Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy

Despite high tumour response rates to platinum-based chemotherapy in ovarian cancer survival is poor due to the emergence of drug resistance. Mechanistic studies in clinical material have been hampered by the unavailability of sensitive methods to detect the critical drug-induced effects in individual cells. A modification of the single cell gel electrophoresis (comet) assay allows the sensitive detection of DNA interstrand crosslinking in both tumour and normal cells derived directly from clinical material. Tumour cells isolated from 50 ovarian cancer patients were treated ex vivo with 100 μM cisplatin for 1 h and crosslink formation and repair (unhooking) measured. No significant difference in the peak level of crosslinking in tumour cells was observed between patients who were either newly diagnosed or previously treated with platinum-based therapy, or between tumour and mesothelial cells from an individual patient. This indicates no difference in cellular mechanisms such as drug transport or detoxification. In contrast, the percentage repair (unhooking) of DNA interstrand crosslinks was much greater in the group of treated patients. At 24 h in the 36 newly diagnosed patient tumour samples, only one gave >50% repair and 23 gave <10% repair; however, 19 out of 22 treated patient samples gave >10% repair and 14 showed >50% repair. The estimated median difference (newly diagnosed minus treated) was −52 (95% CI −67 to −28), and the P-value from a Mann–Whitney test was <0.001. In eight patients, it was possible to obtain tumour samples prior to any chemotherapy, and also on relapse or at interval debulking surgery following platinum-based chemotherapy. In these patients, the mean % repair prior to therapy was 2.85 rising to 71.23 following treatment. These data demonstrate increased repair of DNA interstrand crosslinks in ovarian tumour cells following platinum therapy which may contribute to clinical acquired resistance

Randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in Indigenous Australian infants: rationale and protocol

Background: Acute lower respiratory infections are the commonest cause of morbidity and potentially preventable mortality in Indigenous infants. Infancy is also a critical time for post-natal lung growth and development. Severe or repeated lower airway injury in very young children likely increases the likelihood of chronic pulmonary disorders later in life. Globally, bronchiolitis is the most common form of acute lower respiratory infections during infancy. Compared with non-Indigenous Australian infants, Indigenous infants have greater bacterial density in their upper airways and more severe bronchiolitis episodes. Our study tests the hypothesis that the anti-microbial and anti-inflammatory properties of azithromycin, improve the clinical outcomes of Indigenous Australian infants hospitalised with bronchiolitis.Methods: We are conducting a dual centre, randomised, double-blind, placebo-controlled, parallel group trial in northern Australia. Indigenous infants (aged ≤ 24-months, expected number = 200) admitted to one of two regional hospitals (Darwin, Northern Territory and Townsville, Queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin (30 mg/kg/dose) or placebo administered once weekly for three doses. Clinical data are recorded twice daily and nasopharyngeal swab are collected at enrolment and at the time of discharge from hospital. Primary outcomes are 'length of oxygen requirement' and 'duration of stay,' the latter based upon being judged as 'ready for respiratory discharge'. The main secondary outcome is readmission for a respiratory illness within 6-months of leaving hospital. Descriptive virological and bacteriological (including development of antibiotic resistance) data from nasopharyngeal samples will also be reported.Discussion: Two published studies, both involving different patient populations and settings, as well as different macrolide antibiotics and treatment duration, have produced conflicting results. Our randomised, placebo-controlled trial of azithromycin in Indigenous infants hospitalised with bronchiolitis is designed to determine whether it can reduce short-term (and potentially long-term) morbidity from respiratory illness in Australian Indigenous infants who are at high risk of developing chronic respiratory illness. If azithromycin is efficacious in reducing the morbidly of Indigenous infants hospitalised with bronchiolitis, the intervention would lead to improved short term (and possibly long term) health benefits. Trial registration: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000326099

Ethical judgement in UK business students: relationship with motivation, self-compassion and mental health.

There is growing awareness of mental health problems among UK business students, which appears to be exacerbated by students’ attitudes of shame toward mental health. This study recruited 138 UK business students and examined the relationship between mental health and shame, and mental health and potential protective factors such as self-compassion and motivation. A significant correlation between each of the constructs was observed and self-compassion was identified as an explanatory variable for mental health. Shame moderated the relationship between self-compassion and mental health. Integrating self-compassion training into business study programs may help to improve the mental health of this student group.N/

Neonatal immunology: responses to pathogenic microorganisms and epigenetics reveal an “immunodiverse” developmental state

Neonatal animals have heightened susceptibility to infectious agents and are at increased risk for the development of allergic diseases, such as asthma. Experimental studies using animal models have been quite useful for beginning to identify the cellular and molecular mechanisms underlying these sensitivities. In particular, results from murine neonatal models indicate that developmental regulation of multiple immune cell types contributes to the typically poor responses of neonates to pathogenic microorganisms. Surprisingly, however, animal studies have also revealed that responses at mucosal surfaces in early life may be protective against primary or secondary disease. Our understanding of the molecular events underlying these processes is less well developed. Emerging evidence indicates that the functional properties of neonatal immune cells and the subsequent maturation of the immune system in ontogeny may be regulated by epigenetic phenomena. Here, we review recent findings from our group and others describing cellular responses to infection and developmentally regulated epigenetic processes in the newborn

CSR, Innovation and Human Resource Management. The Renaissance of Olivetti’s humanistic management in Loccioni Group – Italy

This paper addresses the theme of Corporate Social Responsibility (CSR) policies concerning labor and employees by proposing an anthropologically-centered analysis - developed from both the theoretical and empirical profiles - of business and leadership models that are geared toward a multidimensional development, which focuses on the valorization and promotion of the employee. The first part synthesizes the theoretical context in which the empirical analysis is found by proposing a literature review; while the second one analyses the business and leadership models, which have been successfully implemented by a medium-sized Italian firm - Loccioni Group - that is included among the “great place to work” on the national and international scale. This company has, for years, been distinguished for the best CSR-oriented practices regarding human resource management, innovation, environment and furthermore for its capability to “thread networks” with internal and external stakeholders, and is characterized by genuine commitment which is the result of an authentic and solid value-based system and a model of exemplary governance aimed at linking economic well-being, social cohesion and environmental protection. The case study offers an example of best stakeholders’ and employees’ management practices, which co-evolves with the environment, improving, at the same time, the company’s competitiveness and the socio-economic conditions of the local context in which it is deeply embedded. In this context, CSR is part of the DNA and widespread throughout the entire organization. Loccioni Group is an “extreme case” (although not unique in Italy) that is particularly significant and helps develop reflections on the importance of embracing the cultural and anthropological roots of CSR, which are connected to a model of humanistic management, and reinvent the Olivetti’s model of holistic development while conceiving the business as a tool for promoting social, economic, moral and environmental well-being