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Honing CAR T cells to tackle acute myeloid leukemia
Abstract Acute myeloid leukemia (AML) remains a dismal disease with poor prognosis, particularly in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR) therapy has yielded remarkable clinical results in other leukemias and thus has, in principle, the potential to achieve similar outcomes in R/R AML. Redirecting the approved CD19-specific CAR designs against the myeloid antigens CD33, CD123, or CLEC12A has occasionally yielded morphologic leukemia-free states but has so far been marred by threatening myeloablation and early relapses. These safety and efficacy limitations are largely due to the challenge of identifying suitable target antigens and designing adequate receptors for effective recognition and safe elimination of AML. Building on lessons learned from the initial clinical attempts, a new wave of CAR strategies relying on alternative target antigens and innovative CAR designs is about to enter clinical evaluation. Adapted multiantigen targeting, logic gating, and emerging cell engineering solutions offer new possibilities to better direct T-cell specificity and sensitivity toward AML. Pharmacologic modulation and genetic epitope engineering may extend these approaches by augmenting target expression in AML cells or minimizing target expression in normal hematopoietic cells. On/off switches or CAR T-cell depletion may curb excessive or deleterious CAR activity. Investigation of AML-intrinsic resistance and leukemic microenvironmental factors is poised to reveal additional targetable AML vulnerabilities. We summarize here the findings, challenges, and new developments of CAR therapy for AML. These illustrate the need to specifically adapt CAR strategies to the complex biology of AML to achieve better therapeutic outcomes.
Trump’s nominee for NIH chief talks frozen grants and fostering ‘scientific dissent’
Targeting senescent stemlike subpopulations in Philadelphia chromosome–like acute lymphoblastic leukemia
Abstract Philadelphia chromosome–like B-cell acute lymphoblastic leukemia (Ph-like ALL) is driven by genetic alterations that induce constitutive kinase signaling and is associated with chemoresistance and high relapse risk in children and adults. Preclinical studies in the most common CRLF2-rearranged/JAK pathway-activated Ph-like ALL subtype have revealed variable responses to JAK inhibitor-based therapies, suggesting incomplete oncogene addiction and highlighting a need to elucidate alternative biologic dependencies and therapeutic vulnerabilities, whereas the ABL-class Ph-like ALL subtype seems preferentially sensitive to SRC/ABL- or PDGFRB-targeting inhibitors. Which patients may be responsive vs resistant to tyrosine kinase inhibitor (TKI)–based precision medicine approaches remains a critical knowledge gap. Using bulk and single-cell multiomics analyses, we profiled residual cells from CRLF2-rearranged or ABL1-rearranged Ph-like ALL patient–derived xenograft models treated in vivo with targeted inhibitors to identify TKI-resistant subpopulations and potential mechanisms of therapeutic escape. We detected a specific MYC dependency in Ph-like ALL cells and defined a new leukemia cell subpopulation with senescence-associated stem cell-like features regulated by AP-1 transcription factors. This dormant ALL subpopulation was effectively eradicated by dual pharmacologic inhibition of BCL-2 and JAK/STAT or SRC/ABL pathways, a clinically relevant therapeutic strategy. Single cell–derived molecular signatures of this senescence and stem/progenitor-like subpopulation further predicted poor clinical outcomes associated with other high-risk genetic subtypes of childhood B-ALL and thus may have broader prognostic applicability beyond Ph-like ALL.
Ancient puppets that smile or scowl hint at shared rituals
Single-cell epigenetic and clonal analysis decodes disease progression in pediatric acute myeloid leukemia
Abstract Pediatric acute myeloid leukemia (pAML) is a clonal disease with recurrent genetic alterations that affect epigenetic states. However, the implications of epigenetic dysregulation in disease progression remain unclear. Here, we interrogated single-cell and clonal level chromatin accessibility of bone marrow samples from 28 patients with pAML representing multiple subtypes using mitochondrial single-cell assay for transposase-accessible chromatin with sequencing, which revealed distinct differentiation hierarchies and abnormal chromatin accessibility in a subtype-specific manner. Innate immune signaling was commonly enhanced across subtypes and related to improved advantage of clonal competition and unfavorable prognosis, with further reinforcement in a relapse-associated leukemia stem cell–like population. We identified a panel of 31 innate immunity–related genes to improve the risk classification of patients with pAML. By comparing paired diagnosis and postchemotherapy relapse samples, we showed that primitive cells significantly reduced major histocompatibility complex class II signaling, suggesting an immune evasion mechanism to facilitate their expansion at relapse. Key regulators orchestrating cell cycle dysregulation were identified to contribute to pAML relapse in drug-resistant clones. Our work establishes the single-cell chromatin accessibility landscape at clonal resolution and reveals the critical involvement of epigenetic disruption, offering insights into classification and targeted therapies of patients with pAML.
Make hematopoiesis great again: countering oxidative stress!
Azacitidine and venetoclax for HR-MDS: election results pending
DNTT-mediated DNA damage response drives inotuzumab ozogamicin resistance in B-cell acute lymphoblastic leukemia
Abstract Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide interpatient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered that the loss of DNA nucleotidylexotransferase (DNTT) is a primary driver of InO resistance. Mechanistically, the downregulation of DNTT attenuated InO–induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, thereby ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with DNTT expression in ALL blasts with substantial intraleukemia heterogeneity as revealed by single-cell RNA sequencing. Among patients with B-ALL enrolled in the Children's Oncology Group trial AALL1621, we observed consistent DNTT downregulation in residual blasts following InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.
Exclusive: NIH to terminate hundreds of active research grants
The ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma
Abstract Immunomodulatory drugs (IMiDs) are a major class of drugs for treating multiple myeloma (MM); however, acquired resistance to IMiDs remains a significant clinical challenge. Although alterations in cereblon and its pathway are known to contribute to IMiD resistance, they account for only 20% to 30% of cases, and the underlying mechanisms in the majority of the resistance cases remain unclear. Here, we identified adenosine deaminase acting on RNA1 (ADAR1) as a novel driver of lenalidomide resistance in MM. We showed that lenalidomide activates the MDA5-mediated double-stranded RNA (dsRNA)–sensing pathway in MM cells, leading to interferon (IFN)-mediated apoptosis, with ADAR1 as the key regulator. Mechanistically, ADAR1 loss increased lenalidomide sensitivity through endogenous dsRNA accumulation, which in turn triggered dsRNA-sensing pathways and enhanced IFN responses. Conversely, ADAR1 overexpression reduced lenalidomide sensitivity, attributed to increased RNA editing frequency, reduced dsRNA accumulation, and suppression of the dsRNA-sensing pathways. In summary, we report the involvement of ADAR1-regulated dsRNA sensing in modulating lenalidomide sensitivity in MM. These findings highlight a novel RNA-related mechanism underlying lenalidomide resistance and underscore the potential of targeting ADAR1 as a novel therapeutic strategy.
ADAR1 in lenalidomide resistance: still immunomodulation?
Acute myeloid leukemia with <i>RUNX1</i>::<i>CBFA2T3</i> fusion
Superconductivity and quantized anomalous Hall effect in rhombohedral graphene
A super-gel stays supple from −115 ºC to 143 ºC
Engineered heart muscle allografts for heart repair in primates and humans
Abstract Cardiomyocytes can be implanted to remuscularize the failing heart1–7. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques. After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation8, long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed. The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.
Impact of thermal treatment on the quality, total antioxidant and antibacterial properties of fermented camel milk
Abstract This study investigated the impact of thermal treatments on the quality, antioxidant, and antibacterial properties of fermented camel milk during refrigerated storage. Two thermal treatment categories were applied: moderate (63 °C for 30 min and 72 °C for 15 s) and high (85 and 90 °C for 15 s and 30 min). Findings indicated that raw camel milk was found to be microbiologically unacceptable. Heating milk to 90 °C for 30 min notably reduced fermentation time, increased fermented milk viscosity, and altered whey protein electrophoretic patterns. While thermal treatments below 90 °C boosted lactic acid bacteria count in fermented milk compared to raw milk-derived samples (control), all treatments exceeded the recommended standards throughout storage. Thermal treatment decreased the proteolysis degree and DPPH radical scavenging activity but enhanced the ferric-reducing power of fermented milk compared to the control. Among, thermal treatments, samples from milk heated at 90 °C exhibited the highest scavenging activity and reducing power. Antibacterial efficacy against Salmonella Typhimurium surpassed that against Escherichia coli and Staphylococcus aureus; the most pronounced effect was observed in samples from milk heated at 90 °C. In conclusion, thermal treatment of camel milk is crucial to ensure sufficient hygiene for safe milk consumption. Heating camel milk at 90 °C before fermentation positively impacted most of the studied properties.
Extant life detection using label-free video microscopy in analog aquatic environments
The ability of microbial active motion, morphology, and optical properties to serve as biosignatures was investigated by in situ video microscopy in a wide range of extreme field sites where such imaging had not been performed previously. These sites allowed for sampling seawater, sea ice brines, cryopeg brines, hypersaline pools and seeps, hyperalkaline springs, and glaciovolcanic cave ice. In all samples except the cryopeg brine, active motion was observed without any sample treatment. Active motion was observed in the cryopeg brines when samples were subjected to a temperature gradient above in situ. In general, levels of motility were low in the field samples collected at temperatures < 4ºC. Non-motile cells could be distinguished from microminerals by differences in passive motion (e.g., density measured by sinking/floating), refractive index and/or absorbance, or morphology in the case of larger eukaryotes. Dramatic increases in the fraction of motile cells were seen with simple stimuli such as warming or the addition of L-serine. Chemotaxis and thermotaxis were also observed in select samples. An open-source, autonomous software package with computational requirements that can be scaled to spaceflight computers was used to classify the data. These results demonstrate the utility of volumetric light microscopy for life detection, but also suggest the importance of developing methods to stimulate cells in situ and process data using the restrictions imposed by mission bandwidth, as well as instruments to capture cell-like objects for detailed chemical analysis.
A new method of accurate pedicle screw navigation
Performance of pelican optimizer for energy losses minimization via optimal photovoltaic systems in distribution feeders
In distribution grids, excessive energy losses not only increase operational costs but also contribute to a larger environmental footprint due to inefficient resource utilization. Ensuring optimal placement of photovoltaic (PV) energy systems is crucial for achieving maximum efficiency and reliability in power distribution networks. This research introduces the Pelican Optimizer (PO) algorithm to optimally integrate solar PV systems to radial electrical distribution grids. The PO is a novel bio-inspired optimization algorithm that draws inspiration from pelicans’ intelligence and behavior which incorporates unique methods for exploration and exploitation, improving its effectiveness in various optimization challenges. It introduces a hyper-heuristic for phase change, allowing the algorithm to dynamically adjust its strategy based on the problem’s characteristics. The suggested PO aims to reduce the energy losses to the possible minimum value. The developed PO version is tested on the Ajinde 62-bus network, a practical Nigerian distribution system, and a typical IEEE grid with 69 nodes. The simulation findings demonstrate the enhanced PO version’s efficacy, showing a significant decrease in losses of energy. With the Ajinde 62-node grid, the suggested PO version obtains a substantial 30.81% decrease in the total energy loss expenses in contrast to the initial scenario. Similarly, the IEEE 69-node grid achieves a significant decrease of 34.96%. Additionally, the model’s findings indicate that the proposed PO version performs comparably to the Differential Evolution (DE), Particle Swarm Optimization (PSO), and Satin bowerbird optimizer (SBO) algorithms.