The expression of HLA class I molecules and complement regulatory proteins in ovarian cancer

Over recent decades, translational ovarian cancer research has been impeded by its underappreciated molecular heterogeneity and five-year survival has remained poor. One strategy for addressing this problem is to search for molecular biomarkers that can better inform the development and targeting of novel treatments. The aim of this thesis was to construct and validate a tissue microarray of ovarian cancer cases and to survey the expression and prognostic capabilities of immunological molecular markers: specifically HLA class I and the membrane bound complement regulatory proteins CD46, CD55 and CD59. These are central to the efficacy of certain immunotherapies and while they have been shown to have prognostic power in breast and colorectal cancer, they have been investigated less in ovarian cancer. Five copies of a tissue microarray representing 339 cases of ovarian cancer which presented to Derby City General Hospital between 1982 and 1997 were made. The array was stained for CK7, CK20, CA125, CEA, p53 and Bcl-2 following a standard immunohistochemical protocol. A linked clinical database was adapted and assessed for data consistency and subsequently used to analyse the prognostic and clinicopathological associations of the expression data. The array was then stained for HLA class I, B2microglobulin and CD59 using commercial antibodies and for CD55 and CD46 using in-house antibodies. Retained expression of HLA class I molecules independently predicted improved prognosis. High expression of CD55 and CD59 were associated with worse prognosis, though not independently of other factors. CD55 expression was more widespread than previously appreciated. This thesis describes the discovery of a new independent marker of prognosis which suggests that immunoediting occurs in ovarian cancer, describes the distribution of markers known to have a negative impact on immunotherapy in ovarian cancer in a large series for the first time and documents the production of a valuable resource for future studies

Expert Opinion on Benefits of Long-Chain Omega-3 Fatty Acids (DHA and EPA) in Aging and Clinical Nutrition

Life expectancy is increasing and so is the prevalence of age-related non-communicable diseases (NCDs). Consequently, older people and patients present with multi-morbidities and more complex needs, putting significant pressure on healthcare systems. Effective nutrition interventions could be an important tool to address patient needs, improve clinical outcomes and reduce healthcare costs. Inflammation plays a central role in NCDs, so targeting it is relevant to disease prevention and treatment. The long-chain omega-3 polyunsaturated fatty acids (omega-3 LCPUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are known to reduce inflammation and promote its resolution, suggesting a beneficial role in various therapeutic areas. An expert group reviewed the data on omega-3 LCPUFAs in specific patient populations and medical conditions. Evidence for benefits in cognitive health, age- and disease-related decline in muscle mass, cancer treatment, surgical patients and critical illness was identified. Use of DHA and EPA in some conditions is already included in some relevant guidelines. However, it is important to note that data on the effects of omega-3 LCPUFAs are still inconsistent in many areas (e.g., cognitive decline) due to a range of factors that vary amongst the trials performed to date; these factors include dose, timing and duration; baseline omega-3 LCPUFA status; and intake of other nutrients. Well-designed intervention studies are required to optimize the effects of DHA and EPA in specific patient populations and to develop more personalized strategies for their use.<br/

Temporal variations in English Populations of a forest insect pest, the green spruce aphid (Elatobium abietinum), associated with the North Atlantic Oscillation and global warming

Based on an exceptionally long modern ecological dataset (41 years), it has been possible to show that warm weather in England associated with a positive North Atlantic Oscillation (NAO) index causes the spring migration of the green spruce aphid (Elatobium abietinum), a pest species of spruce trees (Picea) to start earlier, continue for longer and contain more aphids. An upward trend in the NAO index during the period 1966-2006 is associated with an increasing population size of E. abietinum. It is important to understand the mechanisms behind the population fluctuations, because this aphid causes considerable damage to Picea plantations. Present day weather associated fluctuations in forest insect pests may be useful analogues in understanding past pest outbreaks in forests

Disruption, control and coping: responses of and to the person with dementia in hospital

This qualitative study aimed to gain insight into the experience of hospitalisation from the perspectives of the older person with dementia, their family care-giver and other patients sharing the ward (co-patients). Non-participant observation of care on 11 acute hospital wards was supplemented by 39 semi-structured interviews with 35 family care-givers and four co-patients following discharge. Constant comparative analysis produced the core problem facing all those involved: disruption from normal routine meaning that the experience of hospitalisation was disrupted by the presence and behaviour of the person with dementia. Disruption adversely affected the person with dementia, triggering constructive, disengaged, distressed and neutral behaviours. Using Kitwood's model of person-centred care, these behaviours were interpreted as attempts by the person with dementia at gaining a sense of control over the unfamiliar environment and experience. Family care-givers' lives and experiences both inside and outside the hospital were disrupted by the hospitalisation. They too attempted to gain a sense of control over the experience and to give a sense of control to the patient, co-patients and staff. Co-patients experienced disruption from sharing space with the person with dementia and were left feeling vulnerable and sometimes afraid. They too attempted to gain a sense of control over their situation and give some control by helping the person with dementia, the family care-giver and the staff

Estimating the effects of stressors on the health, survival and reproduction of a critically endangered, long-lived species

Funding: Office of Naval Research (Grant Number(s): N000142012697, N000142112096); Strategic Environmental Research and Development Program (Grant Number(s): RC20-1097, RC20-7188, RC21-3091).Quantifying the cumulative effects of stressors on individuals and populations can inform the development of effective management and conservation strategies. We developed a Bayesian state–space model to assess the effects of multiple stressors on individual survival and reproduction. In the model, stressor effects on vital rates are mediated by changes in underlying health, allowing for the comparison of effect sizes while accounting for intrinsic factors that might affect an individual's vulnerability and resilience. We applied the model to a 50-year dataset of sightings, calving events and stressor exposure of critically endangered North Atlantic right whales Eubalaena glacialis. The viability of this population is threatened by a complex set of stressors, including vessel strikes, entanglement in fishing gear and fluctuating prey availability. We estimated that blunt and deep vessel strike injuries and severe entanglement injuries had the largest effect on the health of exposed individuals, reinforcing the urgent need for mitigation measures. Prey abundance had a smaller but protracted effect on health across individuals, and estimated long-term trends in survival and reproduction followed the trend of the prey index, highlighting that long-term ecosystem-based management strategies are also required. Our approach can be applied to quantify the effects of multiple stressors on any long-lived species where suitable indicators of health and long-term monitoring data are available.Publisher PDFPeer reviewe

Decreasing body size is associated with reduced calving probability in critically endangered North Atlantic right whales

Funding: This work was supported by the Office of Naval Research (grant nos. N000142012697 and N000142112096) and the Strategic Environmental Research and Development Program (grant nos. RC20-1097, RC20-7188 and RC21-3091). Photogrammetry was supported by NOAA grant no. NA14OAR4320158 to Woods Hole Oceanographic Institution, and by NOAA's Southwest Fisheries Science Center.Body size is key to many life-history processes, including reproduction. Across species, climate change and other stressors have caused reductions in the body size to which animals can grow, called asymptotic size, with consequences for demography. A reduction in mean asymptotic length was documented for critically endangered North Atlantic right whales, in parallel with declines in health and vital rates resulting from human activities and environmental changes. Here, we tested whether smaller body size was associated with lower reproductive output, using a state-space model for individual health, survival and reproduction that quantifies the mechanistic links between these processes. Body size (as represented by the cube of length) was strongly associated with a female's calving probability at each reproductive opportunity. This relationship explained 62% of the variation in calving among reproductive females, along with their decreasing health (20%). The effects of decreasing mean body size on reproductive performance are another concerning indication of the worsening prospects for this species and many others affected by environmental change, requiring a focus of conservation and management interventions on improving conditions that affect reproduction as well as reducing mortality.Peer reviewe

British Gynaecological Cancer Society recommendations and guidance on patient-initiated follow-up (PIFU)

The National Cancer Survivorship Initiative through the National Health Service (NHS) improvement in the UK started the implementation of stratified pathways of patient-initiated follow-up (PIFU) across various tumor types. Now the initiative is continued through the Living With and Beyond Cancer program by NHS England. Evidence from non-randomized studies and systematic reviews does not demonstrate a survival advantage to the long-established practice of hospital-based follow-up regimens, traditionally over 5 years. Evidence shows that patient needs are inadequately met under the traditional follow-up programs and there is therefore an urgent need to adapt pathways to the needs of patients. The assumption that hospital-based follow-up is able to detect cancer recurrences early and hence improve patient prognosis has not been validated. A recent survey demonstrates that follow-up practice across the UK varies widely, with telephone follow-up clinics, nurse-led clinics and PIFU becoming increasingly common. There are currently no completed randomized controlled trials in PIFU in gynecological malignancies, although there is a drive towards implementing PIFU. PIFU aims to individualize patient care, based on risk of recurrence and holistic needs, and optimizing resources. The British Gynaecological Cancer Society wishes to provide the gynecological oncology community with guidance and a recommendations statement regarding the value, indications, and limitations of PIFU in endometrial, cervical, ovarian, and vulvar cancers in an effort to standardize practice and improve patient care. [Abstract copyright: © IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.

On using extreme values to detect global stability thresholds in multi-stable systems: the case of transitional plane Couette flow

Extreme Value Theory (EVT) is exploited to determine the global stability threshold Rg of plane Couette flow ‚ the flow of a viscous fluid in the space between two parallel plates ‚ whose laminar or turbulent behavior depends on the Reynolds number R. Even if the existence of a global stability threshold has been detected in simulations and experiments, its numerical value has not been unequivocally defined. Rg is the value such that for R>Rg, turbulence is sustained, whereas for R>Rg, both the positive and negative extremes are bounded. As the critical Reynolds number is approached from above, the probability of observing a very low minimum increases causing asymmetries in the distributions of maxima and minima. On the other hand, the maxima distribution is unaffected as the fluctuations towards higher values of the perturbation energy remain bounded. This tipping point can be detected by fitting the data to the Generalized Extreme Value (GEV) distribution and by identifying Rg as the value of R such that the shape parameter of the GEV for the minima changes sign from negative to positive. The results are supported by the analysis of theoretical models which feature a bistable behavior