Immunohistochemical analysis of estrogen receptors in the urethra of sexually intact, ovariectomized, and estrogen-substituted ovariectomized sheep

INTRODUCTION AND HYPOTHESIS: Urinary incontinence is prevalent in postmenopausal women and spayed dogs and is associated with decreased estrogen plasma concentrations. The objective of the study was to investigate the expression of estrogen receptors (ER) in the urethra of sexually intact, ovariectomized, and estrogen-substituted ovariectomized ewes. METHODS: Paraffin cross-sections from each urethral quarter were immunohistochemically analyzed. The reactivity of ER was semiquantitatively assessed employing an immunoreactive score (IRS). RESULTS: In contrast to ERβ, ERα was identified in all urethral compartments; the highest IRS was detected in the epithelium of the distal urethra. The immunoreactivity and distribution of ERα did not differ among groups. Highly significant differences in ERα concentrations were observed between consecutive urethral quarters in each group. CONCLUSIONS: Neither ovariectomy nor ovariectomy and estrogen substitution seem to have a significant effect on overall urethral ERα concentration. The results demonstrate that the precise location of the investigated urethral part is crucial to the reliable evaluation or possible comparison of ERα concentrations

Evidence That Gene Activation and Silencing during Stem Cell Differentiation Requires a Transcriptionally Paused Intermediate State

A surprising portion of both mammalian and Drosophila genomes are transcriptionally paused, undergoing initiation without elongation. We tested the hypothesis that transcriptional pausing is an obligate transition state between definitive activation and silencing as human embryonic stem cells (hESCs) change state from pluripotency to mesoderm. Chromatin immunoprecipitation for trimethyl lysine 4 on histone H3 (ChIP-Chip) was used to analyze transcriptional initiation, and 3′ transcript arrays were used to determine transcript elongation. Pluripotent and mesodermal cells had equivalent fractions of the genome in active and paused transcriptional states (∼48% each), with ∼4% definitively silenced (neither initiation nor elongation). Differentiation to mesoderm changed the transcriptional state of 12% of the genome, with roughly equal numbers of genes moving toward activation or silencing. Interestingly, almost all loci (98–99%) changing transcriptional state do so either by entering or exiting the paused state. A majority of these transitions involve either loss of initiation, as genes specifying alternate lineages are archived, or gain of initiation, in anticipation of future full-length expression. The addition of chromatin dynamics permitted much earlier predictions of final cell fate compared to sole use of conventional transcript arrays. These findings indicate that the paused state may be the major transition state for genes changing expression during differentiation, and implicate control of transcriptional elongation as a key checkpoint in lineage specification

Cancer: evolutionary, genetic and epigenetic aspects

There exist two paradigms about the nature of cancer. According to the generally accepted one, cancer is a by-product of design limitations of a multi-cellular organism (Greaves, Nat Rev Cancer 7:213–221, 2007). The essence of the second resides in the question “Does cancer kill the individual and save the species?” (Sommer, Hum Mutat 3:166–169, 1994). Recent data on genetic and epigenetic mechanisms of cell transformation summarized in this review support the latter point of view, namely that carcinogenesis is an evolutionary conserved phenomenon—a programmed death of an organism. It is assumed that cancer possesses an important function of altruistic nature: as a mediator of negative selection, it serves to preserve integrity of species gene pool and to mediate its evolutionary adjustment. Cancer fulfills its task due apparently to specific killer function, understanding mechanism of which may suggest new therapeutic strategy

Microenvironmental regulation of metastasis

Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues

Epithelial cancers in the post-genomic era: should we reconsider our lifestyle?

The age-related epithelial cancers of the breast, colorectum and prostate are the most prevalent and are increasing in our aging populations. Epithelial cells turnover rapidly and mutations naturally accumulate throughout life. Most epithelial cancers arise from this normal mutation rate. All elderly individuals will harbour many cells with the requisite mutations and most will develop occult neoplastic lesions. Although essential for initiation, these mutations are not sufficient for the progression of cancer to a life-threatening disease. This progression appears to be dependent on context: the tissue ecosystem within individuals and lifestyle exposures across populations of individuals. Together, this implies that the seeds may be plentiful but they only germinate in the right soil. The incidence of these cancers is much lower in Eastern countries but is increasing with Westernisation and increases more acutely in migrants to the West. A Western lifestyle is strongly associated with perturbed metabolism, as evidenced by the epidemics of obesity and diabetes: this may also provide the setting enabling the progression of epithelial cancers. Epidemiology has indicated that metabolic biomarkers are prospectively associated with cancer incidence and prognosis. Furthermore, within cancer research, there has been a rediscovery that a switch in cell metabolism is critical for cancer progression but this is set within the metabolic status of the host. The seed may only germinate if the soil is fertile. This perspective brings together the different avenues of investigation implicating the role that metabolism may play within the context of post-genomic concepts of cancer

Glycosylation of 1-aminoimidazole-2 (3H)-thiones

The selectivity of the glycosylation of 1-aminoimidazole-2(3H)-thiones can be controlled. Depending on the chosen conditions, either the kinetically favored S-glycosides or the thermodynamically more stable N-glycosylated compounds are obtained in only one anomeric configuration (beta-anomer).status: publishe