Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
6,974
result(s) for
"Wang, Jia Wen"
Sort by:
FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis
The role of Fat Mass and Obesity-associated protein （FTO） and its substrate N6-methyladenosine （m6A） in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adi- pogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5＇- and 3＇-splice sites, spatially over- lapping with mRNA splicing regulatory serine/arginine-rich （SR） protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenie regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis.
Journal Article
Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase
The methyltransferase like 3 （METTL3）-containing methyltransferase complex catalyzes the N6-methyladenosine （m6A） formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms＇ tumor 1-associating protein （WTAP） and methyltransferase like 14 （METTL14）. WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic ac- tivity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-en- hanced crosslinking and immunoprecipitation （PAR-CLIP） illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
Journal Article
CCR5 gene editing and HIV immunotherapy: current understandings, challenges, and future directions
Human immunodeficiency virus (HIV) infection remains a major global public health challenge. Although highly active antiretroviral therapy (HAART or ART) can effectively control viral replication, it fails to eradicate latent viral reservoirs and poses limitations such as lifelong medication and cumulative drug toxicity. This study focuses on the pivotal role of C-C chemokine receptor 5 (CCR5) gene editing in HIV immunotherapy, particularly highlighting the natural resistance to R5-tropic HIV strains observed in the “Berlin” and “London” patients carrying the homozygous CCR5-Δ32 mutation. We further explore the synergistic potential of multiplex gene editing strategies—including CCR5, CXCR4, and HIV LTR loci—and the combinatorial mechanisms between gene editing technologies and immunotherapy. A personalized treatment framework is proposed to address the clinical heterogeneity among people living with HIV. In addition, we assess the balance between long-term safety and global accessibility of gene-editing approaches such as CRISPR/Cas9, emphasizing strategies to enhance therapeutic efficacy while reducing cost and off-target effects. Our findings suggest that the integration of CCR5-targeted gene editing with immune-based interventions holds great promise for overcoming current therapeutic limitations and achieving functional HIV cure. However, key challenges—such as immune rejection, viral tropism switching, and economic feasibility—must be resolved. This integrative approach provides a robust theoretical and technical foundation for the next generation of HIV treatment paradigms.
Journal Article
Opportunities, challenges, and future perspectives of oncolytic virus therapy for malignant melanoma
Malignant melanoma is characterized by high heterogeneity, aggressive metastatic potential, and a profoundly immunosuppressive “cold” tumor microenvironment, contributing to broad therapeutic resistance and suboptimal responses to immunotherapy. Conventional PD-1 inhibitors yield an ORR of only 38%. As an emerging class of immunotherapeutic agents, oncolytic viruses (OV) induce ICD, promoting the release of DAMPs and activating innate immune pathways such as cGAS-STING, thereby transforming “cold” tumors into “hot” phenotypes and eliciting robust anti-tumor responses. Mechanistically, OV therapy increases the proportion of CD103 + dendritic cells (DCs) in lymph nodes from 5% to 25% and enhances DC–tumor synapse formation by 300%, facilitating efficient cross-presentation of tumor antigens and T-cell priming. Clinically, T-VEC combined with pembrolizumab achieves a 48.6% ORR with grade ≥3 AEs occurring in <20% of patients—superior to either monotherapy or conventional chemoradiotherapy. Nonetheless, OV therapy faces challenges including tumor heterogeneity, core mechanistic limitations, viral shedding risks, and regulatory hurdles. Over the next 5–10 years, single-cell RNA sequencing is expected to unravel molecular heterogeneity in melanoma, while CRISPR/Cas systems may enable the design of tailored OV to overcome resistance. Additional strategies such as serotype switching, JAK/STAT inhibition, and arming OV with hyaluronidase or STING agonists are under investigation to overcome immune and stromal barriers. Integration of artificial intelligence with biomarkers—such as neutralizing antibody titers, ISG expression, and STING methylation—may further enable personalized OV-based therapies. This review discusses OV therapy’s mechanisms, clinical impact, and future prospects in melanoma treatment.
Journal Article
CTLA-4 and PD-1 combined blockade therapy for malignant melanoma brain metastases: mechanisms, challenges, and prospects
Malignant melanoma brain metastases (MBM) represent one of the deadliest complications of melanoma, with an incidence rate of 7.3%. Among patients with acral and mucosal melanoma, the cumulative 5-year incidence can reach 19.5%, accompanied by poor prognosis. The blood-brain barrier (BBB), an immunosuppressive central nervous system (CNS) microenvironment, and tumor immune evasion collectively limit the efficacy of traditional therapies. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), as critical immune checkpoints, play pivotal roles in the progression of MBM. This study systematically analyzes the synergistic mechanisms, clinical outcomes, and challenges of CTLA-4 and PD-1 combined blockade therapy in MBM. The findings indicate that this combination therapy leverages a “priming and boosting” biological mechanism: CTLA-4 blockade broadens T-cell responses during the initial activation phase, while PD-1 blockade sustains T-cell activity during the effector phase, significantly improving intracranial response rates (46%, compared to 20% for monotherapy). Furthermore, the combination therapy increases the CD8+/Treg ratio and promotes memory CD8+ T-cell formation, enabling durable antitumor immune surveillance. However, challenges such as a 54% incidence rate of grade 3–4 adverse events and suboptimal therapeutic regimens remain. To address these issues, this study proposes a multi-tiered adverse event management system, personalized risk assessment models, and treatment optimization strategies based on real-time monitoring and dynamic adjustments. Future directions include developing precision stratified therapies based on immunogenomics, exploring multi-target synergistic approaches, and implementing intelligent adverse event prediction and management systems to maximize therapeutic efficacy and minimize toxicity, providing more effective treatment for MBM patients.
Journal Article
Correlation does not equal causation: the imperative of causal inference in machine learning models for immunotherapy
Machine learning (ML) has played a crucial role in advancing precision immunotherapy by integrating multi-omics data to identify biomarkers and predict therapeutic responses. However, a prevalent methodological flaw persists in immunological studies—an overreliance on correlation-based analysis while neglecting causal inference. Traditional ML models struggle to capture the intricate dynamics of immune interactions and often function as “black boxes.” A systematic review of 90 studies on immune checkpoint inhibitors revealed that despite employing ML or deep learning techniques, none incorporated causal inference. Similarly, all 36 retrospective studies modeling melanoma exhibited the same limitation. This “knowledge–practice gap” highlights a disconnect: although researchers acknowledge that correlation does not imply causation, causal inference is often omitted in practice. Recent advances in causal ML, like Targeted-BEHRT, CIMLA, and CURE, offer promising solutions. These models can distinguish genuine causal relationships from spurious correlations, integrate multimodal data—including imaging, genomics, and clinical records—and control for unmeasured confounders, thereby enhancing model interpretability and clinical applicability. Nevertheless, practical implementation still faces major challenges, including poor data quality, algorithmic opacity, methodological complexity, and interdisciplinary communication barriers. To bridge these gaps, future efforts must focus on advancing research in causal ML, developing platforms such as the Perturbation Cell Atlas and federated causal learning frameworks, and fostering interdisciplinary training programs. These efforts will be essential to translating causal ML from theoretical innovation to clinical reality in the next 5-10 years—representing not only a methodological upgrade, but also a paradigm shift in immunotherapy research and clinical decision-making.
Journal Article
The regulatory effects of PD-1/PD-L1 inhibitors on bone metabolism: opportunities and challenges in osteoporosis management
Programmed death-1 (PD-1) and its ligand PD-L1 inhibitors have become pivotal agents in cancer immunotherapy, demonstrating significant efficacy across multiple malignancies. However, beyond regulating T cell activation, the PD-1/PD-L1 axis also exerts complex and critical effects on bone metabolism. Notably, both clinical observations and mechanistic studies have revealed a paradox: on one hand, PD-1/PD-L1 blockade appears to confer bone-protective benefits; on the other hand, it has been associated with bone-related adverse events (AEs) in up to 69% of patients, including pathological fractures and vertebral compression fractures. This review comprehensively explores the bidirectional regulatory effects of the PD-1/PD-L1 pathway on bone metabolism and investigates the underlying mechanisms contributing to these contradictory findings. The discrepancies may be attributed to a combination of clinical variables, microenvironmental conditions, cell-specific responses, and intricate interactions among multiple signaling pathways, including the Wnt/β-Catenin pathway and the PD-L1–PKM2 axis. We further examine the pathophysiological basis of osteoporosis and fragility fractures occurring during PD-1/PD-L1 inhibitor therapy, and argue for their recognition as a subclass of immune-related adverse events (irAEs). Finally, we propose a framework for bone health surveillance and stratified prevention strategies aimed at preserving antitumor efficacy while improving skeletal health and quality of life—offering novel insights into osteoporosis prevention and management in the context of immune checkpoint inhibition.
Journal Article
Oncolytic virus therapy in the elderly: immune frailty, challenges, and perspectives
With global aging accelerating, cancer incidence among older adults is rapidly increasing. Individuals aged ≥65 years now represent 64% of new cancer cases and 71.3% of cancer-related deaths worldwide. This population exhibits a distinct immune imbalance—driven by tumor-induced immunosuppression, immunosenescence, and inflammaging—which contributes to poor tolerance of standard therapies and suboptimal outcomes with PD-1/PD-L1 inhibitors. As an emerging immunotherapeutic strategy, oncolytic viruses (OVs) selectively infect tumor cells, induce immunogenic cell death (ICD), and activate the cGAS–STING pathway. Although clinical data in elderly patients with esophageal, lung, or pancreatic cancer are scarce, promising outcomes have been reported in melanoma/sarcoma subgroups, including objective response rates of 26.4–32.9% and a median duration of response of 33.7 months, highlighting the potent antitumor potential of OVs. However, age-related immunological vulnerability—manifesting across different frailty stages as reflected by G8 scoring—may predispose elderly patients to immune overload, cytokine storm, and impaired tolerance, while this group remains underrepresented in OV trials. Systematic studies in this context are lacking. This review highlights the immunological characteristics of aging, emphasizes the importance of addressing immunological vulnerability across different age stages (G8 scoring), and outlines emerging challenges and future directions for OV-based therapies tailored to frail elderly populations.
Journal Article
Oncolytic virus therapy for osteosarcoma: mechanisms, opportunities, and challenges
Osteosarcoma (OS), the most common primary malignant bone tumor in children and adolescents, remains a major therapeutic challenge due to its high metastatic potential and limited response to conventional treatments, including immune checkpoint inhibitors (ICIs). Oncolytic viruses (OVs) have emerged as a promising strategy with dual antitumor functions: direct oncolysis and the induction of immunogenic cell death (ICD). By releasing damage-associated molecular patterns (DAMPs) and activating the cGAS-STING pathway, OVs can remodel the immunologically \"cold\" tumor microenvironment (TME) into an inflamed and immune-responsive phenotype, thereby enhancing CD8
T-cell infiltration and improving antitumor immunity. Encouraging preclinical evidence has been reported: VSV-IFNβ-NIS achieved a long-term survival rate of approximately 35% in canine OS models, and synergistic combination regimens have demonstrated tumor inhibition rates exceeding 70%. Despite these advances, OV-based therapies still face critical translational challenges, including the immunosuppressive TME, intratumoral delivery barriers, and safety concerns. This review systematically summarizes the molecular mechanisms underlying OV-mediated antitumor immunity, evaluates current clinical evidence, and highlights future opportunities, such as combination immunotherapy, mesenchymal stem cell (MSC)-based delivery platforms, and AI-driven precision medicine approaches. Our goal is to provide a comprehensive theoretical framework to support the clinical translation and personalized application of OV therapy in osteosarcoma.
Journal Article