Addressing social determinants of health is increasingly recognized as a critical priority in medicine to optimize care delivery to all patients. To support health care providers, researchers, and the hematology field to process and synthesize the rapidly expanding hematology social determinants of health literature, we conducted a scoping review to catalog/describe recent hematology social determinants studies. Our goals were to highlight state of the art in hematology social determinants research, describe trends in this literature across journals/conferences and over time, identify gaps, and inspire efforts to improve health across populations. Our search returned 602 hematology articles and 153 abstracts. Most works examined racial or socioeconomic disparities among adults with hematologic malignancies or who are hematopoietic cell transplant/cell therapy recipients. In contrast, few explored basic science correlates of disparities, approaches to optimize collection, recording, reporting, and use of social determinants of health data, or interventions/educational initiatives to address care inequities. Many vulnerable populations were understudied, including Indigenous peoples; people living with disabilities; transgender/gender-nonbinary peoples; and disparities across parity, religion, or immigration/legal status. Only a minority of works considered intersectionality across multiple dimensions of disparities. Although both the number and proportion of social determinants studies increased over time, there were imbalances in journals in which these studies were published. Overall, this review is an important tool to advance hematology population health, highlight hematology social determinants of health research productivity, inform development of research agendas and priorities for societies/funders, and support researchers to address identified gaps. Closing these gaps will be essential to improve delivery of safe and effective hematologic care for all.
Tissue function emerges from coordinated interactions among diverse cell populations, whereas disruption of these interactions can lead to dysfunction. Recent advances in single-cell and spatial genomics have not only cataloged cellular diversity but also revealed how tissues are organized as dynamic multicellular ecosystems. Moving beyond descriptive cell atlases toward functional, system-level representations represents a major frontier in tissue biology. In this review, we outline conceptual and methodological frameworks for dissecting multicellular coordination, highlight recurrent multicellular ecosystems across physiological and pathological contexts, and explore translational opportunities such as patient stratification, therapeutic reprogramming, and regenerative strategies. Viewing tissues through an ecosystem lens provides a unifying framework that links cellular diversity to emergent tissue function and informs strategies for disease intervention.
Adaptations to changing environments manifest in various cellular activities across multiple timescales, where single-cell responses can occur asynchronously between individual cells. Hence, accurate delineation of transient or rare activities often requires real-time monitoring of single cells over hours or days. While great strides have been made in the throughput of molecular analysis methodologies, most biochemical methods are cell destructive and, therefore, can only provide snapshots of dynamic processes. Noninvasive observations of natural cell behaviors offer unique insights into key dynamic events. In this feature review article, we discuss current toolkits for monitoring real-time dynamics of diverse cellular activities in living cells, as well as their advantages and challenges. We also speculate on new avenues for noninvasive single-cell monitoring that will be feasible in the foreseeable future.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration, muscle wasting, and eventual paralysis. The clinical and genetic complexity along with rapid disease progression has hindered efforts to model the disease and develop effective treatments. Rodent models and human tissue studies point to dysfunction in oligodendrocyte lineage cells early in disease, although the underlying mechanisms remain unclear. Advances in stem cell research have introduced novel platforms to investigate cells in the oligodendrocyte lineage and their interactions with neurons and other glial cells in complex human genetic backgrounds. This Review summarizes the literature implicating oligodendrocyte lineage cells in ALS and discusses both the potential and limitations of in vitro-derived cultures to shed light on their vulnerabilities and cellular interactions.
Red blood cell (RBC) production, or erythropoiesis, serves as a paradigm for studying cellular differentiation in both physiological and pathological contexts. While the transcriptional and epigenetic programs controlling erythropoiesis are well characterized, the metabolic regulation of this complex process remains underexplored. Recent discoveries that pyruvate kinase activators improve outcomes in sickle cell disease and thalassemia underscore the therapeutic potential of targeting metabolism in RBC disorders. However, further progress is limited by an incomplete understanding of the metabolic networks supporting erythropoiesis and RBC function. This review highlights emerging insights into erythroid metabolic reprogramming involving bioenergetic and biosynthetic processes, newly discovered pathways shaping the erythroid metabolome, and the promise and challenges of exploiting metabolic vulnerabilities in inherited and acquired red cell disorders.
Cell competition is a highly conserved mechanism through which cells with lower fitness levels than surrounding cells are actively removed from tissues. Differences in fitness may result from intrinsic tissue heterogeneity or be caused by differentiation, infections, or mutations. The resulting competition dynamics act as a key regulator of various biological processes during development and homeostasis. The underlying mechanical factors often remain unclear. Here, we discuss the biophysical principles of cell competition and elimination via extrusion or delamination. Recent advances have uncovered how fitness is determined by cellular mechanical properties, which can regulate winning or losing, and how cells use forces to outcompete each other. Furthermore, forces can influence the fate and direction of eliminated loser cells, which govern functional tissue development and disease progression.
The endolysosomal system in eukaryotic cells regulates nutrient uptake and maintains the composition of the plasma membrane, among many other functions. In autophagy, it contributes not only to the cellular quality control system to remove damaged organelles, aggregates, and pathogens but also to cellular recycling of amino acids. Transport in the endolysosomal network relies on the correct identity of the involved organelles. Rab GTPases and lipid kinases provide this membrane identity on each organelle, thereby orchestrating the protein machinery for membrane fusion and fission. Dynamic exchange of identity markers provides the basis for adaptations of the endolysosomal system, which is closely linked to cellular nutrient signaling. Here, recent structural and functional insights into the regulation and interplay of Rab regulators, lipid kinases, and tethering complexes are reviewed, focusing on the model organism Saccharomyces cerevisiae.
Tumor-infiltrating lymphocytes (TILs) are recognized as a key component of anticancer immunity and serve as an important prognostic factor in cancer progression. In this review, the latest updates and perspectives on the diverse populations of TILs and their roles in cancer immunity are discussed. The presence and balance between anti-tumorigenic and pro-tumorigenic immune cells in the tumor microenvironment (TME) largely determine tumor progression and fate. Thus, the properties of TILs were reviewed to provide a better insight into the roles of these immune cells within the TME. Additionally, the different factors influencing immune cell infiltration in solid tumors are also described to suggest novel immunotherapeutic approaches for improved TIL infiltration. These recent approaches are then summarised as recommendations to improve infiltration and potentially achieve better clinical outcomes. Overall, this review highlights the critical role of TILs, factors governing immune cell homing and infiltration, and strategic approaches to improve TIL infiltration.
Eosinophils participate in immune regulation through their granule proteins and cytokines. Recent studies demonstrate eosinophil functional versatility through the mechanism of eosinophil extracellular traps (EETs). EET formation occurs via suicidal eosinophil extracellular trap cell death (EETosis) and vital EET release. EETs contain chromatin- or mitochondrial-derived DNA, granule proteins, nuclear proteins, and cytosolic components that vary depending on the type and intensity of stimuli. Synthetic compounds, pathogenic microorganisms, endogenous molecules, and co-stimulatory factors stimulate EET formation via diverse signaling pathways through receptors that rely on or operate independently of NADPH oxidase-mediated reactive oxygen species production and peptidylarginine deiminase-4-dependent histone modification. Necroptosis, pyroptosis, and autophagy pathways also contribute to EET biogenesis and subset heterogeneity. Here, we summarize EET formation, compositional profile, and functional heterogeneity across disease states, as well as the future potential for novel immune intervention.
Lysosomes are sophisticated signaling hubs whose function depends on membrane integrity. A breach of this barrier, known as lysosomal membrane permeabilization, triggers inflammation and cell death, driving pathologies from lysosomal storage disorders to neurodegeneration. Cells counter membrane damage with diverse repair mechanisms, including endosomal sorting complexes required for transport machinery, sphingomyelin scrambling, annexin-mediated scaffolding, lipid transport, and stress granule plugging. This diversity suggests singular strategies are insufficient, posing an 'orchestration challenge' regarding precise initiation, spatial organization, and temporal coordination. This opinion article proposes that biomolecular condensation, initiated by damage cues, acts as a primary organizing principle. We suggest lysosomal injury nucleates de novo 'repair condensates' that stabilize compromised membranes and serve as recruitment and organizational hubs for repair machinery.
Although senescent cells are commonly characterized by stable cell cycle arrest, emerging evidence indicates that senescence is not a uniform state but a collection of highly heterogeneous phenotypes. This heterogeneity stems from biological factors, such as diverse senescence markers, cellular origins, and targeting mechanisms, as well as from technical variations in experimental approaches, notably in the design of transgenic mouse models. By summarizing recent advances in next-generation senolytic strategies, multiomics profiling, and genetically engineered mouse models of senescence, we provide an integrated perspective on the origins and consequences of senescent cell heterogeneity. Such a perspective is essential for refining investigative methodologies and for developing precise therapies that selectively target senescent cell populations whose roles have been experimentally validated in vivo.
Squamous cell carcinoma (SCC) of the larynx and hypopharynx shows subsite-specific patterns, with supraglottic tumors closely resembling hypopharyngeal SCC. This study aimed to analyze 10-year epidemiologic trends, management, and outcomes in a tertiary hospital, with emphasis on prognostic similarities between supraglottic and hypopharyngeal tumors. A retrospective cohort of 454 patients with laryngeal or hypopharyngeal SCC (2012-2022) was evaluated. Demographic characteristics, TNM stage, treatment modality, and 5-year disease-specific survival (DSS) were analyzed. Hypopharyngeal SCC cases were predominantly advanced (T3-T4: 66.4%; N2-N3: 82.7%) and more often metastatic (29.8%), compared with laryngeal SCC (40.6%, 21.1%, and 5.4%, respectively; p<0.0001). Within laryngeal subsites, supraglottic tumors closely resembled hypopharyngeal SCC in stage distribution, nodal burden, metastasis rate (10.3%), and the 5-year DSS (50.0%). Glottic tumors achieved favorable outcomes (5-year DSS 87.3%). Overall, DSS was 73.3% for laryngeal vs. 49.4% for hypopharyngeal SCC (p<0.0001). Treatment trends showed a shift toward organ-preserving strategies in laryngeal SCC, while hypopharyngeal SCC consistently relied on non-surgical therapy. Over the past decade, the incidence, demographics, and stage distribution of laryngeal and hypopharyngeal SCC remained stable. Although laryngeal SCC management increasingly favored organ preservation, hypopharyngeal SCC persisted as an advanced-stage disease primarily treated with non-surgical approaches. Five-year DSS remained substantially poorer for hypopharyngeal SCC. Supraglottic laryngeal tumors shared clinical and prognostic characteristics with hypopharyngeal SCC, including advanced stage, high metastatic rate, and inferior survival. The notable prevalence of distant metastases-nearly 30% in hypopharyngeal and 10% in supraglottic SCC-underscores the importance of incorporating PET/CT or PET/MR into baseline staging and highlights the need for multicenter studies to optimize management of these high-risk subgroups.
The cleavage of full-length transfer RNAs generates functional small RNAs called tRNA-derived small RNAs (tsRNAs or tDRs). This review synthesizes recent advances in our understanding of tDRs, summarizing the molecular mechanisms of their biogenesis and illuminating their function in modulating pathways important in the cellular stress response. Key structural motifs appear to be critical determinants of tDR function by modulating binding to partner proteins and RNAs. Finally, the role of tDRs in the pathogenesis of various diseases and the feasibility of targeting them with novel molecular tools are discussed. In summary, tDRs are an evolutionarily conserved class of small RNAs important for the cellular response to stress and are emerging as a promising target for human diseases.
Exosomes are formally defined as extracellular vesicles, which are formed in compartments with endosomal origin by the inward budding of the endosomal limiting membrane. Recent analyses of the dynamic events within exosome-generating compartments have overturned the dogma that only late endosomal membranes produce exosomes. It is now clear that recycling endosomal, autophagic, regulated secretory, and other organelle membranes contribute to exosome production. In this opinion article, we discuss studies demonstrating the critical roles of membrane origins and mergers, together with intracompartmental microenvironments, in generating intraluminal vesicle and exosome subtypes with diverse physiological and pathological functions, both inside and outside the secreting cell. These findings provide significant opportunities to develop novel strategies that overcome the current challenges of detecting and targeting disease-relevant exosomes.
The glycan makeup of membrane glycoproteins and glycosphingolipids at the cell surface is traditionally viewed as mature and static. Recent findings challenge this view, showing that selective glycan remodeling can redirect membrane glycoproteins back to the Golgi for another go. In this review we discuss the glycosylation processes in cells, with a focus on the terminal glycan chains on proteins and lipids that are capped by sialic acid sugars, and that engage the glycan-binding proteins of the galectin family. We highlight new studies demonstrating that growth factors trigger the removal of sialic acid by endogenous neuraminidases at the cell surface, leading to glycolipid-lectin driven endocytosis and retrograde traffic to the Golgi. This molecular circuit, termed the GlycoSwitch, introduces new perspectives on glycan-mediated regulation of cellular functions.
Telomeres are nucleoprotein elements bound by shelterin that protect chromosome ends from DNA damage signalling and inappropriate repair. A defining architectural feature is the telomere loop (t-loop), a lariat structure formed by 3' overhang invasion into duplex telomeric DNA, which sequesters chromosome ends from damage recognition. T-loop stability is disrupted by the loss of the shelterin component TRF2, and progressive telomere shortening during ageing is predicted to compromise t-loop maintenance. In addition to intrinsic erosion, an active, shelterin-directed mechanism unwinds t-loops during mitotic arrest. This mitotic arrest-dependent telomere deprotection promotes mitotic death, requires Aurora B kinase-dependent shelterin phosphorylation and the BTR complex, and is opposed by WRN. In this review, we review how dynamic t-loop architecture integrates telomere signalling with cell fate decisions.
Neural stem cells (NSCs) span a continuum of cellular states that share fundamental properties with their differentiated glial progeny. Recent single-cell studies have refined our understanding of the diversity within both NSC and glial populations, revealing a highly dynamic and interconnected landscape of cell identities. In this review, we examine the glial nature of NSCs, emphasizing their heterogeneity and the stem- and progenitor-like properties shared with the differentiated glia. We focus particularly on astrocytes and integrate evidence from invertebrate models demonstrating that glial cells possess an intrinsic capacity for neurogenesis. Together, these findings highlight areas of convergence between astrocyte plasticity and NSC-associated properties, with important implications for nervous system regeneration and brain cancer.
The ubiquitin-proteasome system governselective protein turnover in all eukaryotes, and its cullin-Really Interesting New Gene (RING) ligases represent the largest class of E3 ligases. Their substrate receptors (SRs) act as the 'specificity engines' of degradation, yet their contribution to human genetic disease has only recently come into focus. In this review, we provide the first systematic catalogue of 267 SRs, of which 93 are now linked to germline disorders. We synthesise emerging mechanisms, from altered degron recognition to noncanonical SR functions, and highlight how patient variants illuminate pathways for diagnosis and therapy. By connecting proteostasis, rare-disease genetics, and targeted protein degradation, SRs emerge as central nodes with broad implications for precision medicine.
Heme-regulated eukaryotic translation initiation factor 2 alpha kinase (HRI) is highly expressed in red blood cell precursors and plays a critical role in their maturation by coupling globin synthesis to heme availability. HRI plays critical roles in responding to cytoplasmic and mitochondrial unfolded proteins, oxidative stress response, innate immunity, neurobiology, and the suppression of epithelial cancers. HRI activity is regulated by multiple signaling networks, which, in turn, modify cellular homeostatic responses. In this review, we summarize emerging evidence on the role of HRI in normal biology and pathobiology, the molecular underpinnings of HRI's regulation, and discuss chemical modifiers of HRI, which may form the basis of drug development programs for the treatment of human disorders whose pathobiology can be modified by HRI.
Endoplasmic reticulum (ER)-resident ubiquitin ligases are essential to cellular homeostasis and diverse signaling pathways, functioning in protein quality control, lipid metabolism, innate immunity, and interorganelle communication. While best known for their roles in ER-associated degradation (ERAD) of misfolded proteins, accumulating evidence shows that they also mediate the regulated turnover of functional ER proteins and contribute to ER-phagy, thereby expanding their roles in ER homeostasis. This review summarizes recent advances in understanding substrate recognition mechanisms employed by ER ubiquitin ligases and how these enzymes coordinate ERAD and ER-phagy, with a primary focus on mammalian systems. We further discuss their roles in ER homeostasis and immune responses, and how their dysregulation contributes to diseases such as neurodegeneration and immune disorders.