Biologics : Targets & Therapy最新文献

Introduction: Esophageal epithelial cells are essential for esophageal homeostasis and defense against harmful stimuli, but the mechanisms of radiation-induced injury in these cells are poorly understood. The competitive endogenous RNA (ceRNA) network, involved in various physiological processes and diseases, may also play a role in radiation-induced injury, although its mechanism remains unclear. This study aimed to investigate the effects of ionizing radiation on human esophageal epithelial cells and explore the role of the ceRNA network in this injury.

Methods: Cellular phenotype experiments assessed the effects of ionizing radiation on human esophageal epithelial cells. Whole transcriptome sequencing (lncRNA, circRNA, miRNA, and mRNA) was performed on cells exposed to 0, 2, and 4 Gy radiation. Differentially expressed RNAs (dd-DERs) were identified through differential expression analysis and dose-dependent screening. A ceRNA network was constructed using co-expression analysis and binding site prediction. Real-time quantitative PCR validated the expression levels of selected dd-DERs, and gene set enrichment analysis explored affected pathways.

Results: We identified 41 lncRNAs, 18 miRNAs, and 192 mRNAs as dose-dependent differentially expressed RNAs. A ceRNA network comprising 10 lncRNAs, 5 miRNAs, and 55 mRNAs was established. Real-time PCR confirmed the expression levels of 8 dd-DERs within the network. Gene set enrichment analysis showed that radiation disrupted channel activity, cell replication, repair, and immune response. Functional enrichment analysis revealed modulation of metabolic pathways, particularly involving UGT1A family members.

Discussion: This study established a ceRNA network related to radiation-induced esophageal epithelial cell injury, advancing our understanding of its pathophysiology. The ceRNA network may mediate injury through metabolic pathway modulation. Future work should focus on elucidating specific ceRNA interactions and exploring therapeutic potential for mitigating radiation-induced esophageal injury.

Muscle fibrosis, defined by the excessive deposition of extracellular matrix (ECM) components, is a key pathological process that hinders muscle regeneration following injury. Despite muscle's inherent regenerative potential, severe or chronic injuries often result in fibrosis, which compromises muscle function and impedes healing. This review explores a range of therapeutic strategies aimed at modulating the molecular pathways involved in muscle fibrosis, with a focus on the inhibition of myostatin and transforming growth factor-β (TGF-β), as well as the regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Some therapy modalities, including physiotherapy and exercise therapy, which are commonly used, have demonstrated the ability to regulate extracellular matrix (ECM) components and promote muscle repair. In addition, the use of TGF-β inhibitors, herbal plants, and other biochemically relevant compounds, holds promise in controlling fibrosis by targeting key signaling pathways that drive ECM accumulation as well as having anti-fibrotic and anti-inflammatory properties. Regenerative medicine, including therapies using stem cell, secretome, and platelet-rich plasma (PRP), have also been used as single or adjuvant treatment for muscle fibrosis, and represents a novel and minimally invasive approach. Although these therapeutic strategies show considerable promise, translating preclinical findings to clinical practice remains challenging owing to variability in patient responses and the complexity of human muscle injuries. In conclusion, a multifaceted approach targeting ECM regulation, either as single treatment or combined treatment, offers a promising avenue for the treatment of muscle fibrosis.

Background: Rheumatoid arthritis (RA) is a relatively frequent autoimmune disorder with individual and socioeconomic burden, particularly if diagnosed late. Therefore, identifying novel biomarkers for RA that assist in early diagnosis and managing plan is essential. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1), micro-RNA 21 (miR-21) and interleukin 17 (IL17) have emerging roles in the pathogenesis of numerous inflammatory conditions. The present research aims to evaluate NEAT1, miR-21 and IL17 roles in RA manifestations and activity and the possibility of utilizing them as biomarkers or therapeutic targets for the disease. Therefore, expression levels of NEAT1, miR-21 and IL17 in sera of 100 RA cases, and 100 age and sex-matched healthy controls were compared. A subsequent analysis was conducted to examine the correlation of their levels to various RA manifestations and disease activity.

Results: Both NEAT1 and IL17 were significantly up regulated, while miR-21 was significantly down regulated in cases compared to controls. NEAT1 demonstrated a significant positive correlation with tender and swollen joint counts and with the overall DAS-28 score. A significant negative correlation was noted between miR-21 and RA disease duration.

Conclusion: NEAT1, miR-21, and IL17 have differential levels in patients with RA where NEAT1 and IL17 have up regulation, while miR-21 has down regulation. NEAT1 has a significant correlation with RA disease activity. We recommend further research to determine if they could be useful as future biomarkers for RA.

Small-cell lung cancer (SCLC) is the most aggressive lung cancer, mostly diagnosed at advanced stage, and with few therapeutic options for patients failing the first-line treatment. Antibody-based therapies, such as antibody-drug conjugates and T-cell engagers, are emerging as a promising option in the treatment of various solid tumors, including SCLC. T-cell engagers are molecules able to trigger the T-cell-mediated tumor cell death binding, at the same time, a T-cell and a tumor cell target. Tarlatamab is a DLL3-directed bi-specific T-cell engager (BiTE) whose efficacy was evaluated in a Phase 2 study. Antibody-drug conjugates (ADC) consist of a tumor-directed monoclonal antibody conjugated to a cytotoxic payload able to selectively kill tumor cells through different mechanisms. Ifinatamab-deruxtecan is an anti-B7-H3 ADC showing efficacy in pretreated SCLC patients in a phase 2 clinical trial. Sacituzumab govitecan is a Trop-2-directed ADC already used in other tumor types and evaluated in SCLC in the phase 2 TROPiCS-03 trial, with positive results. Bispecific antibodies targeting VEGF and PD-(L)1 showed antitumor activity in phase 1 and 2 clinical trials. Other antibody-based agents are currently at an earlier phase of their clinical development and showed a promising activity. Novel antibody-based agents could potentially acquire a prominent role in the treatment of SCLC, a field with few therapeutic options. Direct comparisons with the current standard of care still lack, however Phase 3 trials are currently ongoing.

Purpose: This review examines recent advances in monoclonal antibody (mAb) manufacturing, focusing on process optimization, cost reduction strategies, and emerging technologies. The analysis addresses critical challenges in current manufacturing processes while evaluating innovative solutions to improve production efficiency and economic viability.

Methods: We conducted a comprehensive analysis of recent literature on mAb manufacturing, examining traditional batch processing, continuous processing, and hybrid systems. The review evaluates cost optimization strategies, including media development and process integration, while assessing the impact of emerging technologies, such as machine learning and advanced analytics, on manufacturing efficiency.

Results: Recent studies demonstrate that continuous processing can achieve up to 35% cost savings compared to traditional batch processing to meet an annual production demand of 100-500 kg, though this gain diminishes at larger scales. Hybrid facilities show accelerated break-even points, reaching profitability 2-2.5 years earlier than traditional facilities. Advanced media optimization strategies, incorporating novel tripeptide delivery methods, have demonstrated up to 35% improvement in mAb titers. Integration of machine learning and advanced analytics has significantly enhanced process control and optimization capabilities.

Conclusion: The evolution of mAb manufacturing technologies offers promising pathways for improving production efficiency and reducing costs. Scale-dependent considerations remain crucial in selecting optimal manufacturing strategies, while emerging technologies present new opportunities for process optimization. Future developments in continuous processing, advanced analytics, and cell line engineering will be essential in meeting growing global demand while ensuring economic viability and accessibility of mAb therapeutics.

Background: Glioblastoma is a highly aggressive brain tumor, and the transition from the proneural to mesenchymal subtype is associated with more aggressive and therapy-resistant features. However, the signaling pathways and genes involved in this transition remain largely undefined.

Methods: We utilized patient-derived xenograft (PDX) samples of glioblastoma, specifically PDX-L14, which exhibit both negative and overexpressed FOSL1 expression. mRNA expression profiles were assessed by RNA sequencing in these samples, followed by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA). Validation of the hub genes was performed using qPCR and immunohistochemistry assays.

Results: Differentially expressed genes (DEGs) between FOSL1 overexpression groups were predominantly involved in ferroptosis, immune response, angiogenesis, vascular mimicry, autophagy, epithelial-mesenchymal transition (EMT), cancer cell stemness, temozolomide (TMZ) resistance, and NF-κB signaling. Downregulated DEGs were associated with TMZ resistance, glioma proliferation, RNA processing, and Wnt/β-catenin signaling. Key enrichment pathways, including NF-κB, Want, and BMP, are all critical for maintaining glioma stemness. FOSL1 was found to regulate RNA processing and ubiquitination. Notably, 8 upregulated (ITGA5, SDC1, PHLDB2, TNFRSF8, ADAM8, TLR7, STEAP3, and POU3F2) and 4 downregulated (IFIT1, FBXO16, ARL3, and BEX1) genes were identified, with implications for glioblastoma prognosis.

Conclusion: This transcriptome investigation emphasizes the diverse functions of FOSL1 in different biological processes and signaling networks during the shift from proneural to mesenchymal state in glioblastoma.

Neuromyelitis optica spectrum disorders (NMOSD) are primarily autoimmune diseases mediated by B cells and AQP4-IgG antibodies, typically affecting the optic nerves and spinal cord, and are characterised by high relapse rates and significant disability. We present two cases of NMOSD patients who also had systemic lupus erythematosus (SLE), with one case additionally complicated by myasthenia gravis (MG). Both patients initially received first-line treatment with corticosteroids; however, no clinical improvement was observed; As a result, the treatment was switched to the dual-target biologic agent, Telitacicept. Following the administration of Telitacicept, both patients demonstrated significant improvements in clinical symptoms, daily functional abilities, and imaging findings. This report highlights the successful use of Telitacicept in treating NMOSD complicated by other autoimmune diseases, which may serve as an important reference for the management of NMOSD.

Background: The increasing prominence of biosimilars in healthcare delivery has created the need for robust financial evaluation methods to assess development opportunities. Unlike traditional generic drugs, biosimilars require substantial investments ($100-250 million) and longer development timelines (6-8 years), necessitating sophisticated evaluation approaches.

Methods: This study presents a comprehensive Net Present Value (NPV) analysis framework specifically designed for biosimilar development projects. Our framework incorporates key technical, regulatory, and commercial factors through a risk-adjusted NPV methodology, validated through case studies of three monoclonal antibody biosimilar development programs.

Results: The analysis reveals that successful projects require minimum peak sales of $250-300 million to achieve a positive NPV, with market share and manufacturing efficiency serving as critical value drivers. Cost analysis shows that clinical development represents the largest share (57%) of total development costs.

Conclusion: The framework demonstrates that early market entry, manufacturing optimization, and market share achievement are key success factors, whereas technical complexity and competitive intensity significantly influence risk-adjusted returns.

Introduction: Autologous platelet concentrates (APC) are widely used in the infiltrative treatment of knee osteoarthritis (OA) to enhance tissue healing and relieve pain. Aim of this study was to identify predictive biomarkers for clinical outcomes in patients with grade I knee OA.

Methods: A panel of growth factors (GFs) and cytokines was determined in peripheral blood (PB) and APC. The Numeric Pain Rating Scale (NPRS) was used as a clinical readout before and after the APC infiltration.

Results: A lower white blood cell (WBC) count and higher Monocyte-chemoattractant Protein-1 levels in PB were associated with APC-induced pain relief. Platelet-derived Growth Factor (PDGF) levels in APC were significantly higher in OA patients displaying a larger NPRS reduction, independent of platelet count. Finally, the simultaneous determination of PDGF, Vascular Endothelial Growth Factor, and Macrophage Inflammatory Protein-1α in APC discriminated OA patients with very poor or no response.

Conclusion: Platelet-released GFs rather than platelet counts may predict clinical outcomes in grade 1 knee OA.

Background: This study investigates the role of DNA topoisomerase IIα (TOP2A) in retinoblastoma (RB), focusing on its involvement in epithelial-mesenchymal transition (EMT) and the potential of TOP2A inhibition as a therapeutic strategy.

Methods: We analyzed TOP2A expression in RB tissues using public gene expression databases (GSE97508, GSE110811, and GSE172170) and conducted functional assays in human RB cell lines (Y79 and WERI-Rb-1) modified to knock down or overexpress TOP2A. Assessments included cell proliferation, migration, invasion, and EMT marker expression via RT-PCR and Western blot. Additionally, we evaluated the effects of TOP2A modulation in subcutaneous and liver metastasis mouse xenograft models.

Results: TOP2A was significantly overexpressed in RB tissues (p < 0.0001). In vitro, TOP2A knockdown inhibited RB cell proliferation, migration, and invasion, and reversed EMT marker expression (p < 0.05), while TOP2A overexpression enhanced these oncogenic processes. In vivo, TOP2A knockdown or inhibition significantly reduced tumor growth and metastasis in both subcutaneous and liver metastasis models (p < 0.05). Combination therapy with TOP2A and EMT inhibitors further enhanced anti-tumor effects, significantly reducing tumor burden and metastatic lesions (p < 0.01).

Conclusion: TOP2A is pivotal in RB pathogenesis and progression, primarily by regulating EMT. Its inhibition not only curtails RB cell proliferation and metastasis but also reverses EMT, underscoring its potential as a therapeutic target. This study lays the groundwork for further exploration of TOP2A-targeted therapies in RB.