ABSTRACT
BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
Subject(s)
PTEN Phosphohydrolase/biosynthesis , Adenocarcinoma, Clear Cell/enzymology , Adenocarcinoma, Clear Cell/mortality , Adenocarcinoma, Clear Cell/pathology , Age Factors , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Carcinoma, Ovarian Epithelial/enzymology , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/mortality , Carcinoma, Ovarian Epithelial/pathology , Cohort Studies , Down-Regulation , Female , Gene Knockout Techniques , Humans , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics , Prospective Studies , Receptors, Androgen/biosynthesis , Receptors, Estrogen/biosynthesis , Receptors, Progesterone/biosynthesis , Tissue Array Analysis , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/deficiencyABSTRACT
A short and efficient synthesis of an advanced intermediate (1) in the Clive route to halichlorine has been achieved in 12 steps and 13.2% yield by a combined two-directional synthesis/tandem reaction strategy.
Subject(s)
Alkaloids/chemical synthesis , Spiro Compounds/chemical synthesisABSTRACT
Two-directional cross-metathesis of a range of alpha,omega dienes with a variety of electron deficient alkenes has been accomplished. It was found that the process is quite general and gives complete selectivity for the E,E-dienes, making this a very useful and high yielding protocol for two-directional chain elongation.
Subject(s)
Alkadienes/chemical synthesis , Alkenes/chemistry , Alkadienes/chemistry , Alkenes/chemical synthesis , Catalysis , Electrons , Molecular Structure , StereoisomerismABSTRACT
BACKGROUND: Hippodamine is a volatile defence alkaloid isolated from ladybird beetles which holds potential as an agrochemical agent and was the subject of a synthesis by our group in 2005. RESULTS: Two enhancements to our previous syntheses of (+/-)-hippodamine and (+/-)-epi-hippodamine are presented which are able to shorten the syntheses by up to two steps. CONCLUSION: Key advances include a two-directional homologation by cross metathesis and a new tandem reductive amination/double intramolecular Michael addition which generates 6 new bonds, 2 stereogenic centres and two rings, giving a single diastereomer in 74% yield.
ABSTRACT
The synthesis of (+/-)-histrionicotoxin has been achieved in just nine steps using a two-directional synthesis strategy. Key reactions include a two-directional cross-metathesis, a tandem oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cycloaddition cascade, a selective Z,Z-bisenyne formation, and a one-pot N-O and bischloroacetylene reduction.
