A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk The objective of the current study was to confirm the superior PFS advantage for 103 fulvestrant versus anastrozole observed in the FIRST study, in a double-blind Phase 3 104 design. The population for FALCON were postmenopausal women with hormone 105 receptor-positive locally advanced or metastatic breast cancer who had not received 106 prior endocrine therapy, in order to avoid reducing efficacy of the control arm through 107 exposure to adjuvant endocrine therapy. 108 METHODS 109 Study design 110The Fulvestrant and AnastrozoLe COmpared in hormonal therapy Naïve advanced 111 breast cancer (FALCON) trial (Clinicaltrials.gov: NCT01602380) is a Phase 3 112 randomised, double-blind, double-dummy, international, multicentre study that 113 compared the efficacy and tolerability of fulvestrant with anastrozole in 114 postmenopausal women with histologically confirmed ER+ and/or PgR+ locally 115 advanced or metastatic breast cancer. 116 Ethical approval 117The study was conducted in accordance with the Declaration of Helsinki and 118International Conference on Harmonisation/Good Clinical Practice guidelines. An 119 Randomisation and masking 133Patients were randomised sequentially (1:1) to fulvestrant 500 mg or anastrozole 1 mg 134 using a computer-generated randomisation scheme and an integrated voice/web 135 response system. Patients were stratified at randomisation according to locally 136 advanced or metastatic breast cancer; prior or no prior treatment with chemotherapy 137 for locally advanced or metastatic breast cancer; and measurable or non-measurable 138 disease. 139Study drugs were labelled using a unique identifier linked to the randomisation 140 scheme. The active study drug and placebo for fulvestrant (pre-filled syringes) and 141 anastrozole (tablets) were identically packaged to maintain blinding. 142 progression. Safety and tolerability were assessed at each study visit, and for up to 8 154 weeks after the last fulvestrant/placebo injection. HRQoL questionnaires were 155 administered at baseline and at 3-monthly intervals. Following disease progression or 156 treatment discontinuation, HRQoL questionnaires will be administered at 6-monthly 157 until a final OS analysis. 158 Outcomes 159The primary endpoint of the study was to demonstrate the superior PFS of patients 160 treated with fulvestrant vs anastrozole. A progression event was determined based on 161 tumour assessments performed locally by each investigator, and was defined by 162Response Evaluation Criteria in Solid Tumours (RECIST) 1·1, or 163 surgery/radiotherapy for worsening of disease, or death from any cause. 164 OS and ORR were tested using a multiple ...

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Staphylococcus aureus is a major community and nosocomial pathogen. Its ability to withstand multiple stress conditions and quickly develop resistance to antibiotics complicates the control of staphylococcal infections. Adaptation to lower temperatures is a key for the survival of bacterial species outside the host. Branched-chain alpha-keto acid dehydrogenase (BKD) is an enzyme complex that catalyzes the early stages of branched-chain fatty acid (BCFA) production. In this study, BKD was inactivated, resulting in reduced levels of BCFAs in the membrane of S. aureus. Growth of the BKD-inactivated mutant was progressively more impaired than that of wild-type S. aureus with decreasing temperature, to the point that the mutant could not grow at 12 degrees C. The growth of the mutant was markedly stimulated by the inclusion of 2-methylbutyrate in the growth medium at all temperatures tested. 2-Methylbutyrate is a precursor of odd-numbered anteiso fatty acids and bypasses BKD. Interestingly, growth of wild-type S. aureus was also stimulated by including 2-methylbutyrate in the medium, especially at lower temperatures. The anteiso fatty acid content of the BKD-inactivated mutant was restored by the inclusion of 2-methylbutyrate in the medium. Fluorescence polarization measurements indicated that the membrane of the BKD-inactivated mutant was significantly less fluid than that of wild-type S. aureus. Consistent with this result, the mutant showed decreased toluene tolerance that could be increased by the inclusion of 2-methylbutyrate in the medium. The BKD-inactivated mutant was more susceptible to alkaline pH and oxidative stress conditions. Inactivation of the BKD enzyme complex in S. aureus also led to a reduction in adherence of the mutant to eukaryotic cells and its survival in a mouse host. In addition, the mutant offers a tool to study the role of membrane fluidity in the interaction of S. aureus with antimicrobial substances.

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