Biologics : Targets & Therapy最新文献

Lupus erythematosus panniculitis (LEP) is a rare and serious skin lesion associated with systemic lupus erythematosus (SLE). In the past, the management of LEP has followed the treatment guidelines for SLE, which is based on the administration of high doses of hormones together with immunosuppressants, with no treatment plans specific for LEP. However, the long-term use of high hormone doses and immunosuppressants can exacerbate skin breakage and calcification. Telitacicep is an approved biological agent demonstrating significant therapeutic efficacy in immune system disorders. We report a case of lupus erythematosus panniculitis in which the patient's clinical symptoms and laboratory test results improved after treatment with a combination of steroids, cyclophosphamide, and the biologic agent Telitacicept. The condition was significantly controlled and alleviated. This report highlights the successful application of Telitacicept in the treatment of lupus panniculitis, providing valuable insights for future management of this condition.

Hidradenitis suppurativa (HS), a chronic inflammatory disorder affecting approximately 1% of the global population, remains challenging to treat due to the limited efficacy of single biologics (TNFa/IL-17/IL-36 inhibitors) against draining tunnels (dTs). A man with refractory HS (Hurley stage III) was treated with recibokibart (anti-IL36R antibody) and secukinumab (anti-IL17A antibody). Disease severity was assessed using previously validated clinical outcome measures and ultrasonography. Rapid clinical improvement was observed in this patient. HiSCR50 was achieved at week 2, and HiSCR100 (complete resolution of inflammatory nodules and abscesses without new dTs) by week 10. The pain score decreased from 8 to 2, and the exudation resolved. The size of the tunnels in the four intertrigonal areas was significantly reduced, as assessed by ultrasound. This case highlights the synergistic potential of dual IL-17/IL-36 blockade, particularly for dTs, and offers a novel therapeutic strategy for treating severe HS.

Migrasomes, vesicle-like organelles observed during cell migration, have emerged as a significant focus in cell biology. These organelles play a pivotal role in intercellular communication, signal transduction, and tissue development through the release of signalling molecules. Evidence indicates that the pathogenesis and progression of various diseases are closely associated with aberrant cell migration, impaired intercellular communication, and disrupted signalling pathways. Notably, migrasomes can facilitate the invasion and metastasis of tumor cells: they carry metastasis-promoting signals and help form an immunosuppressive microenvironment. Additionally, migrasomes mediate viral spread. Migrasomes derived from macrophages can accelerate the progression of cardiovascular and cerebrovascular diseases by promoting neuroinflammation and neuronal damage. Meanwhile, migrasomes derived from podocytes serve as biomarkers for early kidney injury. Thus, elucidating the role of migrasomes in pathological processes and defining their specific functions holds great promise for developing novel therapeutic strategies for diseases. This review synthesizes current advances in migrasome biology, highlighting their potential as diagnostic biomarkers and therapeutic targets for conditions such as cancer, viral infections, and renal disorders.

Osteoarthritis (OA) is a prevalent chronic disease, characterized by progressive joint degeneration and primarily affects older adults. OA leads to reduced functional abilities, a lower quality of life, and an increased mortality rate. Currently, effective treatment options for OA are lacking. Non-coding RNAs (ncRNAs) are functional RNAs transcribed from DNA but not translated into proteins. Among ncRNAs, small interfering RNAs (siRNAs), transfer RNAs (tRNAs), and ribosomal RNAs (rRNAs) have become significant in the field, which is intricately linked to the progression of OA and perform significant regulatory functions in transcription, post-transcription, and post-translation, making them potential biological targets for the prevention, diagnosis, and treatment of OA. This review summarizes the general functions of siRNAs, tRNAs, and rRNAs and their application in OA. The primary focus has been on regulating cartilage degradation. Other participations include regulating synovium, protecting anterior cruciate ligament cells, and diagnosis. No clinical trials were found as challenges such as effective delivery systems, immune responses, long-term effects, and interactions between therapies need to be demonstrated first.

Purpose: Pancreatic cancer is one of the most lethal malignancies, with a five-year survival rate rarely exceeding 10%. Due to its asymptomatic onset, it is frequently diagnosed at an advanced and often inoperable stage. This review assesses current strategies for early detection, including genomic testing, advanced imaging technologies, and biomarker-based platforms, with a focus on their clinical utility and integration into surveillance protocols.

Methods: This narrative review synthesizes findings from published literature on germline genetic testing (GGT), imaging modalities such as endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI), and the latest advancements in biomarker discovery and molecular diagnostics for early pancreatic cancer detection. International guidelines and emerging evidence were assessed to explore their clinical implementation and challenges.

Results: Although EUS and MRI show promise for detecting early pancreatic lesions, both require specialized expertise and are limited by accessibility and cost. Emerging blood-based biomarkers and molecular platforms, however, may offer a more scalable, non-invasive alternative for detecting pancreatic cancer at earlier, treatable stages.

Conclusion: Early detection of pancreatic cancer is pivotal to improving survival outcomes. While imaging techniques and genetic screening have enhanced risk stratification and early diagnosis in high-risk populations, novel biomarker and molecular testing platforms offer an accessible and scalable solution. Future efforts should focus on validating these assays in large-scale prospective cohorts and integrating them into screening protocols, particularly for individuals with genetic susceptibility.

Objective: We aim to evaluate the malignancy risk between Janus kinase inhibitors (JAKi) users and tumor necrosis factor inhibitors (TNFi) users in rheumatoid arthritis (RA) patients, using a large real-world electronic health record database (TriNetX).

Methods: In this retrospective cohort study, we identified adult RA patients initiating JAKi or TNFi therapy between January 1, 2018, and December 31, 2022, within the TriNetX global federated network. The hazard ratio (HR) and confidence intervals (CI) of incident-specific cancers, overall cancer incidence, and all-cause mortality, were calculated between the propensity score matched JAKi and TNFi cohorts. The probability of the outcome of interest was estimated using the Kaplan-Meier analysis.

Results: After propensity score matching, there were 4045 each in JAKi or TNFi user cohorts. The mean (standard deviation) age was 57.7 (13.3) and 57.6 (13.9) years, 81.4% and 80.8% were female, and median (interquartile range) follow-up time 3.69 (2.61) years vs 3.69 (2.68) years, in the JAKi and the TNFi cohorts, respectively. No significant differences were observed in risks of overall cancer incidence and all-cause mortality between the two cohorts. JAKi users had a reduced risk of incident digestive organ cancers compared with TNFi users (adjusted HR: 0.599, 95% CI: 0.439-0.817), mainly observed among females. The risks of incident respiratory and intrathoracic organs cancers were increased in JAKi users compared to TNFi users among females (adjusted HR: 2.582, 95% CI: 1.109-6.011) but not in males.

Conclusion: In a large real-world database, we did not find an increased risk of overall cancer incidence in JAKi compared to TNFi users among RA patients. JAKi users had a lower risk of incident digestive organs cancers, and a higher risk of respiratory cancer in females, when compared with TNFi users.

Purpose: Targeting the distinct genetic and protein expression profiles of keloids necessitates the identification of novel therapeutic targets. This study was aimed to elucidate the role of Bcl-2-associated athanogene 2 (BAG2) in keloid pathology and identify compounds with high-affinity to BAG2.

Patients and methods: Cell migration, and cell proliferation assays, along with flow cytometry, were used to evaluate the effects of BAG2 on keloid fibroblasts (KFs) derived from tissue samples of patients with abdominal or chest keloids. Additionally, histological examinations and Western blotting were performed to investigate BAG2's role in keloids. Surface plasmon resonance (SPR) was employed to identify compounds with high-affinity to BAG2, and the effects of these compounds on keloids was assessed.

Results: Inhibition of BAG2 significantly decreased collagen deposition, cell proliferation and migration in keloid tissues. The modulatory effect of BAG2 on these processes appears to be mediated partly by the MEK signaling pathway. Among the tested compounds, Bazedoxifene acetate and Ponesimod showed high affinity for BAG2 and demonstrated a more pronounced inhibitory effect on collagen deposition of the keloid tissues than other candidates.

Conclusion: This study revealed the pathogenic role of BAG2 in keloid and identified compounds with high-affinity to BAG2, Bazedoxifene acetate and Ponesimod. The therapeutic capabilities of these compounds demonstrated their potential to improve therapeutic strategies for localized, targeted treatment to keloids.

Fecal microbiota transplantation (FMT) has evolved from a niche therapy to a cornerstone in the treatment of recurrent Clostridioides difficile infection (rCDI). Initially introduced in the 1950s, its relevance has surged with the emergence of virulent and antibiotic-resistant C. difficile strains. In recent years, the FDA approved two standardized microbiota-based therapeutics-Rebyota™ (fecal microbiota, live-jslm) and Vowst™ (fecal microbiota spores, live-brpk)-for rCDI prevention. Multiple pivotal trials support the efficacy and safety of both traditional FMT and the FDA-approved prescription FMTs, with sustained response rates surpassing 80% in select populations. In parallel, live biotherapeutic products (LBPs)-donor independent, well-defined microbial consortia produced in laboratory setting are under development. Examples include VE303 and NTCD-M3, a single non-toxigenic C. difficile strain (M3). Beyond the FDA approved therapeutics, conventional FMT is gaining traction as a potential treatment for severe or fulminant CDI, especially in patients not responding to antibiotics and ineligible for surgery. Investigational indications include decolonizing multidrug-resistant organisms and treatment of noninfectious conditions such as inflammatory bowel disease, irritable bowel syndrome, liver disease, and metabolic syndrome. Given the differing pathophysiology of these conditions, a tailored approach supported by rigorous clinical trials is essential. Although there is a growing shift, particularly in the United States, toward the use of FDA-approved FMTs, global practices remain heterogeneous, with conventional FMT still widely employed. Meanwhile, regulatory pathways and clinical guidelines for microbiota-derived biologics and live biotherapeutic products continue to evolve. In this manuscript, we provide an update on the emerging use of FDA-approved prescription microbiota-derived therapeutics for the prevention of rCDI, review data on investigational agents including both donor dependent and donor independent microbial products, and summarize current evidence on the use of conventional FMT for indications beyond prevention of rCDI.

Purpose: This study aimed to explore the effect of activated growth factor (AGF) in anabolic-catabolic regulation pathway in an experimental osteoarthritis (OA) rat model. This investigation was predicated on the critical need for a disease-modifying osteoarthritis drug, seeking to determine if AGF could restore chondral homeostasis by reversing the catabolic-dominant state that defines OA pathology. This is the first study to compare AGF with platelet-rich plasma (PRP) and diclofenac sodium in vivo.

Methods: Fifty-six male Wistar rats were randomly allocated into seven groups (n = 8 per group); normal control (NC), negative control (OA induced, saline-treated), positive control with platelet-rich plasma (PRP) (OA induced + PRP), positive control diclofenac (OA induced + Diclofenac sodium), AGF 0.1 ng/mL (OA induced + AGF with TGF-β at 0.1 ng/mL), AGF 1 ng/mL (OA induced + AGF with TGF-β at 1 ng/mL), AGF 10 ng/mL (OA induced + AGF with TGF-β at 10 ng/mL). Cartilage anabolic-catabolic status was assessed by measuring matrix metalloproteinases (MMP-1, MMP-13), a-disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), SMAD3, aggrecan, and collagen type II (Col2) expression via ELISA and Western blot. Key inflammatory mediators (TNF-α, IL-1β, NF-κB) and histopathological changes were also evaluated.

Results: AGF treatment demonstrated superior efficacy in modulating anabolic-catabolic balance compared to OA controls and PRP. AGF dose-dependently and significantly decreased MMP-1, MMP-13, and ADAMTS-4 levels. Conversely, AGF significantly increased SMAD3 phosphorylation, aggrecan synthesis, and Col2 expression, surpassing the effects of PRP. The 10 ng/mL AGF group showed the most pronounced chondroprotective and anabolic effects, often restoring parameters towards normal levels. Furthermore, AGF significantly reduced TNF-α, IL-1β, and NF-κB levels, and diminished inflammatory cell infiltration, with the 10 ng/mL dose being comparable or superior to Diclofenac in these anti-inflammatory/anti-catabolic effects. PRP showed moderate benefits, generally less than AGF formulations.

Conclusion: Platelet-derived AGF, as an advanced mode of PRP, effectively regulates the anabolic-catabolic processes in OA cartilage. It achieved this by significantly inhibiting key catabolic enzymes and pro-inflammatory mediators, while concurrently promoting crucial anabolic signaling pathways and extracellular matrix synthesis. These findings highlight AGF's substantial therapeutic potential as a disease-modifying biological agent for OA.

Introduction: Ovarian cancer (OC) ranks among the most lethal and aggressive gynecological malignancies. Identifying novel molecular targets is crucial for improving early diagnosis and developing effective therapies. Despite advancements in immunotherapy, its efficacy in OC remains limited due to the absence of well-defined immune-related molecular targets.

Methods: This study offers a comprehensive analysis of YTHDF1, combining multi-omics-based bioinformatics approaches with in vitro and in vivo experimental validation to elucidate its functional role and significance in the progression and treatment of OC.

Results: Our findings reveal that YTHDF1 is significantly upregulated in OC and correlates with poor clinical outcomes. Functional assays confirmed its oncogenic properties, while pathway analyses highlight its involvement in critical tumor-promoting signaling pathways. Importantly, we identified a potential link between YTHDF1 expression and the tumor immune landscape, suggesting its role in modulating immune cell infiltration and driving immunosuppression. Additionally, both computational and in vivo evidence underline the relevance of YTHDF1 in influencing immunotherapeutic responsiveness and chemosensitivity in OC. Mechanistically, we discovered for the first time that YTHDF1 can be encapsulated within tumor-derived exosomes, contributing to the polarization of macrophages toward the immunosuppressive M2a phenotype.

Discussion: These findings position YTHDF1 as a promising prognostic biomarker and therapeutic target for OC. Its role in shaping an immunosuppressive microenvironment and mediating chemoresistance underscores its potential in enhancing immunotherapy and improving chemotherapy outcomes.