Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands-5

Transformed Cy5 (digested) intensities. b: The unmethylated model constructed using 94 mitochondrial sequences as a unmethylation reference. c: The intermediate model constructed through the 97.5 quantile residual. The point X is the 97.5 quantile residual. The microarray probes colored in blue (standardised residual to the intermediate model is less than 2) are selected to construct the methylated model. d: Methylated (in blue) and unmethylated (in red) models in A2780 cell line.<p><b>Copyright information:</b></p><p>Taken from "Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands"</p><p>http://www.biomedcentral.com/1471-2105/9/337</p><p>BMC Bioinformatics 2008;9():337-337.</p><p>Published online 8 Aug 2008</p><p>PMCID:PMC2529322.</p><p></p

Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands-0

Unmethylated spots.<p><b>Copyright information:</b></p><p>Taken from "Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands"</p><p>http://www.biomedcentral.com/1471-2105/9/337</p><p>BMC Bioinformatics 2008;9():337-337.</p><p>Published online 8 Aug 2008</p><p>PMCID:PMC2529322.</p><p></p

Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands-4

Sed on the fitted model (dashed smooth line in red). The red and blue solid line are the positive and negative cut-offs, respectively. b: Scatter plot of sensitive scores against resistant scores in A2780 series cell lines. The hypermethylated loci are colored in red and hypomethylated loci are in blue. The robust regression model is Y = 0.9956X + 0.0019.<p><b>Copyright information:</b></p><p>Taken from "Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands"</p><p>http://www.biomedcentral.com/1471-2105/9/337</p><p>BMC Bioinformatics 2008;9():337-337.</p><p>Published online 8 Aug 2008</p><p>PMCID:PMC2529322.</p><p></p

Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands-3

He increase of CR slowly, but starts to increase dramatically when the CR goes above 140%, at which point the inconsistency rate is generally about 1%. Not all cell lines could reach this point e.g. MCP3.<p><b>Copyright information:</b></p><p>Taken from "Methylation Linear Discriminant Analysis (MLDA) for identifying differentially methylated CpG islands"</p><p>http://www.biomedcentral.com/1471-2105/9/337</p><p>BMC Bioinformatics 2008;9():337-337.</p><p>Published online 8 Aug 2008</p><p>PMCID:PMC2529322.</p><p></p

Inhibition of WEE1 is effective in TP53- and RAS-mutant metastatic colorectal cancer: a randomized trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring

PURPOSE: Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition. METHODS: Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level. RESULTS: FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION: In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.</p