Acute graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (SCT) and can be readily controlled by systemic high-dose steroids in many patients. However, patients whose GVHD is refractory to this therapy have a poor prognosis. Refractory patients have ongoing end-organ damage despite effective immunosuppression with second-line regimens, suggesting pathomechanisms independent from the initiating T-cell attack. To explore whether endothelial damage might contribute to GVHD refractoriness and to study the role of angiopoietin-2 (ANG2) in this process, we have compared kinetics of T-cell activation markers and markers of endothelial dysfunction in the serum of patients with sensitive (n ‫؍‬ 23) and refractory GVHD (n ‫؍‬ 25). Longitudinal measurements of soluble FAS ligand along with other immune markers demonstrate that refractory patients are not exposed to an overwhelming or unresponsive Tcell attack. However, in contrast to sensitive GVHD, refractory GVHD was associated with rising thrombomodulin levels and high ANG2/ vascular endothelialderived growth factor ratios. Patients with refractory GVHD showed significantly increased ANG2 levels already before SCT. These results suggest that endothelial cell vulnerability and dysfunction, rather than refractory T-cell activity, drives treatment refractoriness of GVHD and opens new avenues for prediction and control of this devastating condition. (Blood. 2011; 118(6):1685-1692)

AimsIt is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL).Methods and resultsOne hundred and twenty-four healthy previously inactive individuals completed the 6 months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4 × 4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training—but not RT—acutely increased telomerase activity in CD14+ and in CD34+ leucocytes.Conclusion This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.

In this study, we provide a molecular signature of highly enriched CD34 þ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34 þ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34 þ cells were identified. These include upregulation of genes involved in the transforming growth factorb pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34 þ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34 þ cells showing an increase of the proportion of megakaryocyteerythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.

VDD is a risk factor for elderly patients with DLBCL treated with R-CHOP. That VDD impairs RMCC and substitution improves RMCC strongly suggests that vitamin D substitution enhances rituximab efficacy, which must be confirmed in appropriately designed prospective trials addressing VDD and substitution not only in DLBCL, but also in malignancies treated with other antibodies, of which the major mechanism of action is antibody-dependent cellular cytotoxicity (eg, trastuzumab in breast cancer and cetuximab in colorectal cancer).

Geometries of A4X10 molecules (A = C, Si; X = H, F, Cl, Br, CH3, SiH3) have been optimized at the HF/6-31G* level as a function of the AAAA dihedral angle ω. In addition to the generally known gauche and trans conformational minima, some have an additional (“ortho”) minimum near ω = 90°. This appears only within a certain critical range of sizes of substituents X. It is attributed to a splitting of the ordinary gauche minimum by 1,4 interactions between substituents, similarly as the twisting of the anti minimum from 180° is attributable to 1,3 interactions. A universal model is proposed to rationalize the appearance and subsequent disappearance of the ortho minimum as X increases in size. It contains intrinsic barriers described according to Weinhold, van der Waals interactions described by a Lennard-Jones 6−12 potential, and Coulomb charge−charge interactions.