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The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the 'arms race' with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.1 spike protein by screening nanobody phage display libraries previously generated from llamas immunized with either the Wuhan or Beta spike proteins. The structure and binding properties of three of these nanobodies (A8, H6 and B5-5) have been characterized in detail providing insight into their binding epitopes on the Omicron spike protein. Trimeric versions of H6 and B5-5 neutralized the SARS-CoV-2 variant of concern BA.5 both in vitro and in the hamster model of COVID-19 following nasal administration. Thus, either alone or in combination could serve as starting points for the development of new anti-viral immunotherapeutics.
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Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19 , SARS-CoV-2 , Anticorpos de Domínio Único , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/imunologia , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/farmacologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/química , COVID-19/imunologia , COVID-19/virologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Humanos , Anticorpos Antivirais/imunologia , Camelídeos Americanos/imunologia , Epitopos/imunologia , Epitopos/química , Cricetinae , Ligação Proteica , Modelos MolecularesRESUMO
The number of adults living with cystic fibrosis (CF) has already increased significantly because of drastic improvements in life expectancy attributable to advances in treatment, including the development of highly effective modulator therapy. Chronic airway inflammation in CF contributes to morbidity and mortality, and aging processes like inflammaging and cell senescence influence CF pathology. Our results show that single-cell RNA sequencing data, human primary bronchial epithelial cells from non-CF and CF donors, a CF bronchial epithelial cell line, and Cftr-knockout (Cftr-/-) rats all demonstrated increased cell senescence markers in the CF bronchial epithelium. This was associated with upregulation of fibroblast growth factor receptors (FGFRs) and mitogen-activated protein kinase (MAPK) p38. Inhibition of FGFRs, specifically FGFR4 and to some extent FGFR1, attenuated cell senescence and improved mucociliary clearance, which was associated with MAPK p38 signaling. Mucociliary dysfunction could also be improved using a combination of senolytics in a CF ex vivo model. In summary, FGFR/MAPK p38 signaling contributes to cell senescence in CF airways, which is associated with impaired mucociliary clearance. Therefore, attenuation of cell senescence in the CF airways might be a future therapeutic strategy improving mucociliary dysfunction and lung disease in an aging population with CF.
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Senescência Celular , Fibrose Cística , Mucosa Respiratória , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Humanos , Animais , Ratos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Células Epiteliais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Masculino , Modelos Animais de Doenças , Linhagem Celular , Brônquios/patologia , Brônquios/metabolismo , Transdução de Sinais , FemininoRESUMO
Rationale: The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF. Methods: Bleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with µCT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence. Results: Bleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric µCT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant 'proximalization' repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level. Conclusions: Bleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.
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Although whistleblowing is thought to represent an effective mechanism for detecting and uncovering doping in sport, it has yet to become a widely adopted practice. Understanding the factors that encourage or discourage whistleblowing is of vital importance for the promotion of this practice and the development of pedagogical material to enhance the likelihood of whistleblowing. The current study employed a qualitative methodology to explore the personal and organisational factors that underpin intentions to blow the whistle or that may lead to engagement in whistleblowing behaviours in sport. Thirty-three competitive athletes across a range of sports took part in a semi-structured interview which sought to explore what they would do should they encounter a doping scenario. Content analysis revealed that whistleblowing is a dynamic process characterised by the interaction of a range of personal and organisational factors in determining the intention to report PED use. These factors included moral reasoning, a desire to keep the matter "in-house", perceived personal costs, institutional attitudes to doping, and social support. Analysis revealed a number of "intervening events", including a perceived lack of organisational protection (e.g., ethical leadership) within some sporting sub-cultures, which present an important obstacle to whistleblowing. The intention to report doping was underpinned by a "fairness-loyalty trade-off" which involved athletes choosing to adhere to either fairness norms (which relate to a sense that all people and groups are treated equally) or loyalty norms (which reflect preferential treatment towards an in-group) when deciding whether they would blow the whistle. The promotion of fairness norms that emphasise a group's collective interests might encourage athletes to view whistleblowing as a means of increasing group cohesiveness and effectiveness and thereby increase the likelihood of this practice.
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Background: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disease that is characterized by an excessive accumulation of extracellular matrix (ECM) proteins (e.g. collagens) in the parenchyma, which ultimately leads to respiratory failure and death. While current therapies exist to slow the progression, no therapies are available to resolve fibrosis. Methods: We characterized the O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT)/O-GlcNAc axis in IPF using single-cell RNA-sequencing (scRNA-seq) data and human lung sections and isolated fibroblasts from IPF and non-IPF donors. The underlying mechanism(s) of IPF were further investigated using multiple experimental models to modulate collagen expression and accumulation by genetically and pharmacologically targeting OGT. Furthermore, we hone in on the transforming growth factor-beta (TGF-ß) effector molecule, Smad3, by co-expressing it with OGT to determine if it is modified and its subsequent effect on Smad3 activation. Results: We found that OGT and O-GlcNAc levels are upregulated in patients with IPF compared to non-IPF. We report that the OGT regulates collagen deposition and fibrosis resolution, which is an evolutionarily conserved process demonstrated across multiple species. Co-expression of OGT and Smad3 showed that Smad3 is O-GlcNAc modified. Blocking OGT activity resulted in decreased phosphorylation at Ser-423/425 of Smad3 attenuating the effects of TGF-ß1 induced collagen expression/deposition. Conclusion: OGT inhibition or knockdown successfully blocked and reversed collagen expression and accumulation, respectively. Smad3 is discovered to be a substrate of OGT and its O-GlcNAc modification(s) directly affects its phosphorylation state. These data identify OGT as a potential target in pulmonary fibrosis resolution, as well as other diseases that might have aberrant ECM/collagen accumulation.
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Colágeno , Fibrose Pulmonar Idiopática , N-Acetilglucosaminiltransferases , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Humanos , N-Acetilglucosaminiltransferases/metabolismo , N-Acetilglucosaminiltransferases/genética , Colágeno/metabolismo , Animais , Camundongos , Proteína Smad3/metabolismo , Fibroblastos/metabolismo , Pulmão/patologia , Pulmão/metabolismo , Masculino , Células CultivadasRESUMO
BACKGROUND: Exercise is recommended for office workers with neck pain. However, recent reviews evaluated the effectiveness of workplace interventions only. OBJECTIVES: To evaluate the effect of exercise on pain, disability, and quality of life (QoL) in office workers with chronic neck pain. DESIGN: Systematic review with meta-analysis. METHODS: Electronic databases were searched from inception to April 30, 2022, to identify studies in which participants were adults aged ≥18 years undergoing any form of neck exercises (e.g., strengthening, motor control) or physical activity (e.g., aerobic exercise) performed for a minimum of two-weeks without any other additional treatment besides advice or education. Two reviewers independently screened papers and determined the certainty of the evidence. RESULTS: Eight randomised controlled trials met the eligibility criteria. Seven studies reported a significant decrease in Visual Analogue Scale (VAS) scores for neck pain intensity and five studies reported a significant decrease in Neck Disability Index (NDI) scores following strengthening exercises. Only one study assessed the effect of strengthening exercises on QoL and reported no significant effect. All eight included studies had a high risk of bias and the overall certainty of evidence was low. Meta-analyses demonstrated a significant decrease of neck pain intensity and disability for strengthening exercises compared to a control (p < 0.01). CONCLUSION: There is low certainty of evidence that strengthening of the neck, shoulder and scapular musculature is effective at reducing neck pain and disability in office workers. Further research evaluating the effect of exercise on QoL is required.
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Dor Crônica , Exercício Físico , Cervicalgia , Saúde Ocupacional , Adulto , Humanos , Dor Crônica/terapia , Pescoço , Cervicalgia/terapia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
It has been proposed that autistic people experience a temporal distortion whereby the temporal binding window of multisensory integration is extended. Research to date has focused on autistic children so whether these differences persist into adulthood remains unknown. In addition, the possibility that the previous observations have arisen from between-group differences in response bias, rather than perceptual differences, has not been addressed. Participants completed simultaneity judgements of audiovisual speech stimuli across a range of stimulus-onset asynchronies. Response times and accuracy data were fitted to a drift-diffusion model so that the drift rate (a measure of processing efficiency) and starting point (response bias) could be estimated. In Experiment 1, we tested a sample of non-autistic adults who completed the Autism Quotient questionnaire. Autism Quotient score was not correlated with either drift rate or response bias, nor were there between-group differences when splitting based on the first and third quantiles of scores. In Experiment 2, we compared the performance of autistic with a group of non-autistic adults. There were no between-group differences in either drift rate or starting point. The results of this study do not support the previous suggestion that autistic people have an extended temporal binding window for audiovisual speech. In addition, exploratory analysis revealed that operationalising the temporal binding window in different ways influenced whether a group difference was observed, which is an important consideration for future work.
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Reliable information on population size is fundamental to the management of threatened species. For wild species, mark-recapture methods are a cornerstone of abundance estimation. Here, we show the first application of the close-kin mark-recapture (CKMR) method to a terrestrial species of high conservation value; the Christmas Island flying-fox (CIFF). The CIFF is the island's last remaining native terrestrial mammal and was recently listed as critically endangered. CKMR is a powerful tool for estimating the demographic parameters central to CIFF management and circumvents the complications arising from the species' cryptic nature, mobility, and difficult-to-survey habitat. To this end, we used genetic data from 450 CIFFs captured between 2015 and 2019 to detect kin pairs. We implemented a novel CKMR model that estimates sex-specific abundance, trend, and mortality and accommodates observations from the kin-pair distribution of male reproductive skew and mate persistence. CKMR estimated CIFF total adult female abundance to be approximately 2050 individuals (95% CI (950, 4300)). We showed that on average only 23% of the adult male population contributed to annual reproduction and strong evidence for between-year mate fidelity, an observation not previously quantified for a Pteropus species in the wild. Critically, our population estimates provide the most robust understanding of the status of this critically endangered population, informing immediate and future conservation initiatives.
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Quirópteros , Conservação dos Recursos Naturais , Humanos , Animais , Masculino , Feminino , Espécies em Perigo de Extinção , Densidade Demográfica , Ecossistema , MamíferosRESUMO
Single nucleotide polymorphism (SNP) chromosome microarray is well established for investigation of children with intellectual deficit/development delay and prenatal diagnosis of fetal malformation but has also emerged for uniparental disomy (UPD) genotyping. Despite published guidelines on clinical indications for testing there are no laboratory guidelines published for performing SNP microarray UPD genotyping. We evaluated SNP microarray UPD genotyping using Illumina beadchips on family trios/duos within a clinical cohort (n=98) and then explored our findings in a post-study audit (n=123). UPD occurred in 18.6% and 19.5% cases, respectively, with chromosome 15 most frequent (62.5% and 25.0%). UPD was predominantly maternal in origin (87.5% and 79.2%), highest in suspected genomic imprinting disorder cases (56.3% and 41.7%) but absent amongst children of translocation carriers. We assessed regions of homozygosity among UPD cases. The smallest interstitial and terminal regions were 2.5 Mb and 9.3 Mb, respectively. We found regions of homozygosity confounded genotyping in a consanguineous case with UPD15 and another with segmental UPD due to non-informative probes. In a unique case with chromosome 15q UPD mosaicism, we established the detection limit of mosaicism as â¼5%. From the benefits and pitfalls identified in this study, we propose a testing model and recommendations for UPD genotyping by SNP microarray.
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Polimorfismo de Nucleotídeo Único , Dissomia Uniparental , Criança , Gravidez , Feminino , Humanos , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Genótipo , Impressão Genômica , CromossomosRESUMO
Effective management of protected species requires information on appropriate evolutionary and geographic population boundaries and knowledge of how the physical environment and life-history traits combine to shape the population structure and connectivity. Saltwater crocodiles (Crocodylus porosus) are the largest and most widely distributed of living crocodilians, extending from Sri Lanka to Southeast Asia and down to northern Australia. Given the long-distance movement capabilities reported for C. porosus, management units are hypothesised to be highly connected by migration. However, the magnitude, scale, and consistency of connection across managed populations are not fully understood. Here we used an efficient genotyping method that combines DArTseq and sequence capture to survey ≈ 3000 high-quality genome-wide single nucleotide polymorphisms from 1176 C. porosus sampled across nearly the entire range of the species in Queensland, Australia. We investigated historical and present-day connectivity patterns using fixation and diversity indices coupled with clustering methods and the spatial distribution of kin pairs. We inferred kinship using forward simulation coupled with a kinship estimation method that is robust to unspecified population structure. The results demonstrated that the C. porosus population has substantial genetic structure with six broad populations correlated with geographical location. The rate of gene flow was highly correlated with spatial distance, with greater differentiation along the east coast compared to the west. Kinship analyses revealed evidence of reproductive philopatry and limited dispersal, with approximately 90% of reported first and second-degree relatives showing a pairwise distance of <50 km between sampling locations. Given the limited dispersal, lack of suitable habitat, low densities of crocodiles and the high proportion of immature animals in the population, future management and conservation interventions should be considered at regional and state-wide scales.
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Respiratory tract infection (RTI) remains a significant cause of morbidity and mortality across the globe. The optimal management of RTI relies upon timely pathogen identification via evaluation of respiratory samples, a process which utilises traditional culture-based methods to identify offending microorganisms. This process can be slow and often prolongs the use of broad-spectrum antimicrobial therapy, whilst also delaying the introduction of targeted therapy as a result. Nanopore sequencing (NPS) of respiratory samples has recently emerged as a potential diagnostic tool in RTI. NPS can identify pathogens and antimicrobial resistance profiles with greater speed and efficiency than traditional sputum culture-based methods. Increased speed to pathogen identification can improve antimicrobial stewardship by reducing the use of broad-spectrum antibiotic therapy, as well as improving overall clinical outcomes. This new technology is becoming more affordable and accessible, with some NPS platforms requiring minimal sample preparation and laboratory infrastructure. However, questions regarding clinical utility and how best to implement NPS technology within RTI diagnostic pathways remain unanswered. In this review, we introduce NPS as a technology and as a diagnostic tool in RTI in various settings, before discussing the advantages and limitations of NPS, and finally what the future might hold for NPS platforms in RTI diagnostics.
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Sequenciamento por Nanoporos , Nanoporos , Infecções Respiratórias , Humanos , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/tratamento farmacológico , Antibacterianos/uso terapêutico , Metagenômica/métodosRESUMO
African Horse Sickness (AHS) is a vector-borne viral disease of equids. The disease can be highly lethal with mortality rates of up to 90% in non-immune equine populations. The clinical presentation in the equine host varies, but the pathogenesis underlying this variation remains incompletely understood. Various small animal models of AHS have been developed over the years to overcome the financial, bio-safety and logistical constraints of studying the pathology of this disease in the target species. One of the most successful small animal models is based on the use of interferon-alpha gene knock-out (IFNAR-/-) mice. In order to increase our understanding of African Horse Sickness virus (AHSV) pathogenesis, we characterised the pathology lesions of AHSV infection in IFNAR-/- mice using a strain of AHSV serotype 4 (AHSV-4). We found AHSV-4 infection was correlated with lesions in various organs; necrosis in the spleen and lymphoid tissues, inflammatory infiltration in the liver and brain, and pneumonia. Significant viral antigen staining was only detected in the spleen and brain, however. Together these results confirm the value of the IFNAR-/- mouse model for the study of the immuno-biology of AHSV infections in this particular in vivo system, and its usefulness for evaluating protective efficacy of candidate vaccines in preclinical studies.
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Viruses are microscopic pathogens capable of causing disease and are responsible for a range of human mortalities and morbidities worldwide. They can be rendered harmless or destroyed with a range of antiviral chemical compounds. Cucurbit[n]urils (CB[n]s) are a family of macrocycle chemical compounds existing as a range of homologues; due to their structure, they can bind to biological materials, acting as supramolecular "hosts" to "guests", such as amino acids. Due to the increasing need for a nontoxic antiviral compound, we investigated whether cucurbit[n]urils could act in an antiviral manner. We have found that certain cucurbit[n]uril homologues do indeed have an antiviral effect against a range of viruses, including herpes simplex virus 2 (HSV-2), respiratory syncytial virus (RSV) and SARS-CoV-2. In particular, we demonstrate that CB[7] is the active homologue of CB[n], having an antiviral effect against enveloped and nonenveloped species. High levels of efficacy were observed with 5 min contact times across different viruses. We also demonstrate that CB[7] acts with an extracellular virucidal mode of action via host-guest supramolecular interactions between viral surface proteins and the CB[n] cavity, rather than via cell internalization or a virustatic mechanism. This finding demonstrates that CB[7] acts as a supramolecular virucidal antiviral (a mechanism distinct from other current extracellular antivirals), demonstrating the potential of supramolecular interactions for future antiviral disinfectants.
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COVID-19 , Desinfetantes , Compostos Macrocíclicos , Aminoácidos , Antivirais/farmacologia , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Humanos , Imidazóis/química , Compostos Macrocíclicos/química , Proteínas de Membrana , SARS-CoV-2RESUMO
One aspect of sports retirement that has been overlooked until recently is the manner in which retired athletes relate to, and seek to redefine, the meaning of exercise in their post-sport lives. In this article, three Foucauldian scholars present and analyze a series of vignettes concerning their own sense-making and meaning-making about exercise following their long-term involvement in high-performance soccer (authors one and two) and distance running (author three). In doing so, this paper aims to underline the problematic legacy of high-performance sport for retiring athletes' relationship to movement and exercise, and to highlight how social theory, and Foucauldian theorization in particular, can serve to open new spaces and possibilities for thinking about sports retirement.
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Monitoring programs are fundamental to understanding the state and trend of aquatic ecosystems. Sampling designs are a crucial component of monitoring programs and ensure that measurements evaluate progress toward clearly stated management objectives, which provides a mechanism for adaptive management. Here, we use a well-established marine monitoring program for inshore water quality in the Great Barrier Reef (GBR), Australia to investigate whether a sampling re-design has increased the program's capacity to meet its primary objectives. Specifically, we use bootstrap resampling to assess the change in statistical power to detect temporal water quality trends in a 15-year inshore marine water quality data set that includes data from both before and after the sampling re-design. We perform a comprehensive power analysis for six water quality analytes at four separate study areas in the GBR Marine Park and find that the sampling re-design (i) increased power to detect trends in 23 of the 24 analyte-study area combinations, and (ii) resulted in an average increase in power of 34% to detect increasing or decreasing trends in water quality analytes. This increase in power is attributed more to the addition of sampling locations than increasing the sampling rate. Therefore, the sampling re-design has substantially increased the capacity of the program to detect temporal trends in inshore marine water quality. Further improvements in sampling design need to focus on the program's capability to reliably detect trends within realistic timeframes where inshore improvements to water quality can be expected to occur.
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Recifes de Corais , Qualidade da Água , Austrália , Ecossistema , Monitoramento Ambiental/métodosRESUMO
It has previously been proposed that autistic people have problems with timing which underlie the behavioral and cognitive differences in the condition. However, the nature of this postulated timing issue has not been well specified and the existing experimental literature has generated mixed findings. In the current study, we attempted a systematic investigation of timing processes in autistic adults using scalar expectancy theory as a theoretical framework. Autistic (n = 58) and nonautistic (n = 91) adults matched for age, sex, and full-scale IQ completed a battery of auditory and visual timing tasks measuring basic subsecond duration perception (temporal discrimination thresholds), clock processes (verbal estimation), clock and memory processes (temporal generalization), and event timing (temporal order judgments). Participants also completed suprasecond retrospective duration estimates where the participant was not warned in advanced that they would be required to make a timing judgment, and questionnaires measuring self-reported timing behaviors in daily life. The groups reported differences on questionnaires, but measures of timing performance were comparable overall. In an exploratory analysis, we performed principal components analysis to investigate the relationship between timing judgments and participants' self-reported social-communicative, sensory, and motor traits. Measures of timing performance were not well correlated with these questionnaire scores. The current study, the largest conducted on time and autism to date, shows no clear evidence for reduced timing performance in autistic adults. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Transtorno Autístico , Percepção do Tempo , Adulto , Transtorno Autístico/psicologia , Humanos , Julgamento , Memória , Estudos RetrospectivosRESUMO
KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slow-paced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing.
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The concept of shared decision-making (SDM) has emerged as a key component in the return to play interface as a hallmark of good practice that is athlete focused and allows greater engagement from the athlete. SDM is an appealing, well-intentioned framework that would seemingly lend itself to effectively being implemented. However, in this editorial, we have identified concerns surrounding the social complexities of elite sports and the difficulties of truly applying this concept in practice. In what follows, we explain the dynamics associated, discuss the importance of context when considering the efficacy of this practice and lastly offer what we see as certain key issues that might impede effective SDM.
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It is essential to relate the biology of acute leukaemia to normal blood cell development. In this review, we discuss how modern models of haematopoiesis might inform approaches to diagnosis and management of immature leukaemias, with a specific focus on T-lymphoid and myeloid cases. In particular, we consider whether next-generation analytical tools could provide new perspectives that could improve our understanding of immature blood cancer biology.
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Leucemia Mieloide Aguda , Doença Aguda , Hematopoese , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapiaRESUMO
Infants with MLL-rearranged infant acute lymphoblastic leukemia (MLL-r iALL) undergo intense therapy to counter a highly aggressive malignancy with survival rates of only 30-40%. The majority of patients initially show therapy response, but in two-thirds of cases the leukemia returns, typically during treatment. The glucocorticoid drug prednisone is established as a major player in the treatment of leukemia and the in vivo response to prednisone monotreatment is currently the best indicator of risk for MLL-r iALL. We used two different single-cell RNA sequencing technologies to analyze the expression of a prednisone-dependent signature, derived from an independent study, in diagnostic bone marrow and peripheral blood biopsies. This allowed us to classify individual leukemic cells as either resistant or sensitive to treatment and show that quantification of these two groups can be used to better predict the occurrence of future relapse in individual patients. This work also sheds light on the nature of the therapy-resistant subpopulation of relapse-initiating cells. Leukemic cells associated with high relapse risk are characterized by basal activation of glucocorticoid response, smaller size, and a quiescent gene expression program with cell stemness properties. These results improve current risk stratification and elucidate leukemic therapy-resistant subpopulations at diagnosis.