搜索结果：Translational oncology

Cancer remains a leading cause of mortality worldwide, highlighting the need for therapeutic strategies that reduce systemic toxicity and drug resistance. Resveratrol (RES), a natural polyphenolic stilbenoid, possesses antioxidant, anti-inflammatory, pro-apoptotic, anti-metastatic, and chemosensitizing activities. However, its clinical translation is limited by poor aqueous solubility, chemical instability, rapid metabolic clearance, and consequently low systemic bioavailability. Nanotechnology-based drug delivery systems provide a promising strategy to address these limitations. This review summarizes recent advances in RES-loaded nanoformulations, including polymeric nanoparticles, liposomes, solid lipid nanoparticles, micelles, inorganic nanocarriers, protein-based systems, and biomimetic vesicles. Their therapeutic performance is evaluated across prostate, lung, colorectal, breast, and other cancers, with attention to tumor targeting, controlled release, combination therapy, multidrug-resistance reversal, and modulation of cancer-relevant pathways such as NF-κB, p53, and PI3K/Akt/mTOR. Current oncology-related clinical evidence for RES is still largely based on conventional oral or micronized formulations. Translation of engineered RES nanocarriers therefore requires stronger evidence on scalable manufacturing, carrier-specific safety, heterogeneous tumor delivery, and biomarker-guided trial design. This review also introduces a semi-quantitative prioritization framework based on model-readiness, translational priority, and safety-alert scoring for future PBPK, PK-PD, nano-QSAR, and machine-learning analyses.

Leukemia predominantly affects the elderly, who face unique clinical challenges related to aging physiology, comorbidities, and social determinants of health. These challenges are further exacerbated in underserved regions where diagnostic and treatment resources are scarce, resulting in delayed diagnoses, limited access to effective therapies, and poorer survival outcomes. This review explores the multifaceted barriers to equitable leukemia care for elderly patients in resource-limited settings, emphasizing the urgent need for targeted interventions. Recent therapeutic advances, including hypomethylating agents, targeted oral therapies, and reduced-intensity conditioning regimens, have improved survival and quality of life for older leukemia patients in high-income settings. However, their availability and implementation in underserved regions remain inadequate due to economic, infrastructural, and policy constraints. We discuss emerging strategies such as decentralizing diagnostics, integrating comprehensive geriatric assessments, leveraging telemedicine, and fostering inclusive clinical trials that can help bridge these gaps. Addressing disparities in geriatric leukemia care demands a coordinated approach involving healthcare providers, policymakers, and community stakeholders. By expanding access to diagnostics and novel therapies, strengthening supportive care, and prioritizing research in diverse populations, the global oncology community can move towards equitable care delivery. Ultimately, ensuring that elderly leukemia patients in underserved regions receive personalized, evidence-based treatment is critical to improving outcomes and honoring their dignity.

To evaluate whether [68Ga]Ga-FAPI-46 PET/CT (FAPI PET) is sensitive to neoadjuvant chemotherapy (NAC)-associated changes in peritoneal carcinomatosis (PC) and whether post-NAC FAPI PET parameters and pre-/post-NAC changes are associated with histopathologic and biochemical response. This exploratory translational sub-cohort analysis was conducted within the prospective phase II FAPeCa trial (NCT06061874) recruiting patients with colorectal or ovarian cancer with known/suspected PC. Patients who received recent chemotherapy were included in the current analysis. PET parameters, including SUVmax, peritoneal tumour volume (PTV), and total lesion uptake (TLF/TLG) were analysed both on FAPI and [18F]-FDG PET/CT. Associations with pathological chemotherapy response score (pCRS) and CA-125 change were explored. Pre- and post-NAC paired FAPI PET and FAP immunohistochemical (IHC) analyses were performed. Segment-level correlation between IHC score and FAPI PET uptake was assessed. Twenty-seven patients were included, predominantly with ovarian cancer (26/27), including 10 with paired pre-/post-NAC imaging. All paired FAPI PET parameters declined significantly after NAC. The magnitude of change in paired FAPI PET parameters correlated strongly with pCRS, particularly for SUVmax (ρ=0.866, p=0.005), PTV(2.5) (ρ=0.830, p=0.011), and TLF(2.5) (ρ=0.830, p=0.011), whereas FDG PET parameters and FAPI PTV(40) and TLF(40) showed no significant correlation with pCRS. Changes in FAPI PET parameters also correlated with the CA-125 change. Across the post-NAC cohort, FAPI PET volumetric parameters differed significantly across pCRS categories. Paired IHC demonstrated a significant reduction in FAP expression after NAC, and segment-level FAP IHC score showed a significant moderate correlation with FAPI uptake (SUVmax ρ=0.467, p=0.012; SUVmean ρ=0.554, p=0.005). [68Ga]Ga-FAPI-46 PET/CT demonstrated treatment sensitivity after NAC in PC, with concordant reductions in PET parameters and stromal FAP expression. FAPI PET volumetric parameters were associated with histopathologic response and CA-125 change in this exploratory sub-cohort, supporting further investigation of FAPI PET as an imaging biomarker for response assessment in PC.

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass, deterioration of bone microarchitecture, and increased susceptibility to fragility fractures. Although conventional antiresorptive and anabolic drugs effectively reduce fracture risk in many patients, their clinical utility is restricted by poor tissue specificity, systemic adverse effects, adherence problems, discontinuation-related risks, and their limited capacity to regenerate osteoporotic bone defects after trauma or surgery. Biomaterial-based strategies provide complementary opportunities by combining local structural support, controlled therapeutic delivery, and microenvironmental regulation. In this review, we discuss biomaterial design from an osteoporosis-specific perspective, emphasizing how disease-associated abnormalities-impaired osteoblast function, excessive osteoclast activity, reduced angiogenesis, inflammatory dysregulation, compromised extracellular matrix quality, and weakened mechanical integrity-can be addressed by scaffolds, targeted drug delivery systems, and biologically derived platforms. Ceramic, polymeric, and composite scaffolds are compared with respect to osteoconduction, ion-mediated signaling, mechanical support, and manufacturability. Bone-targeted nanoparticles, injectable hydrogels, and stimuli-responsive carriers are evaluated as strategies for the localized delivery of antiresorptive agents, anabolic molecules, nucleic acids, and osteogenic cues. We further summarize platelet-rich plasma/platelet-rich fibrin, growth factor-loaded matrices, mesenchymal stem cell-laden scaffolds, extracellular vesicle-functionalized systems, and gene-activated matrices as emerging biological or cell-free regenerative platforms. Finally, key translational barriers, including long-term safety, reproducible manufacturing, standardized osteoporotic models, and regulatory pathways for combination products, are discussed. Overall, biomaterials should not be viewed as replacements for established pharmacotherapy but as disease-tailored local interventions that may improve osteoporotic fracture repair and bone regeneration when integrated with rational clinical management.

Quorum sensing (QS) orchestrates virulence, biofilm maturation, and antimicrobial tolerance across clinically dominant pathogens, driving chronic infections and therapeutic failure. Although quorum-sensing inhibitors (QSIs) were developed to attenuate pathogenic coordination without bactericidal pressure, their clinical translation has been constrained by biochemical instability, narrow receptor specificity, limited pharmacokinetic robustness, and emerging adaptive resistance. Molecularly imprinted polymers (MIPs) provide a mechanistically distinct strategy based on structurally defined recognition cavities capable of physically sequestering or catalytically degrading autoinducers with measurable thermodynamic parameters, including the imprinting factor (IF), dissociation constant (K d), and binding capacity. This review critically synthesizes advances in molecularly imprinted polymer design for QS detection and modulation, emphasizing the role of monomer-template complementarity, cross-link density, porogen environment, polymerization strategy, and template removal in governing recognition fidelity and biological performance. Computational modeling has improved monomer selection and prepolymerization complex prediction, yet translational reliability requires integration of solvent dynamics, cross-linker effects, and matrix competition under physiologically relevant conditions. Compared with conventional biosensors and small-molecule QSIs, MIPs demonstrate nanomolar detection limits, resilience in complex media, and up to 80% biofilm inhibition through signal sequestration. Early in vivo studies further support their potential to attenuate the QS-dependent virulence. Despite these advances, barriers remain, including monomer cytotoxicity, nonspecific adsorption in biological fluids, incomplete biodegradation profiling, and the need for standardized in vivo validation frameworks. With rational engineering and regulatory alignment, MIPs represent a programmable materials platform for communication-based infection control, expanding the antivirulence paradigm beyond receptor antagonism toward structurally resilient quorum interception.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Personalized vaccines provide the advantage of patient-specific antigen selection to optimize immune responses, a strategy extensively explored in oncology through neoantigen-targeted peptide, mRNA, and dendritic cell platforms. Peptide vaccines provide simplicity and stability though often elicit limited cytotoxic T-cell responses. What is more, mRNA vaccines lead to rapid, multiplexed neoantigen delivery, endogenous antigen processing and eventually improved immunogenic coverage. Dendritic cell-based vaccines have the potency to prime potent T-cells although this technology requires labor-intensive manufacturing and extensive production timelines. Integration with immune checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses further enhances efficacy, suggesting that rational combinations may be more effective than single modalities. Recent advances in sequencing, computational epitope prediction, and bioinformatics pipelines have facilitated neoantigen prioritization and DC vaccine design, enabling more rapid and precise personalization. Hybrid vaccination strategies, such as ex-vivo mRNA-electroporated dendritic cells and in-vivo DC-targeted platforms, bridge the gap between manufacturing feasibility and potent immune activation. Emerging technologies, including AI-driven neoepitope prediction, receptor-targeted antigen delivery, biomaterial-based modulation, and distributed mRNA manufacturing, seem to be promising approaches to accelerate personalized vaccine development in future. From another point of view, lessons learned from the COVID-19 pandemic accelerated the development, large-scale deployment, and validation of mRNA vaccine platforms for infectious diseases. Host HLA diversity, prior immune history, and viral evolution create heterogeneity in immune responses, highlighting opportunities for semi-personalized or adaptive strategies. In this review, we provide a landscape of personalized vaccines, with a focus on DC-based platforms, and explore translational lessons for viral pathogens. A conceptual framework linking cancer immunotherapy and infectious disease preparedness is proposed, emphasizing hybrid personalization approaches, rapid manufacturing, and AI-enabled epitope selection. This perspective highlights how convergence of immunology, computational biology, and advanced vaccine technologies could expand the scope of personalized vaccination, from oncology to future epidemic and pandemic scenarios as well as the current challenges.

The advent of CRISPR/Cas9 genome editing has significantly transformed the landscape of cancer therapeutics by facilitating precise and programmable manipulation of disease-associated genetic modifications. This review comprehensively evaluates the current clinical and translational landscape of CRISPR/Cas9-based cancer therapies through an analysis of published literature and registered clinical trials. The current CRISPR/Cas9 applications in oncology are primarily centred on three mechanistic strategies: immune cell engineering for enhanced tumor recognition, direct targeting of oncogenic mutations, and modulation of tumor-supportive pathways. Analysis of 32 clinical trials indicates that CRISPR-based interventions have demonstrated encouraging safety profiles and early signs of clinical activity, particularly in ex vivo engineered immune-cell therapies. Notable examples include CRISPR-edited CAR-T cell products targeting CD19 and BCMA, which have achieved objective responses in relapsed or refractory hematological malignancies while demonstrating sustained persistence of edited cells in vivo. In contrast, clinical translation into solid tumors remains comparatively limited due to challenges associated with delivery efficiency, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Technological advancements, including multiplex genome editing, base editing, and prime editing have expanded the precision and versatility of CRISPR-based interventions, while integration with immunotherapy and nanotechnology-based delivery systems continues to broaden therapeutic potential. Despite these advances, several significant challenges still need to be addressed, including off-target editing, manufacturing scalability, delivery limitations, and regulatory considerations. Overall, CRISPR/Cas9 represents a promising yet evolving platform in oncology, with its future clinical success dependent on achieving a balance between precision, safety, scalability, and long-term therapeutic durability.

Cholangiocarcinoma (CCA) is a highly aggressive, molecularly heterogeneous biliary tract malignancy and the second most common primary liver cancer, and it has an increasing global incidence and persistently poor prognosis. Recent updates of international guidelines, including those from the NCCN, ESMO, EASL, CSCO, BSG, and Japanese societies, along with rapid advances in precision oncology, have substantially changed the clinical management of CCA. This review systematically compares current global guidelines, highlighting both areas of consensus and regional differences in epidemiology, risk factors, screening strategies, diagnostic approaches, pathological and molecular classification, staging systems, surgical indications, systemic therapy, and multidisciplinary management. This review also summarizes recent advances in molecular diagnostics, including next-generation sequencing, liquid biopsy, circulating tumor DNA, extracellular vesicles, artificial intelligence-assisted imaging, radiomics, and emerging prognostic biomarkers. The evolving roles of immune checkpoint inhibitors, molecularly targeted therapies against FGFR2, IDH1, HER2, BRAF, NTRK, and MSI-H/dMMR, liver transplantation, locoregional treatment, and conversion (translational) therapy are also discussed. Finally, this review addresses current challenges, including drug resistance, limited access to molecular testing, regional disparities in healthcare resources, and the lack of universally accepted screening strategies. By integrating updated guideline recommendations with the latest clinical evidence, this review provides a comprehensive reference for evidence-based clinical decision-making and future translational research in CCA.

Exosome-mediated delivery of small interfering RNA (siRNA) has emerged as a promising therapeutic strategy for cancer treatment, offering precise gene silencing with minimal off-target effects. Exosomes, naturally secreted extracellular vesicles, provide biocompatible carriers that protect siRNA from enzymatic degradation and facilitate efficient uptake by tumor cells. Their natural tropism, driven by surface proteins such as integrins and tetraspanins, promotes cellular adhesion and interactions within the tumor microenvironment, facilitating the delivery of therapeutic cargo. Preclinical studies have demonstrated that exosome-delivered siRNAs can suppress oncogenes, inhibit tumor growth, reverse chemoresistance, and modulate immune responses by targeting stromal and immune components. Engineering approaches, including surface functionalization and hybrid exosome-nanoparticle systems, further enhance stability, payload capacity, and tumor-homing efficiency. Combination strategies with chemotherapy, immunotherapy, or phototherapy have shown synergistic effects, allowing simultaneous inhibition of survival pathways, promotion of apoptosis, and remodeling of the immunosuppressive microenvironment. Early-phase clinical studies indicate safety, effective biodistribution, and functional gene silencing, highlighting the translational potential of exosome-mediated siRNA therapeutics. Challenges such as scalable production, cargo heterogeneity, and regulatory considerations remain, but ongoing advances in exosome engineering and patient-derived vesicles are poised to overcome these barriers. This review aims to comprehensively summarize the current state, therapeutic applications, and translational prospects of exosome-mediated siRNA delivery in cancer.

Post-transcriptional regulation of gene expression has emerged as a fundamental determinant of cancer initiation, progression, and therapeutic response. Among the RNA-binding proteins (RBPs) involved in mRNA turnover and translational regulation, tristetraprolin (TTP), encoded by the ZFP36 gene, and "Human antigen R" (HuR), encoded by ELAVL1, represent two functionally antagonistic regulators of AU-rich element (ARE)-containing transcripts. TTP promotes the degradation of target mRNAs through recruitment of deadenylation and decay complexes, whereas HuR generally stabilizes and enhances the translation of overlapping mRNA subsets. Because many oncogenic, inflammatory, angiogenic, and metastasis-associated transcripts contain AREs within their 3' untranslated regions, the balance between TTP-mediated decay and HuR-mediated stabilization critically influences tumor biology. Accumulating evidence demonstrates that loss of TTP expression or activity and cytoplasmic accumulation of HuR are recurrent features across multiple cancer types, including breast, colorectal, pancreatic, gastric, liver, ovarian, and lung cancers. Importantly, several studies indicate that the reciprocal interplay between these proteins establishes a post-transcriptional rheostat controlling cancer-associated RNA regulons. This review summarizes current knowledge regarding the molecular biology of TTP and HuR, emphasizing their opposing functions in mRNA metabolism and cancer progression. We discuss mechanisms regulating their expression, localization, phosphorylation, and RNA-binding activity; analyze cancer-specific evidence; and examine models in which both proteins are co-expressed or functionally interconnected. Finally, we evaluate therapeutic strategies aimed at restoring TTP function or inhibiting HuR activity and discuss future perspectives for targeting post-transcriptional regulatory networks in oncology.

The fat mass and obesity-associated protein (FTO), an RNA demethylase acting on both internal m6;A and cap-proximal m6;Am, functions in cancer as a context-dependent epitranscriptomic regulator whose net effect cannot be reduced to an oncogene-tumor-suppressor dichotomy. Its biological output is shaped by tumor lineage, subcellular localization, upstream signaling, and competing m6;A reader activities, predominantly YTHDF2-mediated decay and IGF2BP-mediated stabilization, although both reader families display additional non-canonical functions and are themselves modulated by post-translational modifications. Building on the now well-established context-dependence of FTO biology, which we do not claim as a novel observation, this review synthesizes current evidence on FTO's roles at the intersection of tumor immune contexture, immune checkpoint regulation, metabolic reprogramming, and therapeutic resistance. We examine how FTO may contribute to immune exclusion through metabolic competition, exosomal signaling, and stromal reprogramming; modulate PD-L1 expression through direct and indirect mechanisms; and influence response to chemotherapy, targeted therapy, radiotherapy, and CNS-directed treatment. Emerging FTO inhibitors, FTO-degraders, and combination strategies with immune checkpoint blockade, ferroptosis inducers, or glycolytic inhibitors are evaluated against their underlying preclinical evidence base. The contribution of this review lies less in proposing a new framework than in three forms of integration typically addressed in isolation: explicit calibration of mechanistic claims to evidence tier, systematic separation of tumor-intrinsic from immune-cell-intrinsic FTO functions across lymphoid and myeloid compartments, and translation of reader-network biology into biomarker-stratified trial design. Technical limitations of epitranscriptomic methods are addressed as constraints on inference. To our knowledge, no FTO-targeted strategy has yet entered Phase I oncology evaluation; current combination rationales therefore remain preclinically supported rather than clinically established.

Lactylation, a unique post-translational alteration, has been identified as an important epigenetic regulator of cancer metabolism, immune evasion, and treatment resistance. Recent research reveals that ultrasound-based biophysical stimulation may change tumor microenvironmental variables that affect lactate metabolism and subsequent lactylation processes. The purpose of this study was to better understand the predictive significance of lactylation-associated genes in lung adenocarcinoma (LUAD) and how they could interact with ultrasound-mediated treatment response. Transcriptomic data from 867 LUAD samples were used to identify lactylation-related genes. Consensus clustering was used to separate LUAD cases into various lactylation subtypes. Differentially expressed genes were assessed for functional enrichment, mutation load, and immunological infiltration. A prognostic risk model was created using multivariate Cox regression analysis. Nineteen major lactylation-related genes divided patients with LUAD into three molecular subgroups with different clinical outcomes. A 10-gene prognostic model accurately predicted overall survival and was associated with stronger tumor stemness, increased mutational frequency, and decreased immunotherapy effectiveness in high-risk patients. Notably, computational predictions suggested that metabolic regulation might slow lactylation-driven tumor development, implying a synergistic treatment window. Lactylation-associated gene profiles may serve as prognostic biomarkers and therapeutic modulators in LUAD. The combination of ultrasound-based therapies targeting lactylation pathways could be a viable technique for improving precision oncology and overcoming resistance mechanisms in lung cancer therapy.

Despite remarkable advances in cancer drug treatment, including chemotherapy, targeted therapy, and immunotherapy, therapeutic resistance remains a formidable clinical barrier, limiting durable responses and long-term survival. Drug resistance can be broadly categorized as intrinsic, where tumors fail to respond to initial treatment, or acquired, which emerges during or after therapy due to adaptive or evolutionary processes. A comprehensive understanding of the multifactorial and dynamic nature of resistance is essential for improving treatment efficacy. In this review, we systematically examine the molecular and cellular determinants of drug response and resistance across 22 cancer types, highlighting key resistance mechanisms such as compensatory pathway activation, phenotypic plasticity, immune evasion, enhanced DNA damage repair, and the survival of drug-tolerant persister cells. These mechanisms are further contextualized across major therapeutic modalities, supported by clinical trials. We also present emerging strategies to overcome resistance, including rational drug combinations, novel agents, microbiome modulation, adaptive and intermittent therapies and advanced drug delivery systems, each illustrated with representative clinical studies. Moreover, we discuss cutting-edge tools that are revolutionizing resistance research, including single-cell and spatial multiomic profiling, patient-derived tumor organoid and xenograft (PDO/PDX) models, and artificial intelligence (AI)-powered predictive analytics. By integrating insights across molecular, cellular, and clinical dimensions, this review offers a strategic framework for understanding and tackling cancer drug resistance, with important translational implications for the future of precision oncology.

Protein neddylation is an evolutionarily conserved posttranslational modification that conjugates NEDD8 to its substrate, catalyzed by an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase. Neddylation is essential for cellular homeostasis, and its dysregulation has been implicated in diverse human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, making the process a promising therapeutic target. In this Review, we systematically summarize the biochemical activity and biological functions of neddylation; its alterations in human diseases, particularly in cancers; and its validation as an attractive target for cancer therapy. We provide an overview on the discovery of neddylation inhibitors and the progress of MLN4924 (pevonedistat) and TAS4464 clinical trials and critically evaluate the core challenges and emerging opportunities for therapeutic strategies targeting neddylation.

Soluble CD146 (sCD146) is a key circulating biomarker released from vascular endothelial cells via enzymatic cleavage under conditions of stress or activation.sCD146 not only dynamically reflects the integrity of the microvascular endothelial barrier but also profoundly drives the malignant progression of multisystem diseases through targeted interactions with its receptors (such as angiopoietin AMOT and VEGFR2). In malignant solid tumors, it accelerates tumor invasion and immune evasion by inducing epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) phenotypes; In cardiovascular diseases and early-life developmental abnormalities (such as bronchopulmonary dysplasia), it serves as a highly sensitive marker of tissue stasis and microvascular stress. However, the clinical application of sCD146 currently faces substantial translational hurdles: on the one hand, the lack of a standardized, cross-platform detection system and universally accepted clinical-pathological cutoff values hinders data interoperability across centers; on the other hand, its baseline expression exhibits heterogeneity in complex complications, and whether it serves as a "key mediator" of disease progression or a "bystander" of concomitant injury remains inconclusive in certain pathological states. In light of this, this review breaks down disciplinary barriers to systematically summarize the latest medical advances regarding sCD146 across oncology, cardiovascular, neuroimmunology, and reproductive development fields. It clarifies the core pathogenic mechanisms of sCD146 in different microenvironments, addresses practical challenges in clinical translation, and provides a solid theoretical foundation to advance sCD146 from a laboratory biomarker to a clinical precision diagnostic and therapeutic target.

Breast cancer (BC) is the most common malignancy among women worldwide. Although observational studies have linked carnitine-related metabolites (CRMs) to BC, causal inference has been limited by confounding and reverse causality. This study used Mendelian randomization (MR) analysis to investigate the potential causal link between CRMs and BC. MR analysis was conducted using the Cancer Genome Atlas-BC and CRM-related datasets to explore the potential causal relationship between CRMs and BC. Variants were screened based on criteria encompassing genome-wide significance (p < 5&#xd7;10-8), independence (r 2 < 0.001, kb=10000), and sufficient strength (F-statistic > 10). Various MR techniques, including inverse-variance weighted, MR-Egger, simple mode, weighted mode, and weighted median approaches, were applied to assess these potential causal associations. Single-cell RNA sequencing (scRNA-seq) was employed to investigate the expression and biological functions of biomarkers linked to metabolites. The MR analysis suggested that genetically predicted elevated levels of octanoylcarnitine and decanoylcarnitine were associated with increased risk of BC. Functional enrichment analysis identified 12 candidate genes associated with these metabolites, which are involved in fatty acid &#x3b2;-oxidation (FAO) pathways. ScRNA-seq analysis revealed eight distinct cell subpopulations, with macrophages exhibiting the highest intercellular communication. Six biomarkers were identified as potential contributors to BC development: ACADM, FNIP2, RAPGEF2, RABGGTB, PPID, and ST6GALNAC3. This study provides evidence supporting potential causal associations between octanoylcarnitine and decanoylcarnitine and BC risk. Integrative single-cell transcriptomics revealed six CRM-associated biomarkers and their dynamic expression within tumor microenvironments. Additional experimental and clinical studies are needed to validate these observations and clarify their biological and translational relevance.

Advanced soft tissue sarcoma (STS) is a group of rare and heterogeneous malignancies, requiring better therapeutic strategies. Pazopanib, a widely used second-line treatment, has been suggested to exert immunomodulatory effects, which may be relevant for enhancing response. Specifically, pazopanib reduces immunosuppressive cells like myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) while enhancing the function of dendritic cells, T cells, and NK effectors. Based on this knowledge, we hypothesized that proteins involved in immunomodulation could serve as predictive biomarkers of response to pazopanib. To explore immune-related biomarkers of prognosis and pazopanib response in advanced soft tissue sarcoma using paired pre- and post-treatment tumour samples and complementary preclinical models. Exploratory translational study integrating differential gene expression profiling of clinical specimens with in silico prognostic evaluation and in vitro functional assays in soft tissue sarcoma cell lines treated with pazopanib. HTG transcriptome-direct profiling was performed on paired FFPE tumour samples from pazopanib-treated patients, followed by bioinformatic identification of differentially expressed genes and survival correlations, and subsequent validation of candidate biomarkers, at RNA and protein levels in sarcoma cell lines exposed to pazopanib. Using HTG transcriptomics, we identified 38 differentially expressed genes in post-pazopanib STS samples. Among them, SERPINE1 was the most consistent dynamic biomarker, showing a 4.19-fold increase (FDR = 0.016) and correlating with poor survival (progression-free survival (PFS), p = 0.033; disease-free survival (DFS), p = 0.004). In vitro, SERPINE1 upregulation was observed in STS cell lines CP0024 (24h, 1.47-fold; 48h, 1.71-fold), ICP059 (48h, 1.15-fold), and 93T449 (72h, 2.29-fold), with earlier expression in more sensitive cell lines. Protein validation confirmed these results after 48h of treatment. Our results support SERPINE1 as a biomarker for poor prognosis and suggest its role as an exploratory, hypothesis-generating candidate marker for pazopanib response, warranting further validation in larger cohorts.

Glycosylation is an important post-translational modification that can alter the biological activities of antibodies. In monoclonal antibody biotherapeutic products, glycosylation of the Fc-domain, which is often sensitive to manufacturing conditions, can alter product potency by affecting its interactions with host immune cells. Improving control of antibody glycosylation to produce more chemically defined products and to better understand glycan function is gaining interest, with chemoenzymatic glycan engineering emerging as a powerful technique. This chapter describes methods to obtain purified glycans, including isomers with asymmetric antennae, their enzymatic incorporation into monoclonal antibodies, and a natural killer T cell-based binding assay to determine Fc&#x3b3;RIIIA (CD16A) binding affinity.