Browse Articles

The endothelial mTORC2-Foxo1 axis serves as an iron-responsive sensor governing systemic iron homeostasis

Abstract Liver sinusoidal endothelial cells (LSECs) are essential for maintaining liver function by actively sensing nutrients and producing angiocrine factors. LSECs also regulate systemic iron metabolism by secreting bone morphogenetic proteins (BMPs), which are key modulators of systemic iron homeostasis. However, the mechanism by which LSECs sense iron to regulate iron metabolism remains unclear. Here, we identify that the endothelial transcriptional factor forkhead box protein O1 (Foxo1) and its upstream protein kinase, mechanistic target of rapamycin complex 2 (mTORC2), as critical iron sensors. In response to iron, Foxo1 undergoes acute and dynamic nuclear translocation to activate the transcription of Bmp2 and Bmp6, thereby stimulating the synthesis of iron-regulatory hormone hepcidin in adjacent hepatocytes. Foxo1 directly binds evolutionally conserved Foxo binding sites within the Bmp2 and Bmp6 promoters to mediate this response. Mechanistically, iron triggers the lysosomal degradation of the mTORC2-specific component rapamycin-insensitive companion of mTOR (Rictor), enhancing Foxo1 activation. Endothelial-specific Foxo1 deletion reduces the expressions of hepatic Bmp2/6 and hepcidin, leading to systemic iron overload, whereas endothelial Rictor deletion increases the expressions of hepatic Bmp2/6 and hepcidin, producing an iron-deficient phenotype. Moreover, endothelial-targeted lipid nanoparticles expressing endothelial-specific and constitutively active Foxo1 alleviate iron overload in a murine model of hereditary hemochromatosis. Collectively, our study establishes the endothelial mTORC2-Foxo1 axis as an iron-responsive regulator of Bmp2 and Bmp6 expression and identifies it as a promising target for iron-related disorders.

Rebalancing the hemophilia teeter-totter

A new prognostic index (CLIPI) for advanced cutaneous lymphoma enables precise patient risk stratification

Abstract Advanced mycosis fungoides (MF) and Sézary syndrome (SS) have a poor overall survival (OS) of <5 years. Studies have found the current staging (IA-IVB) is inadequate for risk stratification. The PROCLIPI (Prospective Cutaneous Lymphoma International Prognostic Index) study was launched in 2015 at 46 international expert MF/SS centers, prospectively collecting predefined data sets in patients with newly diagnosed MF/SS, to determine a cutaneous lymphoma IPI (CLIPI). Five hundred fifty-two patients with advanced stage MF/SS were recruited. The 5-year OS was 50.0% for stage IIB, 64.8% for stage IIIA, 43.9% for stage IIIB, 50.8% for stage IVA1, 25.9% for stage IVA2, and 36.9% for stage IVB. Factors at diagnosis associated with a significantly worse survival were N3 status (P < .001), age >60 years (P < .001), raised serum lactate dehydrogenase (P = .005), and large-cell transformation in skin (P = .006). Modeling these 4 independent risk factors into a CLIPI found that there was a worse OS in high- vs low-risk (P < .001), high- vs intermediate-risk (P = .002) and intermediate- vs low-risk (P = .010) groups. Five-year OS was 63.3%, 44.7%, and 18.3% in the low-, intermediate-, and high-risk groups, respectively. In this advanced stage cohort there was a low 5-year survival and increasing stage was not associated with worsening survival. The use of CLIPI to stratify patients into risk groups has the potential to improve outcomes and aid optimal treatment selection. This trial was registered at www.ClinicalTrials.gov as #NCT02848274.

How I treat pediatric pulmonary embolism

Abstract Venous thromboembolism (VTE) affects ∼1 in 200 hospitalized children. The diagnosis of pulmonary embolism (PE), the most severe clinical presentation of VTE, has increased dramatically by ∼200% over the past 2 decades, disproportionately affecting adolescents, and is associated with adverse long-term post-PE sequelae. Nevertheless, the management of pediatric PE remains highly variable. This review focuses on significant advances in pediatric PE, with a focus on published studies within the past decade. Using a representative case, we: (1) summarize existing risk prediction tools for acute pediatric PE, and a shift in clinical practice in the management of acute PE with the implementation of pediatric PE response teams and multidisciplinary decision-making for severe pediatric PE, (2) describe recently completed clinical trials of anticoagulation in children and adolescents, and ongoing work to elucidate the appropriate duration of therapy for children and adolescents with PE, and (3) review advances in understanding post-PE syndrome, and the need for continued refinement of evaluation tools and management approaches. Many unanswered questions remain despite the significant advances in pediatric thrombosis over the past decade.

AML halts neutrophil maturation

Eye structure shapes neuron function in Drosophila motion vision

Abstract Many animals use vision to navigate their environment. The pattern of changes that self-motion induces in the visual scene, referred to as optic flow1, is first estimated in local patches by directionally selective neurons2–4. However, how arrays of directionally selective neurons, each responsive to motion in a preferred direction at specific retinal positions, are organized to support robust decoding of optic flow by downstream circuits is unclear. Understanding this global organization requires mapping fine, local features of neurons across an animal’s field of view3. In Drosophila, the asymmetrical dendrites of the T4 and T5 directionally selective neurons establish their preferred direction, which makes it possible to predict directional tuning from anatomy4,5. Here we show that the organization of the compound eye shapes the systematic variation in the preferred directions of directionally selective neurons across the entire visual field. To estimate the preferred directions across the visual field, we reconstructed hundreds of T4 neurons in an electron-microscopy volume of the full adult fly brain6, and discovered unexpectedly stereotypical dendritic arborizations. We then used whole-head micro-computed-tomography scans to map the viewing directions of all compound eye facets, and found a non-uniform sampling of visual space that explains the spatial variation in preferred directions. Our findings show that the global organization of the directionally selective neurons’ preferred directions is determined mainly by the fly’s compound eye, revealing the intimate connections between eye structure, functional properties of neurons and locomotion control.

Remission conversion drives outcomes after CAR T-cell therapy for multiple myeloma: a registry analysis from the DRST

Abstract Cellular therapies targeting B-cell maturation antigen have shown promise in controlled clinical trials, but their impact in broader, diverse patient populations remains underexplored. This study examines the real-world efficacy and safety in 343 triple-class–exposed patients with relapsed and refractory multiple myeloma who received idecabtagene vicleucel (ide-cel; n = 266) or ciltacabtagene autoleucel (cilta-cel; n = 77) after >3 previous lines of therapy in Germany. Cilta-cel, compared with ide-cel, demonstrated superior outcomes, achieving a higher overall response rate (94% vs 82%) and 10-month progression-free survival (PFS; 76% vs 47%). Cilta-cel also led to higher complete response (CR; 61% vs 39%) and improved response conversion, with more patients achieving CR after starting from less than CR before chimeric antigen receptor T-cell (CAR T) therapy. For those attaining CR after therapy, cilta-cel showed longer PFS, especially in patients who entered treatment with a partial response or worse. Cytokine release syndrome was observed in 85% of cilta-cel and 81% of ide-cel cases, predominantly low grade. Immune effector cell–associated neurotoxicity syndrome was more common with cilta-cel (25% vs 15%), although nonrelapse mortality at 10 months was comparable between therapies (7% vs 5%). Weighted multivariable analysis after propensity score matching confirmed a significant advantage in terms of PFS for cilta-cel, with a hazard ratio of 0.48. Overall, outcomes in our registry analysis were comparable with the pivotal trials that led to approval of the respective agents. Cilta-cel demonstrated a greater capacity for response conversion and durable remission. These findings underscore the need for individualized CAR T therapy selection to optimize patient outcomes.

Machine learning reveals potential consequences of cuts to US research

Marstacimab prophylaxis in hemophilia A/B without inhibitors: results from the phase 3 BASIS trial

Abstract Marstacimab targets the tissue factor pathway inhibitor to rebalance hemostasis. Previous phase 1 and 2 trials established marstacimab safety and efficacy in adults with severe hemophilia A (HA) or B (HB). BASIS is an open-label, marstacimab phase 3 trial in males aged 12 to 74 years with severe HA (factor VIII <1%) or moderately severe to severe HB (factor IX ≤2%). Participants without inhibitors received on-demand (OD) or routine prophylaxis (RP) therapy during a 6-month observational phase (OP) before receiving once-weekly subcutaneous 150 mg marstacimab during a 12-month active treatment phase (ATP). Primary end points were annualized bleeding rate (ABR) for treated bleeds vs previous OD or RP during the OP, and safety. Of 128 participants enrolled in the OP, 116 received marstacimab in the ATP. In the OD group (n = 33), mean ABR decreased from 39.86 (95% confidence interval [CI], 33.05-48.07) in the OP to 3.20 (95% CI, 2.10-4.88) in the ATP, demonstrating superiority of marstacimab (estimated ABR ratio, 0.080 [95% CI, 0.057-0.113]; P < .0001). In the RP group (n = 83), mean ABR decreased from 7.90 (95% CI, 5.14-10.66) in the OP to 5.09 (95% CI, 3.40-6.78) in the ATP, demonstrating noninferiority and superiority of marstacimab (estimated ABR difference, –2.81 [95% CI, –5.42 to –0.20]; P = .0349). There were no deaths or thromboembolic events. Weekly subcutaneous marstacimab reduced ABR vs OD or RP therapy in the OP in individuals with severe HA or moderately severe to severe HB without inhibitors. Marstacimab was safe and well tolerated with no unanticipated side effects. This trial was registered at www.clinicaltrials.gov as #NCT03938792.

Foxo1 unlocks the liver endothelial code to iron sensing

More than skin deep

CAR-DLI for ALL, but not without lymphodepletion

IPSS-M risk and specific sex-associated somatic mutations predict response to ESA therapy in LR-MDS: building a new score

Abstract Acquired somatic mutations are incorporated in the classification and prognosis of myelodysplastic syndromes/neoplasms (MDSs). However, the predictive role of molecular features in MDS needs to be elucidated, especially in the lower-risk subtypes (LR-MDS), where treatment has become heterogeneous and predictive biomarkers are lacking. In this study, we investigated genetic markers associated with erythropoiesis-stimulating agents (ESAs) response in LR-MDS. A European cohort of 535 patients with LR-MDS was analyzed using targeted next-generation sequencing (t-NGS) to calculate molecular prognostic scores (International Prognostic Scoring System, molecular [IPSS-M]). The integration of IPSS-M score among the 2 known variables, serum erythropoietin (sEPO) and transfusion dependence (TD), refined the capability to predict response (area under the curve [AUC], 0.71 vs 0.63, P = .0004). Based on these 3 variables, a molecular predictive score, which we named ESA-PSS-M (–0.05 × [sEPO U/L] –4.5 × [IPSS-M score] –5 × [TD (yes = 1; no = 0)]; specificity 76%; sensitivity 57%), was generated and validated in an external cohort (n = 223 patients with LR-MDS). Despite the impact of IPSS-M score, no single mutated gene was linked to ESA response; however, when we stratified cases by sex at birth, the X-linked STAG2 gene mutations were significantly associated with ESA resistance in males with LR-MDS (odds ratio, 0.13; P = .003). To our knowledge, this is the first study based on a large multicenter cohort of patients suggesting that the integration of IPSS-M score and sex-specific mutations can characterize ESA resistance and guide first-line (1L) therapeutic choices for anemic LR-MDS (ie, ESAs vs luspatercept).

The acute myeloid leukemia microenvironment impairs neutrophil maturation and function through NF-κB signaling

Abstract Acute myeloid leukemia (AML), an aggressive hematological malignancy, is driven by oncogenic mutations in stem and progenitor cells that give rise to AML blasts. Although these mutations are well characterized, their impact on healthy hematopoiesis, those blood cells exposed to AML but not mutated, has not been well characterized. Because the marrow is the major site for granulopoiesis, neutrophils are heavily influenced by AML pathobiology. Indeed, most patients with AML report neutropenia, rendering them susceptible to infections. However, because AML studies use peripheral blood mononuclear cells devoid of neutrophils, the characterization of neutrophil dysfunction remains poorly understood. To investigate AML-exposed neutrophils, a preclinical AML mouse model in which primary leukemic cells were transplanted into nonirradiated neutrophil reporter (Ly6G-tdTomato; Catchup) hosts was used. Neutrophils could not completely mature, suggesting impaired granulopoiesis. Single-cell transcriptomics of AML-exposed neutrophils revealed higher inflammation signatures and expression of CD14, an inflammatory marker. To address the factors contributing to this biology, an ex vivo cytokine screen was performed on marrow neutrophils, and it identified that nuclear factor κB signaling drove CD14 expression. AML-exposed neutrophils displayed widespread chromatin remodeling, and de novo motif discovery predicted increased binding sites for CCAAT enhancer–binding proteins and interferon regulatory factors. Moreover, AML-exposed neutrophils inhibited T-cell proliferation, highlighting their immune-suppressive capability. Finally, a similar biology of immature, inflammatory neutrophils was found in patients with AML, again indicating dysregulated granulopoiesis. Collectively, these data show that AML-associated inflammation alters neutrophil granulopoiesis, impairs neutrophil function, and drives immunosuppression, thereby contributing to patient susceptibility to infection.

In low-risk myelodysplastic syndrome, don’t shoot the <i>STAG2</i>

Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion

Abstract We developed an allogeneic matched donor CD19 chimeric antigen receptor (CAR) product (CAR–donor lymphocyte infusion [DLI]) for adult patients with B-cell acute lymphoblastic leukemia (B-ALL) after failure of allogeneic stem-cell transplantation (allo-SCT). We evaluate the risks and benefits of pre–CAR-DLI lymphodepleting chemotherapy (LD) and the efficacy of repeat CAR-DLI dosing per conventional DLI protocols. Primary outcomes were toxicity and feasibility of CAR-DLI manufacture; secondary outcomes included CAR-DLI engraftment, expansion, and persistence. A total of 17 allo-SCT donors received leukapheresis and 14 patients with B-ALL (median age, 43 years) received infusion. Median disease burden at registration was 50.5% bone marrow blasts (range, measurable residual disease [MRD] to 100%). Patients 1 to 7 received CAR-DLI alone (CAR-DLI-alone); patients 8 through 14 received CAR-DLI and LD with fludarabine/cyclophosphamide (CAR-DLI+LD). CAR-DLI+LD vs CAR-DLI-alone was associated with superior peak CAR-DLI engraftment (93 134 vs 8010 copies per μg genomic DNA [gDNA]), expansion (858 101 vs 39 038 copies per μg gDNA per 28 days) and persistence (median, 197 vs 32 days). CAR-DLI+LD was not associated with more immunotoxicity than CAR-DLI-alone, and graft-versus-host disease (GVHD; grade 1, skin) affected only 2 of 14 patients (14%). CAR-DLI+LD vs CAR-DLI-alone conferred superior event-free-survival and overall survival at 12 months (57% vs 29%; 83% vs 29%). Repeat CAR-DLI dosing was administered to 8 of 14 (57%) patients with morphological/MRD+ relapse, but with minimal engraftment/expansion or toxicity/efficacy. CAR-DLI+LD has a tolerable safety profile without significant GVHD and is associated with significantly better outcomes than CAR-DLI-alone. Repeat CAR-DLI dosing beyond dose 1 was not found to be effective in this analysis. This trial was registered at www.clinicaltrials.gov as #NCT02893189.

AML with mutated TP53, therapy-related, with basophilic differentiation, partial CD22, and ring sideroblasts

DRiving STandard-of-care CAR T cells in real-world Germany

Industry-compatible silicon spin-qubit unit cells exceeding 99% fidelity

Abstract Among the many types of qubit presently being investigated for a future quantum computer, silicon spin qubits with millions of qubits on a single chip are uniquely positioned to enable quantum computing. However, it has not been clear whether the outstanding high-fidelity operations and long coherence times shown by silicon spin qubits fabricated in academic settings1–8 can be reliably reproduced when the qubits are manufactured in a semiconductor foundry9–11. Here we show precise qubit operation of silicon two-qubit devices made with standard semiconductor tooling in a 300-mm foundry environment. Of the key metrics, single- and two-qubit control fidelities exceed 99% for all four devices, and the state preparation and measurement fidelities reach up to 99.9%, as evidenced by gate set tomography. We report spin lifetime and coherence up to T 1 = 9.5 s, $${T}_{2}^{* }=40.6\,{\rm{\mu }}{\rm{s}}$$ T 2 * = 40.6 μ s and $${T}_{2}^{{\rm{Hahn}}}=1.9\,{\rm{ms}}$$ T 2 Hahn = 1.9 ms . We determine that residual nuclear spin-carrying isotopes contribute substantially to operational errors, identifying further isotopic purification as a clear pathway to even higher performance.

Pre-rRNA spatial distribution and functional organization of the nucleolus