Many aspects of the genomes of yeast species in the family Saccharomycetaceae have been well conserved during evolution. They have similar genome sizes, genome contents, and extensive collinearity of gene order along chromosomes. Gene functions can often be inferred reliably by using information from Saccharomyces cerevisiae. Beyond this conservative picture however, there are many instances where a species or a clade diverges substantially from the S. cerevisiae paradigm—for example, by the amplification of a gene family, or by the absence of a biochemical pathway or a protein complex. Here, we review clade-specific features, focusing on genomes sequenced in our laboratory from the post-WGD genera Naumovozyma, Kazachstania and Tetrapisispora, and from the non-WGD species Torulaspora delbrueckii. Examples include the loss of the pathway for histidine synthesis in the cockroach-associated species Tetrapisispora blattae; the presence of a large telomeric GAL gene cluster in To. delbrueckii; losses of the dynein and dynactin complexes in several independent yeast lineages; fragmentation of the MAT locus and loss of the HO gene in Kazachstania africana; and the patchy phylogenetic distribution of RNAi pathway components.
Castrate-resistant prostate cancer (CRPC) is challenging to treat with the androgen receptor (AR), the main target and key focus of resistance. Understanding the mechanisms of AR interaction with co-regulators will identify new therapeutic targets to overcome AR resistance mechanisms. We previously identified the serum response factor (SRF) as a lead target in an in vitro model of CRPC and showed that SRF expression in tissues of CRPC patients was associated with shorter survival. Here, we tested SRF inhibition in vitro and in vivo to assess SRF as a potential target in CRPC. Inhibition of SRF with the small-molecule inhibitor CCG1423 resulted in enhanced response to enzalutamide in vitro and reduced tumour volume of LuCaP 35CR, a CRPC patient-derived xenograft model. Nuclear localisation of AR post-CCG1423 was significantly decreased and was associated with decreased α-tubulin acetylation in vitro and decreased prostate specific antigen (PSA) levels in vivo. SRF immunoreactivity was tested in metastatic tissues from CRPC patients to investigate its role in enzalutamide response. Kaplan–Meier curves showed that high SRF expression was associated with shorter response to enzalutamide. Our study supports the use of SRF inhibitors to improve response to enzalutamide.
Background
Barrett's Esophagus (BE) is well established as the main pathological precursor for esophageal adenocarcinoma (EAC). Progression to high grade dysplasia (HGD) or EAC varies widely between population based studies and specialized BE registries from high volume centers. No such data existed from the Republic of Ireland until 2011 when a multicenter registry was established involving three centers to more accurately determine the risk of progression to EAC in the Irish population.
Methods
A detailed clinical, endoscopic and pathological database includes 3397 patients from January 2008 to July 2017, with BE defined by the presence of specialized intestinal metaplasia (SIM). A prospective web based database was used to gather information from three designated esophageal centers with initial and follow up data abstracted by a data manager and overseen by a project manager.
Results
325 were excluded following a diagnosis of HGD or EAC at index biopsy, or being a tertiary referral, leaving 3072 with a median age of 61 and a 2.1:1 male to female ratio and a median follow up of 3 years, and 5024 person years. 127 (4%) cases progressed to HGD/EAC, 65 after one year of follow up. 55 (2%) developed EAC were identified, 30 of those within one year. The overall incidence HGD/EAC was 2.53% per year, 1.3% if the first year is excluded. The risk of progression to EAC alone was 1.09% per year, 0.5% excluding the first year. Low grade dysplasia (LGD) on index biopsy was associated with a progression rate of 11.7% per year, 4.2% with the first year excluded.
Conclusion
With strict data entry and pathologic quality assurance, progression rates for non-dysplastic BE was several fold higher than population studies, highlighting caution in abstracting from population data. True LGD, as evidenced in a recent report by Kestens et al.1 represent high risk disease, with most of the risk evident within the first year. Reference: 1. Kestens C, Offerhaus G, van Baal J, Siersema PD. Patients wtih Barrett's esophagus and persistent low-grade dysplasia have an increased risk for high- grade dysplasia and cancer. Clin Gastroenterol Hepatol. 2016;14:956–962
Disclosure
All authors have declared no conflicts of interest.
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