Abstract Background This paper presents the latest international descriptive epidemiological data for invasive breast cancer amongst women, including incidence, survival and mortality, as well as ...information on mammographic screening programmes. Results Almost 1.4 million women were diagnosed with breast cancer worldwide in 2008 and approximately 459,000 deaths were recorded. Incidence rates were much higher in more developed countries compared to less developed countries (71.7/100,000 and 29.3/100,000 respectively, adjusted to the World 2000 Standard Population) whereas the corresponding mortality rates were 17.1/100,000 and 11.8/100,000. Five-year relative survival estimates range from 12% in parts of Africa to almost 90% in the United States, Australia and Canada, with the differential linked to a combination of early detection, access to treatment services and cultural barriers. Observed improvements in breast cancer survival in more developed parts of the world over recent decades have been attributed to the introduction of population-based screening using mammography and the systemic use of adjuvant therapies. Conclusion The future worldwide breast cancer burden will be strongly influenced by large predicted rises in incidence throughout parts of Asia due to an increasingly “westernised” lifestyle. Efforts are underway to reduce the global disparities in survival for women with breast cancer using cost-effective interventions.
Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens ...of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM) with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.
Surgery is associated with a post-operative stress response, changes in cardiopulmonary reserve, and metabolic demand. Here recovery after abdominal aortic aneurysm repair is investigated using ...cardiopulmonary exercise testing and patient-reported questionnaires.
Patients undergoing open (n = 21) or endovascular (n = 21) repair undertook cardiopulmonary exercise tests, activity, and health score questionnaires pre-operatively and, 8 and 16 weeks, post-operatively. Oxygen uptake and ventilatory parameters were measured, and routine blood tests were undertaken.
Recovery was characterised by falls in anaerobic threshold, peak oxygen uptake, and oxygen pulse at 8 weeks which appeared to be associated with operative severity; the fall in peak oxygen uptake was greater following open vs. endovascular repair (3.5 vs. 1.6 ml
.
kg
−1.
min
−1
) and anaerobic threshold showed a similar tendency (3.1 vs. 1.7 ml
.
kg
−1.
min
−1
). In the smaller number of patients re-tested these changes resolved by 16 weeks. Reported health and activity did not change.
Aortic repair is associated with falls in the anaerobic threshold, peak oxygen uptake, and oxygen pulse of a magnitude that reflects operative severity and appears to resolve by 16 weeks. Thus, post-operatively patients may be at higher risk of further metabolic insult e.g. infection. This further characterises physiological recovery from aortic surgery and may assist in defining post-operative shielding time.
IMPLICATIONS FOR REHABILITATION
Abdominal aortic aneurysm repair is a life-saving operation, the outcome from which is influenced by pre-operative cardiopulmonary reserve; individuals with poor reserve being at greater risk of peri-operative complications and death. However, for this operation, the physiological impact of surgery has not been studied.
In a relatively small sample, this study suggests that AAA repair is associated with a significant decline in cardiopulmonary reserve when measured 8 weeks post-operatively and appears to recover by 16 weeks. Moreover, the impact may be greater in endovascular vs. open repair.
Inflammation is an important feature of atherosclerotic lesions, and increased production of the acute-phase reactant, C-reactive protein (CRP), is associated with a poor prognosis in severe unstable ...angina. We have investigated the existence and possible significance of the acute-phase responses of CRP and another sensitive reactant, serum amyloid A protein (SAA), in patients with unstable or stable angina.
We used new ultrasensitive immunoassays to measure CRP and SAA concentrations in plasma from 2121 outpatients with angina (1030 unstable, 743 stable, the rest atypical) enrolled in the European Concerted Action on Thrombosis and Disabilities (SCAT) Angina Pectoris Study. All patients underwent coronary angiography and extensive clinical and laboratory assessment at study entry, and were then followed up for 2 years. All suspected coronary events during follow-up were reviewed by an independent endpoint committee.
75 individuals (41 with unstable, 29 with stable, and 5 with atypical angina) had a coronary event during follow-up. Concentrations of CRP at study entry were associated with coronary events in patients with stable or unstable angina: there was about a two-fold increase in the risk of a coronary event in patients whose CRP concentration was in the fifth quintile (>3·6 mg/L), compared with the first four quintiles. A third of the events occurred among patients who had a CRP concentration of more than 3·6 mg/L CRP concentrations were positively correlated with age, smoking, body-mass index, triglycerides, extent of coronary stenosis, history of myocardial infarction, and lower ejection fraction. By contrast, concentrations of SAA were not associated with risk of a coronary event.
We found that raised circulating concentrations of CRP are predictors of coronary events in patients with stable or unstable angina. The modest acute-phase responses of CRP were probably not the result of myocardial necrosis. Whatever the underlying mechanisms, the sensitive measurement of CRP as a prognostic marker may be useful in the management of coronary heart diease.
Hydralazine strongly suppresses the toxicity of acrolein, a reactive aldehyde that contributes to numerous health disorders.
At least two mechanisms may underlie the cytoprotection, both of which ...involve the nucleophilic hydrazine possessed by hydralazine.
Under the simplest scenario, hydralazine directly scavenges free acrolein, decreasing intracellular acrolein availability
and thereby suppressing macromolecular adduction. In a second âadduct-trappingâ mechanism, the drug forms hydrazones with
acrolein-derived Michael adducts in cell proteins, preventing secondary reactions of adducted proteins that may trigger cell
death. To identify the most important mechanism, we explored these two pathways in mouse hepatocytes poisoned with the acrolein
precursor allyl alcohol. Intense concentration-dependent adduct-trapping in cell proteins accompanied the suppression of toxicity
by hydralazine. However, protective concentrations of hydralazine did not alter extracellular free acrolein levels, cellular
glutathione loss, or protein carbonylation, suggesting that the cytoprotection is not due to minimization of intracellular
acrolein availability. To explore ways whereby adduct-trapping might confer cytoprotection, the effect of hydralazine on acrolein-induced
protein cross-linking was examined. Using bovine pancreas ribonuclease A as a model protein, acrolein caused rapid time- and
concentration-dependent cross-linking, with dimerized protein detectable within 45 min of commencing protein modification.
Lysine adduction in monomeric protein preceded the appearance of oligomers, whereas reductive methylation of protein amine
groups abolished both adduction and oligomerization. Hydralazine inhibited cross-linking if added 30 min after commencing
acrolein exposure but was ineffective if added after a 90-min delay. Adduct-trapping closely accompanied the inhibition of
cross-linking by hydralazine. These findings suggest that cross-link blocking may contribute to hydralazine cytoprotection.
In recent years unmanned aerial vehicles (UAVs) have become smaller, cheaper, and more efficient, enabling the use of multiple autonomous drones where previously a single, human-operated drone would ...have been used. This likely includes crisis response and search and rescue missions. These systems will need a method of navigating unknown and dynamic environments. Typically, this would require an incremental heuristic search algorithm, however, these algorithms become increasingly computationally and memory intensive as the environment size increases. This paper used two different Swarm Intelligence (SI) algorithms: Particle Swarm Optimisation and Reynolds flocking to propose an overall system for controlling and navigating groups of autonomous drones through unknown and dynamic environments. This paper proposes Particle Swarm Optimisation Pathfinding (PSOP): a dynamic, cooperative algorithm; and, Drone Flock Control (DFC): a modular model for controlling systems of agents, in 3D environments, such that collisions are minimised. Using the Unity game engine, a real-time application, simulation environment, and data collection apparatus were developed and the performances of DFC-controlled drones—navigating with either the PSOP algorithm or a D* Lite implementation—were compared. The simulations do not consider UAV dynamics. The drones were tasked with navigating to a given target position in environments of varying size and quantitative data on pathfinding performance, computational and memory performance, and usability were collected. Using this data, the advantages of PSO-based pathfinding were demonstrated. PSOP was shown to be more memory efficient, more successful in the creation of high quality, accurate paths, more usable and as computationally efficient as a typical incremental heuristic search algorithm when used as part of a SI-based drone control model. This study demonstrated the capabilities of SI approaches as a means of controlling multi-agent UAV systems in a simple simulation environment. Future research may look to apply the DFC model, with the PSOP algorithm, to more advanced simulations which considered environment factors like atmospheric pressure and turbulence, or to real-world UAVs in a controlled environment.
Acrolein is a highly reactive alpha,beta-unsaturated aldehyde that readily alkylates nucleophilic centers in cell macromolecules. Typically, such reactions proceed via Michael addition chemistry, ...forming adducts that retain an electrophilic carbonyl group. Since these species participate in secondary deleterious reactions, we hypothesize that inactivation of carbonyl adducts may attenuate acrolein toxicity. Indeed, we recently established that the nucleophilic antihypertensive drug hydralazine readily "traps" acrolein adducts in cell proteins and strongly suppresses acrolein-mediated toxicity in isolated hepatocytes. This work sought to determine whether hydralazine prevents the in vivo hepatotoxicity of the acrolein precursor allyl alcohol in whole mice and whether adduct trapping accompanies any such hepatoprotection. Mice received allyl alcohol alone or in conjunction with several doses of hydralazine. Four hours later, mice were sacrificed to allow for the determination of liver enzymes in plasma as markers of hepatic injury, whereas livers were assessed for glutathione and hydralazine-stabilized protein adducts. Hydralazine afforded strong, dose-dependent protection against the increases in plasma marker enzymes but not the hepatic glutathione depletion produced by allyl alcohol. Western blotting revealed intense, dose-dependent adduct trapping by hydralazine in numerous liver proteins over a broad 26- to 200-kDA mass range. In keeping with these findings, immunohistochemical analysis of liver slices indicated diffuse, extranuclear adduct trapping by hydralazine that was uniformly distributed across the liver lobule, with partial localization in parenchymal cell membranes. These findings concur with our hypothesis that hydralazine readily inactivates reactive carbonyl-retaining protein adducts formed by acrolein, thereby preventing secondary reactions that trigger cellular death.
To validate a real-time PCR test for the diagnosis of Glässer's disease, a major pig disease caused by Haemophilus parasuis. The specificity of a real-time PCR amplifying the inf B gene was validated ...with 68 H. parasuis isolates and 36 strains of closely related species. As well, 239 samples of DNA from tissues and fluids of 16 experimentally challenged animals were tested with the real-time PCR, and the results were compared with culture and a conventional PCR. The real-time PCR produced significantly more positive results than the conventional PCR (165 vs 86). The sensitivity of the real-time PCR combined with high specificity makes it a very valuable tool for the diagnosis of Glässer's disease. This new method will improve the ability of laboratories to diagnose Glässer's disease, especially in laboratories where the culture method for H. parasuis is not optimal.
The generation of antitumour immunity depends on the nature of dendritic cell (DC)-tumour interactions. These have been studied mostly by using in vitro-derived DC which may not reflect the natural ...biology of DC in vivo. In breast cancer, only one report has compared blood DC at different stages and no longitudinal evaluation has been performed. Here we conducted three cross-sectional and one one-year longitudinal assessments of blood DC in patients with early (stage I/II, n=137) and advanced (stage IV, n=36) disease compared to healthy controls (n=66). Patients with advanced disease exhibit markedly reduced blood DC counts at diagnosis. Patients with early disease show minimally reduced counts at diagnosis but a prolonged period (1 year) of marked DC suppression after tumour resection. While differing in frequency, DC from both patients with early and advanced disease exhibit reduced expression of CD86 and HLA-DR and decreased immunostimulatory capacities. Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming. We conclude that although circulating DC are compromised by loco-regional and systemic breast cancer, they respond vigorously to ex vivo conditioning, thus enhancing their immunostimulatory capacity and potential for immunotherapy.
The cytochrome P450 monooxygenase CYP101B1 from Novosphingobium aromaticivorans selectively hydroxylated methylene C-H bonds in cycloalkyl rings. Cycloketones and cycloalkyl esters containing C6, C8, ...C10 and C12 rings were oxidised with high selectively on the opposite side of the ring to the carbonyl substituent. Cyclodecanone was oxidised to oxabicycloundecanol derivatives in equilibrium with the hydroxycyclodecanones.
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