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Sun, L.

Publications and source records attributed to Sun, L..

At least 91 records · Page 5Linked to original sources

Convergent and divergent spatial topographies of individualized brain functional networks and their developmental origins

The human brain is intrinsically organized into canonical functional networks with distinct spatial topographies. While precision functional mapping delineates individualized topographies of single networks, the spatial coordination among networks and its developmental origin remains largely unknown. Here, we propose functional topography covariance analysis (FOCA), a novel framework that quantifies convergent and divergent spatial alignments across individualized functional networks and further delineates their internetwork relationships, neurobiological basis, ontogenetic layouts, and cognitive outcomes. Across two well-established task-free functional MRI (fMRI) datasets encompassing both conventional and densely sampled scans, FOCA consistently revealed self-clustered hierarchies in the coordination of functional topographies, closely aligned with existing functional gradients and characterized by convergent couplings within primary systems and divergent couplings in higher-order systems. Such pattern was well predicted by fundamental neurobiological attributes, especially aerobic glycolysis. In a large public neonatal cohort, FOCA matrix exhibited adult-inverted hierarchical couplings and marked changes in auditory and action-mode networks, primarily driven by prominent redistributions of negative couplings. Moreover, neonatal FOCA profiles in the primary visual system significantly predicted neurodevelopmental outcomes at 18 months. Finally, compared with conventional functional connectivity (FC), FOCA proved more robust to global signals and more sensitive to the maturation of negative couplings. These findings highlight the critical role of negative connectivity in brain functional reorganization and advance our understanding of the cooperative and competitive relationships among functional systems and their developmental origins.

neuroscience↗

PPAR-delta rather than PPAR-gamma is likely to be the key modulator of central carbon metabolism in human adipocytes

Adipogenesis involves adipocyte differentiation and synthesis and storage of fats. PPAR-{gamma} is the master regulator of adipogenesis and regulates genes for adipocyte differentiation, lipogenesis, adipocyte survival and adipokine secretion. Central carbon metabolism (CCM) comprises of three key pathways, glycolysis, tricarboxylic acid cycle and pentose phosphate pathway. CCM utilizes carbon sources to provide energy and building blocks for lipogenesis. Although several targets of PPAR-{gamma} have been identified in the CCM pathways, the exact process of how PPAR-{gamma} modulates adipogenesis via CCM remains elusive. In this study, we used real time-qPCR and metabolic arrays for CCM to understand the effect of PPAR activation by PPAR-{gamma} agonist 15d-PGJ2 on CCM and its role in adipogenesis. Our data show that PPAR-{delta} is likely the target of 15d-PGJ2 and the key modulator of adipogenesis in human SGBS adipocytes at least under current experimental conditions. Further studies are warranted to fully understand the regulation of CCM in adipocytes.

molecular biology↗

Lateral plate mesoderm directs human amnion and ventral skin organoid formation

Summary ParagraphEngineering organoids that faithfully replicate the intricate architecture and region-specific features of bodily organs and extraembryonic tissues remains a significant scientific challenge. Previously, we demonstrated that craniofacial skin organoids (cSkOs)--containing epidermis, dermis, and hair--could be generated by co-developing epidermal progenitors with cranial mesenchyme. Building on this approach, we precisely adjusted cellular composition and signaling environments to generate ventral skin organoids (vSkOs) with lateral plate mesoderm (LPM) progenitors, successfully recapitulating features of abdominal or groin skin. Modulating early BMP and FGF signaling redirected these vSkOs toward an extraembryonic fate, producing human amnion-like tissues, termed Amnioids. Like native human amnion, Amnioids rapidly expanded into large, avascular, hairless cysts, in sharp contrast to the primitive vasculature and abundant hair follicles of vSkOs. Single-cell RNA sequencing identified divergent molecular signatures and developmental trajectories, highlighting key roles for NOTCH, WNT, and YAP/Hippo signaling pathways. Functional studies further underscored mesenchymal-epithelial interactions and mechanical forces as critical regulators of epithelial expansion. Together, these models provide potent tools to investigate human development at the embryonic-extraembryonic interface, offering critical insights into congenital skin and amniotic disorders and opening new avenues for precision regenerative therapies.

developmental biology↗

Spatiotemporal control of PIWI compartmentalization by mitochondrial scaffolds defines pachytene piRNA pathway organization

Pachytene piRNAs are the least understood class of piRNAs in the mammalian male germ line. During meiosis, their biogenesis occurs near mitochondrial outer membrane in germ granules known as intermitochondrial cement (IMC). However, how mitochondrial factors regulate the trafficking of PIWI proteins into and out of the IMC remain poorly understood. Here we show that the cytoplasmic PIWI proteins MILI and MIWI are recruited for pachytene piRNA biogenesis via distinct mitochondrial membrane proteins. Loss of the mitochondrial scaffold protein ASZ1 during meiosis in mice disrupts multiple downstream biogenesis steps, leading to misregulation of MILI and MIWI, failure of IMC formation, and a near-complete loss of mature pachytene piRNAs. Strikingly, despite the drastic depletion of pachytene piRNAs, LINE1 transposon silencing remains unaffected. We identify three classes of pachytene piRNA pathway components that coordinate piRNA production and compartmentalization. Our findings reveal that chromatoid body precursors serve as a central hub for the accumulation of pachytene PIWI-piRNA complexes, thus establishing a connection between IMC-based biogenesis and downstream piRNA function.

developmental biology↗

Integrating Mutation and Stop Signals for Improved RNA Structure Analysis and Insight Discovery

BackgroundUnderstanding RNA structures is essential for exploring its diverse cellular roles. Chemical modification-based RNA structure probing remains a key approach to revealing RNA structures in complex in vivo conditions. Practically, chemical modifications generate both mutation and stop signals during reverse transcription within a single experiment. However, traditional analysis pipelines often rely on only one of the two signals without fully leveraging both. ResultsTo address this, we developed a machine learning-based approach, STONE, that integrates both signals from a single experiment. STONE improved RNA structure analysis across multiple independent validation regions, notably 28S rRNA, viral RNA and regulatory RNAs. In genome-wide datasets, especially single-cell data, STONE significantly increased nucleotide coverage per transcript and improved gene detection reliability. In genome-wide datasets, especially single-cell data, STONE substantially enhanced structural information coverage at both transcript and nucleotide levels. This maximized signal utilization, yielding RNA structures in single-cell data comparable to those from bulk datasets. Furthermore, STONE-derived structural scores allow direct identification of RNA-binding protein binding sites directly from a single probing experiment, with results on RNAs such as U1 snRNA, RNase P RNA, and XIST lncRNA closely matching established techniques like CLIP-seq and RNP-MaP. ConclusionsBy integrating mutation and stop signals from one single experiment, STONE advances RNA structure analysis accuracy, extends nucleotide coverage, and facilitates complex RNA-protein interaction studies, broadening the methods applications in RNA-based research.

bioinformatics↗

Modtector: Ultra-Fast Modification Signal Mining on Mapped Sequencing Reads

SummaryCurrent tools for RNA epitranscriptomic modification and structural feature analysis are often fragmented, focusing on single signal types and struggling with processing efficiency, especially as sequencing data volumes increase and single-cell technologies advance. To address this challenge, we developed Modtector, an efficient and versatile tool for unified extraction of modification signals from aligned sequencing data. By integrating dual-signal recognition within a single framework, Modtector employs a "count-then-correct" approach to handle both mutation and stop signals, significantly reducing computational complexity. This results in a multi-fold performance improvement compared to existing tools, particularly when processing large-genome, high-coverage datasets--such as completing the analysis of HEK293 22G data in 5 minutes-- demonstrating its potential for large-scale data analysis. Availability and implementationThe manual is available at Readthedocs (https://modtector.readthedocs.io/), and source code is available at GitHub (https://github.com/TongZhou2017/modtector) and Crate.io (https://crates.io/crates/modtector). Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/681300v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1535c98org.highwire.dtl.DTLVardef@1e40f39org.highwire.dtl.DTLVardef@1a37476org.highwire.dtl.DTLVardef@3315c5_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

Unveiling The Origin of Human High-Grade Serous Ovarian Cancer Using Bulk and Single-Nucleus RNA Sequencing

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy, yet its earliest cellular precursors remain incompletely defined. Here, we integrate bulk and single-nucleus RNA sequencing of human fallopian tubes, ovaries, and primary HGSOC tumors to resolve the epithelial hierarchy of the fallopian tube and examine its relationship to malignant states. We identify a rare LGR5/PGR basal population as putative epithelial stem cells and delineate a large pool of OVGP1/RNPC3 progenitors that give rise to both secretory and ciliated lineages. By jointly analyzing normal and malignant transcriptomes, we find that these progenitor populations show the strongest transcriptional and developmental continuity with multiple HGSOC cell states, suggesting that they represent the epithelial compartments most plausibly poised for oncogenic divergence. Transcription factor network reconstruction highlights SPDEF as a key regulator of progenitor identity and NR2F6 as a candidate oncogenic driver, while inferred copy number variations and microenvironmental collagen-integrin signaling further illuminate the genomic and stromal factors that consolidate malignant fate. Together, these findings refine the cellular landscape of the human fallopian tube and identify progenitor-enriched molecular features that could inform earlier detection, improved risk stratification, and new preventive strategies for women at risk of developing HGSOC. One sentence summaryFallopian tube progenitor cells represent a key intermediate state linking normal epithelial hierarchy to the earliest stages of high-grade serous ovarian cancer development.

cancer biology↗

Augmented prediction of multi-species protein--RNA interactions using evolutionary conservation of RNA-binding proteins

AbstractRNA-binding proteins (RBPs) play critical roles in gene expression regulation. Recent studies have begun to detail the RNA recognition mechanisms of diverse RBPs. However, given the array of RBPs studied so far, it is implausible to experimentally profile RBP-binding peaks for hundreds of RBPs in multiple non-model organisms. Here, we introduce MuSIC (Multi-Species RBP-RNA Interactions using Conservation), a deep learning-based framework for predicting cross-species RBP-RNA interactions by leveraging label smoothing and evolutionary conservation of RBPs across 11 diverse species ranging from human to yeast. MuSIC outperforms state-of-the-art computational methods, and provides predicted RBP-binding peaks across species with high accuracy. The prediction confidence is higher in the closely related species, partially due to the RBP conservation patterns. Finally, the effects of homologous genetic variants on RBP binding can be computationally quantified across species, followed by experimental validations. The target transcripts with disrupted binding events are enriched with the ubiquitination-associated pathways. To summarize, MuSIC provides a useful computational framework for predicting RBP-RNA interactions cross-species and quantifying the effects of genetic variants on RBP binding, offering novel insights into the RBP-mediated regulatory mechanisms implicated in human diseases. HighlightsO_LIMuSIC integrates RBP-binding peaks with conservation-weighted label smoothing to predict RBP-RNA interactions across eleven species C_LIO_LIMuSIC outperforms state-of-the-art computational methods in predicting cross-species RBP-RNA interactions C_LIO_LICross-species prediction accuracy of RBP-binding peaks correlates with the conservation of RBPs C_LIO_LIMuSIC quantifies the effects of homologous SNVs on RBP binding with experimental validation in mouse C_LI

bioinformatics↗

Targeting RAD52 overcomes PARP inhibitor resistance in preclinical Brca2-deficient ovarian cancer model

AbstractBRCA-mutated ovarian cancer commonly develops resistance to poly (ADP-ribose) polymerase (PARP) inhibitors. Here, we investigated the DNA repair protein RAD52 as a potential target to overcome resistance. In analysis of The Cancer Genome Atlas datasets and immunohistochemistry of tissue microarrays, elevated RAD52 expression correlated with poor overall survival in patients with high-grade serous ovarian cancers. We tested two PARP inhibitor-resistant Brca2-deficient mouse ovarian cancer models, ID8-OR and HGS2-OR. HGS2- OR cells had higher RAD52 expression than parental lines. Rad52 knockout or knockdown restored PARP inhibitor sensitivity in both models. In syngeneic mice, ID8-OR cells in which Rad52 was knocked out yielded lower tumor burden and longer overall survival than control cells. Rad52 depletion impaired single-strand annealing and homologous recombination and led to accumulation of DNA double-strand breaks after PARP inhibitor treatment. RNA sequencing demonstrated that PARP inhibitor treatment induced Polq expression in Brca2- and Rad52-deficient cells, suggesting a switch to microhomology-mediated end joining. Finally, the RAD52 inhibitor D-I03 synergized with a PARP inhibitor to reduce cell viability and tumor burden and prolong survival. Collectively, our findings establish RAD52 as a promising therapeutic target to overcome PARP inhibitor resistance in BRCA2-mutated ovarian cancer and offer mechanistic insights to inform future clinical strategies.

cancer biology↗

Shugoshin holds the potential to inhibit APC/C and thereby prevents separase activation

Accurate chromosome segregation during mitosis and meiosis depends on shugoshin protein which localizes at the centromere of chromosomes. Sgo1, a meiosis-specific shugoshin in fission yeast, collaborates with the PP2A phosphatase enzyme to remove phosphate groups from Rec8 cohesin, thereby preventing its cleavage by separase during meiosis. Here we show that ectopic expression of Sgo1 causes chromosome segregation errors during mitosis, especially in cut1-206 separase mutant cells, but that the D-box mutant Sgo1 has no effect in cut1-206 cells. Our molecular genetic analyses suggest that the D-box of Sgo1 directly binds Slp1/CDC20 and inhibits APC/C-dependent separase activation, thereby preventing cleavage of Rad21 cohesin. In contrast, during meiosis, the Sgo1 D-box mutant makes the cut1-206 mutant more difficult to cleave Rec8 cohesin. This is because the D-box mutation increases the amount of Sgo1 protein during meiosis, thereby enhancing its canonical protective ability against Rec8 cohesin. Thus, our studies using a separase mutant have revealed that Sgo1 has multiple faces to protect coheisn.

cell biology↗

Protection and deprotection of the Rec8 cohesin complex during meiosis

In the first meiotic division, the cohesin Rec8 is cleaved by separase along the chromosome arms but is protected at the centromere by shugoshin (Sgo1), maintaining centromeric cohesion throughout meiosis I. Another meiotic regulator, meikin (Moa1), supports the protective function of Sgo1 primarily by phosphorylating S450 of Rec8. Both Sgo1 and Moa1 are meiosis I-specific proteins. Unlike fission yeast Sgo1, mammalian shugoshin (SGO2) persists at centromeres throughout meiosis I and II, but REC8 cohesin is protected only during meiosis I. Here, we show that fission yeast Moa1 and Sgo1 appear at kinetochores/centromeres from prophase I to metaphase I and are degraded during anaphase I by the APC/C-Slp1 pathway. We expressed non-degradable versions of Moa1 and Sgo1 in meiosis II and investigated how these proteins protect the cohesin Rec8 during meiosis II. Our analyses suggest that the localization of Sgo1 and the phosphorylation of Rec8 at S449 and S450 are necessary and sufficient events for protecting Rec8 cohesin during meiosis II. The absence of either event leads to deprotection at meiosis II.

cell biology↗

Host Phosphatase PPM1G Governs Influenza vRNP Homeostasis by Orchestrating NP Phosphorylation Dynamics and Autophagy

The influenza viral ribonucleoprotein (vRNP) serves as the machinery for viral RNA replication. It self - assembles from the RNA - dependent RNA polymerase (RdRp), viral RNA, and nucleoprotein (NP). During vRNP replication, NP proteins must rapidly switch between monomeric and polymeric states to sustain dynamic equilibrium, which relies on NP phosphorylation-dephosphorylation cycling and is crucial for viral nucleic acid replication. However, the regulatory mechanisms controlling this process remain poorly understood. In this study, we employed an RdRp/vRNP-targeted affinity mass spectrometry-based differential analysis method, discovered that the cellular protein phosphatase Mg2+/Mn2+-dependent 1G (PPM1G) is a phosphatase of NP and required for maintaining viral polymerase activity. Overexpression of PPM1G decreased viral replication. In ppm1g flox/flox-Sftpc Cre mice, lethal influenza infection led to survival and mild disease, as well as reduced lung viral loads and inflammation. These results suggest that PPM1G is a key host molecule for maintaining steady state of viral replication. PPM1G expression is upregulated upon influenza virus infection. This heightened expression occurs in response to increased viral protein production, simultaneously leading to elevated dephosphorylation of NP, which accelerates NP polymerization to promote viral replication. Meanwhile, surplus NP can be degraded through the ATG7 autophagylysosome pathway. Our research elucidates a mechanism that PPM1G maintains viral replication homeostasis by regulating NP status and fate.

microbiology↗

Patch-Clamp Single-Cell Proteomics in Acute Brain Slices: A Framework for Recording, Retrieval, and Interpretation

Single-cell proteomics (SCP) is a powerful method for interrogating the molecular composition of neurons, yet its application to acute brain slices has remained limited. Patch-clamp electrophysiology provides direct information on neuronal excitability, synaptic inputs, and ion channel function, making it a natural partner for SCP. However, combining these techniques introduces unique challenges. For instance, after patch-clamping a neuron, its soma must be physically retrieved, and variability during extraction from the brain slice may influence how well proteomic measurements reflect in situ physiology. Here, we introduce a framework for contextualizing patch-SCP outcomes, with an emphasis on retrieval quality (material yield and soma-enriched synaptic content). We used an indiscriminate shotgun strategy in which all patched neurons were collected regardless of electrophysiological outcome to assess soma retrieval in an exploratory dataset of rat medial prefrontal cortex pyramidal neurons. Capacitance during gigaseal-preserved retrieval correlated with protein identifications, suggesting that proteome yield could be linked to soma size. Preservation of neuronal spiking during relocation tended to be associated with broader synaptic enrichment and recovery of transmembrane proteins. By comparison, torn or aspirated neurons produced small proteomes with poor synaptic representation and neurons with little to no characterization displayed more variable outcomes. These results demonstrate that patch-SCP can be used to assess soma retrieval and they provide a framework for interpreting how electrophysiological context and soma retrieval quality shape single-neuron proteomic measurements in semi-intact circuits.

neuroscience↗

Separately prestored proteasome components to prevent polyspermy

To ensure genome stability across generations, an egg must be fertilized by only a single sperm. However, how sperm actively contribute to preventing polyspermy has remained unknown. Here, we demonstrate that testis-specific 20S proteasome core particles (CPs) are pre-stored within the sperm heads of both mice and humans. Upon fertilization, these testis-specific 20S CPs assemble with oocyte-derived 19S regulatory particles (RPs), forming chimeric proteasomes that efficiently degrade Fetuin B, which is ubiquitinated by the E3 ligase MARCH3. The clearance of Fetuin B triggers ZP2 cleavage and subsequent zona pellucida hardening, thereby blocking additional sperm entry. The newly assembled chimeric proteasome in the zygote represents a novel strategy to prevent polyspermy during fertilization in mammals.

developmental biology↗

Cross-ancestry information transfer framework improves protein abundance prediction and protein-trait association identification

Genetics-informed proteome-wide association studies (PWAS) provide an effective way to map the complex molecular landscape of biological mechanisms for complex diseases. PWAS relies on an ancestry-matched reference panel to model protein expression using genetic variants as features and determine the proteins impact on phenotype. However, reference panels from underrepresented populations remain relatively limited. In this study, we developed an analytic framework that borrows information from potentially multiple ancestries to boost the protein abundance prediction accuracy in an underrepresented population. We illustrate the frameworks utility and reproducibility through application to PWAS in East Asians: BioBank Japan (BBJ), Korean Genome and Epidemiology Study (KoGES), and Taiwan Biobank (TWB). An ensemble of information-sharing approaches was integrated to build the Multi-Ancestry-based Best-performing Model (MABM). MABM substantially improved the prediction performance with higher performance observed in both cross-validation and an external validation dataset (Tongji-Huaxi-Shuangliu Birth Cohort). Leveraging the BBJ, we identified three times as many significant PWAS associations with MABM as with the baseline Lasso model. Notably, 47.5% of the MABM specific associations were reproduced in independent East Asian datasets with concordant effect sizes. Furthermore, MABM enhanced gene/protein prioritization for downstream functional validation by (1) confirming a greater number of well-established gene/protein-trait associations and (2) identifying previously uncharacterized trait-associated genes. The benefits of MABM were further validated in additional ancestries and demonstrated in brain tissue-based PWAS, underscoring its broad applicability. Our findings close critical gaps in multi-omics research, develop a new reference resource of genetic models of protein abundance, and facilitate trait-relevant protein discovery in underrepresented populations.

genomics↗

CHAMP1 Complex Promotes Heterochromatin Assembly and Reduces Replication Stress

Replication stress is a major driver of genomic instability and a hallmark of cancer cells. Although dynamic heterochromatin remodeling has been implicated in replication stress response, the precise mechanisms remain unclear. Here, we identify the CHAMP1 complex, composed of CHAMP1, POGZ, HP1, and the H3K9 methyltransferase SETDB1, as a critical regulator of heterochromatin assembly at stalled replication forks. Upon replication stress, the CHAMP1 complex is recruited to stalled forks where it facilitates H3K9me3 deposition, creating a repressive chromatin environment that shields replication forks from MRE11-mediated degradation. The complex promotes the recruitment of the origin recognition complex (ORC) to sites of replication stress, such as the telomeric heterochromatin in alternative lengthening of telomeres (ALT)-positive tumor cells, thereby supporting efficient telomeric DNA replication. Loss of CHAMP1 disrupts ORC2 recruitment and impairs fork restart, leading to increased micronuclei formation and heightened sensitivity to replication stress. Notably, CHAMP1 deficiency induces synthetic lethality with FANCM inhibition in ALT-positive tumor cells, and the CHAMP1 complex is essential for the survival of CCNE1-amplified ovarian cancers. These findings uncover a chromatin-based mechanism of replication fork stabilization and suggest that CHAMP1 may represent a candidate therapeutic vulnerability in cancers with elevated replication stress.

molecular biology↗

Subtype-Specific Roles of Nigrostriatal Dopaminergic Neurons in Motor and Associative Learning

Nigrostriatal dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) comprise distinct subtypes defined by unique gene expression profiles and anatomical characteristics. However, their specific contributions to motor and non-motor functions remain elusive. Using Calbindin 1 (Calb1) and Aldehyde dehydrogenase 1a1 (Aldh1a1) as molecular markers, we investigated the functions of these nigrostriatal DAN subtypes in mice. Through intersectional genetics and chemogenetic manipulation, we selectively inhibited Calb1+ or Aldh1a1+ DANs by stereotactically delivering an adeno-associated viral vector (AAV-CreOn-FlpOn-hM4Di-P2A-mCherry) into the SNc of ThFlp; Calb1IRESCre or ThFlp; Aldh1a1CreERT2 double knock-in (KI) mice. This approach enabled subtype-specific neuronal inhibition via designer receptors exclusively activated by designer drugs (DREADD). Following DREADD ligand administration, both Calb1+ and Aldh1a1+ DAN-inhibited mice exhibited significant reduction in voluntary movement and impaired motor skill learning, demonstrating their essential roles in motor function. However, only Calb1+ DAN inhibition affected early associative-learning behavior, suggesting a unique role in reinforcement learning. These findings establish Calb1+ and Aldh1a1+ nigrostriatal DANs as key regulators of movement and motor learning, with Calb1+ neurons additionally modulating reward-based associative learning. This study advances our understanding of the functional heterogeneity of nigrostriatal DAN subtypes and identifies potential therapeutic targets for addressing motor and non-motor deficits in Parkinsons disease.

neuroscience↗

A Human Tumor-Immune Organoid Model of Glioblastoma

A major obstacle to identifying effective therapies for the aggressive brain tumor glioblastoma is the lack of human-specific, immunocompetent models that reflect the human tumor microenvironment. To address this, we developed the immune-Human Organoid Tumor Transplantation (iHOTT) model. This is an autologous co-culture platform that integrates patient-derived tumor cells and matched peripheral blood mononuclear cells (PBMCs) within human cortical organoids, enabling the study of the patient-specific immune response to the tumor and tumor-immune interactions. This platform preserves tumor and immune populations, immune signaling, and cell-cell interactions observed in patient tumors. Treatment of iHOTT with pembrolizumab, a checkpoint inhibitor, mirrored cell type shifts and cell interactions observed in patients. TCR sequencing further revealed pembrolizumab-driven expansion of stem-like CD4-T-cell clonotypes exhibiting patient-specific repertoires. These findings establish iHOTT as a physiologically relevant platform for exploring autologous tumor-immune interactions and underscore the critical need for antigen-targeted strategies to enhance immunotherapy in glioblastoma.

cancer biology↗