The manuscript describes the “digital transcriptome atlas” of the developing mouse embryo, a powerful resource to determine co-expression of genes, to identify cell populations and lineages and to identify functional associations between genes relevant to development and disease.

Apples contain several classes of polyphenols: monomers (catechins, epicatechins) and oligomers/polymers, such as the procyanidins. Our aim was (i) to study anti-proliferative mechanisms on human metastatic colon carcinoma (SW620 cells) of apple polyphenol fractions (monomers or procyanidins) and (ii) to evaluate their anti-carcinogenic properties in vivo. Two polyphenol-enriched fractions were isolated from apples. Fraction non-procyanidins contained 73% phenolic monomers and no procyanidins, while fraction procyanidins contained 78% procyanidins and no monomers. Inhibition of SW620 cell growth was only observed with fraction P (IC50 = 45 microg/ml). After a 24-h exposure of cells to fraction P, protein kinase C activity was inhibited by 70% and a significant increase in extracellular signal-regulated kinases 1 and 2 and c-jun N-terminal kinases expression was observed together with the down-regulation of polyamine biosynthesis and the activation of caspase-3. Colon carcinogenesis was induced in rats by intraperitoneal injections of azoxymethane, once a week for 2 weeks. Seven days after the last injection, Wistar rats received fraction P (0.01%) dissolved in drinking water. After 6 weeks of treatment, the colon of rats receiving procyanidins showed a significant (P < 0.01) reduction of the number of preneoplastic lesions when compared with controls receiving water. The total number of hyperproliferative crypts and of aberrant crypt foci was reduced by 50% in rats receiving 0.01% apple procyanidins in their drinking water. Our results show that apple procyanidins alter intracellular signaling pathways, polyamine biosynthesis and trigger apoptosis in tumor cells. These compounds antagonize cancer promotion in vivo. In contrast with absorbable drugs, these natural, non toxic, dietary constituents reach the colon where they are able to exert their antitumor effects.

An age-dependent decline in skeletal muscle mass, strength, and endurance during the aging process is a physiological development, but several factors may exacerbate this process, leading to the threatening state of sarcopenia, frailty, and eventually higher mortality rates. Obesity appears to be such a promoting factor and has been linked in several studies to sarcopenia. The reason for this causal association remains poorly understood. Notwithstanding the fact that a higher body mass might simply lead to diminished physical activity and therefore contribute to a decline in skeletal muscle, several molecular mechanisms have been hypothesized. There could be an obesity derived intracellular lipotoxicity (i.e., elevated intramuscular levels of lipids and their derivatives), which induces apoptosis by means of an elevated oxidative stress. Paracrine mechanisms and inflammatory cytokines, such as CRP and IL-6 could be confounders of the actual underlying pathological mechanism. Due to a cross-talk of the hypothalamo-pituitary axis with nutritional status, obese subjects are more in a catabolic state of metabolism, with a higher susceptibility to muscle wasting under energy restriction. Obesity induces insulin resistance in the skeletal muscle, which consequently leads to perturbed metabolism, and misrouted signaling in the muscle cells. In obesity, muscle progenitor cells could differentiate to an adipocyte-like phenotype as a result of paracrine signals from (adipo)cytokines leading to a reduced muscular renewal capacity. The present review outlines current knowledge concerning possible pathways, which might be involved in the molecular pathogenesis of sarcopenic obesity.

Purpose: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in medulloblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in medulloblastoma. Experimental Design: The expression pattern and functions of class I A PI3K isoforms were investigated in medulloblastoma tumour samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110a, p110h, or p110y by means of RNA interference or inhibition with isoform-specific PI3K inhibitors. Results: Overexpression of the catalytic p110a isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110a expression by RNA interference impaired the growth of medulloblastoma cells, induced apoptosis, and led to decreased migratory capacity of the cells.This effect was selective, because RNA interference targeting of p110h or p110y did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110ainhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110a inhibitors further displayed reduced activation of Akt and the ribosomal protein S6 kinase in response to stimulation with hepatocyte growth factor and insulin-like growth factor-I. Conclusions:Together, our data reveal a novel function of p110a in medulloblastoma growth and survival.

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Geraniol, a natural component of plant essential oils, has antiproliferative effects on human colon cancer cells. To obtain more insight into its mechanism of action, we studied its effect on the resting membrane potential and on the expression of proteins involved in cell signaling pathways. Since geraniol is a well known inhibitor of mevalonate metabolism, the effect of mevalonate supplementation on geraniol-triggered growth inhibition was also determined. Geraniol (400 M) induced membrane depolarization with a decrease of membrane resistance due to local perforation of the cell membrane. Incubation of Caco-2 cells with geraniol (400 M) for 6 h caused a 60% reduction of protein kinase C (PKC) activity. After 16 h of incubation, geraniol decreased by 50% the amount of active forms of p44/p42 extracellular signal-regulated protein kinases (ERK). Mevalonate supplementation did not reverse inhibition of cell growth by geraniol. These results indicate that the antiproliferative effect of geraniol on Caco-2 cells was not related to a limitation of the mevalonate pool but was directly linked to the perturbation of cell membrane function leading to the reduction of PKC activity and to the decreased expression of p44/p42 ERK active forms.

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Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6-44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8-57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6-44.5 vs. 52.6, 95 % CI = 47.5-57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.