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1.  Non-Lethal Control of the Cariogenic Potential of an Agent-Based Model for Dental Plaque 
PLoS ONE  2014;9(8):e105012.
Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments.
PMCID: PMC4140729  PMID: 25144538
2.  Myelodysplastic Syndromes 
PMCID: PMC4000017  PMID: 23847220
NCCN Clinical Practice Guidelines; NCCN Guidelines; myelodysplastic syndromes; chronic myelomonocytic leukemia; refractory anemia; cytopenias; treatment
3.  Prospects of oral disease control in the future – an opinion 
Journal of Oral Microbiology  2014;6:10.3402/jom.v6.26176.
The mouth supports a diverse microbiota which provides major benefits to the host. On occasions, this symbiotic relationship breaks down (dysbiosis), and disease can be a consequence. We argue that progress in the control of oral diseases will depend on a paradigm shift away from approaches that have proved successful in medicine for many diseases with a specific microbial aetiology. Factors that drive dysbiosis in the mouth should be identified and, where possible, negated, reduced or removed, while antimicrobial agents delivered by oral care products may function effectively, even at sub-lethal concentrations, by modulating the activity and growth of potentially pathogenic bacteria. In this way, the beneficial activities of the resident oral microbiota will be retained and the risk of dysbiosis occurring will be reduced.
PMCID: PMC4247391  PMID: 25432790
plaque control; biofilm; oral microbiome; antimicrobial agents; modelling
4.  Myelodysplastic Syndromes 
PMCID: PMC3768131  PMID: 21233243
NCCN Clinical Practice Guidelines; NCCN Guidelines; myelodysplastic syndromes; chronic myelomonocytic leukemia; refractory anemia; cytopenias; treatment
5.  Spindles and active vortices in a model of confined filament-motor mixtures 
BMC Biophysics  2011;4:18.
Robust self-organization of subcellular structures is a key principle governing the dynamics and evolution of cellular life. In fission yeast cells undergoing division, the mitotic spindle spontaneously emerges from the interaction of microtubules, motor proteins and the confining cell walls, and asters and vortices have been observed to self-assemble in quasi-two dimensional microtubule-kinesin assays. There is no clear microscopic picture of the role of the active motors driving this pattern formation, and the relevance of continuum modeling to filament-scale structures remains uncertain.
Here we present results of numerical simulations of a discrete filament-motor protein model confined to a pressurised cylindrical box. Stable spindles, nematic configurations, asters and high-density semi-asters spontaneously emerge, the latter pair having also been observed in cytosol confined within emulsion droplets. State diagrams are presented delineating each stationary state as the pressure, motor speed and motor density are varied. We further highlight a parameter regime where vortices form exhibiting collective rotation of all filaments, but have a finite life-time before contracting to a semi-aster. Quantifying the distribution of life-times suggests this contraction is a Poisson process. Equivalent systems with fixed volume exhibit persistent vortices with stochastic switching in the direction of rotation, with switching times obeying similar statistics to contraction times in pressurised systems. Furthermore, we show that increasing the detachment rate of motors from filament plus-ends can both destroy vortices and turn some asters into vortices.
We have shown that discrete filament-motor protein models provide new insights into the stationary and dynamical behavior of active gels and subcellular structures, because many phenomena occur on the length-scale of single filaments. Based on our findings, we argue the need for a deeper understanding of the microscopic activities underpinning macroscopic self-organization in active gels and urge further experiments to help bridge these lengths.
PMCID: PMC3253673  PMID: 22087580
6.  Innovative Analyses Support a Role for DNA Damage and an Aberrant Cell Cycle in Myelodysplastic Syndrome Pathogenesis 
Bone Marrow Research  2011;2011:950934.
We used flow cytometry to analyze the cell cycle, DNA damage, and apoptosis in hematopoietic subsets in MDS marrow. Subsets were assigned using CD45, side scatter, CD34, and CD71. Cell cycle fractions were analyzed using DRAQ 5 (DNA content) and MPM-2 (mitoses). DNA damage was assessed using p-H2A.X, and apoptosis using Annexin V. Compared to controls, MDS patients demonstrated no increased mitoses in erythroid, myeloid, or CD34+ cells. Myeloid progenitors demonstrated increased G2 cells, which with no increased mitoses suggested delayed passage through G2. Myeloid progenitors demonstrated increased p-H2A.X, consistent with DNA damage causing this delay. Annexin V reactivity was equivalent in MDS and controls. Results for each parameter varied among hematopoietic compartments, demonstrating the need to analyze compartments separately. Our results suggest that peripheral cytopenias in MDS are due to delayed cell cycle passage of marrow progenitors and that this delayed passage and leukemic progression derive from excessive DNA damage.
PMCID: PMC3200066  PMID: 22046573
7.  High Prevalence of Obesity in Acute Promyelocytic Leukemia (APL): Implications for Differentiating Agents in APL and Metabolic Syndrome 
Between January 1999 and December 2008, 469 patients treated for acute myeloid leukemia (AML) were included in this single-institution study.
We performed a case-control analysis to study the rate of obesity among patients with acute promyelocytic leukemia (APL) and non-APL AML.
A total of 81% of APL patients analyzed were obese compared with 41.7% in the non-APL group (p < 0.001). Body mass index (BMI) >30 was seen in 57% of APL patients compared with 31% for the non-APL group (p = 0.01). Neither obesity nor the chemotherapy dosing based on ideal body weight affected survival.
Our findings generate the hypothesis that APL and metabolic syndromes may share a common pathogenic pathway via retinoic acid receptors (RARs), the ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. If this link is confirmed in larger studies, our data will instigate further studies using RXR and RAR modulators as a preventive strategy among obese individuals.
PMCID: PMC3573402  PMID: 23556085
acute promyelocytic leukemia; body mass index; obesity; prevention; RAR; RXR
8.  Dexamethasone, High-dose Cytarabine, and Carboplatin (DAC) Combination is Effective for Childhood Advanced Large-Cell Non-Hodgkin Lymphoma 
Cancer  2008;113(4):782-790.
To purpose of this study was to evaluate the activity and toxicity of dexamethasone, high-dose cytarabine, and carboplatin (DAC) combination therapy in children with newly diagnosed large-cell non-Hodgkin lymphoma (NHL) and to estimate the event-free and overall survival rates achieved when DAC is incorporated into a conventional regimen.
Patients and Methods
From 1991 to 1997, 20 boys and 5 girls aged 4.2 to 17.7 years who had stage III (n=21) or stage IV (n=4) large-cell NHL were treated on this study. DAC therapy was administered at the beginning of the induction phase in 2 sequential cycles and incorporated throughout a continuation phase (modified from the ACOP+ regimen) with doxorubicin, cyclophosphamide, vincristine and dexamethasone. The total duration of treatment was approximately 10 months.
DAC therapy yielded a response in 22 of 25 patients (88%, 95% CI 68%-97%): complete remission in 13 cases (52%) and partial response in 9 (36%). After additional treatment with doxorubicin, cyclophosphamide, vincristine, and dexamethasone, complete remission was attained in 18 patients (72%) and partial remission in 3 (12%). The event-free survival rate (±SE) was 64% ± 9% and the overall survival rate was 80% ± 8% at 5 years.
The DAC regimen is well tolerated and effective for pediatric large-cell NHL.
PMCID: PMC2975596  PMID: 18618501
Dexamethasone; Cytarabine; Carboplatin; Childhood; Large cell; Lymphoma

Results 1-8 (8)