[show abstract][hide abstract] ABSTRACT: HIV infection is characterized by gradual immune system collapse and hematopoietic dysfunction. We recently showed that HIV enters multipotent hematopoietic progenitor cells and establishes both active cytotoxic and latent infections that can be reactivated by myeloid differentiation. However, whether these multipotent progenitors include long-lived hematopoietic stem cells (HSCs) that could establish viral reservoirs for the life of the infected person remains unknown. Here we provide direct evidence that HIV targets long-lived HSCs and show that infected HSCs yield stable, multilineage engraftment in a xenograft model. Furthermore, we establish that the capacity to use the chemokine receptor CXCR4 for entry determines whether a virus will enter multipotent versus differentiated progenitor cells. Because HSCs live for the life span of the infected person and are crucial for hematopoietic health, these data may explain the poor prognosis associated with CXCR4-tropic HIV infection and suggest HSCs as long-lived cellular reservoirs of latent HIV.
[show abstract][hide abstract] ABSTRACT: HIV causes a chronic infection characterized by depletion of CD4(+) T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.
Nature medicine 03/2010; 16(4):446-51. · 27.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic myeloid leukemia is defined by the acquired genetic mutation, t(9;22), which leads to the fusion-protein BCR-ABL. Prior to the development of imatinib mesylate (Gleevec), treatment was limited and provided only limited survival benefit. Imatinib has dramatically changed the course of the disease and has led to the significantly prolonged survival in the majority of patients. However, there is growing concern for resistance to imatinib and to subsequent second generation tyrosine kinase inhibitors (dasatinib and nilotinib) due to the T315I mutation. With no currently approved effective treatment for TKI-resistant CML with the T315I mutation, molecularly-based, targeted drug development has focused on several strategies to overcome resistance. In this review, we describe agents which overcome the T315I mutation, as well as native BCR-ABL, via several mechanisms, including increased degradation of BCR-ABL, optimization of direct inhibition of the BCR-ABL kinase, inhibition of BCR-ABL-mediated cell growth via interruption of the BCR-ABL-mediated transcription, protein synthesis or post-translational modification, all of which lead to decreased proliferation and malignant cell death.
[show abstract][hide abstract] ABSTRACT: The standard dose of clofarabine is 52 mg/m2 for pediatrics and 40 mg/m2 in adults. Clofarabine dosed at 52 mg/m2 was used in adult patients with refractory ALL to maximize response before allo-HSCT. All patients had a significant response to therapy. Published pharmacokinetic analysis revealed no difference in peak plasma or intracellular concentrations at clofarabine dosed above 40 mg/m2, yet inhibition of replication in leukemia cells was only sustained over 24 hr at 55 mg/m2. Despite this, there have been no reports of high dose clofarabine used in this setting. Our experience implies that there may be a niche role for clofarabine in reducing disease burden before allo-HSCT for adults with relapsed ALL.
American Journal of Hematology 05/2009; 84(4):228-30. · 4.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Erythropoiesis stimulating agents (ESAs) are some of the most widely used agents in oncology. Yet, the use of ESAs to treat chemotherapy induced anemia in cancer patients has raised issues of concern since 2003, when the two initial studies that were powered to detect meaningful differences in survival with ESA therapy were either halted early, or concluded with deleterious effects on survival. Several trials since then have caused both guideline writers and the FDA to recommend that ESAs should not employed to drive the hemoglobin to greater than 12 g/dL. It is still unclear what role these agents will play in cancer patients with hemoglobin of less than 12 g/dL. In myelodysplastic syndrome, however, these agents are likely part of a core of supportive care measures for low-grade disease, and need to be readily available for these patients. In this review, we attempt to describe the relevant experimental data on ESAs, their current role in clinical oncology, and the research and discoveries that may widen the scope, and enhance the benefit of these agents.
The Cancer Journal 01/2008; 14(2):75-84. · 3.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: To compare the ability of 2 types of dressings to contain vaccinia virus after smallpox vaccination.
Prospective, nonrandomized trial.
The smallpox vaccination clinic in a medium-sized military hospital.
Ninety-seven active-duty military members who received smallpox vaccination in accordance with US Department of Defense and Centers for Disease Control and Prevention guidelines.
The first 40 participants enrolled were instructed to cover their vaccination sites with a semipermeable membrane placed over a separate gauze pad, and the subsequent 57 participants were given a semipermeable membrane bonded to an absorbent pad. Swab samples of the external surface of the dressing were collected 7 and 21 days after vaccination. Real-time quantitative polymerase chain reaction was used to detect vaccinia DNA in the samples.
The rate of vaccinia DNA detection was significantly higher for samples obtained from vaccinees who were using the separate gauze and semipermeable membrane, compared with the vacinees who were using the gauze-impregnated semipermeable membrane (22% vs 2.2%; ; odds ratio, 12.3 [95% confidence interval, 1.4-567.4]).
A gauze-impregnated semipermeable membrane more effectively reduced viral passage to the external surface of the dressing than did a semipermeable membrane placed over a separate gauze pad. Routine use of such dressings following smallpox vaccination might reduce the incidence of autoinoculation and secondary transmission.
Infection Control and Hospital Epidemiology 01/2008; 28(12):1339-43. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Emergency medical services (EMS), hospital emergency departments, and cardiologists have taken steps to reduce time to reperfusion therapy by implementation of aggressive acute myocardial infarction treatment and triage protocols. Data indicate that significant myocardial salvage requires reperfusion within 2 hours, and the current American College of Cardiology guideline is 90 minutes after hospital emergency department admission.
To minimize delays in time to reperfusion in an urban-rural North Carolina County, Guilford County EMS and the Moses Cone Hospital have collaborated to implement transmission of EMS electrocardiographs (ECGs) to the emergency department. The study population included 92 patients who were transported by EMS and received primary coronary intervention during the second, third, and fourth years after initiation of this intervention in 1993.
The median time from symptom onset to the initial ECG was 77 minutes. There was an additional 23 minutes between the availability of this ECG and the arrival of the patient at the emergency department. In the first year of the intervention, the time from hospital arrival to percutaneous coronary intervention was 80 minutes. In years 2 through 4, they were 93, 85, and 94 minutes, respectively. In 2003, 10 years after the intervention, the time from hospital arrival to percutaneous coronary intervention was 113 minutes.
Initial gains in the time from hospital arrival to percutaneous coronary intervention, attributed to acquisition of the ECG in the prehospital setting, were not sustained over 10 years.
Journal of Electrocardiology 05/2006; 39(2):136-41. · 1.09 Impact Factor