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1.  Severe Painful Vaso-Occlusive Crises and Mortality in a Contemporary Adult Sickle Cell Anemia Cohort Study 
PLoS ONE  2013;8(11):e79923.
Frequent painful vaso-occlusive crises (VOCs) were associated with mortality in the Cooperative Study of Sickle Cell Disease (CSSCD) over twenty years ago. Modern therapies for sickle cell anemia (SCA) like hydroxyurea are believed to have improved overall patient survival. The current study sought to determine the relevance of the association between more frequent VOCs and death and its relative impact upon overall mortality compared to other known risk factors in a contemporary adult SCA cohort.
Two hundred sixty four SCA adults were assigned into two groups based on patient reported outcomes for emergency department (ED) visits or hospitalizations for painful VOC treatment during the 12 months prior to evaluation.
Higher baseline hematocrit (p = 0.0008), ferritin (p = 0.005), and HDL cholesterol (p = 0.01) were independently associated with 1 or more painful VOCs requiring an ED visit or hospitalization for acute pain. During a median follow-up of 5 years, mortality was higher in the ED visit/hospitalization group (relative risk [RR] 2.68, 95% CI 1.1-6.5, p = 0.03). Higher tricuspid regurgitatant jet velocity (TRV) (RR 2.41, 95% CI 1.5-3.9, p < 0.0001), elevated ferritin (RR 4.00, 95% CI 1.8-9.0, p = 0.001) and lower glomerular filtration rate (RR=2.73, 95% CI 1.6-4.6, p < 0.0001) were also independent risk factors for mortality.
Severe painful VOCs remain a marker for SCA disease severity and premature mortality in a modern cohort along with other known risk factors for death including high TRV, high ferritin and lower renal function. The number of patient reported pain crises requiring healthcare utilization is an easily obtained outcome that could help to identify high risk patients for disease modifying therapies.
Trial Registration NCT00011648
PMCID: PMC3818240  PMID: 24224021
2.  Directed Therapy for Patients with Myelodysplastic Syndromes (MDS) by Suppression of Cyclin D1 with ON 01910.Na 
Leukemia Research  2012;36(8):982-989.
We previously demonstrated upregulation of c-myc, survivin, and cyclin D1 in CD34+ bone marrow mononuclear cells (BMMNCs) of patients with trisomy 8 and monosomy 7 myelodysplastic syndromes (MDS). “Knockdown” of cyclin D1 by RNA interference decreased trisomy 8 cell growth, suggesting that this might be a therapeutic target in MDS.
Experimental Design
We performed preclinical studies using BMMNCs from patients with MDS and AML to examine the effects of the styryl sulfone ON 01910.Na on cyclin D1 accumulation, aneuploidy, and CD34+ blast percentage. We next treated twelve patients with higher risk MDS and two trisomy 8 AML patients with ON01910.Na on a phase I clinical protocol (NCT00533416).
ON 01910.Na inhibited cyclin D1 expression, and was selectively toxic to trisomy 8 cells in vitro. Flow cytometry studies demonstrated increased mature CD15+ myeloid cells and decreased CD34+ blasts. Three patients treated with ON01910.Na on a clinical had decreased bone marrow blasts by ≥50%, and three patients had hematologic improvements, one of which was sustained for 33 months. Patients with hematologic responses to ON 01910.Na had decreased cyclin D1 expression in their CD34+ cells.
The preclinical results and responses of patients on a clinical trial warrant further investigation of ON 01910.Na as a potential novel targeted therapy for higher risk MDS patients.
PMCID: PMC3381873  PMID: 22524974
MDS; Treatment; ON 01910.Na; Cyclin D1
3.  Combining Censored and Uncensored Data in a U-Statistic: Design and Sample Size Implications for Cell Therapy Research 
The assumptions that anchor large clinical trials are rooted in smaller, Phase II studies. In addition to specifying the target population, intervention delivery, and patient follow-up duration, physician-scientists who design these Phase II studies must select the appropriate response variables (endpoints). However, endpoint measures can be problematic. If the endpoint assesses the change in a continuous measure over time, then the occurrence of an intervening significant clinical event (SCE), such as death, can preclude the follow-up measurement. Finally, the ideal continuous endpoint measurement may be contraindicated in a fraction of the study patients, a change that requires a less precise substitution in this subset of participants.
A score function that is based on the U-statistic can address these issues of 1) intercurrent SCE's and 2) response variable ascertainments that use different measurements of different precision. The scoring statistic is easy to apply, clinically relevant, and provides flexibility for the investigators' prospective design decisions. Sample size and power formulations for this statistic are provided as functions of clinical event rates and effect size estimates that are easy for investigators to identify and discuss. Examples are provided from current cardiovascular cell therapy research.
PMCID: PMC3154087  PMID: 21841940
U-statistic; clinical trials; score function; stem cells
4.  Apolipoprotein E Negatively Regulates House Dust Mite–induced Asthma via a Low-Density Lipoprotein Receptor–mediated Pathway 
Rationale: Distinct sets of corticosteroid-unresponsive genes modulate disease severity in asthma.
Objectives: To identify corticosteroid-unresponsive genes that provide new insights into disease pathogenesis and asthma therapeutics.
Methods: Experimental murine asthma was induced by nasal administration of house dust mite for 5 days per week. Dexamethasone and apolipoprotein E (apo E) mimetic peptides were administered via osmotic minipumps.
Measurements and Main Results: Genome-wide expression profiling of the lung transcriptome in a house dust mite–induced model of murine asthma identified increases in apo E mRNA levels that persisted despite corticosteroid treatment. House dust mite–challenged apo E−/− mice displayed enhanced airway hyperreactivity and goblet cell hyperplasia, which could be rescued by administration of an apo E(130–149) mimetic peptide. Administration of the apo E(130–149) mimetic peptide to house dust mite–challenged apo E−/− mice also inhibited eosinophilic airway inflammation, IgE production, and the expression of Th2 and Th17 cytokines. House dust mite–challenged low-density lipoprotein receptor (LDLR) knockout mice displayed a similar phenotype as apo E−/− mice with enhanced airway hyperreactivity, goblet cell hyperplasia, and mucin gene expression, but could not be rescued by the apo E(130–149) mimetic peptide, consistent with a LDLR-dependent mechanism.
Conclusions: These findings for the first time identify an apo E–LDLR pathway as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in asthma. Furthermore, our results demonstrate that strategies that activate the apo E–LDLR pathway, such as apo E mimetic peptides, might be developed into a novel treatment approach for patients with asthma.
PMCID: PMC3001262  PMID: 20622028
asthma; house dust mite; apolipoprotein E; LDL receptor
5.  Direct Injection of Autologous Mesenchymal Stromal Cells Improves Myocardial Function 
Cell-based therapies have been employed with conflicting results. Whether direct injection of ex-vivo expanded autologous marrow stromal cells (MSCs) would improve the function of ischemic myocardium and enhance angiogenesis is not well defined. In a porcine model of chronic ischemia, MSCs were isolated and cultured for 4 weeks. Sixteen animals were random divided into two groups to receive either direct intramyocardial injection of autologous MSCs, or equal volumes and injections sites of saline. Cine MRI and epicardial echocardiography were performed just prior to the injections and again 6 weeks later at the time of sacrifice at which point tissue was also analyzed. Myocardial function as assessed by regional wall thickening (as measured by dobutamine stress echocardiograms) demonstrated a 40.9% improvement after cell treatment of the ischemic zone (p = 0.016) whereas the saline treated animals only had a 3.7% change (p = 0.82) compared to baseline. The left ventricular ejection fractions of MSC group showed 19.5% improvement from baseline 35.9 ± 3.8% to 42.9 ± 5.8% (p = 0.049). Increased vascularity was found in the MSC group compared to controls (0.80 ± 0.30 vs 0.50 ± 0.19 capillary/myocyte ratio, p = 0.018). Direct injection of autologous MSCs promotes angiogenesis and enhances the functional improvements following chronic myocardial ischemia. This suggests that the angiogenesis engendered by cell treatment may be physiologically meaningful by improving the contractility of ischemic myocardium.
PMCID: PMC2788037  PMID: 19852944
Mesenchymal stromal Cells; Myocardial Ischemia; Myocardial Function
6.  Comparison of Genotyping Helicobacter pylori Directly from Biopsy Specimens and Genotyping from Bacterial Cultures 
Journal of Clinical Microbiology  2003;41(7):3336-3338.
PCR for vacA and cagA genotypes of Helicobacter pylori using DNA isolated from infected gastric biopsy specimens was approximately equal to genotyping using bacterial DNA from cultures. Inconsistent results were associated with low H. pylori density in biopsies. A higher proportion of mixed infection was found when biopsies were used.
PMCID: PMC165374  PMID: 12843087

Results 1-6 (6)