KIF11 inhibition for glioblastoma treatment: reason to hope or a struggle with the brain?

<p>Abstract</p> <p>Background</p> <p>Glioblastomas (GBM) are typically comprised of morphologically diverse cells. Despite current advances in therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM remains poor. Unfortunately, most patients die within 2 years of diagnosis of their disease. Molecular abnormalities vary among individual patients and also within each tumor. Indeed, one of the distinguishing features of GBM is its marked genetic heterogeneity. Due to the brain location of the tumor, the potential target inhibition for anticancer therapy must exhibit a manageable neurotoxicity profile in the concentration range in which the compounds show anti-proliferative activity.</p> <p>Kinesin KIF11 inhibition by small molecules such as Monastrol or Ispinesib is currently under investigation in the field of malignant tumors. In the current study we have assessed the relevance of the anti-mitotic Kinesin-like protein KIF11 in human GBM cell-lines.</p> <p>Results</p> <p>In this study the target was validated using a set of well characterised and potentially specific small molecule inhibitors of KIF11: an ispinesib analog, Monastrol, a Merck compound and 3 simplified derivatives of the Merck compound. Following an <it>in silico </it>selection, those compounds predicted to bear a favorable BBB permeation profile were assessed for their phenotypic effect on cell lines derived both from primary (U87MG) as well as treated (DBTRG-05-MG) glioblastomas. For some compounds, these data could be compared to their effect on normal human astrocytes, as well as their neurotoxicity on primary rat cortical neurons. The ispinesib analogue 1 showed an anti-proliferative effect on GBM cell lines by blocking them in the G2/M phase in a concentration range which was shown to be harmless to primary rat cortical neurons. Furthermore, ispinesib analog increased caspase 3/7-induced apoptosis in U87MG cells.</p> <p>Conclusion</p> <p>In the area of cell cycle inhibition, KIF11 is critical for proper spindle assembly and represents an attractive anticancer target. Our results suggest that KIF11 inhibitors, when able to permeate the blood-brain-barrier, could represent an interesting class of anticancer drugs with low neurotoxic effects in the treatment of brain tumors.</p

Expression and Function of Gonadotropin-releasing Hormone (GnRH) Receptor in Human Olfactory GnRH-secreting Neurons AN AUTOCRINE GnRH LOOP UNDERLIES NEURONAL MIGRATION

Olfactory neurons and gonadotropin-releasing hormone (GnRH) neurons share a common origin during organogenesis. Kallmann's syndrome, clinically characterized by anosmia and hypogonadotropic hypogonadism, is due to an abnormality in the migration of olfactory and GnRH neurons. We recently characterized the human FNC-B4 cell line, which retains properties present in vivo in both olfactory and GnRH neurons. In this study, we found that FNC-B4 neurons expressed GnRH receptor and responded to GnRH with time- and dose-dependent increases in GnRH gene expression and protein release (up to 5-fold). In addition, GnRH and its analogs stimulated cAMP production and calcium mobilization, although at different biological thresholds (nanomolar for cAMP and micromolar concentrations for calcium). We also observed that GnRH triggered axon growth, actin cytoskeleton remodeling, and a dose-dependent increase in migration (up to 3-4-fold), whereas it down-regulated nestin expression. All these effects were blocked by a specific GnRH receptor antagonist, cetrorelix. We suggest that GnRH, secreted by olfactory neuroblasts, acts in an autocrine pattern to promote differentiation and migration of those cells that diverge from the olfactory sensory lineage and are committed to becoming GnRH neurons

Clinical Outcome after Adoptive Infusion of BPX-501 Cells (donor T cells transduced with iC9 suicide gene) in Children with Thalassemia Major (TM) Given Alfa/Beta T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (HSCT)

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The detector control unit of the fine guidance sensor instrument on-board the ARIEL mission: design status

ARIEL is an ESA mission whose scientific goal is to investigate exoplanetary atmospheres. The payload is composed by two instruments: AIRS (ARIEL IR Spectrometer) and FGS (Fine Guidance System). The FGS detection chain is composed by two HgCdTe detectors and by the cold Front End Electronics (SIDECAR), kept at cryogenic temperatures, interfacing with the F-DCU (FGS Detector Control Unit) boards that we will describe thoroughly in this paper. The F-DCU are situated in the warm side of the payload in a box called FCU (FGS Control Unit) and contribute to the FGS VIS/NIR imaging and NIR spectroscopy. The F-DCU performs several tasks: drives the detectors, processes science data and housekeeping telemetries, manages the commands exchange between the FGS/DPU (Data Processing Unit) and the SIDECARs and provides high quality voltages to the detectors. This paper reports the F-DCU status, describing its architecture, the operation and the activities, past and future necessary for its development

The instrument control unit of the ARIEL payload: design evolution following the unit and payload subsystems SRR (system requirements review)

ARIEL (Atmospheric Remote-sensing InfraRed Large-survey) is a medium-class mission of the European Space Agency, part of the Cosmic Vision program, whose launch is foreseen by early 2029. ARIEL aims to study the composition of exoplanet atmospheres, their formation and evolution. The ARIEL’s target will be a sample of about 1000 planets observed with one or more of the following methods: transit, eclipse and phase-curve spectroscopy, at both visible and infrared wavelengths simultaneously. The scientific payload is composed by a reflective telescope having a 1m-class elliptical primary mirror, built in solid Aluminium, and two focal-plane instruments: FGS and AIRS. FGS (Fine Guidance System)1 has the double purpose, as suggested by its name, of performing photometry (0.50-0.55 µm) and low resolution spectrometry over three bands (from 0.8 to 1.95 µm) and, simultaneously, to provide data to the spacecraft AOCS (Attitude and Orbit Control System) with a cadence of 10 Hz and contributing to reach a 0.02 arcsec pointing accuracy for bright targets. AIRS (ARIEL InfraRed Spectrometer) instrument will perform IR spectrometry in two wavelength ranges: between 1.95 and 3.9 µm (with a spectral resolution R > 100) and between 3.9 and 7.8 µm with a spectral resolution R > 30. This paper provides the status of the ICU (Instrument Control Unit), an electronic box whose purpose is to command and supply power to AIRS (as well as acquire science data from its two channels) and to command and control the TCU (Telescope Control Unit)

Booster Vaccination With GVGH Shigella sonnei 1790GAHB GMMA Vaccine Compared to Single Vaccination in Unvaccinated Healthy European Adults: Results From a Phase 1 Clinical Trial

The investigational Shigella sonnei vaccine (1790GAHB) based on GMMA (generalized modules for membrane antigens) is immunogenic, with an acceptable safety profile in adults. However, pre-vaccination anti-S. sonnei lipopolysaccharide (LPS) antibody levels seemed to impact vaccine-related immune responses. This phase 1, open-label, non-randomized extension study (ClinicalTrials.gov: NCT03089879) evaluated immunogenicity of a 1790GAHB booster dose in seven adults with undetectable antibodies prior to priming with three 1790GAHB vaccinations 2–3 years earlier (boosted group), compared to one dose in 28 vaccine-naïve individuals (vaccine-naïve group). Anti-S. sonnei LPS serum IgG geometric mean concentrations and seroresponse (increase of ≥25 EU or ≥50% from baseline antibody ≤ 50 EU and ≥50 EU, respectively) rates were calculated at vaccination (day [D]1), D8, D15, D29, D85. Safety was assessed. Geometric mean concentrations at D8 were 168 EU (boosted group) and 32 EU (vaccine-naïve group). Response peaked at D15 (883 EU) and D29 (100 EU) for the boosted and vaccine-naïve groups. Seroresponse rates at D8 were 86% (boosted group) and 24% (vaccine-naïve group) and increased at subsequent time points. Across both groups, pain (local) and fatigue (systemic) were the most frequent solicited adverse events (AEs). Unsolicited AEs were reported by 57% of boosted and 25% of vaccine-naïve participants. No deaths, serious AEs, or AEs of special interest (except one mild neutropenia case, possibly vaccination-related) were reported. One 1790GAHB dose induced a significant booster response in previously-primed adults, regardless of priming dose, and strong immune response in vaccine-naïve individuals. Vaccination was well tolerated

Age-dependent acquisition of IgG antibodies to Shigella serotypes—a retrospective analysis of seroprevalence in Kenyan children with implications for infant vaccination

BackgroundShigellosis mainly affects children under 5 years of age living in low- and middle-income countries, who are the target population for vaccination. There are, however, limited data available to define the appropriate timing for vaccine administration in this age group. Information on antibody responses following natural infection, proxy for exposure, could help guide vaccination strategies.MethodsWe undertook a retrospective analysis of antibodies to five of the most prevalent Shigella serotypes among children aged &lt;5 years in Kenya. Serum samples from a cross-sectional serosurvey in three Kenyan sites (Nairobi, Siaya, and Kilifi) were analyzed by standardized ELISA to measure IgG against Shigella sonnei and Shigella flexneri 1b, 2a, 3a, and 6. We identified factors associated with seropositivity to each Shigella serotype, including seropositivity to other Shigella serotypes.ResultsA total of 474 samples, one for each participant, were analyzed: Nairobi (n = 169), Siaya (n = 185), and Kilifi (n = 120). The median age of the participants was 13.4 months (IQR 7.0–35.6), and the male:female ratio was 1:1. Geometric mean concentrations (GMCs) for each serotype increased with age, mostly in the second year of life. The overall seroprevalence of IgG antibodies increased with age except for S. flexneri 6 which was high across all age subgroups. In the second year of life, there was a statistically significant increase of antibody GMCs against all five serotypes (p = 0.01–0.0001) and a significant increase of seroprevalence for S. flexneri 2a (p = 0.006), S. flexneri 3a (p = 0.006), and S. sonnei (p = 0.05) compared with the second part of the first year of life. Among all possible pairwise comparisons of antibody seropositivity, there was a significant association between S. flexneri 1b and 2a (OR = 6.75, 95% CI 3–14, p &lt; 0.001) and between S. flexneri 1b and 3a (OR = 23.85, 95% CI 11–54, p &lt; 0.001).ConclusionChildren living in low- and middle-income settings such as Kenya are exposed to Shigella infection starting from the first year of life and acquire serotype-specific antibodies against multiple serotypes. The data from this study suggest that Shigella vaccination should be targeted to infants, ideally at 6 or at least 9 months of age, to ensure children are protected in the second year of life when exposure significantly increases

T-REX OU4 HIRES: the high resolution spectrograph for the E-ELT

The goal of this unit was to consolidate the project for the construction of the high resolution spectrometer of the E-ELT (HIRES). The task included the development of scientific cases and tools to predict the instrumental performances. From the technical point of view it included several R&D activities in collaboration with highly specialized Italian companies; it culminated with the detailed design of a highly modular instrument based on well established technologies. From the management point of view it lead to the consolidation of a large international consortium that spans over 12 countries and includes most of the European and ESO-related institutes interested in high resolution spectroscopy. This consortium is led by INAF; its formal creation is awaiting the official call by ESO for the phase-A study for the HIRES instrument of the E-ELT