48 research outputs found

    Juxtaposition of system dynamics and agent-based simulation for a case study in immunosenescence

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    Advances in healthcare and in the quality of life significantly increase human life expectancy. With the aging of populations, new un-faced challenges are brought to science. The human body is naturally selected to be well-functioning until the age of reproduction to keep the species alive. However, as the lifespan extends, unseen problems due to the body deterioration emerge. There are several age-related diseases with no appropriate treatment; therefore, the complex aging phenomena needs further understanding. It is known that immunosenescence is highly correlated to the negative effects of aging. In this work we advocate the use of simulation as a tool to assist the understanding of immune aging phenomena. In particular, we are comparing system dynamics modelling and simulation (SDMS) and agent-based modelling and simulation (ABMS) for the case of age-related depletion of naive T cells in the organism. We address the following research questions: Which simulation approach is more suitable for this problem? Can these approaches be employed interchangeably? Is there any benefit of using one approach compared to the other? Results show that both simulation outcomes closely fit the observed data and existing mathematical model; and the likely contribution of each of the naive T cell repertoire maintenance method can therefore be estimated. The differences observed in the outcomes of both approaches are due to the probabilistic character of ABMS contrasted to SDMS. However, they do not interfere in the overall expected dynamics of the populations. In this case, therefore, they can be employed interchangeably, with SDMS being simpler to implement and taking less computational resources

    Evaluating the role of quality assessment of primary studies in systematic reviews of cancer practice guidelines

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    BACKGROUND: The purpose of this study was to evaluate the role of study quality assessment of primary studies in cancer practice guidelines. METHODS: Reliable and valid study quality assessment scales were sought and applied to published reports of trials included in systematic reviews of cancer guidelines. Sensitivity analyses were performed to evaluate the relationship between quality scores and pooled odds ratios (OR) for mortality and need for blood transfusion. RESULTS: Results found that that whether trials were classified as high or low quality depended on the scale used to assess them. Although the results of the sensitivity analyses found some variation in the ORs observed, the confidence intervals (CIs) of the pooled effects from each of the analyses of high quality trials overlapped with the CI of the pooled odds of all trials. Quality score was not predictive of pooled ORs studied here. CONCLUSIONS: Had sensitivity analyses based on study quality been conducted prospectively, it is highly unlikely that different conclusions would have been found or that different clinical recommendations would have emerged in the guidelines

    The use of preoperative radiotherapy in the management of patients with clinically resectable rectal cancer: a practice guideline

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    BACKGROUND: This systematic review with meta-analysis was designed to evaluate the literature and to develop recommendations regarding the use of preoperative radiotherapy in the management of patients with resectable rectal cancer. METHODS: The MEDLINE, CANCERLIT and Cochrane Library databases, and abstracts published in the annual proceedings of the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology were systematically searched for evidence. Relevant reports were reviewed by four members of the Gastrointestinal Cancer Disease Site Group and the references from these reports were searched for additional trials. External review by Ontario practitioners was obtained through a mailed survey. Final approval of the practice guideline report was obtained from the Practice Guidelines Coordinating Committee. RESULTS: Two meta-analyses of preoperative radiotherapy versus surgery alone, nineteen trials that compared preoperative radiotherapy plus surgery to surgery alone, and five trials that compared preoperative radiotherapy to alternative treatments were obtained. Randomized trials demonstrate that preoperative radiotherapy followed by surgery is significantly more effective than surgery alone in preventing local recurrence in patients with resectable rectal cancer and it may also improve survival. A single trial, using surgery with total mesorectal excision, has shown similar benefits in local recurrence. CONCLUSION: For adult patients with clinically resectable rectal cancer we conclude that: • Preoperative radiotherapy is an acceptable alternative to the previous practice of postoperative radiotherapy for patients with stage II and III resectable rectal cancer; • Both preoperative and postoperative radiotherapy decrease local recurrence but neither improves survival as much as postoperative radiotherapy combined with chemotherapy. Therefore, if preoperative radiotherapy is used, chemotherapy should be added postoperatively to at least patients with stage III disease

    Multi-objective optimization of genome-scale metabolic models: the case of ethanol production

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    Ethanol is among the largest fermentation product used worldwide, accounting for more than 90% of all biofuel produced in the last decade. However current production methods of ethanol are unable to meet the requirements of increasing global demand, because of low yields on glucose sources. In this work, we present an in silico multi-objective optimization and analyses of eight genome-scale metabolic networks for the overproduction of ethanol within the engineered cell. We introduce MOME (multi-objective metabolic engineering) algorithm, that models both gene knockouts and enzymes up and down regulation using the Redirector framework. In a multi-step approach, MOME tackles the multi-objective optimization of biomass and ethanol production in the engineered strain; and performs genetic design and clustering analyses on the optimization results. We find in silico E. coli Pareto optimal strains with a knockout cost of 14 characterized by an ethanol production up to 19.74mmolgDW−1h−1 (+832.88% with respect to wild-type) and biomass production of 0.02h−1 (−98.06% ). The analyses on E. coli highlighted a single knockout strategy producing 16.49mmolgDW−1h−1 (+679.29% ) ethanol, with biomass equals to 0.23h−1 (−77.45% ). We also discuss results obtained by applying MOME to metabolic models of: (i) S. aureus; (ii) S. enterica; (iii) Y. pestis; (iv) S. cerevisiae; (v) C. reinhardtii; (vi) Y. lipolytica. We finally present a set of simulations in which constrains over essential genes and minimum allowable biomass were included. A bound over the maximum allowable biomass was also added, along with other settings representing rich media compositions. In the same conditions the maximum improvement in ethanol production is +195.24%

    The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer

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    <p>Background: It is increasingly recognised that host-related factors may be important in determining cancer outcome. The aim was to examine the relationship between patient physiology, the systemic inflammatory response and survival after colorectal cancer resection.</p> <p>Methods: Patients undergoing potentially curative resection of colorectal cancer were identified from a prospectively maintained database. Patient physiology was assessed using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) criteria. The systemic inflammatory response was assessed using the modified Glasgow Prognostic Score (mGPS). Multivariate 5-year survival analysis was carried out with calculation of hazard ratios (HR).</p> <p>Results: A total of 320 patients were included. During follow-up (median 74 months), there were 136 deaths: 83 colorectal cancer related and 53 non-cancer related. Independent predictors of cancer-specific survival were age (HR: 1.46, P<0.01), Dukes stage (HR: 2.39, P<0.001), mGPS (HR: 1.78, P<0.001) and POSSUM physiology score (HR: 1.38, P=0.02). Predictors of overall survival were age (HR: 1.64, P<0.001), smoking (HR: 1.52, P=0.02), Dukes stage (HR: 1.64, P<0.001), mGPS (HR: 1.60, P<0.001) and POSSUM physiology score (HR: 1.27, P=0.03). A relationship between mGPS and POSSUM physiology score was also established (P<0.006).</p> <p>Conclusion: The POSSUM physiology score and the systemic inflammatory response are strongly associated and both are independent predictors of cancer specific and overall survival in patients undergoing potentially curative resection of colorectal cancer.</p&gt

    Follow-up of patients with curatively resected colorectal cancer: a practice guideline

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    BACKGROUND: A systematic review was conducted to evaluate the literature regarding the impact of follow-up on colorectal cancer patient survival and, in a second phase, recommendations were developed. METHODS: The MEDLINE, CANCERLIT, and Cochrane Library databases, and abstracts published in the 1997 to 2002 proceedings of the annual meeting of the American Society of Clinical Oncology were systematically searched for evidence. Study selection was limited to randomized trials and meta-analyses that examined different programs of follow-up after curative resection of colorectal cancer where five-year overall survival was reported. External review by Ontario practitioners was obtained through a mailed survey. Final approval of the practice guideline report was obtained from the Practice Guidelines Coordinating Committee. RESULTS: Six randomized trials and two published meta-analyses of follow-up were obtained. Of six randomized trials comparing one follow-up program to a more intense program, only two individual trials detected a statistically significant survival benefit favouring the more intense follow-up program. Pooling of all six randomized trials demonstrated a significant improvement in survival favouring more intense follow-up (Relative Risk Ratio 0.80 (95%CI, 0.70 to 0.91; p = 0.0008). Although the rate of recurrence was similar in both of the follow-up groups compared, asymptomatic recurrences and re-operations for cure of recurrences were more common in patients with more intensive follow-up. Trials including CEA monitoring and liver imaging also had significant results, whereas trials not including these tests did not. CONCLUSION: Follow-up programs for patients with curatively resected colorectal cancer do improve survival. These follow-up programs include frequent visits and performance of blood CEA, chest x-rays, liver imaging and colonoscopy, however, it is not clear which tests or frequency of visits is optimal. There is a suggestion that improved survival is due to diagnosis of recurrence at an earlier, asymptomatic stage which allows for more curative resection of recurrence. Based on this evidence and consideration of the biology of colorectal cancer and present practices, a guideline was developed. Patients should be made aware of the risk of disease recurrence or second bowel cancer, the potential benefits of follow-up and the uncertainties requiring further clinical trials. For patients at high-risk of recurrence (stages IIb and III) clinical assessment is recommended when symptoms occur or at least every 6 months the first 3 years and yearly for at least 5 years. At the time of those visits, patients may have blood CEA, chest x-ray and liver imaging. For patients at lower risk of recurrence (stages I and Ia) or those with co-morbidities impairing future surgery, only visits yearly or when symptoms occur. All patients should have a colonoscopy before or within 6 months of initial surgery, and repeated yearly if villous or tubular adenomas >1 cm are found; otherwise repeat every 3 to 5 years. All patients having recurrences should be assessed by a multidisciplinary team in a cancer centre

    The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

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    Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

    Alignment of the ALICE Inner Tracking System with cosmic-ray tracks

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    37 pages, 15 figures, revised version, accepted by JINSTALICE (A Large Ion Collider Experiment) is the LHC (Large Hadron Collider) experiment devoted to investigating the strongly interacting matter created in nucleus-nucleus collisions at the LHC energies. The ALICE ITS, Inner Tracking System, consists of six cylindrical layers of silicon detectors with three different technologies; in the outward direction: two layers of pixel detectors, two layers each of drift, and strip detectors. The number of parameters to be determined in the spatial alignment of the 2198 sensor modules of the ITS is about 13,000. The target alignment precision is well below 10 micron in some cases (pixels). The sources of alignment information include survey measurements, and the reconstructed tracks from cosmic rays and from proton-proton collisions. The main track-based alignment method uses the Millepede global approach. An iterative local method was developed and used as well. We present the results obtained for the ITS alignment using about 10^5 charged tracks from cosmic rays that have been collected during summer 2008, with the ALICE solenoidal magnet switched off.Peer reviewe

    The proportion of cancer-related entries in PubMed has increased considerably; is cancer truly "The Emperor of All Maladies"?

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    In this work, the public database of biomedical literature PubMed was mined using queries with combinations of keywords and year restrictions. It was found that the proportion of Cancer-related entries per year in PubMed has risen from around 6% in 1950 to more than 16% in 2016. This increase is not shared by other conditions such as AIDS, Malaria, Tuberculosis, Diabetes, Cardiovascular, Stroke and Infection some of which have, on the contrary, decreased as a proportion of the total entries per year. Organ-related queries were performed to analyse the variation of some specific cancers. A series of queries related to incidence, funding, and relationship with DNA, Computing and Mathematics, were performed to test correlation between the keywords, with the hope of elucidating the cause behind the rise of Cancer in PubMed. Interestingly, the proportion of Cancer-related entries that contain "DNA", "Computational" or "Mathematical" have increased, which suggests that the impact of these scientific advances on Cancer has been stronger than in other conditions. It is important to highlight that the results obtained with the data mining approach here presented are limited to the presence or absence of the keywords on a single, yet extensive, database. Therefore, results should be observed with caution. All the data used for this work is publicly available through PubMed and the UK's Office for National Statistics. All queries and figures were generated with the software platform Matlab and the files are available as supplementary material
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