Morphological stability for in silico models of avascular tumors

The landscape of computational modeling in Cancer Systems Biology is diverse, offering a spectrum of models and frameworks, each with its own trade-offs and advantages. Ideally, models are meant to be useful in refining hypotheses, to sharpen experimental procedures and, in the longer run, even for applications in personalized medicine. One of the greatest challenges is to balance model realism and detail with experimental data to eventually produce useful data-driven models. We contribute to this quest by developing a transparent, highly parsimonious, first principle in silico model of a growing avascular tumor. We initially formulate the physiological considerations and the specific model within a stochastic cell-based framework. We next formulate a corresponding mean-field model using partial differential equations which is amenable to mathematical analysis. Despite a few notable differences between the two models, we are in this way able to successfully detail the impact of all parameters in the stability of the growth process and on the eventual tumor fate of the stochastic model. This facilitates the deduction of Bayesian priors for a given situation, but also provides important insights into the underlying mechanism of tumor growth and progression. Although the resulting model framework is relatively simple and transparent, it can still reproduce the full range of known emergent behavior. We identify a novel model instability arising from nutrient starvation and we also discuss additional insight concerning possible model additions and the effects of those. Thanks to the framework's flexibility, such additions can be readily included whenever the relevant data become available.Comment: 27 pages, 9 figure

The genus Metretopus (Ephemeroptera, Siphlonuridae) in Fennoscandia - identification, faunistics and natural history

Morphological characters are presented for the separation of nymphs and winged stages of Metretopus alter Bengtsson, 1930, from those of M. borealis (Eaton, 1871) based on Fennoscandian material. The known records of both species in Finland and Sweden are mapped, and a recent record of M. alter from Norway is given. Habitat preferences and phenological data of both species are presented. The documented wide distribution of M. alter in Fennoscandia indicates that it previously has been confused with M. borealis

Short-term and one-year outcome of infective endocarditis in adult patients treated in a Finnish teaching hospital during 1980–2004

<p>Abstract</p> <p>Background</p> <p>Previous studies on factors predicting the prognosis of infective endocarditis have given somewhat conflicting results. Our aim was to define the factors predicting the outcome of patients treated in a Finnish teaching hospital.</p> <p>Methods</p> <p>A total of 326 episodes of infective endocarditis in 303 patients treated during 1980–2004 were evaluated for short-term and 1-year outcome and complications.</p> <p>Results</p> <p>Infection of 2 native valves and the occurrence of neurological complications, peripheral emboli, or heart failure significantly predicted both in-hospital and 1-year mortality, while age ≥65 years or the presence of a major criterion or vegetation on echocardiography predicted death within 1 year. A significant trend was observed between the level of serum C-reactive protein (CRP) on admission and both the short-term and 1-year outcome. In the patients who had CRP values ≥100 mg/l on admission, the hazard ratio for in-hospital death was 2.9-fold and the hazard ratio for 1-year death was 3.9-fold as compared to those with lower CRP values. Male sex and age < 64 years significantly predicted a need for both in-hospital and 1-year surgery, as did the development of heart failure or the presence of a major criterion or vegetation on echocardiography. Peripheral emboli were associated with a need for in-hospital surgery, while <it>Streptococcus pneumoniae </it>as the causative agent or infection of 2 native valves predicted a need for surgery within 1 year from admission.</p> <p>Conclusion</p> <p>Some of the factors (e.g. heart failure, neurological complications, peripheral emboli) predicting a poor prognosis and/or need for surgery were the same observed in previous studies. A new finding was that high CRP values (≥100 mg/l) on admission significantly predicted both short-term and 1-year mortality.</p

Cardiovascular magnetic resonance of the myocardium at risk in acute reperfused myocardial infarction: comparison of T2-weighted imaging versus the circumferential endocardial extent of late gadolinium enhancement with transmural projection

<p>Abstract</p> <p>Background</p> <p>In the situation of acute coronary occlusion, the myocardium supplied by the occluded vessel is subject to ischemia and is referred to as the myocardium at risk (MaR). Single photon emission computed tomography has previously been used for quantitative assessment of the MaR. It is, however, associated with considerable logistic challenges for employment in clinical routine. Recently, T2-weighted cardiovascular magnetic resonance (CMR) has been introduced as a new method for assessing MaR several days after the acute event. Furthermore, it has been suggested that the endocardial extent of infarction as assessed by late gadolinium enhanced (LGE) CMR can also be used to quantify the MaR. Hence, we sought to assess the ability of endocardial extent of infarction by LGE CMR to predict MaR as compared to T2-weighted imaging.</p> <p>Methods</p> <p>Thirty-seven patients with early reperfused first-time ST-segment elevation myocardial infarction underwent CMR imaging within the first week after percutaneous coronary intervention. The ability of endocardial extent of infarction by LGE CMR to assess MaR was evaluated using T2-weighted imaging as the reference method.</p> <p>Results</p> <p>MaR determined with T2-weighted imaging (34 ± 10%) was significantly higher (p < 0.001) compared to the MaR determined with endocardial extent of infarction (23 ± 12%). There was a weak correlation between the two methods (r²= 0.17, p = 0.002) with a bias of -11 ± 12%. Myocardial salvage determined with T2-weighted imaging (58 ± 22%) was significantly higher (p < 0.001) compared to myocardial salvage determined with endocardial extent of infarction (45 ± 23%). No MaR could be determined by endocardial extent of infarction in two patients with aborted myocardial infarction.</p> <p>Conclusions</p> <p>This study demonstrated that the endocardial extent of infarction as assessed by LGE CMR underestimates MaR in comparison to T2-weighted imaging, especially in patients with early reperfusion and aborted myocardial infarction.</p

Infarct evolution in man studied in patients with first-time coronary occlusion in comparison to different species - implications for assessment of myocardial salvage

<p>Abstract</p> <p>Background</p> <p>The time course of infarct evolution, i.e. how fast myocardial infarction (MI) develops during coronary artery occlusion, is well known for several species, whereas no direct evidence exists on the evolution of MI size normalized to myocardium at risk (MaR) in man. Despite the lack of direct evidence, current literature often refers to the "golden hour" as the time during which myocardial salvage can be accomplished by reperfusion therapy. Therefore, the aim of the present study was to investigate how duration of myocardial ischemia affects infarct evolution in man in relation to previous animal data. Consecutive patients with clinical signs of acute myocardial ischemia were screened and considered for enrollment. Particular care was taken to assure uniformity of the patients enrolled with regard to old MI, success of revascularization, collateral flow, release of biochemical markers prior to intervention etc. Sixteen patients were ultimately included in the study. Myocardium at risk was assessed acutely by acute Myocardial Perfusion Single photon emission computed tomography (MPS) and by T2 imaging (T2-STIR) cardiovascular magnetic resonance (CMR) after one week in 10 of the 16 patients. Infarct size was measured by late gadolinium enhancement (LGE) at one week.</p> <p>Results</p> <p>The time to reach 50% MI of the MaR (T₅₀) was significantly shorter in pigs (37 min), rats (41 min) and dogs (181 min) compared to humans (288 min). There was no significant difference in T₅₀when using MPS compared to T2-STIR (p = 0.53) for assessment of MaR (288 ± 23 min vs 310 ± 22 min, T₅₀± standard error). The transmural extent of MI increased progressively as the duration of ischemia increased (R²= 0.56, p < 0.001).</p> <p>Conclusion</p> <p>This is the first study to provide direct evidence of the time course of acute myocardial infarct evolution in relation to MaR in man with first-time MI. Infarct evolution in man is significantly slower than in pigs, rats and dogs. Furthermore, infarct evolution assessments in man are similar when using MPS acutely and T2-STIR one week later for determination of MaR, which significantly facilitates future clinical trials of cardioprotective therapies in acute coronary syndrome by the use of CMR.</p

Increased B-Type Natriuretic Peptide Concentration Is Associated with Reduced Coronary Vasoreactivity in Patients with Dilated Cardiomyopathy but Not in Healthy Young Subjects

Background/Aims. Natriuretic peptides are associated with the cardiovascular disease risk under a range of different circumstances. However, less is known about whether this association is found also in young healthy subjects. Methods. 9 patients with dilated cardiomyopathy and 26 healthy young subjects were studied. The myocardial blood flow measurements were performed basally and during adenosine infusion using PET. Results. S-proBNP concentrations were significantly higher (2153 ± 1964 versus 28 ± 17 ng/L, P = .000002) and adenosine-stimulated flow lower (1.6 ± 0.8 versus 3.6 ± 1.1 mL·g−1·min−1, P = .00001) in patients with dilated cardiomyopathy when compared to healthy subjects. S-proBNP concentration was inversely associated with adenosine stimulated flow in patients with dilated cardiomyopathy (r = −0.75, P = .019) but not in healthy subjects (r = −0.06, P = .84). Conclusions. Natriuretic peptides are inversely associated with coronary vasoreactivity in patients with dilated cardiomyopathy but not in healthy young subjects. Since reduced coronary vasoreactivity seems to be one of the earliest abnormalities in the development of coronary artery disease, this might indicate that natriuretic peptides are not predictor of cardiovascular disease risk in healthy young subjects