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Abstract Hairy cell leukemia is an uncommon B‐cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. However, purine analogs are known to be highly immunosuppressive and the infection burden in this patient population with current therapies is unknown. We therefore conducted a retrospective cohort study following 149 patients. Median follow‐up time was 6.9 years. Thirty‐six percent developed an opportunistic or serious infection requiring hospitalization. Most cases were bacterial and most coincided with neutropenia and/or CD4 T‐lymphopenia. No single treatment agent was significantly associated with increased or decreased incidence of infection. Reassuringly, the cumulative incidence of infections plateaued 2 months after initial treatment suggesting clinically significant immune recovery. Only one patient in our cohort passed away due to infection. Estimated 10‐year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

Abstract The WD repeat-containing protein 4 (WDR4) has repeatedly been associated with primary microcephaly, a condition of impaired brain and skull growth. Often, faulty centrosomes cause microcephaly, yet aberrant cilia may also be involved. Here, we show using a combination of approaches in human fibroblasts, zebrafish embryos and patient-derived cells that WDR4 facilitates cilium formation. Molecularly, we associated WDR4 loss-of-function with increased protein synthesis and concomitant upregulation of proteasomal activity, while ubiquitin precursor pools are reduced. Inhibition of proteasomal activity as well as supplementation with free ubiquitin restored normal ciliogenesis. Proteasome inhibition ameliorated microcephaly phenotypes. Thus, we propose that WDR4 loss-of-function impairs head growth and neurogenesis via aberrant cilia formation, initially caused by disturbed protein and ubiquitin homeostasis.

Abstract Our study employs pooled CRISPR screens, integrating 2D and 3D culture models, to identify miRNAs critical in Breast Cancer (BC) tumoursphere formation. These screens combine with RNA-seq experiments allowing identification of miRNA signatures and targets essential for tumoursphere growth. miR-4787-3p exhibits significant up-regulation in BC, particularly in basal-like BCs, suggesting its association with aggressive disease. Surprisingly, despite its location within the 5’UTR of a protein coding gene, which defines DROSHA-independent transcription start site (TSS)-miRNAs, we find it dependant on both DROSHA and DICER1 for maturation. Inhibition of miR-4787-3p hinders tumoursphere formation, highlighting its potential as a therapeutic target in BC. Our study proposes elevated miR-4787-3p expression as a potential prognostic biomarker for adverse outcomes in BC. We find that protein-coding genes positively selected in the CRISPR screens are enriched of miR-4787-3p targets. Of these targets, we select ARHGAP17, FOXO3A, and PDCD4 as known tumour suppressors in cancer and experimentally validate the interaction of miR-4787-3p with their 3’UTRs. Our work illuminates the molecular mechanisms underpinning miR-4787-3p’s oncogenic role in BC. These findings advocate for clinical investigations targeting miR-4787-3p and underscore its prognostic significance, offering promising avenues for tailored therapeutic interventions and prognostic assessments in BC.

BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.

Skateboarding has become a common means of transportation and physical activity among adolescents and adults going to and from work or across college campuses, further highlighting why its implementation as a physical education unit makes sense. This article gives readers a more robust understanding of skateboarding, why it could be advantageous to include in physical education curricula, the general cost of equipment, and an example eight-day skateboarding unit. The aim is to encourage more educators to consider including it in their physical education curriculum.

Objectives CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer. Methods This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response. Results Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment. Conclusions CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored.

BackgroundBrexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care.MethodsAdults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3.ResultsAfter 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively.ConclusionsThese data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population.Trial registrationNCT02614066.

PurposeStandard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy.Patients and methodsOne hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital.ResultsMean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed.ConclusionSubjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Loot boxes are purchasable randomized rewards in video games that share structural and psychological similarities with gambling. Systematic review evidence has established reproducible associations between loot box purchasing and both problem gambling and problem video gaming, perhaps driven by a range of overlapping psychological processes (e.g. impulsivity, gambling-related cognitions, etc.) It has also been argued that loot box engagement may have negative influences on player financial and psychological wellbeing. We conducted a pre-registered survey of 1495 loot box purchasing gamers (LB cohort) and 1223 gamers who purchase other, non-randomized game content (nLB cohort). Our survey confirms 15 of our 23 pre-registered hypotheses against our primary outcome (risky loot box engagement), establishing associations with problem gambling, problem gaming, impulsivity, gambling cognitions, experiences of game-related ‘flow’ and specific ‘distraction and compulsion’ motivations for purchase. Results with hypotheses concerning potential harms established that risky loot box engagement was negatively correlated with wellbeing and positively correlated with distress. Overall, results indicate that any risks from loot boxes are liable to disproportionately affect various ‘at risk’ cohorts (e.g. those experiencing problem gambling or video gaming), thereby reiterating calls for policy action on loot boxes.

ZUMA-1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi-cel), an autologous CD19-directed chimaeric antigen receptor (CAR)-T cell therapy, in refractory large B-cell lymphoma. To reduce treatment-related toxicity, several exploratory safety management cohorts were added to ZUMA-1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end-points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days -5 through -3), 2 × 106  CAR-T cells/kg (day 0) and once-daily oral dexamethasone [10 mg, day 0 (before axi-cel) through day 2]. Forty patients received axi-cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty-eight per cent of patients did not experience CRS or NEs within 72 h of axi-cel. With a median follow-up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.

The authors inadvertently included grant numbers OT3HL147741 & U24CA233032, which are grant-specific. This was an oversight on the authors’ part as these grants did not support the research in this publication.

Abstract Background The main role of the chromosomal passenger complex is to ensure that Aurora B kinase is properly localized and activated before and during mitosis. Borealin, a member of the chromosomal passenger complex, shows increased expression during G2/M phases and is involved in targeting the complex to the centromere and the spindle midzone, where it ensures proper chromosome segregation and cytokinesis. Borealin has a consensus CDK1 phosphorylation site, threonine 106 and can be phosphorylated by Aurora B Kinase at serine 165 in vitro. Results Here, we show that Borealin is phosphorylated during mitosis in human cells. Dephosphorylation of Borealin occurs as cells exit mitosis. The phosphorylated form of Borealin is found in an INCENP-containing complex in mitosis. INCENP-containing complexes from cells in S phase are enriched in the phosphorylated form suggesting that phosphorylation may encourage entry of Borealin into the chromosomal passenger complex. Although Aurora B Kinase is found in complexes that contain Borealin, it is not required for the mitotic phosphorylation of Borealin. Mutation of T106 or S165 of Borealin to alanine does not alter the electrophoretic mobility shift of Borealin. Experiments with cyclohexamide and the phosphatase inhibitor sodium fluoride suggest that Borealin is phosphorylated by a protein kinase that can be active in interphase and mitosis and that the phosphorylation may be regulated by a short-lived phosphatase that is active in interphase but not mitosis. Conclusion Borealin is phosphorylated during mitosis. Neither residue S165, T106 nor phosphorylation of Borealin by Aurora B Kinase is required to generate the mitotic, shifted form of Borealin. Suppression of phosphorylation during interphase is ensured by a labile protein, possibly a cell cycle regulated phosphatase.