8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia

Nucleoside analogs represent the backbone of several distinct chemotherapy regimens for acute myeloid leukemia (AML) and combination with tyrosine kinase inhibitors has improved survival of AML patients, including those harboring the poor-risk FLT3-ITD mutation. Although these compounds are effective in killing proliferating blasts, they lack activity against quiescent leukemia stem cells (LSCs), which contributes to initial treatment refractoriness or subsequent disease relapse. The reagent 8-chloro-adenosine (8-Cl-Ado) is a ribose-containing, RNA-directed nucleoside analog that is incorporated into newly transcribed RNA rather than in DNA, causing inhibition of RNA transcription. In this report, we demonstrate antileukemic activities of 8-Cl-Ado in vitro and in vivo and provide mechanistic insight into the mode of action of 8-Cl-Ado in AML. 8-Cl-Ado markedly induced apoptosis in LSC, with negligible effects on normal stem cells. 8-Cl-Ado was particularly effective against AML cell lines and primary AML blast cells harboring the FLT3-ITD mutation. FLT3-ITD is associated with high expression of miR-155. Furthermore, we demonstrate that 8-Cl-Ado inhibits miR-155 expression levels accompanied by induction of DNA-damage and suppression of cell proliferation, through regulation of miR-155/ErbB3 binding protein 1(Ebp1)/p53/PCNA signaling. Finally, we determined that combined treatment of NSG mice engrafted with FLT3-ITD (+) MV4-11 AML cells with 8-Cl-Ado and the FLT3 inhibitor AC220 (quizartinib) synergistically enhanced survival, compared with that of mice treated with the individual drugs, suggesting a potentially effective approach for FLT3-ITD AML patients.Peer reviewe

Identification of odor active substances in human amniotic fluid

Poster P326 session VII: Olfactory Psychophysics & Clinical Studies; Central OlfactionObjectives. Physiological evidence indicates that olfaction could. already function in the human fetus [1]. Right after birth the odor. of amniotic fluid (AF) is detectable to newborns and seems to. attract [2] and calm them [3]. Such early attraction may derive. from fetal learning/memory, and may help newborns adapt to the. postnatal environment. The chemosensory basis of AF. attractiveness has not been investigated yet, and this study aimed. to characterize odor active compounds therein. Methods. The. flavor profile of AF was monitored by descriptive sensory. evaluation using an adult panel, while the identification of the. predominant odor substances was carried out by senso-analytical techniques like gas chromatography-olfactometry and. comparative dilution assays. Results. The prevailing AF odor. impressions were described as blood- and raw meat-like. Several. odor active substances were identified, amongst them some. carbonyl compounds, as well as androstenone. Conclusions. Human AF contains a wide range of odorous substances, such as. odor active steroids or ketones. These substances could have the. potential ability to promote attention and hush the newborn, for. example during noxious medical examination. References. [1]. Schaal et al. 2004. Clin Perinatol 31:261-81 [2] Schaal et al. 1995. Biol Neonate 67, 397-406. [3] Varendi et al 1998. Early Hum Dev. 51:47-55. Acknowledgements: Financed by the German Federal. Ministry of Education and Research (BMBF) and the Bavarian. Research Foundation

Do overlapping odor constituents explain undifferentiated neonatal attraction to amniotic fluid and human milk?

ISBN-10: 3-938896-38-9 ISBN-13: 978-3-938896-38-9International audienc

Sperm-Activating Odorous Substances in Human Follicular Fluid and Vaginal Secretion : Identification by Gas Chromatography-Olfactometry and Ca2+ Imaging

Human sperm chemotaxis to follicular fluid has been well established, but the molecular mechanism(s) for this phenomenon are still largely unclear. Studies indicate that odorant receptors expressed on spermatozoa could play a role in this scenario. It has recently been shown that several synthetic floral scents activate the receptors OR1D2, OR4D1, and OR7A5 in vitro and evoke distinct sperm motility patterns in vivo. However, all agonists found so far are of synthetic origin and, thus, the presence of endogenous structural analogues in female bodily fluids is subject to speculation. Therefore, the aim of the study reported herein was to investigate the occurrence of odor compounds in vaginal secretions and follicular fluid by using gas chromatography- olfactometry. Chemically identified constituents of either bodily fluid were then analyzed for activation of recombinant chemoreceptors and candidate ligands were further tested for induction of sperm Ca2+ signals. Through using this approach, two novel odorant receptor-ligand pairs are reported and human sperm Ca2+ elevations in response to both odorous substances, namely 5-androst-16-en-3-one and 4-hydroxy-2,5-dimethyl-3(2H)-furanone, are shown

Human neonatal responses to androstenone

Poster P327 session VII: Olfactory Psychophysics & Clinical Studies; Central OlfactionAims. Human newborns show equal attraction to the odors of amniotic. fluid (AF) and mothers’ colostrum [1]. As 5-a-androst-16-en-3-. one (An) has been found in both fluids [2, 3], we studied it as a. potential vector of this perinatal odor continuity and of neonatal. attraction to the smell of breast and milk [4]. Methods. Two studies. were run. 1) We recorded the behavior of 16 newborns (3 days) and. 26 adults exposed to a saturating water solution of An and to 3. reference odorants [butyric acid, B; vanilla, V; water, W]. 2) We videotaped. 26 newborns (3 days) being administered 7 stimuli: 4 dilution. steps of An and 3 reference odorants [familiar milk, V, W]. Oral. and facial actions to each odorant were quantified in infants, while. verbal responses were recorded in adults. Results. In study 1, 12/16 neonates reacted with negative facial actions to An, while 10, 3 and. 2 responded in such way to B, V and W, respectively. In contrast,. 11/26 adults rated An as unpleasant, while 26 rated B as negative,. and V and W as positive/neutral. In study 2, 24/26 newborns. increased the relative duration of negative facial actions and/or. decreased the duration of oro-cephalic movements when exposed. to An as compared to W. Conclusions.Agreat majority of newborns. detect An and, as adults who are osmic to An, respond to An in. showing unpleasantness. Thus, the status of specific anosmia to. An clearly differs in neonates and adults ( 50% being. non responsive, respectively). Finally, the negative responsiveness. to a compound met prenatally appears paradoxical when considering. previous data on fetal odor learning. References. [1] Schaal B. et al. (1998). Behav Neurosci, 112, 1438-49; [2] Doucet S et al., submitted;. [3] Buettner A (2007). Flav Fragr J, 22, 465-73; [4] Doucet S. et al. (2007). Dev Psychobiol, 49, 129–38. Acknowledgements: SD. was supported by Bavarian Research Foundation and Region Burgundy. CH and AB were funded by the German Federal Ministry of. Education and Research (BMBF), and BS by CNRS (EAL 549)