No abstract

The manganese transport regulator (MntR) represses the expression of genes involved in manganese uptake in Bacillus subtilis. It selectively responds to Mn2+ and Cd2+ over other divalent metal cations including Fe2+, Co2+ and Zn2+. Previous work has shown that MntR forms binuclear complexes with Mn2+ or Cd2+ at two binding sites, labeled A and C, that are separated by 4.4 Å. Zinc activates MntR poorly and binds only to the A site, forming a mononuclear complex. The difference in metal binding stoichiometry suggested a mechanism for selectivity in MntR. Larger metal cations are strongly activating because they can form the binuclear complex, while smaller metal ions cannot bind with the geometry needed to fully occupy both metal-binding sites. To investigate this hypothesis, structures of MntR in complex with two other non-cognate metal ions, Fe2+ and Co2+, have been solved. Each metal forms a mononuclear complex with MntR with the metal ion bound in the A site, supporting the conclusions drawn from the Zn2+ complex. Additionally, we investigated two site-specific mutants of MntR, E11K and H77A, that contain substitutions to metal binding residues in the A site. While metal binding in each mutant is significantly altered relative to wild-type MntR, both mutants retain activity and selectivity for Mn2+ in vitro and in vivo. That observation, coupled with previous studies, suggests that the A and C sites both contribute to the selectivity of MntR.

BackgroundDespite advances in cancer diagnosis and treatment have significantly improved survival rates, patients post-treatment-related health needs are often not adequately addressed by current health services. The aim of the Women’s Wellness after Cancer Program (WWACP), which is a digitised multimodal lifestyle intervention, is to enhance health-related quality of life in women previously treated for blood, breast and gynaecological cancers.MethodsA single-blinded, multi-centre randomized controlled trial recruited a total of 330 women within 24 months of completion of chemotherapy (primary or adjuvant) and/or radiotherapy. Women were randomly assigned to either usual care or intervention using computer-generated permuted-block randomisation. The intervention comprises an evidence-based interactive iBook and journal, web interface, and virtual health consultations by an experienced cancer nurse trained in the delivery of the WWACP. The 12 week intervention focuses on evidence-based health education and health promotion after a cancer diagnosis. Components are drawn from the American Cancer Research Institute and the World Cancer Research Fund Guidelines (2010), incorporating promotion of physical activity, good diet, smoking cessation, reduction of alcohol intake, plus strategies for sleep and stress management. The program is based on Bandura’s social cognitive theoretical framework. The primary outcome is health-related quality of life, as measured by the Functional Assessment of Cancer Therapy-General (FACT-G). Secondary outcomes are menopausal symptoms as assessed by Greene Climacteric Scale; physical activity elicited with the Physical Activity Questionnaire Short Form (IPAQ-SF); sleep measured by the Pittsburgh Sleep Quality Index; habitual dietary intake monitored with the Food Frequency Questionnaire (FFQ); alcohol intake and tobacco use measured by the Australian Health Survey and anthropometric measures including height, weight and waist-to-hip ratio. All participants were assessed with these measures at baseline (at the start of the intervention), 12 weeks (at completion of the intervention), and 24 months (to determine the level of sustained behaviour change). Further, a simultaneous cost-effectiveness evaluation will consider if the WWACP provides value for money and will be reported separately.DiscussionWomen treated for blood, breast and gynaecological cancers demonstrate increasingly good survival rates. However, they experience residual health problems that are potentially modifiable through behavioural lifestyle interventions such as the WWACP.Trial registrationThe protocol for this study was registered with the Australian and New Zealand Clinical Trials Registry, Trial ID: ACTRN12614000800628, July 28, 2014.

In this study, women after treatment for breast cancer reported a broad range of bothersome climacteric symptoms. Similar symptom clusters were also noted for women with and without a history of breast cancer, though correlates differed across groups, and might reflect different underlying etiologies.

The Pink Women's Wellness Program is effective in decreasing menopausal symptoms, thus improving HRQoL. This being a pilot study, further research is recommended to investigate the benefits of combining nonpharmacological interventions for women with breast cancer to reduce their treatment-related menopausal symptoms.