Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS:Results from the nordic NMDSG08A phase II trial

This prospective phase II study evaluated the efficacy of azacitidine (Aza) + erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo + granulocyte colony stimulation factors for 48 weeks and a transfusion need of ≥ 4 units over 8 weeks were included. Aza 75mgm -2 d-1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ≥ one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza + Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n = 3) and DNMT3A (n = 4) were only observed in nonresponders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations

emm gene diversity, superantigen gene profiles and presence of SlaA among clinical isolates of group A, C and G streptococci from western Norway

In order to investigate molecular characteristics of beta-hemolytic streptococcal isolates from western Norway, we analysed the entire emm gene sequences, obtained superantigen gene profiles and determined the prevalence of the gene encoding streptococcal phospholipase A2 (SlaA) of 165 non-invasive and 34 contemporary invasive group A, C and G streptococci (GAS, GCS and GGS). Among the 25 GAS and 26 GCS/GGS emm subtypes identified, only emm3.1 was significantly associated with invasive disease. M protein size variation within GAS and GCS/GGS emm types was frequently identified. Two non-invasive and one invasive GGS possessed emm genes that translated to truncated M proteins as a result of frameshift mutations. Results suggestive of recombinations between emm or emm-like gene segments were found in isolates of emm4 and stG485 types. One non-invasive GGS possessed speC, speG, speH, speI and smeZ, and another non-invasive GGS harboured SlaA. speA and SlaA were over-represented among invasive GAS, probably because they were associated with emm3. speGdys was identified in 83% of invasive and 63% of non-invasive GCS/GGS and correlated with certain emm subtypes. Our results indicate the invasive potential of isolates belonging to emm3, and show substantial emm gene diversity and possible lateral gene transfers in our streptococcal population

MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias

CXCR4 is a negative prognostic marker in acute myeloid leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-leukemia drugs, for development of new therapeutic strategies

SARS-CoV-2 specific immune responses in overweight and obese COVID-19 patients

Obesity is a known risk factor for severe respiratory tract infections. In this prospective study, we assessed the impact of being obese or overweight on longitudinal SARS-CoV-2 humoral and cellular responses up to 18 months after infection. 274 patients provided blood samples at regular time intervals up to 18 months including obese (BMI ≥30, n=32), overweight (BMI 25-29.9, n=103) and normal body weight (BMI 18.5-24.9, n=134) SARS-CoV-2 patients. We determined SARS-CoV-2 spike-specific IgG, IgA, IgM levels by ELISA and neutralising antibody titres by neutralisation assay. RBD- and spike-specific memory B cells were investigated by ELISpot, spike- and non-spike-specific IFN-γ, IL-2 and IFN-γ/IL-2 secreting T cells by FluoroSpot and T cell receptor (TCR) sequencing was performed. Higher BMI correlated with increased COVID-19 severity. Humoral and cellular responses were stronger in overweight and obese patients than normal weight patients and associated with higher spike-specific IgG binding titres relative to neutralising antibody titres. Linear regression models demonstrated that BMI, age and COVID-19 severity correlated independently with higher SARS-CoV-2 immune responses. We found an increased proportion of unique SARS-CoV-2 specific T cell clonotypes after infection in overweight and obese patients. COVID-19 vaccination boosted humoral and cellular responses irrespective of BMI, although stronger immune boosting was observed in normal weight patients. Overall, our results highlight more severe disease and an over-reactivity of the immune system in overweight and obese patients after SARS-CoV-2 infection, underscoring the importance of recognizing overweight/obese individuals as a risk group for prioritisation for COVID-19 vaccination

Water management in space – examples of hydration systems for cultivation in microgravity and future prospects

The movement of water in, across and out of the plant is a key factor when growing plants as part of a closed regenerative life support system required for long duration space missions. Under microgravity conditions, it has been proven that transpiration rate of leaves is suppressed by retarding the water vapour transfer due to restricted free air convection. Previous experiments on Mir and the International Space Station (ISS) illustrated the importance of monitoring the water status of plants in space. A frequently reported cause for loss of science in space experiments is wilting of seedlings because the water supply system in the growth facility (hardware) was not working properly. This could possibly have been detected earlier and prevented if better tools for monitoring the plant water status were available. Currently, experiments in existing growth facilities on the ISS, as well as new hardware, are being designed to assess and monitor plant water uptake and transport in microgravity. However, finding suitable watering technologies and methods for monitoring water status in space facilities has proven to be challenging. These challenges include the confined environment, the limited amount of available water, as well as restrictions on upload mass and crew time on the ISS. Examples of hydration systems for plants grown on Mir and the ISS and technologies used for monitoring the water status in the growth media in previous space experiments, as well as future prospects will be presented

Effects of the Extraterrestrial Environment on Plants: Recommendations for Future Space Experiments for the MELiSSA Higher Plant Compartment

Abstract: Due to logistical challenges, long-term human space exploration missions require a life support system capable of regenerating all the essentials for survival. Higher plants can be utilized to provide a continuous supply of fresh food, atmosphere revitalization, and clean water for humans. Plants can adapt to extreme environments on Earth, and model plants have been shown to grow and develop through a full life cycle in microgravity. However, more knowledge about the long term effects of the extraterrestrial environment on plant growth and development is necessary. The European Space Agency (ESA) has developed the Micro-Ecological Life Support System Alternative (MELiSSA) program to develop a closed regenerative life support system, based on micro-organisms and higher plant processes, with continuous recycling of resources. In this context, a literature review to analyze the impact of the space environments on higher plants, with focus on gravity levels, magnetic fields and radiation, has been performed. This communication presents a roadmap giving directions for future scientific activities within space plant cultivation. The roadmap aims to identify the research activities required before higher plants can be included in regenerative life support systems in space

Exploration of plant growth and development using the European Modular Cultivation System facility on the International Space Station

Plant Biol.ISI Document Delivery No.: AE5RITimes Cited: 1Cited Reference Count: 35Kittang, A. -I. Iversen, T. -H. Fossum, K. R. Mazars, C. Carnero-Diaz, E. Boucheron-Dubuisson, E. Le Disquet, I. Legue, V. Herranz, R. Pereda-Loth, V. Medina, F. J.French Space Agency (CNES); Norwegian Research Council; Spanish National Plan for Research, Development and Innovation; ELIPS Programme of the European Space Agency (ESA); ESAWe thank Prof. John Z. Kiss (University of Mississippi, USA), Prof. Gerald Perbal (University P. and M. Curie, France) and Dr. Imara Y. Perera (North Carolina State University, USA) for their contribution to some parts of this article. Experimental work reported in this paper and performed in the authors' laboratories was supported by the French Space Agency (CNES), the Norwegian Research Council, the Spanish National Plan for Research, Development and Innovation (different grants) and the ELIPS Programme of the European Space Agency (ESA). Specifically, the activities related to the 'Arabidopsis Topical team' were supported by an ESA grant.Wiley-blackwellHobokenSpace experiments provide a unique opportunity to advance our knowledge of how plants respond to the space environment, and specifically to the absence of gravity. The European Modular Cultivation System (EMCS) has been designed as a dedicated facility to improve and standardise plant growth in the International Space Station (ISS). The EMCS is equipped with two centrifuges to perform experiments in microgravity and with variable gravity levels up to 2.0g. Seven experiments have been performed since the EMCS was operational on the ISS. The objectives of these experiments aimed to elucidate phototropic responses (experiments TROPI-1 and -2), root gravitropic sensing (GRAVI-1), circumnutation (MULTIGEN-1), cell wall dynamics and gravity resistance (Cell wall/Resist wall), proteomic identification of signalling players (GENARA-A) and mechanism of InsP(3) signalling (Plant signalling). The role of light in cell proliferation and plant development in the absence of gravity is being analysed in an on-going experiment (Seedling growth). Based on the lessons learned from the acquired experience, three preselected ISS experiments have been merged and implemented as a single project (Plant development) to study early phases of seedling development. A Topical Team initiated by European Space Agency (ESA), involving experienced scientists on Arabidopsis space research experiments, aims at establishing a coordinated, long-term scientific strategy to understand the role of gravity in Arabidopsis growth and development using already existing or planned new hardware