A model of quiescent tumour microregions for evaluating multicellular resistance to chemotherapeutic drugs

The quiescent cell population of tumours poses a barrier to the success of many cancer therapies. Most chemotherapeutic drugs target proliferating cells, but the growth fraction of many tumours is low. Based on the multicellular tumour spheroid model, a system was developed using human colon adenocarcinoma (DLD-1) cells to mimic the microenvironment of quiescent microregions of solid tumours. The quiescent tumour spheroids (TSQ) showed decreased expression of the proliferation marker Ki-67 and increased expression of the quiescence marker p27kip1 compared to proliferating spheroids (TSP). The quiescent status of the TSQ was confirmed by long-term growth assessment. The quiescence was completely reversible demonstrating that the TSQ retained the ability to proliferate and morphological assessment by light microscopy confirmed the absence of significant apoptosis. When the efficacy of widely used chemotherapeutic drugs was determined, vinblastine, doxorubicin, cisplatin and 5-fluorouracil (5-FU) all produced significant cell death in the TSP. However, while still effective, the potencies of doxorubicin and cisplatin were significantly reduced in TSQ. In contrast, 5-FU and vinblastine did not produce cell death in the TSQ. In summary, TSQ show considerable resistance to a panel of established chemotherapeutic agents and represent a useful model for evaluating the efficacy of drugs and other cancer therapies in quiescent tumours

Cadmium Induces p53-Dependent Apoptosis in Human Prostate Epithelial Cells

Cadmium, a widespread toxic pollutant of occupational and environmental concern, is a known human carcinogen. The prostate is a potential target for cadmium carcinogenesis, although the underlying mechanisms are still unclear. Furthermore, cadmium may induce cell death by apoptosis in various cell types, and it has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. We investigated the in vitro effects produced by cadmium exposure in normal or tumor cells derived from human prostate epithelium, including RWPE-1 and its cadmium-transformed derivative CTPE, the primary adenocarcinoma 22Rv1 and CWR-R1 cells and LNCaP, PC-3 and DU145 metastatic cancer cell lines. Cells were treated for 24 hours with different concentrations of CdCl2 and apoptosis, cell cycle distribution and expression of tumor suppressor proteins were analyzed. Subsequently, cellular response to cadmium was evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. The cell lines exhibited different sensitivity to cadmium, and 24-hour exposure to different CdCl2 concentrations induced dose- and cell type-dependent apoptotic response and inhibition of cell proliferation that correlated with accumulation of functional p53 and overexpression of p21 in wild type p53-expressing cell lines. On the other hand, p53 silencing was able to suppress cadmium-induced apoptosis. Our results demonstrate that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis

Changes in physical activity during the retirement transition: a series of novel n-of-1 natural experiments.

BACKGROUND: Existing evidence about the impact of retirement on physical activity (PA) has primarily focused on the average change in PA level after retirement in group-based studies. It is unclear whether findings regarding the direction of PA change after retirement from group-based studies apply to individuals. This study aimed to explore changes in PA, PA determinants and their inter-relationships during the retirement transition at the individual level. METHODS: A series of n-of-1 natural experiments were conducted with seven individuals who were aged 55-76 years and approaching retirement. PA was measured by tri-axial accelerometry. Twice-daily self-report and ecological momentary assessments of evidence- and theory-based determinants of PA (e.g. sleep length/quality, happiness, tiredness, stress, time pressure, pain, intention, perceived behavioural control, priority, goal conflict and goal facilitation) were collected via a questionnaire for a period of between 3 and 7 months, which included time before and after the participant's retirement date. A personalised PA determinant was also identified by each participant and measured daily for the duration of the study. Dynamic regression models for discrete time binary data were used to analyse data for each individual participant. RESULTS: Two participants showed a statistically significant increase in the probability of engaging in PA bouts after retirement and two participants showed a significant time trend for a decrease and increase in PA bouts over time during the pre- to post-retirement period, respectively. There was no statistically significant change in PA after retirement for the remaining participants. Most of the daily questionnaire variables were significantly associated with PA for one or more participants but there were no consistent pattern of PA predictors across participants. For some participants, the relationship between questionnaire variables and PA changed from pre- to post-retirement. CONCLUSIONS: The findings from this study demonstrate the impact of retirement on individual PA trajectories. Using n-of-1 methods can provide information about unique patterns and determinants of individual behaviour over time, which has been obscured in previous research. N-of-1 methods can be used as a tool to inform personalised PA interventions for individuals within the retirement transition

Persian cats under first opinion veterinary care in the UK:demography, mortality and disorders

Persian cats are a popular cat breed worldwide, and especially in the US, Europe and Asia. This study aimed to describe the demography, common disorders and mortality in Persians under general practice veterinary care in 2013 in the UK. The study population of 285,547 cats overall included 3235 (1.1%) Persians. Mean adult Persian bodyweight was 3.9 kg (SD 0.9) and median age was 7.0 years (IQR 3.3–11.6). At least one disorder was recorded in 2099 (64.9%) Persians. The most common specific disorders were haircoat disorders (411, 12.7%), periodontal disease (365, 11.3%), overgrown nails (234, 7.2%), and ocular discharge (188, 5.8%). The most common disorder groups were dermatological (578, 17.9%), ophthalmological (496, 15.3%) and dental (397, 12.3%). Median longevity was 13.5 years (IQR 9.9–16.0). The most common grouped causes of death were renal disease (102, 23.4%), neoplasia (37, 8.5%) and mass-associated disorder (35, 8.0%). This is the first study to use general practice data to examine the overall health of Persian cats. With haircoat, ocular and dental disorders being the predominant disorders identified, this study highlights the need for increased owner awareness to manage and prevent the typical health problems associated with this breed’s phenotype

Assessing palaeobathymetry and sedimentation rates using palynomaceral analysis: a study of modern sediments from the Gulf of Papua, offshore Papua New Guinea

© 2015 © 2015 AASP - The Palynological Society. Palynologists interested in better understanding the sedimentation and energy of depositional environments have often included studies of palynomaceral fragments, particularly when performing palynofacies analyses. Due to the difficult nature of classifying these fragments, researchers have developed numerous, often overlapping, classification schemes. These different schemes make it difficult to compare and contrast between research projects. Determining the appropriate scheme to apply when counting these fragments can be confusing, and application of these schemes can yield inconclusive results, especially when sedimentation and energy are in constant flux. A scheme of five categories, including brown wood (palynomaceral 1-2), leaf cuticle (palynomaceral 3), black debris (palynomaceral 4), structureless organic matter (SOM) and resin, is utilised here. It is applied to the analysis of 64 modern samples from the top 0-4 cm of sediment collected throughout the Gulf of Papua, Papua New Guinea. These samples span a suite of common marine depositional environments: river mouths and deltas, the proximal portion of the continental shelf dominated by a large clinoform, and turbidite and hemipelagic/pelagic deposits on the slope and in the deep ocean basin. Principal component analysis (PCA) confirms this simplified classification scheme provides an indirect means of assessing distance from shore and shelf-slope break, overall water depth and sediment accumulation rate, but other factors, such as processing technique, marine productivity, sediment source, time in transport and residence and bioturbation, are taken into account to fully explain distribution