to mitogenic, survival, and chemotactic responses in a variety of mesenchymal cell types during development and in the adult. We have studied the importance of phosphatidylinositol-3 kinase (PI3K) signaling in these responses by mutating the PI3K-binding sites in the PDGF-␤ receptor by gene targeting in embryonic stem cells. Homozygous mutant mice developed normally; however, cells derived from the mutants were less chemotactic and had largely lost their ability to contract collagen gels in response to PDGF. Injection of a mast cell degranulating agent in mice led to a decrease in interstitial f luid pressure resulting in edema formation. In contrast to wild-type mice, mutant mice were unable to normalize the pressure after treatment with PDGF. Taken together, these observations suggest a function for PDGF signaling through PI3K in interstitial f luid homeostasis by modulating the tension between cells and extracellular matrix structures.Platelet-derived growth factor (PDGF) isoforms are potent mitogens, survival factors, and chemoattractants for many mesenchymal cell types. PDGF consists of homo-or heterodimers of A-and B-polypeptide chains, which exert their biological effects by binding to two structurally related tyrosine kinase receptors, PDGF-␣ receptor and ␤ receptor (1).The PDGF signal transduction machinery has been analyzed extensively for the PDGF-␤ receptor (for reviews, see refs. 2 and 3). Upon ligand binding, PDGF receptors homo-or heterodimerize and phosphorylate each other in trans on specific tyrosine residues, initiating signaling cascades that lead to growth, actin cytoskeleton rearrangements, and chemotaxis (1). A large body of evidence indicates that the latter two effects are dependent on activation of phosphatidylinositol-3Ј kinase (PI3K) through binding to two phosphorylated tyrosines (tyrosines 739 and 750 in the mouse sequence; refs. 4 and 5). These two tyrosines are located in Tyr-Xaa-Xaa-Met motifs and thus are recognized by the Src homology 2 (SH2) domains of p85, the regulatory subunit of the PI3K. p85, in turn, associates with the catalytic subunit p110, which phosphorylates the membrane lipids phosphatidylinositol (4)-phosphate and phosphatidylinositol (4,5)-bisphosphate in the D-3 position of their inositol rings to the corresponding (3,4)-diphosphate and (3,4,5)-triphosphate derivatives (reviewed in ref. 6). The effect of PI3K on the actin cytoskeleton, resulting in formation of lamellipodia, probably is mediated by activation of the small GTP-binding protein Rac (7-9).

1. The present experiments describe a role for platelet-derived growth factor-BB and cellular adhesion receptors towards extracellular matrix molecules (/1-integrins) in control of interstitial fluid pressure (Pif). and decreased to -2-50 + 0 35 mmHg (P < 0 05) and -3-88 + 1P45 mmHg (P < 0 05) at anti-a2/11 concentrations of 0-56 and 1P12 mg ml-', respectively.4. The effect of anti-a0231 was abolished when platelet-derived growth factor-BB (PDGF-BB) (200 ng ml-') was injected together with anti-ca2/1. 5. The time-and dose-responses of PDGF-BB to counteract increased negativity of Pif were studied further using dextran anaphylaxis as an experimental model inducing increased negativity of Pif in skin. Control Pif averaged -0 33 + 0A43 mmHg and fell to -4-10 + 1P47 mmHg within 10 min after dextran (P < 0-01). Subsequent subdermal injection of PDGF-BB at 200 ng ml-' normalized Pif in 10-20 min which became -1-37 + 1-23 mmHg (P < 0'01 versus dextran, P > 0.05 versus control). PDGF-BB had little or no effect at 50 ng ml-. PDGF-AA and basic fibroblast growth factor had no effect on Pif.6. The in vivo function reported for PDGF-BB has not been described previously and provides further evidence for active participation of connective tissue cells in control of Pif by altering tension on extracellular matrix structures.During the initial stage of several acute inflammatory reactions, loose connective tissues will 'actively' enhance transcapillary fluid flux and oedema formation in skin and airways, since an increased negativity of interstitial fluid pressure (Pif) from -1 to between -5 and -10 inmHg will provide an increased driving pressure for fluid filtration

In nephrotic patients with idiopathic membranous nephropathy, treatment with ACTH 1 mg twice per week was associated with significant long-term improvements in serum lipoprotein pattern and glomerular function.

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In the last years, the interest in sport nutrition has increased. The purpose of this study was to quantify the nutritional status of eleven cyclists of a professional team (age: 28.7+/-4.2 yr; height: 181.0+/-4.2 cm; weight: 71.0+/-5.2 kg; body fat: 10.2+/-2.4%), during basic pre-season training. The athletes trained on five days (160 km per day) and respected one rest-day (33 km). The food of the cyclists, which was chosen by the riders themselves, was weighed and recorded for six days, the protocols were analysed through the PRODI 4.3 EXPERT database. The daily energy intake which averaged 13.5 MJ (59% carbohydrates, 19% proteins, and 21% fat), was compared to the mean daily consumption of energy (19.1 MJ), which was calculated from the basal metabolic rate and the energy turnover while training (directly measured through the SRM Training system). The daily energy expenditure was 30% higher than the daily energy intake. The analysis of the food diary showed that these experienced riders composed a carbohydrate-rich and low-fat diet by themselves as recommended for high-performance endurance athletes. When compared to nutritional guidelines, the composition of the diet in the present study can be considered as adequate.

Acute inflammation in skin is accompanied by increased negativity of interstitial fluid pressure (PIF), which will increase capillary fluid filtration and thereby potentiate edema formation. A series of studies indicates that the connective tissue cells in rat dermis are involved in the control of PIF and mediate this response. The present study describes a novel effect of prostaglandin (PG) E1 isopropyl ester, carbaprostacyclin (PGI2 analog), and latanoprost (PGF2α analog) on edema formation and PIF in parallel with their action on the fibroblast-populated collagen gel contraction assay. The prostaglandins were injected subdermally in pentobarbital-anesthetized rats. PIF was measured with a servo-controlled counterpressure system after circulatory arrest had been induced with saturated potassium chloride. Circulatory arrest was induced to limit edema formation that would raise interstitial fluid volume and thereby attenuate a possible increased negativity of PIF. PGE1 (0.91 mM) and carbaprostacyclin (1.28 mM) lowered PIF from a control value of −0.8 ± 0.4 mmHg to −3.0 ± 0.4 ( P < 0.01) and −3.7 ± 0.9 ( P < 0.01) mmHg, respectively, within 45 min in a dose-dependent manner. Edema formation was measured in separate experiments. PGE1 and carbaprostacyclin significantly increased interstitial fluid volume (extravascular51Cr-EDTA space) at concentrations as low as 0.1 and 1.1 μM, respectively. Latanoprost had no effect on PIF or edema formation. However, latanoprost reversed, in a dose-dependent manner, an increased negativity of PIF accompanying the anaphylactic reaction to dextran. In the gel contraction assay with human diploid fibroblasts (AG 1518), a corresponding specificity was observed where PGE1 and carbaprostacyclin effectively inhibited gel contraction although latanoprost had no effect. Thus the present data demonstrate a novel effect of prostaglandins and provide further evidence for active modulation of PIF via loose connective tissue cells.