DYSGRAPHIA

Introduction: Every teacher has probably experienced having a good student whose only problem seems to be that they take too long on writing assignments. When the student finally does turn in their work, it is sloppy, incomplete, and has several spelling errors

Targeting CXCR4 in AML and ALL

The interaction of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) blasts with the bone marrow microenvironment regulates self-renewal, growth signaling, as well as chemotherapy resistance. The chemokine receptor, CXC receptor 4 (CXCR4), with its ligand chemokine ligand 12 (CXCL12), plays a key role in the survival and migration of normal and malignant stem cells to the bone marrow. High expression of CXCR4 on AML and ALL blasts has been shown to be a predictor of poor prognosis for these diseases. Several small molecule inhibitors, short peptides, antibodies, and antibody drug conjugates have been developed for the purposes of more effective targeting and killing of malignant cells expressing CXCR4. In this review we will discuss recent results and strategies in targeting CXCR4 with these agents in patients with AML or ALL

Mobilized peripheral blood: An updated perspective

Enforced egress of hematopoietic stem cells (HSCs) out of the bone marrow (BM) into the peripheral circulation, termed mobilization, has come a long way since its discovery over four decades ago. Mobilization research continues to be driven by the need to optimize the regimen currently available in the clinic with regard to pharmacokinetic and pharmacodynamic profile, costs, and donor convenience. In this review, we describe the most recent findings in the field and how we anticipate them to affect the development of mobilization strategies in the future. Furthermore, the significance of mobilization beyond HSC collection, i.e. for chemosensitization, conditioning, and gene therapy as well as a means to study the interactions between HSCs and their BM microenvironment, is reviewed. Open questions, controversies, and the potential impact of recent technical progress on mobilization research are also highlighted

Innovations in hematopoietic stem-cell mobilization: A review of the novel CXCR4 inhibitor motixafortide

Hematopoietic stem-cell transplantation (HCT) and stem-cell-based gene therapies rely on the ability to collect sufficient CD34+ hematopoietic stem and progenitor cells (HSPCs), typicall

Definition of anatomical zero positions for assessing shoulder pose with 3D motion capture during bilateral abduction of the arms

Background: Surgical interventions at the shoulder may alter function of the shoulder complex. Clinically, the outcome can be assessed by universal goniometry. Marker-based motion capture may not resemble these results due to differing angle definitions. Methods: The clinical inspection of bilateral arm abduction for assessing shoulder dysfunction is performed with a marker based 3D optical measurement method. An anatomical zero position of shoulder pose is proposed to determine absolute angles according to the Neutral-0-Method as used in orthopedic context. Static shoulder positions are documented simultaneously by 3D marker tracking and universal goniometry in 8 young and healthy volunteers. Repetitive bilateral arm abduction movements of at least 150° range of motion are monitored. Similarly a subject with gleno-humeral osteoarthritis is monitored for demonstrating the feasibility of the method and to illustrate possible shoulder dysfunction effects. Results: With mean differences of less than 2°, the proposed anatomical zero position results in good agreement between shoulder elevation/depression angles determined by 3D marker tracking and by universal goniometry in static positions. Lesser agreement is found for shoulder pro-/retraction with systematic deviations of up to 6°. In the bilateral arm abduction movements the volunteers perform a common and specific pattern in clavicula-thoracic and gleno-humeral motion with maximum shoulder angles of 32° elevation, 5° depression and 45° protraction, respectively, whereas retraction is hardly reached. Further, they all show relevant out of (frontal) plane motion with anteversion angles of 30° in overhead position (maximum abduction). With increasing arm anteversion the shoulder is increasingly retroverted, with a maximum of 20° retroversion. The subject with gleno-humeral osteoarthritis shows overall less shoulder abduction range of motion but with increased out-of-plane movement during abduction. Conclusions: The proposed anatomical zero definition for shoulder pose fills the missing link for determining absolute joint angles for shoulder elevation/depression and pro-/retraction. For elevation-/depression the accuracy suits clinical expectations very well with mean differences less than 2° and limits of agreement of 8.6° whereas for pro-/retraction the accuracy in individual cases may be inferior with limits of agreement of up to 24.6°. This has critically to be kept in mind when applying this concept to shoulder intervention studies

Comet outbursts and polymers of HCN

Dramatic cometary outbursts have been noted by observers for many years. These outbursts can sometimes increase the apparent brightness of a comet up to 9 mag and release energy on the order of 10 exp 19 ergs. A number of mechanisms have been suggested for outburst activity; however, none has been generally accepted. HCN is a known constituent of both interstellar icy grain mantles and cometary nuclei, and HCN polymers have been postulated to exist on the dark surface of comets such as P/Halley. Since polymerization is a strongly exothermic process, we investigate the possibility that HCN polymerization can provide the energy needed for outbursts. Polymerization may be continuing in the inhomogeneous interior of comets. In addition, the reactive CN groups in these oligomers can be hydrolyzed and may contribute to CO2 and CO pressure buildup in the interior of comets

Suicide genes: Monitoring cells in patients with a safety switch

Clinical trials increasingly incorporate suicide genes either as direct lytic agents for tumors or as safety switches in therapies based on genetically modified cells. Suicide genes can also be used as non-invasive reporters to monitor the biological consequences of administering genetically modified cells to patients and gather information relevant to patient safety. These genes can monitor therapeutic outcomes addressable by early clinical intervention. As an example, our recent clinical trial used 18F-9-(4-fluoro-3-hydroxymethylbutyl)guanine (18FHBG) and PET/CT scans to follow T cells transduced with herpes simplex virus thymidine kinase (TK) after administration to patients. Guided by preclinical data we ultimately hope to discern whether a particular pattern of transduced T cell migration within patients reflects early development of Graft vs. Host Disease (GvHD). Current difficulties in terms of choice of suicide gene, biodistribution of radiolabeled tracers in humans versus animal models, and threshold levels of genetically modified cells needed for detection by PET/CT are discussed. As alternative suicide genes are developed, additional radiolabel probes suitable for imaging in patients should be considered

Various Stages of Immune Synapse Formation Are Differently Dependent on the Strength of the TCR Stimulus

Cytotoxic T lymphocytes (CTL) are key players of the adaptive immune system that target tumors and infected cells. A central step to that is the formation of a cell–cell contact zone between the CTL and its target called an immune synapse (IS). Here, we investigate the influence of the initial T cell receptor (TCR) trigger of a cytolytic IS on the distinct steps leading to cytotoxic granule (CG) exocytosis. We stimulated primary CTLs from mouse using lipid bilayers with varying anti-CD3 but constant ICAM concentrations. We fluorescently labeled molecular markers of distinct IS zones such as actin, CD3, granzyme B, and Synaptobrevin2 in CTLs and imaged cytolytic IS formation by total internal reflection fluorescence microscopy (TIRFM). We found that an intermediate anti-CD3 concentration of 10 µg/mL induces the fastest adhesion of CTLs to the bilayers and results in maximal CG fusion efficiency. The latency of actin ring formation, dwell time, and maximum surface area at the IS exhibit different dependencies on the stimulatory anti-CD3 concentrations. The number and surface area of CD3 clusters at the IS seem to show a different dependency to the TCR trigger when compared to their dwell time. Finally, the mode of full CG exocytosis appears to be independent of the TCR trigger