WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Overexpression of ribosomal RNA in prostate cancer is common but not linked to rDNA promoter hypomethylation

Alterations in nucleoli, including increased numbers, increased size, altered architecture and increased function are hallmarks of prostate cancer cells. The mechanisms that result in increased nucleolar size, number and function in prostate cancer have not been fully elucidated. The nucleolus is formed around repeats of a transcriptional unit encoding a 45S ribosomal RNA (rRNA) precursor that is then processed to yield the mature 18S, 5.8S and 28S RNA species. Although it has been generally accepted that tumor cells overexpress rRNA species, this has not been examined in clinical prostate cancer. We find that indeed levels of the 45S rRNA, 28S, 18S and 5.8S are overexpressed in the majority of human primary prostate cancer specimens as compared with matched benign tissues. One mechanism that can alter nucleolar function and structure in cancer cells is hypomethylation of CpG dinucleotides of the upstream rDNA promoter region. However, this mechanism has not been examined in prostate cancer. To determine whether rRNA overexpression could be explained by hypomethylation of these CpG sites, we also evaluated the DNA methylation status of the rDNA promoter in prostate cancer cell lines and the clinical specimens. Bisulfite sequencing of genomic DNA revealed two roughly equal populations of loci in cell lines consisting of those that contained densely methylated deoxycytidine residues within CpGs and those that were largely unmethylated. All clinical specimens also contained two populations with no marked changes in methylation of this region in cancer as compared with normal. We recently reported that MYC can regulate rRNA levels in human prostate cancer; here we show that MYC mRNA levels are correlated with 45S, 18S and 5.8S rRNA levels. Further, as a surrogate for nucleolar size and number, we examined the expression of fibrillarin, which did not correlate with rRNA levels. We conclude that rRNA levels are increased in human prostate cancer, but that hypomethylation of the rDNA promoter does not explain this increase, nor does hypomethylation explain alterations in nucleolar number and structure in prostate cancer cells. Rather, rRNA levels and nucleolar size and number relate more closely to MYC overexpression

Dicer Is Associated with Ribosomal DNA Chromatin in Mammalian Cells

Background: RNA silencing is a common term for pathways utilizing small RNAs as sequence-specific guides to repress gene expression. Components of the RNA silencing machinery are involved in different aspects of chromatin function in numerous organisms. However, association of RNA silencing with chromatin in mammalian cells remains unclear. Methodology/Principal Findings: Immunostaining of mitotic chromosomes with antibodies visualizing either endogenous or ectopically expressed Dicer in mammalian cells revealed association of the protein with ribosomal DNA (rDNA) repeats. Chromatin immunoprecipitations and bisulfite sequencing experiments indicated that Dicer is associated with transcribed regions of both active and silenced genes in rDNA arrays of interphase chromosomes. Metabolic labeling of the mouse embryonic stem (ES) cells lacking Dicer did not reveal apparent defect in rRNA biogenesis though pre-rRNA synthesis in these cells was decreased, likely as a consequence of their slower growth caused by the loss of miRNAs. We analyzed in detail chromatin structure of rDNA but did not find any epigenetic changes at rDNA loci in Dicer 2/2 ES cells. Instead, we found that rDNA methylation is rather low in primary tissues, contrasting with rDNA methylation patterns in transformed cell lines. Conclusion/Significance: We found that Dicer, a key component of RNA silencing pathways, can be detected in association with rDNA chromatin in mammalian cells. The role of this particular localization of Dicer is not readily apparent since th

Corporate Entrepreneurship:From Structures to Mindset

Corporate entrepreneurship dispersed throughout an organization and leveraging the entrepreneurial potential of all its employees bears significant benefits for those organizations that embrace it. However, it appears more difficult to instill and requires strong investment in the development of human capital and entrepreneurial mindset among the employees and across the organization. In this chapter, we discuss the essence of corporate entrepreneurship mindset and show that across an organization, there might be different entrepreneurial mindsets that correspond to different people, opportunities, and contexts. Although different, they all lead to enactment of entrepreneurial projects. This chapter, thus, contributes to the discussion regarding the nature of corporate entrepreneurial mindsets, and their development and stimulation within an organization, from both academic and practical view

The global, regional, and national burden of gastro-oesophageal reflux disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Background Gastro-oesophageal reflux disease is a common chronic ailment that causes uncomfortable symptoms and increases the risk of oesophageal adenocarcinoma. We aimed to report the burden of gastro-oesophageal reflux disease in 195 countries and territories between 1990 and 2017, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Methods We did a systematic review to identify measurements of the prevalence of gastro-oesophageal reflux disease in geographically defined populations worldwide between 1990 and 2017. These estimates were analysed with DisMod-MR, a Bayesian mixed-effects meta-regression tool that incorporates predictive covariates and adjustments for differences in study design in a geographical cascade of models. Fitted values for broader geographical units inform prior distributions for finer geographical units. Prevalence was estimated for 195 countries and territories. Reports of the frequency and severity of symptoms among individuals with gastro-oesophageal reflux disease were used to estimate the prevalence of cases with no, mild to moderate, or severe to very severe symptoms at a given time; these estimates were multiplied by disability weights to estimate years lived with disability (YLD). Findings Data to estimate gastro-oesophageal reflux disease burden were scant, totalling 144 location-years (unique measurements from a year and location, regardless of whether a study reported them alongside measurements for other locations or years) of prevalence data. These came from six (86%) of seven GBD super-regions, 11 (52%) of 21 GBD regions, and 39 (20%) of 195 countries and territories. Mean estimates of age-standardised prevalence for all locations in 2017 ranged from 4408 cases per 100 000 population to 14 035 cases per 100 000 population. Age-standardised prevalence was highest (>11 000 cases per 100 000 population) in the USA, Italy, Greece, New Zealand, and several countries in Latin America and the Caribbean, north Africa and the Middle East, and eastern Europe; it was lowest (<7000 cases per 100 000 population) in the high-income Asia Pacific, east Asia, Iceland, France, Denmark, and Switzerland. Global prevalence peaked at ages 75–79 years, at 18 820 (95% uncertainty interval [95% UI] 13 770–24 000) cases per 100 000 population. Global age-standardised prevalence was stable between 1990 and 2017 (8791 [95% UI 7772–9834] cases per 100 000 population in 1990 and 8819 [7781–9863] cases per 100 000 population in 2017, percentage change 0·3% [–0·3 to 0·9]), but all-age prevalence increased by 18·1% (15·6–20·4) between 1990 and 2017, from 7859 (6905–8851) cases per 100  000 population in 1990 to 9283 (8189–10 400) cases per 100  000 population in 2017. YLDs increased by 67·1% (95% UI 63·5–70·3) between 1990 and 2017, from 3·60 million (1·93–6·12) in 1990 to 6·01 million (3·22–10·19) in 2017. Interpretation Gastro-oesophageal reflux disease is common worldwide, although less so in much of eastern Asia. The stability of our global age-standardised prevalence estimates over time suggests that the epidemiology of the disease has not changed, but the estimates of all-age prevalence and YLDs, which increased between 1990 and 2017, suggest that the burden of gastro-oesophageal reflux disease is nonetheless increasing as a result of ageing and population growth. Funding Bill & Melinda Gates Foundation

Current management of the gastrointestinal complications of systemic sclerosis.

Systemic sclerosis is a multisystem autoimmune disorder that involves the gastrointestinal tract in more than 90% of patients. This involvement can extend from the mouth to the anus, with the oesophagus and anorectum most frequently affected. Gut complications result in a plethora of presentations that impair oral intake and faecal continence and, consequently, have an adverse effect on patient quality of life, resulting in referral to gastroenterologists. The cornerstones of gastrointestinal symptom management are to optimize symptom relief and monitor for complications, in particular anaemia and malabsorption. Early intervention in patients who develop these complications is critical to minimize disease progression and improve prognosis. In the future, enhanced therapeutic strategies should be developed, based on an ever-improving understanding of the intestinal pathophysiology of systemic sclerosis. This Review describes the most commonly occurring clinical scenarios of gastrointestinal involvement in patients with systemic sclerosis as they present to the gastroenterologist, with recommendations for the suggested assessment protocol and therapy in each situation