BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors

B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential

Plantar calcaneal spurs in older people: longitudinal traction or vertical compression?

<p>Abstract</p> <p>Background</p> <p>Plantar calcaneal spurs are common, however their pathophysiology is poorly understood. This study aimed to evaluate the prevalence and correlates of plantar calcaneal spurs in a large sample of older people.</p> <p>Methods</p> <p>Weightbearing lateral foot radiographs of 216 people (140 women and 76 men) aged 62 to 94 years (mean age 75.9, <smcaps>SD</smcaps> 6.6) were examined for plantar calcaneal and Achilles tendon spurs. Associations between the presence of spurs and sex, body mass index, radiographic measures of foot posture, self-reported co-morbidities and current or previous heel pain were then explored.</p> <p>Results</p> <p>Of the 216 participants, 119 (55%) had at least one plantar calcaneal spur and 103 (48%) had at least one Achilles tendon spur. Those with plantar calcaneal spurs were more likely to have Achilles tendon spurs (odds ratio [OR] = 2.0, 95% confidence interval [CI] 1.2 to 3.5). Prevalence of spurs did not differ according to sex. Participants with plantar calcaneal spurs were more likely to be obese (OR = 7.9, 95% CI 3.6 to 17.0), report osteoarthritis (OR = 2.6, 95% CI 1.6 to 4.8) and have current or previous heel pain (OR = 4.6, 95% CI 2.3 to 9.4). No relationship was found between the presence of calcaneal spurs and radiographic measures of foot posture.</p> <p>Conclusion</p> <p>Calcaneal spurs are common in older men and women and are related to obesity, osteoarthritis and current or previous heel pain, but are unrelated to radiographic measurements of foot posture. These findings support the theory that plantar calcaneal spurs may be an adaptive response to vertical compression of the heel rather than longitudinal traction at the calcaneal enthesis.</p

Clinical practice: The care of children with Down syndrome

Down syndrome (DS) is one of the most common chromosomal abnormalities. Because of medical advances and improvements in overall medical care, the median survival of individuals with DS has increased considerably. This longer life expectancy requires giving the necessary care to the individual with DS over their total longer lifespan. DS medical guidelines are designed for the optimal care of the child in whom a diagnosis of DS has been confirmed. We present an overview of the most important issues related to children with DS based on the most relevant literature currently available

A Qualitative Analysis of Experiential Challenges Associated with Meditation Practice

Although empirical interest in meditation has flourished in recent years, few studies have addressed possible downsides of meditation practice, particularly in community populations. In-depth interviews were conducted with 30 male meditators in London, UK, recruited using principles of maximum variation sampling, and analysed using a modified constant comparison approach. Having originally set out simply to inquire about the impact of various meditation practices (including but not limited to mindfulness) on men’s wellbeing, we uncovered psychological challenges associated with its practice. While meditation was generally reported to be conducive to wellbeing, substantial difficulties accounted for approximately one quarter of the interview data. Our paper focuses specifically on these issues in order to alert health professionals to potential challenges associated with meditation. Four main problems of increasing severity were uncovered: Meditation was a difficult skill to learn and practise; participants encountered troubling thoughts and feelings which were hard to manage; meditation reportedly exacerbated mental health issues, such as depression and anxiety; and in a few cases, meditation was associated with psychotic episodes. Our paper raises important issues around safeguarding those who practise meditation, both within therapeutic settings and in the community

The Epitope and Neutralization Mechanism of AVFluIgG01, a Broad-Reactive Human Monoclonal Antibody against H5N1 Influenza Virus

The continued spread of highly pathogenic avian influenza (HPAI) H5N1 virus underscores the importance of effective antiviral approaches. AVFluIgG01 is a potent and broad-reactive H5N1-neutralizing human monoclonal antibody (mAb) showing great potential for use either for therapeutic purposes or as a basis of vaccine development, but its antigenic epitope and neutralization mechanism have not been finely characterized. In this study, we first demonstrated that AVFluIgG01 targets a novel conformation-dependent epitope in the globular head region of H5N1 hemagglutinin (HA). By selecting mimotopes from a random peptide library in combination with computational algorithms and site-directed mutagenesis, the epitope was mapped to three conserved discontinuous sites (I-III) that are located closely at the three-dimensional structure of HA. Further, we found that this HA1-specific human mAb can efficiently block both virus-receptor binding and post-attachment steps, while its Fab fragment exerts the post-attachment inhibition only. Consistently, AVFluIgG01 could inhibit HA-mediated cell-cell membrane fusion at a dose-dependent manner and block the acquisition of pH-induced protease sensitivity. These results suggest a neutralization mechanism of AVFluIgG01 by simultaneously blocking viral attachment to the receptors on host cells and interfering with HA conformational rearrangements associated with membrane fusion. The presented data provide critical information for developing novel antiviral therapeutics and vaccines against HPAI H5N1 virus

A Deep Insight into the Sialome of Rhodnius neglectus, a vector of chagas disease

Background Triatomines are hematophagous insects that act as vectors of Chagas disease. Rhodnius neglectus is one of these kissing bugs found, contributing to the transmission of this American trypanosomiasis. The saliva of hematophagous arthropods contains bioactive molecules responsible for counteracting host haemostatic, inflammatory, and immuneresponses. Methods/Principal Findings Next generation sequencing and mass spectrometry-based protein identification were performed to investigate the content of triatomine R. neglectus saliva.We deposited 4,230 coding DNA sequences (CDS) in GenBank. A set of 636 CDS of proteins of putative secretory nature was extracted from the assembled reads, 73 of them confirmed by proteomic analysis. The sialome of R. neglectus was characterized and serine protease transcripts detected. The presence of ubiquitous protein families was revealed, including lipocalins, serine protease inhibitors, and antigen-5. Metalloproteases, disintegrins, and odorant binding protein families were less abundant. Conclusions/Significance The data presented improve our understanding of hematophagous arthropod sialomes, and aid in understanding hematophagy and the complex interplay among vectors and their vertebrate hosts

Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia

Lack of suitable in vitro culture conditions for primary acute lymphoblastic leukaemia (ALL) cells severely impairs their experimental accessibility and the testing of new drugs on cell material reflecting clonal heterogeneity in patients. We show that Nestin-positive human mesenchymal stem cells (MSCs) support expansion of a range of biologically and clinically distinct patient-derived ALL samples. Adherent ALL cells showed an increased accumulation in the S phase of the cell cycle and diminished apoptosis when compared with cells in the suspension fraction. Moreover, surface expression of adhesion molecules CD34, CDH2 and CD10 increased several fold. Approximately 20% of the ALL cells were in G0 phase of the cell cycle, suggesting that MSCs may support quiescent ALL cells. Cellular barcoding demonstrated long-term preservation of clonal abundance. Expansion of ALL cells for >3 months compromised neither feeder dependence nor cancer initiating ability as judged by their engraftment potential in immunocompromised mice. Finally, we demonstrate the suitability of this co-culture approach for the investigation of drug combinations with luciferase-expressing primograft ALL cells. Taken together, we have developed a preclinical platform with patient-derived material that will facilitate the development of clinically effective combination therapies for ALL

Monitoring contractility in cardiac tissue with cellular resolution using biointegrated microlasers

Funding: This research was financially supported by the European Research Council under the European Union’s Horizon 2020 Framework Programme (FP/2014-2020)/ERC grant agreement no. 640012 (ABLASE), by EPSRC (grant no. EP/P030017/1) and by the RS Macdonald Charitable Trust. S.J.P. acknowledges funding by the Royal Society of Edinburgh (Biomedical Fellowship) and the British Heart Foundation (grant no. FS/17/9/32676). S.J.P. and G.B.R. acknowledge support from The Wellcome Trust Institutional Strategic Support Fund to the University of St Andrews (grant no. 204821/Z/16/A). M.S. acknowledges funding by the European Commission (Marie Skłodowska-Curie Individual Fellowship, 659213) and the Royal Society (Dorothy Hodgkin Fellowship, DH160102; grant no. RGF\R1\180070).The contractility of cardiac cells is a key parameter that describes the biomechanical characteristics of the beating heart, but functional monitoring of three-dimensional cardiac tissue with single-cell resolution remains a major challenge. Here, we introduce microscopic whispering-gallery-mode lasers into cardiac cells to realize all-optical recording of transient cardiac contraction profiles with cellular resolution. The brilliant emission and high spectral sensitivity of microlasers to local changes in refractive index enable long-term tracking of individual cardiac cells, monitoring of drug administration, accurate measurements of organ-scale contractility in live zebrafish, and robust contractility sensing through hundreds of micrometres of rat heart tissue. Our study reveals changes in sarcomeric protein density as an underlying factor to cardiac contraction. More broadly, the use of novel micro- and nanoscopic lasers as non-invasive, biointegrated optical sensors brings new opportunities to monitor a wide range of physiological parameters with cellular resolution.PostprintPeer reviewe

The cytokine tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 have a neuroprotective effect in the central nervous system

<p>Abstract</p> <p>Background</p> <p>Cerebral cortical neurons have a high vulnerability to the harmful effects of hypoxia. However, the brain has the ability to detect and accommodate to hypoxic conditions. This phenomenon, known as preconditioning, is a natural adaptive process highly preserved among species whereby exposure to sub-lethal hypoxia promotes the acquisition of tolerance to a subsequent lethal hypoxic injury. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are found in neurons and their expression is induced by exposure to sub-lethal hypoxia. Accordingly, in this work we tested the hypothesis that the interaction between TWEAK and Fn14 induces tolerance to lethal hypoxic and ischemic conditions.</p> <p>Methods</p> <p>Here we used <it>in vitro </it>and <it>in vivo </it>models of hypoxic and ischemic preconditioning, an animal model of transient middle cerebral artery occlusion and mice and neurons genetically deficient in TWEAK, Fn14, or tumor necrosis factor alpha (TNF-α) to investigate whether treatment with recombinant TWEAK or an increase in the expression of endogenous TWEAK renders neurons tolerant to lethal hypoxia. We used enzyme-linked immunosorbent assay to study the effect of TWEAK on the expression of neuronal TNF-α, Western blot analysis to investigate whether the effect of TWEAK was mediated by activation of mitogen-activated protein kinases and immunohistochemical techniques and quantitative real-time polymerase chain reaction analysis to study the effect of TWEAK on apoptotic cell death.</p> <p>Results</p> <p>We found that either treatment with recombinant TWEAK or an increase in the expression of TWEAK and Fn14 induce hypoxic and ischemic tolerance <it>in vivo </it>and <it>in vitro</it>. This protective effect is mediated by neuronal TNF-α and activation of the extracellular signal-regulated kinases 1 and 2 pathway via phosphorylation and inactivation of the B-cell lymphoma 2-associated death promoter protein.</p> <p>Conclusions</p> <p>Our work indicate that the interaction between TWEAK and Fn14 triggers the activation of a cell signaling pathway that results in the induction of tolerance to lethal hypoxia and ischemia. These data indicate that TWEAK may be a potential therapeutic strategy to protect the brain from the devastating effects of an ischemic injury.</p