Aims: 1Nitric oxide is generated from sweat nitrite in the acidic environment of the skin surface and is thought to contribute to protection against infection. This study examined the sensitivity of Trichophyton mentagrophytes, T. rubrum, Candida albicans, Streptococcus pyogenes, Staphylococcus aureus and Propionibacterium acnes to acidi®ed nitrite. Methods and Results: Organisms were cultured in varying concentrations of nitrite and pH for different lengths of time, before being transferred to recovery medium. With the exception of Strep. pyogenes, addition of nitrite increased the antimicrobial activity of acid solutions against all organisms tested. The rank order of sensitivity was: C. albicans < T. rubrum < T. mentagrophytes < Staph. aureus < P. acnes, with P. acnes being most sensitive. Conclusions: This work has shown that acidi®ed nitrite is microbiocidal to common cutaneous pathogens. The concentrations of nitrite required to kill pathogenic fungi and bacteria in in vitro assays were higher than the concentrations of nitrite measured in sweat. However, additional co-factors in vivo and in sweat may potentiate the effect of acidi®ed nitrite. Signi®cance and Impact of the Study: Pharmacological preparations of acidi®ed nitrite are novel antimicrobial agents. These data suggest skin organisms which may be sensitive to this treatment.

Transcriptionally silent heterochromatin is associated with repetitive DNA. It is poorly understood whether and how heterochromatin differs between different organisms and whether its structure can be remodelled in response to environmental signals. Here, we address this question by analysing the chromatin state associated with DNA repeats in the human fungal pathogen Candida albicans. Our analyses indicate that, contrary to model systems, each type of repetitive element is assembled into a distinct chromatin state. Classical Sir2-dependent hypoacetylated and hypomethylated chromatin is associated with the rDNA locus while telomeric regions are assembled into a weak heterochromatin that is only mildly hypoacetylated and hypomethylated. Major Repeat Sequences, a class of tandem repeats, are assembled into an intermediate chromatin state bearing features of both euchromatin and heterochromatin. Marker gene silencing assays and genome-wide RNA sequencing reveals that C. albicans heterochromatin represses expression of repeat-associated coding and non-coding RNAs. We find that telomeric heterochromatin is dynamic and remodelled upon an environmental change. Weak heterochromatin is associated with telomeres at 30 °C, while robust heterochromatin is assembled over these regions at 39 °C, a temperature mimicking moderate fever in the host. Thus in C. albicans, differential chromatin states controls gene expression and epigenetic plasticity is linked to adaptation.

. (2016). Phase II randomized preoperative window-of-opportunity study of the PI3K inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer. Journal of Clinical Oncology, 34(17), 1987-1994. DOI: 10.1200/JCO.2015 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. PurposePreclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Patients and MethodsIn this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. ResultsThere was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, $ 79.0%) for the combination and 66.0% (95% CI, # 75.4%) for anastrozole (geometric mean ratio [combination: anastrozole], 0.48; 95% CI, # 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, # 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. ConclusionAdd...