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Newton P.K.,University of Southern California | Mason J.,University of Southern California | Bethel K.,Scripps Clinic Torrey Pines | Bazhenova L.A.,University of California at San Diego | And 2 more authors.
PLoS ONE | Year: 2012

A stochastic Markov chain model for metastatic progression is developed for primary lung cancer based on a network construction of metastatic sites with dynamics modeled as an ensemble of random walkers on the network. We calculate a transition matrix, with entries (transition probabilities) interpreted as random variables, and use it to construct a circular bi-directional network of primary and metastatic locations based on postmortem tissue analysis of 3827 autopsies on untreated patients documenting all primary tumor locations and metastatic sites from this population. The resulting 50 potential metastatic sites are connected by directed edges with distributed weightings, where the site connections and weightings are obtained by calculating the entries of an ensemble of transition matrices so that the steady-state distribution obtained from the long-time limit of the Markov chain dynamical system corresponds to the ensemble metastatic distribution obtained from the autopsy data set. We condition our search for a transition matrix on an initial distribution of metastatic tumors obtained from the data set. Through an iterative numerical search procedure, we adjust the entries of a sequence of approximations until a transition matrix with the correct steady-state is found (up to a numerical threshold). Since this constrained linear optimization problem is underdetermined, we characterize the statistical variance of the ensemble of transition matrices calculated using the means and variances of their singular value distributions as a diagnostic tool. We interpret the ensemble averaged transition probabilities as (approximately) normally distributed random variables. The model allows us to simulate and quantify disease progression pathways and timescales of progression from the lung position to other sites and we highlight several key findings based on the model. © 2012 Newton et al. Source


Breitbach C.J.,Jennerex Inc. | Reid T.,University of California at San Diego | Burke J.,Billings Clinic | Bell J.C.,Jennerex Inc. | And 3 more authors.
Cytokine and Growth Factor Reviews | Year: 2010

Chemotherapy remains a common mode of anticancer treatment even though in most cancer indications the therapeutic approach is not effective and ultimately associated with the onset of chemoresistance. A better understanding of genetic differences in tumors ushered in the era of targeted therapy which has revolutionized the treatment of certain cancer types. However, generally targeted therapies are only cytostatic and a proportion of the patient population may be non-responsive to targeted therapy due to mutations of other genes in the same pathway (e.g. ras mutations in patients with colorectal cancer treated with EGFR targeted therapy). Therefore, there exists a need for a radically new approach to cancer therapy. Oncolytic viruses (OVs) possess many properties of an ideal cancer therapeutic. OVs are cytotoxic and target cancers via multiple mechanisms of action while at the same time exploiting validated genetic pathways known to be dysregulated in many cancers. Indeed, promising safety and efficacy data has emerged from Phase 1 and Phase 2 trials with diverse OVs (e.g. JX-594, a targeted oncolytic poxvirus). Though the field has lagged behind with pivotal, randomized Phase 3 trials, these are currently being initiated for a number of OVs. In addition, the field must ensure a continued clinical development of newly developed OVs; a strategy for the clinical development of novel cancer therapeutics is outlined. © 2010 Elsevier Ltd. Source


Lyle C.A.,Billings Clinic | Sidonio R.F.,Childrens Healthcare Of Atlanta | Goldenberg N.A.,Johns Hopkins Hospital | Goldenberg N.A.,Johns Hopkins University
Current Opinion in Pediatrics | Year: 2015

PURPOSE OF REVIEW: Pediatric venous thromboembolism (VTE) can affect children of all ages, requiring considerable pharmacologic intervention and is often associated with significant morbidity. Current research efforts are directed toward the development of risk-stratified VTE prevention strategies employing pharmacologic thromboprophylaxis, the optimization of conventional anticoagulation, and the investigation of the safety and efficacy of target-specific oral anticoagulants (TSOACs) in children. RECENT FINDINGS: Recent research has considerably improved the understanding of risk factors of hospital-acquired VTE and how these factors may be employed in risk-stratified paradigms for VTE prevention in children. Additional insight has been gained in the optimization of conventional anticoagulants in special populations such as neonates and children with inflammatory conditions, and in improving the overall safety and compliance with periprocedural anticoagulation and the use of home International Normalized Ratio monitoring. Furthermore, the use of TSOACs has been described in children and is the focus of numerous ongoing clinical trials that are evaluating the safety and efficacy of these agents in children with VTE. SUMMARY: Identification of hospital-acquired VTE risk factors may inform pediatric VTE prevention strategies. Although initial use of TSOACs may be promising, investigation of safety and efficacy in children is still underway. © 2015 Wolters Kluwer Health, Inc. Source


Gillespie M.A.,Johns Hopkins Hospital | Lyle C.A.,Billings Clinic | Goldenberg N.A.,Johns Hopkins Hospital | Goldenberg N.A.,Johns Hopkins University
Current Opinion in Hematology | Year: 2015

Purpose of review The occurrence of pediatric venous thromboembolism (VTE) and the associated sequelae are increasing. The purpose of this PubMed-based review was to summarize the evidence published between 1 August 2014 and 31 March 2015 regarding pediatric VTE epidemiology, risk factors and risk scores, as well as the results from clinical prevention and treatment studies in children. We also sought to provide an update regarding ongoing clinical trials in pediatric VTE prevention and treatment, based on a recent (31 March 2015) search of the clinicaltrials.gov and EudraCT clinical trial registration databases. Recent findings Recent research has defined and/or substantiated risk factors and risk models for pediatric VTE. Studies of pharmacokinetics/pharmacodynamics and safety/efficacy of fondaparinux and dalteparin have also been reported, in addition to findings of the pilot/feasibility phase of a randomized controlled trial on duration of anticoagulation. With regard to oral direct anticoagulants, to date 14 pediatric clinical trials have been registered on clinicaltrials.gov and EudraCT, some of which represent US/North American instances of trials previously launched in Europe. Summary The present findings on published studies and registered trials in pediatric VTE mark an ongoing period of remarkable activity and advancement in the field of pediatric VTE. Copyright © 2015 Wolters Kluwer Health, Inc. Source


Newton P.K.,University of Southern California | Mason J.,University of Southern California | Bethel K.,Scripps Clinic Medical Group | Bazhenova L.,University of California at San Diego | And 3 more authors.
Cancer Research | Year: 2013

The classic view of metastatic cancer progression is that it is a unidirectional process initiated at the primary tumor site, progressing to variably distant metastatic sites in a fairly predictable, although not perfectly understood, fashion. A Markov chain Monte Carlo mathematical approach can determine a pathway diagram that classifies metastatic tumors as "spreaders" or "sponges" and orders the timescales of progression from site to site. In light of recent experimental evidence highlighting the potential significance of self-seeding of primary tumors, we use a Markov chain Monte Carlo (MCMC) approach, based on large autopsy data sets, to quantify the stochastic, systemic, and often multidirectional aspects of cancer progression. We quantify three types of multidirectional mechanisms of progression: (i) self-seeding of the primary tumor, (ii) reseeding of the primary tumor from a metastatic site (primary reseeding), and (iii) reseeding of metastatic tumors (metastasis reseeding). The model shows that the combined characteristics of the primary and the first metastatic site to which it spreads largely determine the future pathways and timescales of systemic disease. Cancer Res; 73(9); 2760-9. © 2013 AACR. Source

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