A stochastic model for topographically influenced cell migration.

Migrating cells traverse a range of topographic configurations presented by the native extracellular environment to conduct their physiologic functions. It is well documented cells can modulate their behaviour in response to different topographic features, finding promising applications in biomaterial and bioimplant design. It is useful, in these areas of research, to be able to predict which topographic arrangements could be used to promote certain patterns of migration prior to laboratory experimentation. Despite a profusion of study and interest shown in these fields by experimentalists, the related modelling literature is as yet relatively sparse and tend to focus more on either cell-matrix interaction or morphological responses of cells. We propose a mathematical model for individual cell migration based on an Ornstein-Uhlenbeck process, and set out to see if the model can be used to predict migration patterns on 2-d isotropic and anisotropic topographies, whose characteristics can be broadly described as either uniform flat, uniform linear with variable ridge density or non-uniform disordered with variable feature density. Results suggest the model is capable of producing realistic patterns of migration for flat and linear topographic patterns, with calibrated output closely approximating NIH3T3 fibroblast migration behaviour derived from an experimental dataset, in which migration linearity increased with ridge density and average speed was highest at intermediate ridge densities. Exploratory results for non-uniform disordered topographies suggest cell migration patterns may adopt disorderedness present in the topography and that 'distortion' introduced to linear topographic patterns may not impede linear guidance of migration, given its magnitude is bounded within certain limits. We conclude that an Ornstein-Uhlenbeck based model for topographically influenced migration may be useful to predict patterns of migration behaviour for certain isotropic (flat) and anisotropic (linear) topographies in the NIH3T3 fibroblast cell line, but additional investigation is required to predict with confidence migration patterns for non-uniform disordered topographic arrangements.

Reducing dietary protein and supplementation with starch or rumen-protected methionine and its effect on performance and nitrogen efficiency in dairy cows fed a red clover and grass silage-based diet.

The increasing cost of milk production, in association with tighter manure N application regulations and challenges associated with ammonia emissions in many countries, has increased interest in feeding lower crude protein (CP) diets based on legume silages. Most studies have focused on alfalfa silage, and little information is available on low-CP diets based on red clover silage. Our objectives were to examine the effects of dietary CP content and supplementing a low-CP diet with dietary starch or rumen-protected Met (RPMet) on the performance, metabolism, and nitrogen use efficiency (NUE; milk N output/N intake) in dairy cows fed a red clover and grass silage-based diet. A total of 56 Holstein-Friesian dairy cows were blocked and randomly allocated to 1 of 4 diets over a 14-wk feeding period. Diets were based on red clover and grass silages at a ratio of 50:50 on a dry matter (DM) basis and were fed as a total mixed ration, with a 53:47 ratio of forage to concentrate (DM basis). The diets were formulated to supply a similar metabolizable protein (MP) content, and had a CP concentration of either 175 g/kg DM (control [CON]) or 150 g/kg DM (low-protein [LP]), or LP supplemented with either additional barley as a source of starch (LPSt; +64 g/kg DM) or RPMet (LPM; +0.3 g/100 g MP). At the end of the 14-wk feeding period, 20 cows (5 per treatment) continued to be fed the same diets for a further 6 d, and total urine output and fecal samples were collected. We observed that dietary treatment did not affect DM intake, with a mean of 21.5 kg/d; however, we also observed an interaction between diet and week with intake being highest in cows fed LPSt in wk 4 and CON in wk 9 and 14. Mean milk yield, 4% fat-corrected milk, and energy-corrected milk were not altered by treatment. Similarly, we found no effect of dietary treatment on milk fat, protein, or lactose content. In contrast, milk and plasma urea concentrations were highest in cows fed CON. The concentration of blood plasma ß-hydroxybutyrate was highest in cows receiving LPM and lowest in LPSt. Apparent NUE was 28.6% in cows fed CON and was higher in cows fed any of the low-protein diets (LP, LPSt, or LPM), with a mean value of 34.2%. The sum of milk fatty acids with a chain length below C16:0 was also highest in cows fed CON. We observed that dietary treatment did not affect the apparent whole-tract nutrient digestibility of organic matter, N, neutral detergent fiber, and acid detergent fiber, with mean values of 0.785, 0.659, 0.660, and 0.651 kg/kg respectively, but urinary N excretion was approximately 60 g/d lower in cows fed the low-CP diets compared with CON. We conclude that reducing the CP content of red clover and grass silage-based diets from 175 to 150 g/kg DM while maintaining MP supply did not affect performance, but reduced the urinary N excretion and improved NUE, and that supplementing additional starch or RPMet had little further effect.

Feeding lower-protein diets based on red clover and grass or alfalfa and corn silage does not affect milk production but improves nitrogen use efficiency in dairy cows.

Reducing the dietary crude protein (CP) concentration can decrease the financial cost and lower the environmental impact of milk production. Two studies were conducted to examine the effects of reducing the dietary CP concentration on animal performance, nutrient digestibility, milk fatty acid (FA) profile, and nitrogen use efficiency (NUE; milk N/N intake) in dairy cows fed legume silage-based diets. Thirty-six multiparous Holstein-Friesian dairy cows that were 76 ± 14 (mean ± SD) days in milk and 698 ± 54 kg body weight were used in a 3 × 3 Latin square design in each of 2 studies, with 3 periods of 28 d. In study 1, cows were fed diets based on a 50:50 ratio of red clover to grass silage [dry matter (DM) basis] containing 1 of 3 dietary CP concentrations: high (H) = 175 g of CP/kg of DM; medium (M) = 165 g of CP/kg of DM; or low (L) = 150 g of CP/kg of DM. In study 2, cows were fed 175 g of CP/kg of DM with a 50:50 ratio of alfalfa to corn silage (H50) or 1 of 2 diets containing 150 g of CP/kg of DM with either a 50:50 (L50) or a 60:40 (L60) ratio of alfalfa to corn silage. Cows in both studies were fed a total mixed ration with a forage-to-concentrate ratio of 52:48 (DM basis). All diets were formulated to meet the MP requirements, except L (95% of MP requirements). In study 1, cows fed L ate 1.6 kg of DM/d less than those fed H or M, but milk yield was similar across treatments. Mean milk protein, fat, and lactose concentrations were not affected by diet. However, the apparent total-tract nutrient digestibility was decreased in cows fed L. The NUE was 5.7 percentage units higher in cows fed L than H. Feeding L also decreased milk and plasma urea concentrations by 4.4 mg/dL and 0.78 mmol/L, respectively. We found no effect of dietary treatment on the milk saturated or monounsaturated FA proportion, but the proportion of polyunsaturated FA was increased, and milk odd- and branched-chain FA decreased in cows fed L compared with H. In study 2, DM intake was 2 kg/d lower in cows receiving L50 than H50. Increasing the alfalfa content and feeding a low-CP diet (L60) did not alter DMI but decreased milk yield and milk protein concentration by 2 kg/d and 0.6 g/kg, respectively, compared with H50. Likewise, milk protein and lactose yield were decreased by 0.08 kg/d in cows receiving L60 versus H50. Diet had no effect on apparent nutrient digestibility. Feeding the low-CP diets compared with H50 increased the apparent NUE by approximately 5 percentage units and decreased milk and plasma urea concentrations by 7.2 mg/dL and 1.43 mmol/L, respectively. Dietary treatment did not alter milk FA profile except cis-9,trans-11 conjugated linoleic acid, which was higher in milk from cows receiving L60 compared with H50. We concluded that reducing CP concentration to around 150 g/kg of DM in red clover and grass or alfalfa and corn silage-based diets increases the apparent NUE and has little effect on nutrient digestibility or milk performance in dairy cows.

A neglected source of household air pollution: a preliminary, mixed methods study of purposely produced household smoke in Wollo, Ethiopia.

BACKGROUND: Ill health associated with household air pollution (HAP) is increasingly recognized as a public health problem in sub-Saharan Africa. To date, attempts to reduce HAP have focussed on smoke from cooking fires and have ignored traditional cultural practices which generate purposely produced smoke (PPS). This study aimed to investigate PPS prevalence, reasons for use and safety perceptions. METHODS: The study was conducted in Wollo, Ethiopia, and used a mixed methods approach of quantitative surveys (analysed descriptively) and qualitative interviews with householders and healthcare workers (analysed thematically). RESULTS: PPS use was reported by 99% of survey respondents and it was considered a fundamental part of life. Although reasons for use included housekeeping, culture/religion and well-being, coffee ceremony was most commonly cited (44% of respondents). Both householders and healthcare workers appeared to assume PPS is safe, except for people with certain underlying conditions. Healthcare workers felt the lack of evidence of harm from PPS meant there was no justification for intervention. CONCLUSION: This study, the first in-depth study of PPS, has shown its use to be widespread, with many perceived benefits and thus a very important part of local culture in this sample Ethiopian community. Consequently, any public health interventions aimed at reducing HAP in this setting need to consider PPS.

A mathematical model of antibody-dependent cellular cytotoxicity (ADCC).

Immunotherapies exploit the immune system to target and kill cancer cells, while sparing healthy tissue. Antibody therapies, an important class of immunotherapies, involve the binding to specific antigens on the surface of the tumour cells of antibodies that activate natural killer (NK) cells to kill the tumour cells. Preclinical assessment of molecules that may cause antibody-dependent cellular cytotoxicity (ADCC) involves co-culturing cancer cells, NK cells and antibody in vitro for several hours and measuring subsequent levels of tumour cell lysis. Here we develop a mathematical model of such an in vitro ADCC assay, formulated as a system of time-dependent ordinary differential equations and in which NK cells kill cancer cells at a rate which depends on the amount of antibody bound to each cancer cell. Numerical simulations generated using experimentally-based parameter estimates reveal that the system evolves on two timescales: a fast timescale on which antibodies bind to receptors on the surface of the tumour cells, and NK cells form complexes with the cancer cells, and a longer time-scale on which the NK cells kill the cancer cells. We construct approximate model solutions on each timescale, and show that they are in good agreement with numerical simulations of the full system. Our results show how the processes involved in ADCC change as the initial concentration of antibody and NK-cancer cell ratio are varied. We use these results to explain what information about the tumour cell kill rate can be extracted from the cytotoxicity assays.

Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade.

Since the first attempt of pig-to-primate liver xenotransplantation (LXT) in 1968, survival has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous posttransplant infusion of human prothrombin concentrate complex, and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone, and costimulation blockade (belatacept, n = 3 or anti-CD40 mAb, n = 1) to extend survival. Baboon 1 remained well until postoperative day (POD) 25, when euthanasia was required because of cholestasis and plantar ulcers. Baboon 2 was euthanized following a seizure on POD 5, despite normal liver function tests (LFTs) and no apparent pathology. Baboon 3 demonstrated initial stable liver function but was euthanized on POD 8 because of worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis, and a focal cytomegalovirus inclusion. Baboon 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations and rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation, or thrombotic microangiopathy. Thus, nearly 1-mo rejection-free survival has been achieved following LXT in two of four consecutive recipients, demonstrating that the porcine liver can support life in primates for several weeks and has encouraging potential for clinical application as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.

Direct Measurement of the Key E_{c.m.}=456 keV Resonance in the Astrophysical

We have performed a direct measurement of the ^{19}Ne(p,γ)^{20}Na reaction in inverse kinematics using a beam of radioactive ^{19}Ne. The key astrophysical resonance in the ^{19}Ne+p system has been definitely measured for the first time at E_{c.m.}=456_{-2}^{+5} keV with an associated strength of 17_{-5}^{+7} meV. The present results are in agreement with resonance strength upper limits set by previous direct measurements, as well as resonance energies inferred from precision (^{3}He, t) charge exchange reactions. However, both the energy and strength of the 456 keV resonance disagree with a recent indirect study of the ^{19}Ne(d, n)^{20}Na reaction. In particular, the new ^{19}Ne(p,γ)^{20}Na reaction rate is found to be factors of ∼8 and ∼5 lower than the most recent evaluation over the temperature range of oxygen-neon novae and astrophysical x-ray bursts, respectively. Nevertheless, we find that the ^{19}Ne(p,γ)^{20}Na reaction is likely to proceed fast enough to significantly reduce the flux of ^{19}F in nova ejecta and does not create a bottleneck in the breakout from the hot CNO cycles into the rp process.

High incidence of xenogenic bone marrow engraftment in pig-to-baboon intra-bone bone marrow transplantation.

Previous attempts of α-1,3-galactocyltransferase knockout (GalTKO) pig bone marrow (BM) transplantation (Tx) into baboons have demonstrated a loss of macro-chimerism within 24 h in most cases. In order to achieve improved engraftment with persistence of peripheral chimerism, we have developed a new strategy of intra-bone BM (IBBM) Tx. Six baboons received GalTKO BM cells, with one-half of the cells transplanted into the bilateral tibiae directly and the remaining cells injected intravenously (IBBM/BM-Tx) with a conditioning immunosuppressive regimen. In order to assess immune responses induced by the combined IBBM/BM-Tx, three recipients received donor SLA-matched GalTKO kidneys in the peri-operative period of IBBM/BM-Tx (Group 1), and the others received kidneys 2 months after IBBM/BM-Tx (Group 2). Peripheral macro-chimerism was continuously detectable for up to 13 days (mean 7.7 days; range 3-13) post-IBBM/BM-Tx and in three animals, macro-chimerism reappeared at days 10, 14 and 21. Pig CFUs, indicating porcine progenitor cell engraftment, were detected in the host BM in four of six recipients on days 14, 15, 19 and 28. In addition, anti-pig unresponsiveness was observed by in vitro assays. GalTKO/pCMV-kidneys survived for extended periods (47 and 60 days). This strategy may provide a potent adjunct for inducing xenogeneic tolerance through BM-Tx.

Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes.

BACKGROUND: A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. PATIENTS AND METHODS: This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. RESULTS: HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. CONCLUSIONS: The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. CLINICAL TRIALS NUMBERS: Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172. UK GENETIC PROSTATE CANCER STUDY: Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.

Exact Equations for SIR Epidemics on Tree Graphs.

We consider Markovian susceptible-infectious-removed (SIR) dynamics on time-invariant weighted contact networks where the infection and removal processes are Poisson and where network links may be directed or undirected. We prove that a particular pair-based moment closure representation generates the expected infectious time series for networks with no cycles in the underlying graph. Moreover, this "deterministic" representation of the expected behaviour of a complex heterogeneous and finite Markovian system is straightforward to evaluate numerically.

Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.

BACKGROUND: Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated. METHODS: Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified. RESULTS: We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56-2.42). CONCLUSIONS: These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread.

Insulin resistance, and not ß-cell impairment, mediates association between Mycobacterium tuberculosis sensitization and type II diabetes mellitus among US adults.

Type 2 diabetes mellitus (T2DM) may be a long-term sequela of infection with Mycobacterium tuberculosis (M.tb) by mechanisms that remain to be fully explained. We evaluated association between M.tb sensitization and T2DM among U.S adults and, via formal mediation analysis, the extent to which this association is mediated by insulin resistance and/or ß-cell failure. These evaluations accounted for demographic, socio-economic, behavioral and clinical characteristics. T2DM was assessed by fasting plasma glucose, 2-hour oral glucose tolerance testing and HbA1c; homoeostasis model assessment 2 (HOMA2) was used to estimate ß-cell dysfunction (HOMA2-B) and insulin resistance (HOMA2-IR); while M.tb sensitization status was ascertained by tuberculin skin testing (TST). Exposure to M.tb was associated with increased risk for T2DM, likely driven by an increase in insulin resistance. Definitive prospective studies examining incident T2DM following tuberculosis are warranted. Research in Context: What is already known about this subject?: Accumulating evidence suggests that pre-diabetes and new-onset type 2 diabetes mellitus (T2DM) may be a long-term complication of exposure to Mycobacterium tuberculosis ( M.tb ) via mechanisms that remain to be unraveled What is the key question?: To what extent do insulin resistance and ß-cell failure mediate the association between M.tb sensitization with T2DM among US adults? What are the new findings?: M.tb sensitization is characterized by distinct glucose metabolic disturbances manifesting as increased risk of T2DM and isolated impaired fasting glucose (IFG) Insulin resistance, and not ß-cell impairment, likely independently mediate the observed diabetogenic effects of M.tb sensitization How might this impact on clinical and/or public health practice in the foreseeable future?: If corroborated by prospective studies, both TB programs and individual clinical care must incorporate monitoring of serum glucose and long-term metabolic outcomesThis will be particularly urgent in sub-Saharan Africa and South-East Asia where scarce health resources coincide with overlapping endemic TB and epidemic T2DM.

Prevalence, incidence and determinants of QuantiFERONTM positivity in South African schoolchildren.

BACKGROUND: TB control requires the understanding and disruption of TB transmission. We describe prevalence, incidence and risk factors associated with childhood TB infection in Cape Town, South Africa. METHODS: We report cross-sectional baseline and prospective incidence data from a large trial among primary school children living in high TB burden communities. Prevalent infection was defined as QuantiFERON™-TB Gold Plus (QFT-Plus) positivity as assessed at baseline. Subsequent conversion to QFT-Plus positivity was measured 3 years later among those QFT-Plus-negative at baseline. Multivariable logistic regression models examined factors associated with TB infection. RESULTS: QuantiFERON-positivity at baseline (prevalence: 22.6%, 95% CI 20.9-24.4), was independently associated with increasing age (aOR 1.24 per additional year, 95% CI 1.15-1.34) and household exposure to TB during the participant's lifetime (aOR 1.87, 95% CI 1.46-2.40). QFT-Plus conversion at year 3 (12.2%, 95% CI 10.5-14.0; annual infection rate: 3.95%) was associated with household exposure to an index TB case (aOR 2.74, 95% CI 1.05-7.18). CONCLUSION: Rates of QFT-diagnosed TB infection remain high in this population. The strong association with household TB exposure reinforces the importance of contact tracing, preventative treatment and early treatment of infectious disease to reduce community transmission.

CONTEXTE: La lutte contre la TB nécessite la compréhension et la perturbation de la transmission de la TB. Nous décrivons la prévalence, l'incidence et les facteurs de risque associés à l'infection tuberculeuse infantile au Cap, en Afrique du Sud. MÉTHODES: Nous rapportons des données transversales de référence et d'incidence prospective provenant d'un vaste essai mené auprès d'enfants d'écoles primaires vivant dans des communautés à forte charge de morbidité tuberculeuse. La prévalence de l'infection a été définie comme la positivité au QuantiFERON™-TB Gold Plus (QFT-Plus) telle qu'évaluée au départ. La conversion subséquente en QFT-Plus positif a été mesurée 3 ans plus tard chez les QFT-Plus négatifs au départ. Des modèles de régression logistique multivariée ont examiné les facteurs associés à l'infection tuberculeuse. RÉSULTATS: La positivité QuantiFERON-au départ (prévalence : 22,6%, IC à 95% 20,9­24,4), était indépendamment associée à l'augmentation de l'âge (aOR 1,24 par année supplémentaire, IC à 95% 1,15­1,34) et à l'exposition du ménage à la TB au cours de la vie du participant (aOR 1,87 ; IC à 95% 1,46­2,40). La conversion QFT-Plus à l'année 3 (12,2%, IC à 95% 10,5­14,0 ; taux d'infection annuel : 3,95%) était associée à l'exposition du ménage à un cas de tuberculose index (aOR 2,74 ; IC à 95% 1,05­7,18). CONCLUSION: Les taux d'infection tuberculeuse diagnostiquée par QFT restent élevés dans cette population. La forte association avec l'exposition à la TB dans les ménages renforce l'importance de la recherche des contacts, du traitement préventif et du traitement précoce des maladies infectieuses pour réduire la transmission communautaire.

Digital pattern recognition-based image analysis quantifies immune infiltrates in distinct tissue regions of colorectal cancer and identifies a metastatic phenotype.

BACKGROUND: Several studies in colorectal cancer (CRC) indicate a relationship between tumour immune infiltrates and clinical outcome. We tested the utility of a digital pattern recognition-based image analysis (DPRIA) system to segregate tissue regions and facilitate automated quantification of immune infiltrates in CRC. METHODS: Primary CRC with matched hepatic metastatic (n=7), primary CRC alone (n=18) and primary CRC with matched normal (n=40) tissue were analysed immunohistochemically. Genie pattern recognition software was used to segregate distinct tissue regions in combination with image analysis algorithms to quantify immune cells. RESULTS: Immune infiltrates were observed predominately at the invasive margin. Quantitative image analysis revealed a significant increase in the prevalence of Foxp3 (P<0.0001), CD8 (P<0.0001), CD68 (<0.0001) and CD31 (<0.0001) positive cells in the stroma of primary and metastatic CRC, compared with tumour cell mass. A direct comparison between non-metastatic primary CRC (MET-) and primary CRC that resulted in metastasis (MET+) showed an immunosuppressive phenotype, with elevated Foxp3 (P<0.05) and reduced numbers of CD8 (P<0.05) cells in the stroma of MET+ compared with MET- samples. CONCLUSION: By combining immunohistochemistry with DPRIA, we demonstrate a potential metastatic phenotype in CRC. Our study accelerates wider acceptance and use of automated systems as an adjunct to traditional histopathological techniques.

Physical activity levels in female breast cancer patients and survivors in Ekurhuleni, South Africa.

Background: By using complementary therapies, such as exercise rehabilitation during and after cancer treatment, breast cancer patients and survivors can improve their quality of life and overall health while also negating the deleterious effects of breast cancer and its treatment. Objectives: The aim of this study was to determine the physical activity levels of female breast cancer patients and survivors in Ekurhuleni, South Africa. Methods: The International Global Physical Activity Questionnaire (2002) determined participants' physical activity levels during work, travel and leisure. The questionnaire was disseminated to medical facilities in hard copy format and online via the Google Forms platform. Statistics were computed using the Statistical Package for Social Science (SPSS) with the level of significance set at 95% (p < 0.05). Results: One hundred female breast cancer patients and survivors with a mean age of 55 years from Ekurhuleni, South Africa participated in this study. The findings reflected that most participants (59%) were meeting the American College of Sports Medicine's physical activity guidelines when considering activity done during work, travel and leisure. No significant difference was seen in physical activity participation between breast cancer patients and breast cancer survivors, or those attending private and public facilities. Conclusion: For the breast cancer patient, physical activity and exercise may be a promising and effective adjuvant treatment both during and after anticancer therapies, improving quality of life, playing a role in increasing treatment tolerance, mitigating a range of symptoms and side effects brought on by cancer diagnosis and treatments and enhancing outcomes.

United we thrive: friendship and subsequent physical, behavioural and psychosocial health in older adults (an outcome-wide longitudinal approach).

AIMS: Three factors converge to underscore the heightened importance of evaluating the potential health/well-being effects of friendships in older adulthood. First, policymakers, scientists, and the public alike are recognizing the importance of social relationships for health/well-being and creating national policies to promote social connection. Second, many populations are rapidly aging throughout the world. Third, we currently face what some call a 'friendship recession'. Although, growing research documents associations between friendship with better health and well-being, friendship can also have a 'dark side' and can potentially promote negative outcomes. To better capture friendship's potential heterogeneous effects, we took an outcome-wide analytic approach. METHODS: We analysed data from 12,998 participants in the Health and Retirement Study (HRS) - a prospective and nationally representative cohort of U.S. adults aged >50, and, evaluated if increases in friendship strength (between t0; 2006/2008 and t1; 2010/2012) were associated with better health/well-being across 35 outcomes (in t2; 2014/2016). To assess friendship strength, we leveraged all available friendship items in HRS and created a composite 'friendship score' that assessed the following three domains: (1) friendship network size, (2) friendship network contact frequency and (3) friendship network quality. RESULTS: Stronger friendships were associated with better outcomes on some indicators of physical health (e.g. reduced risk of mortality), health behaviours (e.g. increased physical activity) and nearly all psychosocial indicators (e.g. higher positive affect and mastery, as well as lower negative affect and risk of depression). Friendship was also associated with increased likelihood of smoking and heavy drinking (although the latter association with heavy drinking did not reach conventional levels of statistical significance). CONCLUSIONS: Our findings indicate that stronger friendships can have a dual impact on health and well-being. While stronger friendships appear to mainly promote a range of health and well-being outcomes, stronger friendships might also promote negative outcomes. Additional research is needed, and any future friendship interventions and policies that aim to enhance outcomes should focus on how to amplify positive outcomes while mitigating harmful ones.

Elevated plasma matrix metalloproteinases associate with Mycobacterium tuberculosis blood stream infection and mortality in HIV-associated tuberculosis.

Mortality from HIV-associated tuberculosis (HIV-TB) is high, particularly among hospitalised patients. In 433 people living with HIV admitted to hospital with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality and Mycobacterium tuberculosis (Mtb) blood stream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10 and procollagen III N-terminal propeptide (PIIINP) associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.

Defining the Optimal Treatment Strategy in Patients With Uterine Serous Carcinoma.

AIMS: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with high rates of relapse and death. As adjuvant therapy might be beneficial in early-stage disease, the impact of standard complete surgical staging is questioned. Therefore, we wanted to explore the optimal treatment strategy for women diagnosed with USC. MATERIALS AND METHODS: A retrospective multicentre study of women diagnosed with primary USC in the UK and the Netherlands. Treatment strategy in relation to overall survival and progression-free survival was recorded and evaluated with Kaplan-Meier and Cox regression analysis. Furthermore, primary surgical staging and/or adjuvant treatment in relation to patterns of recurrence were evaluated. RESULTS: In total, 272 women with a median age of 70 years were included. Most patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage I disease (44%). Overall, 48% of patients developed recurrent disease, most (58%) with a distant component. Women treated with chemotherapy showed significantly better overall survival (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P = 0.005) and progression-free survival (hazard ratio 0.48, 95% confidence interval 0.28-0.80; P = 0.04) in multivariable analysis. Furthermore, even in surgically staged women with FIGO stage IA disease, a high recurrence rate of 42% was seen. CONCLUSION: Women with USC who received adjuvant chemotherapy showed better survival rates compared with those who received other or no adjuvant treatment. The benefit of adjuvant chemotherapy was observed across all tumour stages, including surgically staged FIGO stage IA. These data question the role of surgical staging in the absence of macroscopic disease in USC.

The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models.

BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy. METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations. RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib. CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.

Germline BRCA1 mutations increase prostate cancer risk.

BACKGROUND: Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set. METHODS: We screened 913 cases aged 36­86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases. RESULTS: We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45%; three of the mutation carriers were affected at age 65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ~3.75-fold, (95% confidence interval 1.02­9.6) translating to a 8.6% cumulative risk by age 65. CONCLUSION: This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments.