Micro Regional Heterogeneity of ⁶⁴Cu-ATSM and ¹⁸F-FDG Uptake in Canine Soft Tissue Sarcomas: Relation to Cell Proliferation, Hypoxia and Glycolysis

Tumour microenvironment heterogeneity is believed to play a key role in cancer progression and therapy resistance. However, little is known about micro regional distribution of hypoxia, glycolysis and proliferation in spontaneous solid tumours. The overall aim was simultaneous investigation of micro regional heterogeneity of 64Cu-ATSM (hypoxia) and 18F-FDG (glycolysis) uptake and correlation to endogenous markers of hypoxia, glycolysis, proliferation and angiogenesis to better therapeutically target aggressive tumour regions and prognosticate outcome.Exploiting the different half-lives of 64Cu-ATSM (13 h) and 18F-FDG (2 h) enabled simultaneous investigation of micro regional distribution of hypoxia and glycolysis in 145 tumour pieces from four spontaneous canine soft tissue sarcomas. Pairwise measurements of radioactivity and gene expression of endogenous markers of hypoxia (HIF-1α, CAIX), glycolysis (HK2, GLUT1 and GLUT3), proliferation (Ki-67) and angiogenesis (VEGFA and TF) were performed. Dual tracer autoradiography was compared with Ki-67 immunohistochemistry.Micro regional heterogeneity in hypoxia and glycolysis within and between tumour sections of each tumour piece was observed. The spatial distribution of 64Cu-ATSM and 18F-FDG was rather similar within each tumour section as reflected in moderate positive significant correlations between the two tracers (ρ = 0.3920-0.7807; p = 0.0180 -<0.0001) based on pixel-to-pixel comparisons of autoradiographies and gamma counting of tumour pieces. 64Cu-ATSM and 18F-FDG correlated positively with gene expression of GLUT1 and GLUT3, but negatively with HIF-1α and CAIX. Significant positive correlations were seen between Ki-67 gene expression and 64Cu-ATSM (ρ = 0.5578, p = 0.0004) and 18F-FDG (ρ = 0.4629-0.7001, p = 0.0001-0.0151). Ki-67 gene expression more consistently correlated with 18F-FDG than with 64Cu-ATSM.Micro regional heterogeneity of hypoxia and glycolysis was documented in spontaneous canine soft tissue sarcomas. 64Cu-ATSM and 18F-FDG uptakes and distributions showed significant moderate correlations at the micro regional level indicating overlapping, yet different information from the tracers.18F-FDG better reflected cell proliferation as measured by Ki-67 gene expression than 64Cu-ATSM

Coronary artery disease-associated genetic variants and biomarkers of inflammation

Introduction: Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers. Methods: We genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers. Results: The minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]). The inflammatory markers tested showed no association with the remaining 44 SNPs or with the genetic risk score. Conclusions: In stable CAD patients, the risk allele of a common CAD-associated marker at the TOMM40/APOE locus was associated with lower hsCRP levels. No other genetic variants or the combined effect of all variants were associated with the five inflammatory biomarkers

Veterinary decision making in relation to metritis - a qualitative approach to understand the background for variation and bias in veterinary medical records

<p>Abstract</p> <p>Background</p> <p>Results of analyses based on veterinary records of animal disease may be prone to variation and bias, because data collection for these registers relies on different observers in different settings as well as different treatment criteria. Understanding the human influence on data collection and the decisions related to this process may help veterinary and agricultural scientists motivate observers (veterinarians and farmers) to work more systematically, which may improve data quality. This study investigates qualitative relations between two types of records: 1) 'diagnostic data' as recordings of metritis scores and 2) 'intervention data' as recordings of medical treatment for metritis and the potential influence on quality of the data.</p> <p>Methods</p> <p>The study is based on observations in veterinary dairy practice combined with semi-structured research interviews of veterinarians working within a herd health concept where metritis diagnosis was described in detail. The observations and interviews were analysed by qualitative research methods to describe differences in the veterinarians' perceptions of metritis diagnosis (scores) and their own decisions related to diagnosis, treatment, and recording.</p> <p>Results</p> <p>The analysis demonstrates how data quality can be affected during the diagnostic procedures, as interaction occurs between diagnostics and decisions about medical treatments. Important findings were when scores lacked consistency within and between observers (variation) and when scores were adjusted to the treatment decision already made by the veterinarian (bias). The study further demonstrates that veterinarians made their decisions at 3 different levels of focus (cow, farm, population). Data quality was influenced by the veterinarians' perceptions of collection procedures, decision making and their different motivations to collect data systematically.</p> <p>Conclusion</p> <p>Both variation and bias were introduced into the data because of veterinarians' different perceptions of and motivations for decision making. Acknowledgement of these findings by researchers, educational institutions and veterinarians in practice may stimulate an effort to improve the quality of field data, as well as raise awareness about the importance of including knowledge about human perceptions when interpreting studies based on field data. Both recognitions may increase the usefulness of both within-herd and between-herd epidemiological analyses.</p

Managing ethnic conflict : the menu of institutional engineering

The debate on institutional engineering offers options to manage ethnic and other conflicts. This contribution systematically assesses the logic of these institutional designs and the empirical evidence on their functioning. Generally, institutions can work on ethnic conflict by either accommodating (“consociationalists”) or denying (“integrationists”) ethnicity in politics. Looking at individual and combined institutions (e.g. state structure, electoral system, forms of government), the literature review finds that most designs are theoretically ambivalent and that empirical evidence on their effectiveness is mostly inconclusive. The following questions remain open: a) Is politicized ethnicity really a conflict risk? b) What impact does the whole “menu” (not just single institutions) have? and c) How are effects conditioned by the exact nature of conflict risks

Validity of Thermal Ramping Assays Used to Assess Thermal Tolerance in Arthropods

Proper assessment of environmental resistance of animals is critical for the ability of researchers to understand how variation in environmental conditions influence population and species abundance. This is also the case for studies of upper thermal limits in insects, where researchers studying animals under laboratory conditions must select appropriate methodology on which conclusions can be drawn. Ideally these methods should precisely estimate the trait of interest and also be biological meaningful. In an attempt to develop such tests it has been proposed that thermal ramping assays are useful assays for small insects because they incorporate an ecologically relevant gradual temperature change. However, recent model-based papers have suggested that estimates of thermal resistance may be strongly confounded by simultaneous starvation and dehydration stress. In the present study we empirically test these model predictions using two sets of independent experiments. We clearly demonstrate that results from ramping assays of small insects (Drosophila melanogaster) are not compromised by starvation- or dehydration-stress. Firstly we show that the mild disturbance of water and energy balance of D. melanogaster experienced during the ramping tests does not confound heat tolerance estimates. Secondly we show that flies pre-exposed to starvation and dehydration have “normal” heat tolerance and that resistance to heat stress is independent of the energetic and water status of the flies. On the basis of our results we discuss the assumptions used in recent model papers and present arguments as to why the ramping assay is both a valid and ecologically relevant way to measure thermal resistance in insects

Financing of International Collective Action for Epidemic and Pandemic Preparedness.

The global pandemic response has typically followed cycles of panic followed by neglect. We are now, once again, in a phase of neglect, leaving the world highly vulnerable to massive loss of life and economic shocks from natural or human-made epidemics and pandemics. Quantifying the size of the losses caused by large-scale outbreaks is challenging because the epidemiological and economic research in this field is still at an early stage. Research on the 1918 influenza H1N1 pandemic and recent epidemics and pandemics has shown a range of estimated losses (panel).1; 2; 3; 4; 5; 6 ; 7 A limitation in assessing the economic costs of outbreaks is that they only capture the impact on income. Fan and colleagues8 recently addressed this limitation by estimating the “inclusive” cost of pandemics: the sum of the cost in lost income and a dollar valuation of the cost of early death. They found that for Ebola and severe acute respiratory syndrome (SARS), the true (“inclusive”) costs are two to three times the income loss. For extremely serious pandemics such as that of influenza in 1918, the inclusive costs are over five times income loss. The inclusive costs of the next severe influenza pandemic could be US$570 billion each year or 0·7$1 billion over 5 years, is developing vaccines against known emerging infectious diseases as well as platforms for rapid development of vaccines against outbreaks of unknown origin. The WHO R&D Blueprint for Action to Prevent Epidemics12 is a new mechanism for coordinating and prioritising the development of drugs and diagnostics for emerging infectious diseases. Consolidating and enhancing donor support for these new initiatives would be an efficient way to channel resources aimed at improving global outbreak preparedness and response. Crucial components of the global and regional system for outbreak control include surge capacity (eg, the ability to urgently deploy human resources); providing technical guidance to countries in the event of an outbreak; and establishing a coordinated, interlinked global, regional, and national surveillance system. These activities are the remit of several essential WHO financing envelopes that all face major funding shortfalls. The Contingency Fund for Emergencies finances surge outbreak response for up to 3 months. The fund has a capitalisation target of $100 million of flexible voluntary contributions, which needs to be replenished with about$25–50 million annually, depending on the extent of the outbreak in any given year. However, as of April 30, 2017, only $37·65 million had been contributed, with an additional$4 million in pledges.13 The WHO Health Emergencies and Health Systems Preparedness Programmes face an annual shortfall of $225 million in funding their epidemic and pandemic prevention and control activities.14 Previous health emergencies have shown that it can take time to organise global collective action and provide financing to the national and local level. In such situations, a global mechanism should offer a rapid injection of liquidity to affected countries. The World Bank\u27s Pandemic Emergency Financing Facility (PEF) is a proposed global insurance mechanism for pandemic emergencies.15 It aims to provide surge funding for response efforts to help respond to rare, high-burden disease outbreaks, preventing them from becoming more deadly and costly pandemics. The PEF currently proposes a coverage of$500 million for the insurance window; increasing the current coverage will require additional donor commitments. In addition, the PEF has a $50–100 million replenishable cash window. As the world\u27s health ministers meet this month for the World Health Assembly, we propose five key ways to help prevent mortality and economic shocks from disease outbreaks. First, to accelerate development of new technologies to control outbreaks, donors should expand their financing for CEPI and support the WHO R&D Blueprint for Action to Prevent Epidemics. Second, funding gaps in the WHO Contingency Fund for Emergencies and the WHO Health Emergencies Programme should be urgently filled and the PEF should be fully financed. Third, all nations should support their own and other countries\u27 national preparedness efforts, including committing to the JEE process. Fourth, we believe it would be valuable to create and maintain a regional and country-level pandemic risk and preparedness index. This index could potentially be used as a way to review preparedness in International Monetary Fund article IV consultations (regular country reports by staff to its Board). Finally, we call for a new global effort to develop long-term national, regional, and global investment plans to create a world secure from the threat of devastation from outbreaks. This article summarises the recommendations of a workshop held at the National Academy of Medicine, Washington, DC, USA, co-hosted by the Center for Policy Impact in Global Health at Duke University, Durham, NC, USA and the Coalition for Epidemic Preparedness Innovations, Oslo, Norway. Participants\u27 travel and accommodation were supported by the Center for Policy Impact in Global Health. BO is a consultant to Metabiota, a private company engaged in infectious disease risk modelling and analytical services. In this capacity, he has led the development of an index measuring national capacity to respond to epidemic and pandemic disease outbreaks

Molecular detection (k-ras) of exfoliated tumour cells in the pelvis is a prognostic factor after resection of rectal cancer?

<p>Abstract</p> <p>Background</p> <p>After total mesorectal excision (TME) for rectal cancer around 10% of patients develops local recurrences within the pelvis. One reason for recurrence might be spillage of cancer cells during surgery. This pilot study was conducted to investigate the incidence of remnant cancer cells in pelvic lavage after resection of rectal cancer. DNA from cells obtained by lavage, were analysed by denaturing capillary electrophoresis with respect to mutations in hotspots of the <it>k-ras </it>gene, which are frequently mutated in colorectal cancer.</p> <p>Results</p> <p>Of the 237 rectal cancer patients analyzed, 19 had positive lavage fluid. There was a significant survival difference (p = 0.006) between patients with <it>k-ras </it>positive and negative lavage fluid.</p> <p>Conclusion</p> <p>Patients with <it>k-ras </it>mutated cells in the lavage immediately after surgery have a reduced life expectation. Detection of exfoliated cells in the abdominal cavity may be a useful diagnostic tool to improve the staging and eventually characterize patients who may benefit from aggressive multimodal treatment of rectal cancer.</p