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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN® nucleases. In this study, we examine the antitumor activity of UCART123 in preclinical models of BPDCN. We report that UCART123 have selective antitumor activity against CD123-positive primary BPDCN samples (while sparing normal hematopoietic progenitor cells) in the in vitro cytotoxicity and T cell degranulation assays; supported by the increased secretion of IFNγ by UCART123 cells when cultured in the presence of BPDCN cells. UCART123 eradicate BPDCN and result in long-term disease-free survival in a subset of primary patient-derived BPDCN xenograft mouse models. One potential challenge of CD123 targeting therapies is the loss of CD123 antigen through diverse genetic mechanisms, an event observed in one of three BPDCN PDX studied. In summary, these results provide a preclinical proof-of-principle that allogeneic UCART123 cells have potent anti-BPDCN activity.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDC). BPDCN occurs at least three times more frequently in men than in women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN, and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation. SIGNIFICANCE: Sex bias in cancer is well recognized, but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs dendritic cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.This article is highlighted in the In This Issue feature, p. 275.

SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis-related genes. Further, robust basal stem cell activation contributed to neuroepithelial regeneration and restored ACE2 expression postinfection. Together, our study characterized the nasal tropism of SARS- CoV-2 strains, immune clearance, and regeneration after infection. The shifting characteristics of viral infection at the airway portal provide insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention., Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen in the worldwide pandemic of coronavirus disease 2019 (COVID-19), is readily transmitted via respiratory droplets during close contact. The [...]

A growing body of research has investigated the virtues and complexities of mentoring in sports coaching. Yet, a paucity of research exists to consider 'how' both mentors and mentees come to understand their respective role(s). Attempting to redress this gap in research, the aim of this project was to examine the developmental experiences of mentors (and mentees) while participating in a mentoring programme within a University undergraduate sport coaching module. In doing so, this study specifically attended to the critical experiences of mentors and mentees in order to determine how, over the course of the module, mentors and mentees were able to operationalise their role within the coaching context. Data were collected through a series of focus group interviews with 10 mentors and 12 mentees, which were repeated over multiple time-points throughout the mentoring programme. The data were subject to a reflexive thematic analysis to yield three interrelated themes; initiating meaningful mentoring; the relationality of mentoring; and finally, putting 'mentoring' to work. The findings demonstrated the ability (and inability) of learners to develop the reflexive awareness required to negotiate and align their identities within the pedagogical context under study. Drawing upon the explanatory work of Goffman and Crossley, the study contributes to the deconstruction of mentoring practice more specifically, and the wider understanding of complexity of socialisation in coaching and education more generally.

Although the principles behind assessment "for" and "as" learning are well-established, there can be a struggle when reforming traditional assessment "of" learning to a program which encompasses assessment "for" and "as" learning. When introducing and reporting reforms, tensions in faculty may arise because of differing beliefs about the relationship between assessment and learning and the rules for the validity of assessments. Traditional systems of assessment "of" learning privilege objective, structured quantification of learners' performances, and are done "to" the students. Newer systems of assessment promote assessment "for" learning, emphasise subjectivity, collate data from multiple sources, emphasise narrative-rich feedback to promote learner agency, and are done "with" the students. This contrast has implications for implementation and evaluative research. Research of assessment which is done to students typically asks, "what works", whereas assessment that is done "with" the students focuses on more complex questions such as "what works, for whom, in which context, and why?" We applied such a critical realist perspective drawing on the interplay between structure and agency, and a systems approach to explore what theory says about introducing programmatic assessment in the context of pre-existing traditional approaches. Using a reflective technique, the internal conversation, we developed four factors that can assist educators considering major change to assessment practice in their own contexts. These include enabling positive learner agency and engagement; establishing argument-based validity frameworks; designing purposeful and eclectic evidence-based assessment tasks; and developing a shared narrative that promotes reflexivity in appreciating the complex relationships between assessment and learning.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.

Objective: To evaluate the association between smell loss and other aspects of disease, and evaluate dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate or severe smell loss. Methods: This post-hoc analysis of the SINUS-24/52 studies (NCT02912468/NCT02898454) analyzed nasal polyp score (NPS, 0−8), nasal congestion/obstruction (NC, 0−3), Lund-Mackay CT-scan score (LMK-CT, 0−24), rhinosinusitis severity visual analog scale (RS-VAS, 0-10), and 22-item Sinonasal Outcome Test (SNOT-22, 0−110) according to baseline monthly average patient-reported loss of smell scores (LoS, 0−3) of >1 to 2 (moderate) or >2 to 3 (severe) in patients randomized to dupilumab 300 mg or placebo every 2 weeks. Results: Of 724 patients randomized, baseline LoS was severe in 601 (83%) and moderate in 106 (15%). At baseline, severe versus moderate LoS was associated with 1-point greater severity of NC (odds ratio [OR] 6.01 [95% confidence interval, (CI) 3.95, 9.15]), 5-point greater severity of LMK-CT (OR 2.19 [1.69, 2.85]), and 8.9-point greater severity of SNOT-22 (OR 1.35 [1.20, 1.49]). At Week 24, least squares mean differences (95% CI) dupilumab versus placebo in change from baseline were: NPS −1.90 (−2.56, −1.25) and −1.95 (−2.20, −1.70) in the moderate and severe baseline LoS subgroups, respectively; NC −.35 (−.64, −.06) and −1.00 (−1.13, −.87); LMK-CT −6.30 (−7.88, −4.72) and −6.22 (−6.82, −5.63); RS-VAS −1.18 (−2.20, −.16) and −3.47 (−3.90, −3.03); and SNOT-22 −7.52 (−14.55, −.48) and −21.72 (−24.63, −18.82); all nominal P <.05 versus placebo. Improvements with dupilumab in NC, RS-VAS, and SNOT-22 were statistically greater in patients with severe versus moderate baseline LoS. Conclusion: Significant smell impairment in severe CRSwNP is associated with significant disease (NC, RS-VAS, LMK), health-related quality of life impairment (SNOT-22), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease. Dupilumab significantly improved NPS, NC, LMK-CT, RS-VAS, and SNOT-22 in subjects with moderate and severe baseline smell loss. [ABSTRACT FROM AUTHOR]

We describe a male with adrenal hypoplasia congenita (AHC) caused by a novel mutation in NR0B1, who was noted at 9 months of age to have central precocious puberty (CPP). A 3-week-old full-term male presented with hypothermia and lethargy, and a 0.3 kg weight loss since birth. Labs were consistent with adrenal crisis, he was stabilized with stress dose hydrocortisone (HC), insulin, and antibiotics, and he was admitted to the Pediatric Intensive Care Unit. Subsequent labs revealed primary adrenal insufficiency with abdominal ultrasound remarkable for nonvisualization of the adrenal glands. Genetic testing identified a novel pathogenic c.707G>A [p.Trp236ter] nonsense variant in the DNA-binding domain of NR0B1 (DAX-1) confirming AHC. The patient was discharged with HC, fludrocortisone, and sodium supplementation with good tolerance and interval weight gain and normal electrolytes. At 9 months of age, the patient developed signs of precocious puberty, which failed to self-resolve or diminish with increased dosing of HC, and by the age of 15 months, he was treated with leuprolide acetate. Historically, hypogonadotropic hypogonadism has been observed in 76 % of adolescent patients with AHC who have alterations in NR0B1. CPP has been infrequently described in AHC, and the natural history and management of CPP in this setting is not established. Our observations may contribute to the understanding of factors influencing normal and abnormal puberty in infants. Increased awareness of the possibility of CPP in AHC will aid clinicians in the earlier clinical and laboratory detection of this complication. [ABSTRACT FROM AUTHOR]

This study examined the effects of coach encouragement (CE) on psychophysiological responses and technical actions in different small-sided soccer games (SSGs) in young soccer players. Twenty male soccer players (17.3 ± 1.4 years of age) performed four bouts of 2, 3 and 4-a-side SSGs with two minutes of rest between bouts at three-day intervals. Heart rate (HR) responses and technical actions were continuously monitored and recorded during all SSGs. The rating of perceived exertion (RPE), enjoyment (PACES), and mood (Profile of Mood of States: POMS) were also determined at the end of the last bout of each SSGs. Results demonstrated that CE + SSGs induced higher psychophysiological responses such as HR, RPE, and PACES responses (p ≤ 0.05, d values ranging from 0,76 to 2,25 [moderate to very large effect]). Furthermore, the CE + SSGs demonstrated significantly higher technical actions in terms of successful passes and shots (p ≤ 0.05, d values ranging from 0,84 to 3,25 [moderate to very large effect]) when compared to SSGs without CE (CE-SSGs). Conversely, the CE-SSGs induced higher unpleasant mood responses in terms of tension, anger, and fatigue in young soccer players. The results of this study suggest that if coaches want players to perform under higher-intensity conditions, they should encourage players in game-based training. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusion\nPLAIN LANGUAGE SUMMARYLoss of sense of smell is a cardinal symptom of chronic rhinosinusitis with nasal polyps (CRSwNP) and significantly impacts health-related quality-of-life. Dupilumab significantly improved smell outcomes (loss of smell [LoS] score; University of Pennsylvania Smell Identification Test [UPSIT]) versus placebo in the phase 3 SINUS-24/-52 studies (clinicaltrials.gov, NCT02898454/NCT02912468) in patients with severe CRSwNP. This post hoc analysis investigated the effect of dupilumab on olfaction using UPSIT smell impairment categories.Patients with baseline smell impairment (UPSIT ≤34/≤33 [women/men; score range 0–40] AND LoS score ≥1 [0–3] AND smell/taste item of the 22-item Sinonasal Outcome Test >0 [SNOT-22; 0–5]) treated with dupilumab 300 mg or placebo once every 2 weeks on background intranasal corticosteroids were analyzed.Of 724 patients, 665 (91.9%) had smell impairment at baseline; most had anosmia (UPSIT 0–18) (dupilumab/placebo: 80.9%/79.8%). At week 24, the proportion of dupilumab-treated patients with anosmia decreased to 28.5%, while 14.9% achieved normosmia; most placebo-group patients (79.2%) remained anosmic and only 1.2% achieved normosmia (odds ratio = 17.3; 95% confidence interval = 5.1–59.0; p <.0001); results were similar at week 52. Improvements in Nasal Polyp Score, nasal congestion, and SNOT-22 total score were moderately correlated with improvements in UPSIT at weeks 24 and 52 (r = −.38 to −.50).Most patients with severe CRSwNP had anosmia at baseline. Dupilumab treatment significantly improved smell versus placebo, with 14.9% achieving normosmia by week 24. There was a trend for better clinical outcomes in patients with greater smell improvement.Chronic rhinosinusitis with nasal polyps (CRSwNP) is a condition that causes partial or complete blockage of the nose, making it difficult to breathe. This has a negative effect on many aspects of a person’s life, with loss of sense of smell one of the most common and troublesome symptoms. A drug called dupilumab, which is injected under the skin every other week, has been approved for use in people with CRSwNP. This article presents results from two studies where dupilumab was tested to see if it helped people with CRSwNP, including whether it could improve sense of smell. At the start of the trial, about 80% of people had completely lost their sense of smell, known as anosmia. After 24 weeks, fewer people taking dupilumab had no sense of smell (28.5%) and more had a completely normal sense of smell (14.9%) compared with people who took a placebo (79.2% had no sense of smell; 1.2% had a normal sense of smell). Smell was assessed again after 52 weeks and dupilumab continued to provide a similar benefit. Dupilumab also improved other aspects of CRSwNP, including reducing polyp size, clearing nose blockage, and improving quality-of-life. In summary, most people with CRSwNP at the start of the dupilumab studies had completely lost their sense of smell, and dupilumab improved smell for most people within 24 weeks. This shows the benefit of dupilumab in dealing with this bothersome and difficult-to-treat symptom of CRSwNP. [ABSTRACT FROM AUTHOR]

Microtubule remodeling is critical for cellular and developmental processes underlying morphogenetic changes and for the formation of many subcellular structures. Katanins are conserved microtubule severing enzymes that are essential for spindle assembly, ciliogenesis, cell division, and cellular motility. We have recently shown that a related protein, Katanin-like 2 (KATNAL2), is similarly required for cytokinesis, cell cycle progression, and ciliogenesis in cultured mouse cells. However, its developmental expression pattern, localization, and in vivo role during organogenesis have yet to be characterized. Here, we used Xenopus embryos to reveal that Katnal2 (1) is expressed broadly in ciliated and neurogenic tissues throughout embryonic development; (2) is localized to basal bodies, ciliary axonemes, centrioles, and mitotic spindles; and (3) is required for ciliogenesis and brain development. Since human KATNAL2 is a risk gene for autism spectrum disorders, our functional data suggest that Xenopus may be a relevant system for understanding the relationship of mutations in this gene to autism and the underlying molecular mechanisms of pathogenesis.

The key factors underlying the development of allergic diseases-the propensity for a minority of individuals to develop dysfunctional responses to harmless environmental molecules-remain undefined. We report a pathway of immune counter-regulation that suppresses the development of aeroallergy and shrimp-induced anaphylaxis. In mice, signaling through epithelially expressed dectin-1 suppresses the development of type 2 immune responses through inhibition of interleukin-33 (IL-33) secretion and the subsequent recruitment of IL-13-producing innate lymphoid cells. Although this homeostatic pathway is functional in respiratory epithelial cells from healthy humans, it is dramatically impaired in epithelial cells from asthmatic and chronic rhinosinusitis patients, resulting in elevated IL-33 production. Moreover, we identify an association between a single-nucleotide polymorphism (SNP) in the dectin-1 gene loci and reduced pulmonary function in two cohorts of asthmatics. This intronic SNP is a predicted eQTL (expression quantitative trait locus) that is associated with reduced dectin-1 expression in human tissue. We identify invertebrate tropomyosin, a ubiquitous arthropod-derived molecule, as an immunobiologically relevant dectin-1 ligand that normally serves to restrain IL-33 release and dampen type 2 immunity in healthy individuals. However, invertebrate tropomyosin presented in the context of impaired dectin-1 function, as observed in allergic individuals, leads to unrestrained IL-33 secretion and skewing of immune responses toward type 2 immunity. Collectively, we uncover a previously unrecognized mechanism of protection against allergy to a conserved recognition element omnipresent in our environment.