RAB family gene expression in breast cancer cells under influence of paclitaxel

The aim of this study was to investigate the role of paclitaxel on RAB family of genes in primary breast cancer cell lines. The cancer breast cells obtained from 40 women during mastectomy were used to address this issue. The group included patients with intraductal breast cancer - lesions in I or II advancement level by TNM classification and G1-G2 by Bloom classification. (tumor dimensions up to 2.0 cm without metastases to lymph nodes). Cytostatic drugs before surgery were not administered to these patients. The cultures were conducted in 25 cm^2^ plastic containers at RPMI medium with addiction of 10% fetal bovine serum (FBS) at the standard conditions. After reaching concentration levels of 10 000/ml of the cells, the cultures were treated with 60 ng/ml and 300 ng/ml doses of paclitaxel. The concentrations were calculated in relation to therapeutic doses of paclitaxel, applied in polytherapy in patients with breast cancer. The cell cultures untreated for cytostatic were used as a control group. Analysis was conducted for RAB family of genes: RAB3D, RAB5B, RAB5C, RAB7, RAB7L1, RAB9P1, RAB10. RAB11A, RAB311B, RAB13, RAB18, RAB22A, RAB23, RAB26, RAB27A, RAB27B, RAB28, RAB30, RAB31, RAB33A, RAB3D6, RAB 38, RABL2B Total RNA was extracted from the harvest control group and the treated cells, and this was followed by cDNA synthesis, which was used for hybridization assays using arrays. A lower dose of paclitaxel (60 ng/ml) treatment resulted in an increase (2-4 fold- statistically significant), whereas a higher dose (300 ng/ml) caused a decrease (2-fold - statistically insignificant) in expression of examined oncogenes, compared to that of the control group.In summary, this data indicates that 60 ng/ml paclitaxel dose induced the RAB gene expression in an up-regulated pathway. A higher concentration of cytostatic (300 ng/ml) is a toxic dose for primary breast cells in vitro

Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

Auteurs : the PRECISION investigatorsInternational audienceBackground Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. Methods PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12•5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. Findings The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was-15•3 (SE 0•9) mm Hg for aprocitentan 12•5 mg,-15•2 (0•9) mm Hg for aprocitentan 25 mg, and-11•5 (0•9) mm Hg for placebo, for a difference versus placebo of-3•8 (1•3) mm Hg (97•5% CI-6•8 to-0•8, p=0•0042) and-3•7 (1•3) mm Hg (-6•7 to-0•8; p=0•0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was-4•2 mm Hg (95% CI-6•2 to-2•1) and-5•9 mm Hg (-7•9 to-3•8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5•8 mm Hg, 95% CI 3•7 to 7•9, p<0•0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12•5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment. Interpretation In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40