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How seahorses and pipefish inspired the design of a boat propeller
Introduction to a review series on acute lymphoblastic leukemia
Our understanding of the biology of acute lymphoblastic leukemia (ALL) continues to be refined, and these advances naturally lead to improvements in therapy and outcomes for pediatric and adult patients. Associate Editor Hervé Dombret introduces this series of reviews that bring readers up to date with the biology of both B-cell and T-cell ALL (B-ALL and T-ALL) as well as the latest approaches to first-line therapy. Passet et al discuss the different genetic subtypes of B-ALL and their implications, while Pölönen and colleagues discuss T-ALL, highlighting how biology informs classification and in turn prognostication and therapy. Badar and coauthors explore how the incorporation of immunotherapy is revolutionizing treatment regimens. Finally, Rampotas and Roddie focus specifically on the role of chimeric antigen receptor T cells in management of patients with B-ALL now and in the future.
Phosphoglucomutase 5 gene transcripts are expressed by the human placenta and differentially regulated in placental dysfunction
Progressive chromatin rewiring by ETO2::GLIS2 revealed in a genome-edited human iPSC model of pediatric leukemia initiation
Abstract Pediatric acute myeloid leukemia frequently harbors fusion oncogenes associated with poor prognosis, including KMT2A, NUP98, and GLIS2 rearrangements. Although murine models have demonstrated their leukemogenic activities, the steps from a normal human cell to leukemic blasts remain unclear. Here, we precisely reproduced the inversion of chromosome 16 resulting in the ETO2::GLIS2 fusion in human induced pluripotent stem cells (iPSCs). iPSC-derived ETO2::GLIS2-expressing hematopoietic cells showed differentiation alterations in vitro and efficiently induced in vivo development of leukemia that closely phenocopied human acute megakaryoblastic leukemia (AMKL), reflected by flow cytometry and single-cell transcriptomes. Comparison of iPS-derived cells with patient-derived cells revealed altered chromatin accessibility at early and later bona fide leukemia stages, with aberrantly higher accessibility and expression of the osteogenic homeobox factor DLX3 that preceded increased accessibility to ETS factors. DLX3 overexpression in normal CD34+ cells increased accessibility to ETS motifs and reduced accessibility to GATA motifs. A DLX3 transcriptional module was globally enriched in both ETO2::GLIS2 AMKL and some aggressive pediatric osteosarcoma. Importantly, DLX3 knockout abrogated leukemia initiation in this ETO2::GLIS2 iPSC model. Collectively, the characterization of a novel human iPSC-derived AMKL model revealed that hijacking of the osteogenic homeobox transcription factor DLX3 is an essential early step in chromatin changes and leukemogenesis driven by the ETO2::GLIS2 fusion oncogene.
Nature-based solutions could offset coastal squeeze of tidal wetlands from sea-level rise on the U.S. Pacific coast
Abstract In this study, we explored the opportunities for tidal wetland landward migration in response to sea-level rise on the Pacific Coast of the United States. By employing a systematic spatial approach, we quantified the available space for wetland migration with sea-level rise across 61 estuarine drainage areas. Although many of the existing tidal wetlands are small patches, our analyses show that 63% of the estuaries lacked the landward migration space needed to replace current tidal wetland extent, thereby threatening a wide range of protected species and ecosystem services. Developed lands and steep topography represent common barriers to migration along the Pacific coast, especially in central and southern California. The available wetland migration space consists primarily of agriculture, pasture, and freshwater wetlands, with most of the area available for migration occurring in just a few watersheds. In most watersheds tidal wetland migration would only occur with human intervention or facilitation. The greatest amount of area available for wetland migration was in the San Francisco Bay-Delta and Columbia River estuaries, together accounting for 58% of all available migration space on the Pacific Coast. Nature-based solutions to reduce tidal wetland loss from sea-level rise can include restoration in suitable areas, removal of barriers to tidal wetland migration, and elevation building approaches. Tidal wetland restoration opportunities could increase area by 59%, underscoring it as a plausible approach to prevent tidal wetland loss in those estuaries and a viable Nature-based solution. 54% of estuaries building elevations of existing tidal wetlands may be the most feasible approach needed. Our analyses illustrate the importance of management efforts that use Nature-based approaches to prevent tidal wetland ecosystem and species loss over the coming decades from sea-level rise.
The global scientific community must keep studying LGBT+ health
The immunotherapy real estate of Hodgkin lymphoma
Difficulty aware programming knowledge tracing via large language models
Action needed to mitigate effects of slashing USAID
The present and future of CAR T-cell therapy for adult B-cell ALL
Abstract Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has transformed the management of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), with the US Food and Drug Administration approval of tisagenlecleucel for pediatric/young adult patients and brexucabtagene autoleucel for adults. Efficacy is contingent upon several factors including disease burden. Emerging data suggest that bridging therapy, lymphodepletion, and, for some patients, consolidation therapy have an important role in the success of treatment. Furthermore, strategies to define and manage immunotoxic side effects including hematotoxicity is critical to safe delivery. Advancements in CAR-T design beyond CD19 represent an ongoing therapeutic evolution. Overall, CAR-T signifies a paradigm shift in B-ALL management, with the potential for improved remission and survival in a historically challenging patient population.
Divergent dimerization mechanisms and conserved DNA-binding function in PFam12 proteins of Borrelia burgdorferi
How to get rid of toxic ‘forever chemical’ pollution
Chromoplexy and <i>FNDC3B</i>::<i>RARB</i> fusion: deciphering a rare case of <i>PML</i>::<i>RARA</i>-negative APL
Investigating the mediating role of classroom achievement emotions in the relationship between school physical environment and physical literacy of adolescents
Six roadblocks to net zero — and how to get around them
Giant cytoplasmic inclusions (Alder-Reilly bodies) in Hurler syndrome (mucopolysaccharidosis type 1H)
Proof of concept study on differentiating metastatic brain samples by their originating organ using multimodal autofluorescence spectroscopy
Style over substance? What birds’ mating behaviours reveal about sexual selection
Odronextamab monotherapy in R/R DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study
Abstract Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post–CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell–associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.