Project description:Depression is a leading cause of disease burden, disability and distress for millions of older adults. Thus, prevention of late-life depression is a priority research area. This article addresses the science of late-life depression prevention with the following: 1) an introduction to the Institute of Medicine framework of universal, selective and indicated prevention as it pertains to late-life depression, with particular attention to successes of indicated and selective prevention in primary care; 2) a discussion of how biomarkers can be integrated into prevention research, using interferon-alpha-induced depression as a model; 3) an outline for expansion of prevention to non-specialist care delivery systems in Low and Middle Income Countries - thus, extending the reach of current successful approaches; 4) a description of a novel approach to simultaneous testing of universal, selective and indicated prevention in late-life depression, with emphasis on study design features required to achieve practical, scalable tests of health impact.
Project description:The anticancer activity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol) has been widely reported in preclinical models. However, systematic investigation into the chemopreventive potential of calcitriol against the spectrum of oral carcinogenesis has not been performed. To address this gap in knowledge, we conducted a preclinical prevention trial of calcitriol in the 4-nitroquinoline-1-oxide (4NQO) oral carcinogenesis model. C57BL/6 mice were exposed to the carcinogen 4NQO in drinking water for 16 weeks and randomized to control (4NQO only) or calcitriol arms. Calcitriol (0.1 μg i.p, Monday, Wednesday, and Friday) was administered for (i) 16 weeks concurrently with 4NQO exposure, (ii) 10 weeks post completion of 4NQO exposure, and, (iii) a period of 26 weeks concurrent with and following 4NQO exposure. Longitudinal magnetic resonance imaging (MRI) was performed to monitor disease progression until end point (week 26). Correlative histopathology of tongue sections was performed to determine incidence and multiplicity of oral dysplastic lesions and squamous cell carcinomas (SCC). Vitamin D metabolites and calcium were measured in the serum using liquid chromatography-mass spectrometry (LC-MS/MS) and colorimetric assay, respectively. Renal CYP24A1 (24-hydroxylase) and CYP27B1 (1α-hydroxylase) expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunostaining of tongue sections for vitamin D receptor (VDR), CYP24A1, and Ki67 was also performed. Non-invasive MRI enabled longitudinal assessment of lesions in the oral cavity. Calcitriol administered concurrently with 4NQO for 16 weeks significantly (P < .001) decreased the number of premalignant lesions by 57% compared to 4NQO only controls. Mice treated with calcitriol for 26 weeks showed highest renal CYP24A1, lowest serum 1,25(OH)2D3 levels and highest incidence of invasive SCC. Immunohistochemistry revealed increased VDR, CYP24A1 and Ki67 staining in dysplastic epithelia compared to normal epithelium, in all four groups. Collectively, our results show that the effects of calcitriol on oral carcinogenesis are critically influenced by the stage of intervention and duration of exposure and provide the basis for exploring the potential of calcitriol for prevention of OSCC in the clinical setting.
Project description:Anti-tumour T cell responses play a crucial role in controlling the progression of colorectal cancer (CRC), making this disease a promising candidate for immunotherapy. However, responses to immune-targeted therapies are currently limited to subpopulations of patients and specific types of cancer. Clinical studies have therefore focussed on identifying biomarkers that predict immunotherapy responses and elucidating the immunological landscapes of different cancers. Meanwhile, our understanding of how preclinical tumour models resemble human disease has fallen behind, despite their crucial role in immune-targeted drug development. A deeper understanding of these models is therefore needed to improve the development of immunotherapies and the translation of findings made in these systems. MC38 colon adenocarcinoma is a widely used preclinical model, yet how it recapitulates human colorectal cancer remains poorly defined. This study investigated the tumour-T cell immune landscape of MC38 tumours using histology, immunohistochemistry, and flow cytometry. We demonstrate that early-stage tumours exhibit a nascent TME, lacking important immune-resistance mechanisms of clinical interest, while late-stage tumours exhibit a mature TME resembling human tumours, with desmoplasia, T cell exhaustion, and T cell exclusion. Consequently, these findings clarify appropriate timepoint selection in the MC38 model when investigating both immunotherapies and mechanisms that contribute to immunotherapy resistance. Overall, this study provides a valuable resource that will enable appropriate application of the MC38 model and expedite the development and clinical translation of new immunotherapies.
Project description:Established and emerging data demonstrate that a 'preclinical' period of disease precedes the onset of clinical rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as other autoimmune rheumatic diseases (ARDs).This preclinical stage of development of disease is characterized by abnormalities in disease-related biomarkers before the onset of the clinically apparent signs and symptoms. Numerous genetic and environmental risk factors for ARDs have also been identified, and many of these factors are likely to act before the clinical appearance of tissue injury to initiate and/or propagate autoimmunity and autoimmune disease. Thus, biomarkers representative of these autoimmune processes could potentially be used in conjunction with other clinical parameters during the preclinical period of ARDs to predict the future development of clinically apparent disease. This Review focuses on the preclinical stages of RA and SLE, as our current understanding of these diseases can be used to present an overall model of the development of ARDs that might ultimately be used to develop screening programmes and preventive strategies. Important considerations for the future development of such approaches, in particular, the issues that require additional research and how they might be addressed, are also discussed.
Project description:MicroRNAs play important roles in regulating biological processes, including organ morphogenesis and maturation. However, little is known about specific pathways regulated by miRNA during lung development. Between the canalicular and saccular stages of the developing lung several important cellular events occur, including the onset of surfactant synthesis, microvascular remodeling and structural preparation for subsequent alveolarization. The miRNAs that are actively regulated, and the identity of their targets during this important developmental interval in the lung remain elusive.Using TLDA low density real-time PCR arrays, the expression of 376 miRNAs in male and female fetal mouse lungs of gestational days E15 - E18 were profiled. Statistical analyses identified 25 and 37 miRNAs that changed significantly between sexes and with gestation, respectively. In silico analysis using Ingenuity Pathway Analysis (IPA) identified specific pathways and networks known to be targets of these miRNAs which are important to lung development. Pathways that are targeted by sex regulated miRNAs include retinoin, IGFR1, Tp53 and Akt. Pathways targeted by gestation-regulated miRNAs include VEGFA and mediators of glucose metabolism.MiRNAs are differentially regulated across time and between sexes during the canalicular and saccular stages of lung development. Sex-associated differential miRNA expression may regulate the differences in structural and functional male and female lung development, as shown by networks generated using in silico analysis. These data provide a valuable resource to further enhance the understanding of miRNA control of lung development and maturation.
Project description:High-density lipoprotein (HDL) particles transport (among other molecules) cholesterol (HDL-C). In epidemiological studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease. It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, several recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased cardiovascular disease risk, giving rise to a controversy regarding whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. The evidence from preclinical and (limited) clinical studies shows that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. Although more research will be needed regarding basic mechanisms and to establish that these changes translate clinically to reduced cardiovascular disease events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent but rather emphasizes the important distinction between HDL function and plasma levels of HDL-C.
Project description:Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions.
Project description:Preclinical studies have shown benefit of apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL) raising in atherosclerosis; however, this has not yet translated into a successful clinical therapy. Our studies demonstrate that apoA-I raising is more effective at reducing early-stage atherosclerosis than late-stage disease, indicating that the timing of HDL raising is a critical factor in its atheroprotective effects. To date, HDL-raising clinical trials have only been performed in aged patients with advanced atherosclerotic disease. Our findings therefore provide insight, related to important temporal aspects of HDL raising, as to why the clinical trials have thus far been largely neutral.
Project description:Alongside government driven management initiatives to achieve sustainable fisheries management, there remains a role for market-based mechanisms to improve fisheries outcomes. Market-based mechanisms are intended to create positive economic incentives that improve the status and management of fisheries. Research to understand consumer demand for certified fish is central but needs to be mirrored by supply side understanding including why fisheries decide to gain or retain certification and the impact of certification on them and other stakeholders involved. We apply semi-structured interviews in seven different Marine Stewardship Council (MSC) certified fisheries that operate in (or from) Western Australia with the aim of better understanding fisheries sector participation in certification schemes (the supply side) and the impacts and unintended benefits and costs of certification. We find that any positive economic impacts of certification were only realised in a limited number of MSC fisheries in Western Australia, which may be explained by the fact that only a small proportion of Western Australian state-managed fisheries are sold with the MSC label and ex-vessel or consumer market price premiums are therefore mostly not obtained. Positive impacts of certification in these Western Australian fisheries are more of a social and institutional nature, for example, greater social acceptability and increased efficiency in the governance process respectively. However, opinion is divided on whether the combined non-monetary and monetary benefits outweigh the costs.
Project description:SignificanceTo effectively study preclinical animal models, medical imaging technology must be developed with a high enough resolution and sensitivity to perform anatomical, functional, and molecular assessments. Photoacoustic (PA) tomography provides high resolution and specificity, and fluorescence (FL) molecular tomography provides high sensitivity; the combination of these imaging modes will enable a wide range of research applications to be studied in small animals.AimWe introduce and characterize a dual-modality PA and FL imaging platform using in vivo and phantom experiments.ApproachThe imaging platform's detection limits were characterized through phantom studies that determined the PA spatial resolution, PA sensitivity, optical spatial resolution, and FL sensitivity.ResultsThe system characterization yielded a PA spatial resolution of 173±17 μm in the transverse plane and 640±120 μm in the longitudinal axis, a PA sensitivity detection limit not less than that of a sample with absorption coefficient μa=0.258 cm-1 , an optical spatial resolution of 70 μm in the vertical axis and 112 μm in the horizontal axis, and a FL sensitivity detection limit not <0.9 μM concentration of IR-800. The scanned animals displayed in three-dimensional renders showed high-resolution anatomical detail of organs.ConclusionsThe combined PA and FL imaging system has been characterized and has demonstrated its ability to image mice in vivo, proving its suitability for biomedical imaging research applications.