The past and future of CD33 as therapeutic target in acute myeloid leukemia

CD33 is a myeloid differentiation antigen with endocytic properties. It is broadly expressed on acute myeloid leukemia (AML) blasts and, possibly, some leukemic stem cells and has therefore been exploited as target for therapeutic antibodies for many years. The improved survival seen in many patients when the antibody-drug conjugate, gemtuzumab ozogamicin, is added to conventional chemotherapy validates this approach. However, many attempts with unconjugated or conjugated antibodies have been unsuccessful, highlighting the challenges of targeting CD33 in AML. With the development of improved immunoconjugates and CD33-directed strategies that harness immune effector cells, therapeutics with enhanced efficacy may soon become available. Toxic effects on normal hematopoietic cells may increase in parallel with this increased efficacy and demand new supportive care measures, including possibly rescue with donor cells, to minimize morbidity and mortality from drug-induced cytopenias and to optimize treatment outcomes with these agents in patients with AML.     

The efficacy and safety of venetoclax therapy in elderly patients with relapsed,refractory chronic lymphocytic leukaemia

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.     

From confluent human iPS cells to self-forming neural retina and retinal pigmented epithelium

Progress in retinal-cell therapy derived from human pluripotent stem cells currently faces technical challenges that require the development of easy and standardized protocols. Here, we developed a simple retinal differentiation method, based on confluent human induced pluripotent stem cells (hiPSC), bypassing embryoid body formation and the use of exogenous molecules, coating, or Matrigel. In 2 wk, we generated both retinal pigmented epithelial cells and self-forming neural retina (NR)-like structures containing retinal progenitor cells (RPCs). We report sequential differentiation from RPCs to the seven neuroretinal cell types in maturated NR-like structures as floating cultures, thereby revealing the multipotency of RPCs generated from integration-free hiPSCs. Furthermore, Notch pathway inhibition boosted the generation of photoreceptor precursor cells, crucial in establishing cell therapy strategies. This innovative process proposed here provides a readily efficient and scalable approach to produce retinal cells for regenerative medicine and for drug-screening purposes, as well as an in vitro model of human retinal development and disease.Irreversible blindness caused by retinal diseases, such as inherited retinopathies, age-related macular degeneration (AMD), or glaucoma, is mainly due to the impairment or loss of function of photoreceptor cells, supporting retinal pigmented epithelium (RPE) or retinal ganglion cells (RGCs). Rescuing the degenerated retina is a major challenge for which specific cell replacement is one of the most promising approaches (1, 2). Pluripotent stem cells, like human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs), have the ability to be expanded indefinitely in culture and could be used as an unlimited source of retinal cells for the treatment of retinal degenerative diseases (3, 4). Several publications have indicated that hESCs and hiPSCs can be differentiated into RPE cells spontaneously after fibroblast growth factor (FGF) 2 removal (5–7) or by different floating aggregate methods (8–11). Concerning neural retinal cells, a growing body of convergent data has demonstrated the ability of hESCs or hiPSCs to be committed into the neural retinal lineage and further differentiated into cells expressing photoreceptor markers (12–15). Recent innovative approaches using 3D cultures from embryoid bodies (EBs) of hESCs or hiPSCs allowed the self-formation of optic cup (OC) structures (16) or the generation of optic vesicle (OV)-like structures (17), depending on the addition of exogenous molecules and different substrates used. These protocols require multiple steps and trained handling, which are not always compatible with the manufacturing process for therapeutic approach or drug screening that need a large-scale production of cells of interest. Therefore, very simple and reliable approaches minimizing the use of exogenous molecules should be developed to generate hESCs or hiPSC-derived retinal cells.In the present study, we report a new retinal differentiation process using confluent hiPSCs, without cell clumps or EB formation and in the absence of Matrigel or serum. We demonstrate that integration-free hiPSCs derived from adult human dermal fibroblasts (AHDFs) cultured in proneural medium can simultaneously generate RPE cells and self-forming neural retinal (NR)-like structures within 2 wk and that, when switched to floating cultures, structures containing retinal progenitor cells (RPCs) can differentiate into all retinal cell types, including RGCs and precursors of photoreceptors, needed for therapeutic applications.     

A novel tissue culture model for evaluating the effect of aging on stem cell fate in adult microvascular networks

GeroScience - In vitro models of angiogenesis are valuable tools for understanding the underlying mechanisms of pathological conditions and for the preclinical evaluation of therapies. Our...     

Dynamic knee valgus in competitive alpine skiers: Observation from youth to elite and influence of biological maturation

Numerous studies investigated the association between dynamic knee valgus and injury risk in post-pubertal and elite athletes; however, normative reference scores for competitive alpine skiers and observations on the development process throughout and beyond athletes' growth spurt are lacking. Thus, the aim of this study was to describe the dynamic knee valgus of competitive alpine skiers during drop jump landings (DJ) and single-leg squats (SLS) with respect to sex, sportive level, and biological maturation. Thirty-seven elite and 104 youth competitive alpine skiers around the growth spurt (U15) were examined for their maximal medial knee displacement (MKD) during DJ and SLS by a marker-based 3D motion analysis evaluating dynamic knee valgus. Additionally, skiers' age, anthropometry and biological maturation were assessed. MKD of youth and elite alpine skiers during DJ was comparable and did not improve with increasing training age. Female U15 skiers (on average further matured) had significantly larger MKD values during DJ than male U15 skiers (less matured) (P < .01). Moreover, MKD during DJ was directly associated with the athlete's individual biological maturation status. MKD values obtained from DJ significantly differed from those obtained during SLS (P < .01). The gender-specific difference in MKD values during DJ and their relationship with maturity offset highlight the fundamental changes to the neuromuscular control system during the growth spurt. Thus, biological maturation needs to be considered as a confounding factor for knee valgus screening. Caution is required when evaluating MKD by using high- and low-dynamic tasks, as corresponding information can differ.