CD34(+)/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin

Background

CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias.

Design and Methods

We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined.

Results

As assessed by flow cytometry, stem cell-enriched CD34⁺/CD38⁻/CD123⁺ leukemic cells expressed significantly higher levels of CD33 compared to normal CD34⁺/CD38⁻ stem cells. Moreover, highly enriched leukemic CD34⁺/CD38⁻ cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34⁺/CD38⁻ cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells.

Conclusions

CD33 is expressed abundantly on immature CD34⁺/CD38⁻ stem cells and may serve as a stem cell target in chronic myeloid leukemia.     

Neural correlates of tinnitus duration and Distress: A positron emission tomography study

Cerebral ¹⁸F‐deoxyglucose positron emission tomography (FDG‐PET) has shown altered auditory pathway activity in tinnitus. However, the corresponding studies involved only small samples and analyses were restricted to the auditory cortex in most studies. Evidence is growing that also limbic, frontal, and parietal areas are involved in the pathophysiology of chronic tinnitus. These regions are considered to mediate perceptual, attentional, and emotional processes. Thus, the aim of the present study was the systematic evaluation of metabolic brain activity in a large sample of tinnitus patients. Ninety one patients with chronic tinnitus underwent FDG‐PET. The effects of tinnitus severity (assessed by a tinnitus questionnaire score), duration and laterality were evaluated with statistical parametric mapping (SPM) in whole brain analyses. In addition, region of interest analyses were performed for primary auditory areas. Tinnitus duration correlated positively with brain metabolism in right inferior frontal, right ventro‐medial prefrontal, and right posterior cingulate cortex. Tinnitus distress correlated positively with activation of left and right posterior inferior temporal gyrus as well as left and right posterior parahippocampal–hippocampal interface. Region of interest analysis demonstrated an overactivation of left in contrast to right Heschl's gyrus independently from tinnitus laterality and anatomical hemispheric differences. Tinnitus duration and distress were associated with areas involved in attentional and emotional processing. This is in line with recent findings indicating the relevance of higher order areas in the pathophysiology of tinnitus. Earlier results of asymmetric activation of the auditory cortices in tinnitus were confirmed, i.e., left‐sided overactivation was found independently from tinnitus laterality. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

A retrospective analysis of the therapeutic effects of 0.01% atropine on axial length growth in children in a real-life clinical setting

Graefe's Archive for Clinical and Experimental Ophthalmology - Several randomized controlled studies have demonstrated the beneficial effects of 0.01% atropine eye drops on myopia progression...     

Synthetic hydrogel scaffold is an effective vehicle for delivery of INFUSE (rhBMP2) to critical‐sized calvaria bone defects in rats

Medtronic's INFUSE Bone Graft provides surgeons with a potent tool for stimulating bone formation. Current delivery vehicles that rely on Absorbable Collagen Sponges (ACS) require excessive quantities of the active ingredient in INFUSE, recombinant human Bone Morphogenic Protein‐2 (rhBMP2), to achieve physiologically relevant concentrations of the growth factor, driving up the cost of the product and increasing the likelihood of undesirable side effects in neighboring tissues. We demonstrate that a simple light‐mediated, thiol‐ene chemistry can be used to create an effective polymer delivery vehicle for rhBMP2, eliminating the use of xenographic materials and reducing the dose of rhBMP2 required to achieve therapeutic effects. Comprised entirely of synthetic components, this system entraps rhBMP2 within a biocompatible hydrogel scaffold that is degraded by naturally occurring remodeling enzymes, clearing the way for new tissue formation. When tested side‐by‐side with ACS in a critical‐sized bone defect model in rats, this polymeric delivery system significantly increased bone formation over ACS controls. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 401–406, 2013     

Associations of motor abilities with biological,sociodemographic, and behavioural factors in children: results from the ToyBox study

Sport Sciences for Health - In this cross-sectional study, we examined the association of selected basic motor abilities with biological (sex, age, and BMI), sociodemographic [socio-economic status...     

Enteral sedation: safety, efficacy, and controversy

This article reviews the safety and efficacy of enteral sedation use by dentists to provide an evidence-based perspective on the current controversy associated with the use and training requirements for enteral sedation in dental outpatients. Despite the many benefits to patients and dental practitioners, the administration of anxiolytic agents by the oral, sublingual, or rectal route (collectively referred to as enteral sedation) is controversial and has engendered efforts to limit its use and increase training requirements to levels similar to those for parenteral sedation. Factors contributing to this controversy include the off-label use of sedative-hypnotics for outpatient sedation, idiosyncratic reactions to triazolam, and incremental dosing. Evidence supports the continued need and demand for anesthesia and sedation services to ensure access to care for highly anxious and phobic patients, the very young, and special-needs patients. The published evidence and vast clinical experience for oral sedation with benzodiazepines also supports the safety of administering benzodiazepines for anxiety relief with little evidence of deleterious effects when administered incrementally to patients undergoing a dental procedure or at doses greater than those used for hypnosis. Enteral sedation with benzodiazepines remains a time-tested, safe, and widely used modality that needs to be maintained as part of general practice to ensure adequate access to dental care for the many patients for whom fear of dentistry remains a significant barrier to oral health care.