A Mathematical Framework for Modelling the Metastatic Spread of Cancer

Cancer is a complex disease that starts with mutations of key genes in one cell or a small group of cells at a primary site in the body. If these cancer cells continue to grow successfully and, at some later stage, invade the surrounding tissue and acquire a vascular network, they can spread to distant secondary sites in the body. This process, known as metastatic spread, is responsible for around 90% of deaths from cancer and is one of the so-called hallmarks of cancer. To shed light on the metastatic process, we present a mathematical modelling framework that captures for the first time the interconnected processes of invasion and metastatic spread of individual cancer cells in a spatially explicit manner—a multigrid, hybrid, individual-based approach. This framework accounts for the spatiotemporal evolution of mesenchymal- and epithelial-like cancer cells, membrane-type-1 matrix metalloproteinase (MT1-MMP) and the diffusible matrix metalloproteinase-2 (MMP-2), and for their interactions with the extracellular matrix. Using computational simulations, we demonstrate that our model captures all the key steps of the invasion-metastasis cascade, i.e. invasion by both heterogeneous cancer cell clusters and by single mesenchymal-like cancer cells; intravasation of these clusters and single cells both via active mechanisms mediated by matrix-degrading enzymes (MDEs) and via passive shedding; circulation of cancer cell clusters and single cancer cells in the vasculature with the associated risk of cell death and disaggregation of clusters; extravasation of clusters and single cells; and metastatic growth at distant secondary sites in the body. By faithfully reproducing experimental results, our simulations support the evidence-based hypothesis that the membrane-bound MT1-MMP is the main driver of invasive spread rather than diffusible MDEs such as MMP-2

Theory and particle tracking simulations of a resonant radiofrequency deflection cavity in TM110_{110} mode for ultrafast electron microscopy

We present a theoretical description of resonant radiofrequency (RF) deflecting cavities in TM$_{110}$ mode as dynamic optical elements for ultrafast electron microscopy. We first derive the optical transfer matrix of an ideal pillbox cavity and use a Courant-Snyder formalism to calculate the 6D phase space propagation of a Gaussian electron distribution through the cavity. We derive closed, analytic expressions for the increase in transverse emittance and energy spread of the electron distribution. We demonstrate that for the special case of a beam focused in the center of the cavity, the low emittance and low energy spread of a high quality beam can be maintained, which allows high-repetition rate, ultrafast electron microscopy with 100 fs temporal resolution combined with the atomic resolution of a high-end TEM. This is confirmed by charged particle tracking simulations using a realistic cavity geometry, including fringe fields at the cavity entrance and exit apertures

Preliminary study on the assessment of visceral adipose tissue using dual-energy x-ray absorptiometry in chronic obstructive pulmonary disease

Background: Visceral adipose tissue (VAT) was shown to be increased in patients with chronic obstructive pulmonary disease (COPD) compared to control subjects with comparable body mass index (BMI). Our aim was to determine the relation of VAT by dual-energy x-ray absorptiometry (DEXA) in patients with COPD by disease severity, BMI, other indices of body composition and static lung volumes. Methods: 294 COPD patients admitted for rehabilitation were studied. Lung function, static lung volumes and body composition (i.e. BMI, waist circumference, fat-free mass, fat mass and fat distribution between android and gynoid fat mass) were assessed before entering pulmonary rehabilitation. VAT was estimated within the android region by using DEXA. Patients were stratified for gender, BMI (cut-off of 25 kg/m2) and GOLD stage. To assess the impact of VAT on lung volumes, patients were also stratified for VAT less and above 50th percentile. Results: Both male and female patients with more severe airflow limitation had significantly lower VAT values, but these differences disappeared after stratification for BMI. VAT was significantly and strongly correlated with other body composition parameters (all p < 0.001). Patients with moderate to severe airflow limitation and lower VAT had increased static lung hyperinflation and lower diffusing capacity for carbon monoxide. Nevertheless, multivariate stepwise regression models including for BMI, age, gender and forced expiratory volume in 1 s (FEV1) as confounders did not confirm an independent role for VAT on static lung hyperinflation and diffusion capacity. Conclusion: After stratification for BMI, VAT is comparable in moderate to very severe COPD patients. Furthermore, BMI and demographics, but not VAT, were independent predictors of static lung hyperinflation and diffusing capacity in COPD

Dordt College 2003-2004 Catalog

Academic Catalog for 2003-04https://digitalcollections.dordt.edu/academic_catalogs/1012/thumbnail.jp

Restricted spirometry and cardiometabolic comorbidities: Results from the international population based BOLD study

Background: Whether restricted spirometry, i.e. low Forced Vital Capacity (FVC), predicts chronic cardiometabolic disease is not definitely known. In this international population-based study, we assessed the relationship between restricted spirometry and cardiometabolic comorbidities. Methods: A total of 23,623 subjects (47.5% males, 19.0% current smokers, age: 55.1 ± 10.8 years) from five continents (33 sites in 29 countries) participating in the Burden of Obstructive Lung Disease (BOLD) study were included. Restricted spirometry was defined as post-bronchodilator FVC < 5th percentile of reference values. Self-reports of physician-diagnosed cardiovascular disease (CVD; heart disease or stroke), hypertension, and diabetes were obtained through questionnaires. Results: Overall 31.7% of participants had restricted spirometry. However, prevalence of restricted spirometry varied approximately ten-fold, and was lowest (8.5%) in Vancouver (Canada) and highest in Sri Lanka (81.3%). Crude odds ratios for the association with restricted spirometry were 1.60 (95% CI 1.37–1.86) for CVD, 1.53 (95% CI 1.40–1.66) for hypertension, and 1.98 (95% CI 1.71–2.29) for diabetes. After adjustment for age, sex, education, Body Mass Index (BMI) and smoking, the odds ratios were 1.54 (95% CI 1.33–1.79) for CVD, 1.50 (95% CI 1.39–1.63) for hypertension, and 1.86 (95% CI 1.59–2.17) for diabetes. Conclusion: In this population-based, international, multi-site study, restricted spirometry associates with cardiometabolic diseases. The magnitude of these associations appears unattenuated when cardiometabolic risk factors are taken into account

All-cause admissions following a first-ever exacerbation-related hospitalization in COPD

Background Hospital admissions are important contributors to the overall burden of chronic obstructive pulmonary disease (COPD). Understanding the patterns and causes of hospital admissions will help to identify targets for preventive interventions. This study aimed to determine the 5-year all-cause hospital admission trajectories of patients with COPD following their first ever exacerbation-related hospitalisation. Methods Patients with COPD were identified from the Danish national registries. Patients experiencing their first ever exacerbation-related hospitalisation, defined as the index event, between 2000 and 2014 were included. All-cause hospital admissions were examined during a subsequent 5-year follow-up period, and categorised using the International Classification of Diseases, 10th revision. Results In total, 82 964 patients with COPD were included. The mean±sd age was 72±10 years and 48% were male. Comorbidities were present in 58%, and 65% of the patients collected inhalation medication ≤6 months prior to the index event. In total, 337 066 all-cause hospital admissions were identified, resulting in a 5-year admission rate of 82%. Most admissions were due to nonrespiratory causes (59%), amongst which cardiac events were most common (19%). Conclusion Hospital admissions following a first exacerbation-related hospitalisation are common; nonrespiratory events constitute the majority of admissions. Besides the respiratory causes, treatment targeting the nonrespiratory causes of hospital admission should be considered to effectively decrease the burden of hospitalisation in COPD

The host immune response contributes to Haemophilus influenzae virulence

SummaryBackgroundThere is compelling evidence that infections with non-typeable Haemophilus influenzae (NTHi) are associated with exacerbations in COPD patients. However, NTHi has also been isolated frequently during clinically stable disease. In this study we tested the hypothesis that genetically distinct NTHi isolates obtained from COPD patients differ in virulence which could account for dissimilarities in the final outcome of an infection (stable vs. exacerbation).ResultsNTHi isolates (n = 32) were obtained from stable COPD patients, or during exacerbations. Genetically divergent NTHi isolates were selected and induction of inflammation was assessed as an indicator of virulence using different in vitro models. Despite marked genomic differences among NTHi isolates, in vitro studies could not distinguish between NTHi isolates based on their inflammatory capacities. Alternatively, when using a whole blood assay results demonstrated marked inter-, but not intra-individual differences in cytokine release between healthy volunteers irrespective of the origin of the NTHi isolate used.ConclusionResults suggest that the individual immune reactivity might be an important predictor for the clinical outcome (exacerbation vs. no exacerbation) following NTHi infection

Change in cervical length after arrested preterm labor and the risk of preterm birth

ACKNOWLEDGMENTS B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds stock options for ObsEva. B.W.J.M. has received research funding from Guerbet and Merck.Peer reviewedPublisher PD