Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy

Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Treatment of KMT2A-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL

Combined distributed turbo coding and space frequency block coding techniques

The distributed space-time (frequency) coding and distributed channel turbo coding used independently represent two cooperative techniques that can provide increased throughput and spectral efficiency at an imposed maximum Bit Error Rate (BER) and delay required from the new generation of cellular networks. This paper proposes two cooperative algorithms that employ jointly the two types of techniques, analyzes their BER and spectral efficiency performances versus the qualities of the channels involved, and presents some conclusions regarding the adaptive employment of these algorithms. © 2010 V. Bota et al.FP7/ICT/2007/21547

Combined distributed turbo coding and space frequency block coding techniques

The distributed space-time (frequency) coding and distributed channel turbo coding used independently represent two cooperative techniques that can provide increased throughput and spectral efficiency at an imposed maximum Bit Error Rate (BER) and delay required from the new generation of cellular networks. This paper proposes two cooperative algorithms that employ jointly the two types of techniques, analyzes their BER and spectral efficiency performances versus the qualities of the channels involved, and presents some conclusions regarding the adaptive employment of these algorithms. © 2010 V. Bota et al.FP7/ICT/2007/21547

Combined distributed turbo coding and space frequency block coding techniques

The distributed space-time (frequency) coding and distributed channel turbo coding used independently represent two cooperative techniques that can provide increased throughput and spectral efficiency at an imposed maximum Bit Error Rate (BER) and delay required from the new generation of cellular networks. This paper proposes two cooperative algorithms that employ jointly the two types of techniques, analyzes their BER and spectral efficiency performances versus the qualities of the channels involved, and presents some conclusions regarding the adaptive employment of these algorithms. © 2010 V. Bota et al.FP7/ICT/2007/21547

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Allergy-Specific Phenome-Wide Association Study For Immunogenes In Turkish Children

To dissect the role of immunogenetics in allergy and asthma, we performed a phenome-wide association study in 974 Turkish children selected from a cross-sectional study conducted using ISAAC (International Study of Asthma and Allergies in Children) Phase II tools. We investigated 9 loci involved in different immune functions (ADAM33, ADRB2, CD14, IL13, IL4, IL4R, MS4A2, SERPINE1, and TNF) with respect to 116 traits assessed through blood tests, hypertonic saline challenge tests, questionnaires, and skin prick tests. Multiple associations were observed for ADAM33: rs2280090 was associated with reduced MEF240% (i.e., the ratio of Mean Expiratory Flow after 240s of hypertonic saline inhalation with respect to the age-and ancestry-matched reference value) and with an increased risk of allergic bronchitis (p = 1.77*10(-4) and p = 7.94*10(-4), respectively); rs3918396 was associated with wheezing and eczema comorbidity (p = 3.41*10(-4)). IL4 rs2243250 was associated with increased FEV240 (Forced Expiratory Flow Volume after 240s of hypertonic saline inhalation; p = 4.81*10(-4)) and CD14 rs2569190 was associated with asthma diagnosis (p = 1.36*10(-3)). ADAM33 and IL4 appeared to play a role in the processes linked to allergic airway inflammation and lung function. Due to its association with wheezing and eczema comorbidity, ADAM33 may also be involved in the atopic march.WoSScopu

Maintenance and preservation of ectomycorrhizal and arbuscular mycorrhizal fungi

Short- to long-term preservation of mycorrhizal fungi is essential for their in-depth study and, in the case of culture collections, for safeguarding their biodiversity. Many different maintenance/preservation methods have been developed in the last decades, from soil- and substrate-based maintenance to preservation methods that reduce (e.g., storage under water) or arrest (e.g., cryopreservation) growth and metabolism; all have advantages and disadvantages. In this review, the principal methods developed so far for ectomycorrhizal and arbuscular mycorrhizal fungi are reported and described given their distinct biology/ecology/evolutionary history. Factors that are the most important for their storage are presented and a protocol proposed which is applicable, although not generalizable, for the long-term preservation at ultra-low temperature of a large panel of these organisms. For ECM fungi, isolates should be grown on membranes or directly in cryovials until the late stationary growth phase. The recommended cryopreservation conditions are: a cryoprotectant of 10 % glycerol, applied 1-2 h prior to cryopreservation, a slow cooling rate (1 °C min-1) until storage below -130 °C, and fast thawing by direct plunging in a water bath at 35-37 °C. For AMF, propagules (i.e., spores/colonized root pieces) isolated from cultures in the late or stationary phase of growth should be used and incorporated in a carrier (i.e., soil or alginate beads), preferably dried, before cryopreservation. For in vitro-cultured isolates, 0.5 M trehalose should be used as cryoprotectant, while isolates produced in vivo can be preserved in dried soil without cryoprotectant. A fast cryopreservation cooling rate should be used (direct immersion in liquid nitrogen or freezing at temperatures below -130 °C), as well as fast thawing by direct immersion in a water bath at 35 °C. © 2013 Springer-Verlag Berlin Heidelberg