Adjuvant Aspirin Treatment in PIK3CA Mutated Colon Cancer Patients: The SAKK 41/13 - Prospective Randomized Placebo-Controlled Double-Blind Trial.

Purpose: We assessed the benefit of adjuvant aspirin in resected PIK3CA-mutated colon cancer patients.

Patients & Methods: This was a phase III, prospective, randomized, placebo-controlled, double-blind, multicenter, and multinational trial. Patients with resected colon cancer stage II and III harbouring an activating PIK3CA mutation were included.

SAKK 21/12: a phase II trial of transdermal CR1447 in breast cancer patients.

Objective: CR1447, a novel transdermal formulation of 4-hydroxytestosterone, has aromatase-inhibiting and androgen receptor (AR)-modulating properties (IC4.4 nM) with antitumor effects against AR-positive tumor cells This trial investigated the efficacy and safety of CR1447 for patients with metastatic estrogen receptor-positive (A) and AR-positive triple-negative breast cancers (B).

Design And Methods: (A) included patients with at most one prior endocrine therapy line without progression ≥6 months, whereas (B) included patients with ≤2 prior chemotherapy lines, all displaying advanced signs of disease.

Plasma HER2ECD a promising test for patient prognosis and prediction of response in HER2 positive breast cancer: results of a randomized study - SAKK 22/99.

Background: The HER2 extracellular domain shed in blood (HER2) is reported to rise and fall in parallel with HER2+ breast cancer behavior. In this study, we evaluated the clinical relevance of plasma HER2 values in patients with metastatic breast cancer treated in the SAKK22/99 trial comparing trastuzumab monotherapy followed by trastuzumab-chemotherapy combination at progression versus upfront combination therapy.

Methods: Quantitative assessment of plasma HER2 was performed in 133 patients at baseline; after 2-24 h; at 3 weeks; at first response evaluation (8-9 weeks); and at tumor progression.

Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients.

CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy.

SIRT2 regulates NF-κB dependent gene expression through deacetylation of p65 Lys310.

NF-κB regulates the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation and survival. In this study, we identified SIRT2 as a deacetylase of the transcription factor p65. SIRT2 is a member of the family of sirtuins, which are NAD(+)-dependent deacetylases involved in several cellular processes.

SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis.

Aims: Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis.

Methods And Results: Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation.

Acetylation of p65 at lysine 314 is important for late NF-kappaB-dependent gene expression.

Background: NF-kappaB regulates the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation and survival. We have earlier reported that p65, a subunit of NF-kappaB, is acetylated in vitro and in vivo at three different lysines (K310, K314 and K315) by the histone acetyltransferase p300.

Results: In this study, we describe that site-specific mutation of p65 at lysines 314 and 315 enhances gene expression of a subset of NF-kappaB target genes including Mmp10 and Mmp13.

CARM1 but not its enzymatic activity is required for transcriptional coactivation of NF-kappaB-dependent gene expression.

Coactivator-associated arginine methyltransferase 1 (CARM1) belongs to the protein arginine methyltransferase family. It was reported to methylate histone as well as non-histone proteins and thus to be involved in transcriptional activation and mRNA degradation/stability. Here we report the genetic complementation of carm1-/- cells with wild-type CARM1 or an enzymatic inactive mutant of CARM1 to investigate the requirement of CARM1 and its enzymatic activity for nuclear factor kappaB (NF-kappaB)-dependent gene expression.

Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65.

Nuclear factor kappaB (NF-kappaB) plays an important role in the transcriptional regulation of genes involved in immunity and cell survival. We show here in vitro and in vivo acetylation of RelA/p65 by p300 on lysine 314 and 315, two novel acetylation sites. Additionally, we confirmed the acetylation on lysine 310 shown previously.