Biologics : Targets & Therapy最新文献

Tumor-to-tumor metastasis (TTM) is defined as the metastasis of one distinct malignancy to another independent tumor without directly extending into the substance of a histologically distinct and separate tumor. TTM is an extremely rare phenomenon that constitutes a very small percentage of all tumor metastases. The detailed histogenic mechanisms of TTM remain unclear. TTM is easily confused with composite tumors and synchronous tumors. Due to the rarity and complexity of the disease, it presents significant challenges in providing accurate diagnoses and appropriate treatment options. The exploration of TTM not only provides an in-depth understanding of the metastasis process, but also has significant implications for the management and treatment of patients with multiple primary malignant tumors, underscoring the necessity of comprehensive diagnostic and treatment strategies. The purpose of this review is to increase awareness of tumor-to-tumor metastasis, with a focus on pathogenesis, diagnosis, and treatment.

Background: Ischemia-reperfusion (I/R) injury is a major contributor to myocardial dysfunction and tissue damage. A natural alkaloid-Berberine having a wide range of pharmacological properties, has garnered interest for its potential cardioprotective properties. This study aimed to investigate the protective effects of berberine on myocardial tissue in a rat model of myocardial ischemia-reperfusion (I/R) injury. Additionally, the study explored the role of the miR-184/NOTCH1 signaling pathway in mediating these effects.

Methods: Male Wistar rats were randomly assigned to five groups: sham-operated control, I/R injury, I/R treated with berberine, I/R treated with inhibitor NC and I/R treated with a miR-184 inhibitor. The I/R injury was induced by ligating the left anterior descending (LAD) coronary artery for 30 minutes, followed by 2 hours of reperfusion. Berberine was administered orally at 100 mg/kg/day for 2 weeks, and the miR-184 inhibitor was administered via intraperitoneal injection. Hemodynamic parameters were recorded using a pressure sensor connected to a catheter inserted into the left ventricle. Myocardial infarct size was assessed using TTC staining, while histological and molecular changes were evaluated through H&E staining, TUNEL assay, and Western blotting. The expression levels of target genes were analyzed using quantitative real-time PCR (qRT-PCR).

Results: Berberine significantly reduced myocardial infarct size and improved hemodynamic parameters compared to the untreated I/R group. Additionally, berberine treatment attenuated apoptosis as evidenced by decreased TUNEL-positive cells. The miR-184 inhibitor also demonstrated protective effects by modulating key signaling pathways involved in myocardial injury. Western blot analysis revealed downregulation of NOTCH1 and HES1 expression in treated groups, indicating a potential mechanism for the observed cardio protection.

Conclusion: Berberine and miR-184 inhibition offer significant protection against myocardial ischemia-reperfusion injury. These findings suggest that targeting miR-184 and associated pathways may be a promising therapeutic strategy for reducing cardiac damage following ischemia-reperfusion.

Introduction: ATF3, a stress-induced transcription factor, has been implicated in the injury processes of various cell types, including neurons. It is recognized as a common marker for neuronal damage following neurotrauma. However, its role in other types of glial cells, particularly astrocytes, in response to ischemic injury remains unclear. Mitochondrial dysfunction is a key factor in the pathogenesis of ischemic stroke, and impaired mitochondrial function in astrocytes is associated with astrocyte activation. This study aimed to explore the relationship between mitochondrial damage and ischemic stroke and to investigate how ATF3 regulates mitochondrial dysfunction and astrocyte activation in the context of ischemic injury.

Methods: In a transient middle cerebral artery occlusion (tMCAO) mouse model, we knocked down ATF3 and assessed infarct size, motor deficits, astrocyte activation, and mitochondrial damage. In vitro, we used oxygen-glucose deprivation and reoxygenation (OGD-R) to simulate ischemia and evaluated the impact of ATF3 knockdown on astrocyte activation and mitochondrial function.

Results: ATF3 knockdown exacerbated infarct size, motor deficits, and astrocyte activation in vivo, with increased mitochondrial damage. In vitro, ATF3 depletion worsened mitochondrial dysfunction and astrocyte activation. ATF3 interacted with Drp1 via Akt2, inhibiting mitochondrial fission and protecting astrocytes.

Conclusion: ATF3 regulates mitochondrial fission and protects astrocytes in ischemic stroke, highlighting its potential as a therapeutic target for stroke recovery.

Introduction: Nasopharyngeal cancer (NPC) is a multifaceted disease characterized by genetic and epigenetic modifications. While Epstein-Barr virus (EBV) infection is a known risk factor, recent studies highlight the significant role of DNA methylation in NPC pathogenesis. Aberrant methylation, particularly at CpG sites, can silence tumour suppressor genes, promoting uncontrolled cell growth. This study aims to analyse the methylation patterns in Indonesian NPC patients through whole-epigenome sequencing.

Methods: Seven clinical nasopharyngeal cancer samples were collected and confirmed histopathologically. DNA was extracted, sequenced using Oxford Nanopore technology, and aligned to the GRCh38 human reference genome. Methylation analysis was performed using modkit and statistical analysis with R software. Enriched pathways and processes were identified using ClusterProfiler in R, and gene overlap analysis was conducted.

Results: The analysis identified both globally hypermethylated and hypomethylated NPC samples. Key tumour suppressor genes, such as PRKCB, PLCB3, ITGB3, EPHA2, PLCE1, PRKCD, CDKN2A, CDKN2B, RPS6KA2, ERBB4, LRRC4, AKT1, PPP2R5C, and STK11 were frequently hypermethylated and confirmed to have lower expression in an independent NPC transcriptome cohort, suggesting their role in NPC carcinogenesis. Enriched KEGG pathways included PI3K-Akt signalling, ECM-receptor interaction, and focal adhesion. The presence of EBV DNA was confirmed in all samples, implicating its role in influencing methylation patterns.

Discussion: This study provides comprehensive insights into the epigenetic landscape of NPC, underscoring the role of CpG methylation in tumour suppressor gene silencing. These findings pave the way for targeted therapies and highlight the need for region-specific approaches in NPC management.

Purpose: Chronic suppurative otitis media (CSOM) is a prominent contributor to preventable hearing loss globally. Probiotic therapy has attracted research interest in human infectious and inflammatory disease. As the most prevalent probiotic, the role of Lactobacillus in CSOM remains poorly defined. This study aimed to investigate the antipathogenic effects and underlying mechanism of Lactobacillus on CSOM.

Methods: RNA sequencing of granulation of middle ear cavity from CSOM patients and lavage fluid of middle ear from normal volunteer was conducted. Human middle ear epithelial cells (HMEEC) and rats infected with Bacillus cereus (B. cereus) and Staphylococcus aureus (S. aureus) were used for CSOM constructing. Western blot, qPCR and Vybrant™ Alexa Fluor™ 488 lipid raft labeling were performed to explore the possible molecular mechanism by which lipid raft linker (RFTN1) regulates lipid raft/toll-like receptor 4 (TLR4). ELISA and HE staining was utilized to evaluate the effect of Lactobacillus on the progression of CSOM in vivo.

Results: Based on RNA Sequence analysis, a total of 3646 differentially expressed genes (1620 up-regulated and 2026 down-regulated) were identified in CSOM. RFTN1 was highly expressed in CSOM. Inhibition of RFTN1 not only reduced the inflammatory response of CSOM but also suppressed the formation of lipid rafts. Further investigation revealed that RFTN1 inhibition could reduce the expression of TLR4, which also localizes to the lipid rafts. TLR4 responds to RFTN1-mediated inflammatory responses in CSOM. We treated the CSOM model with Lactobacillus, which has great potential for alleviating the inflammatory response, and found that Lactobacillus attenuated the development of CSOM by reducing RFTN1 and TLR4 expression.

Conclusion: In conclusion, these findings suggest a crucial role for Lactobacillus in alleviating CSOM progression and uncovered the molecular mechanism involving Lactobacillus-regulated inhibition of the RFTN1-lipid raft-TLR4 signaling pathway under CSOM conditions.

Introduction: The translation of traditional Chinese medicine (TCM), which is experience-based, into evidence-based frameworks of Western medicine poses significant challenges due to differences in conceptualization, diagnosis, and evaluation methodologies. A critical need exists to bridge these disparities to enhance the integration of TCM into modern medical practices.

Methods: This study proposes a novel statistical methodology, leveraging confidence interval-based mapping, to calibrate subjective TCM diagnostic outcomes (eg, instruments or questionnaires) with objective Western clinical endpoints (eg, analytical test results). A quantitative mapping formula was developed to determine TCM diagnostic cutoff values based on the concept of confidence intervals, aligning them with Western clinical standards. The methodology was rigorously evaluated using clinical trial simulations.

Results: Simulation results demonstrated that the proposed method enhances the accuracy and consistency of diagnostic calibration. Furthermore, it effectively addresses potential misclassification issues, thereby improving the reliability of aligning TCM diagnostic outcomes with Western clinical endpoints.

Discussion: The findings underscore the potential of this methodology to refine the calibration process between TCM and Western medicine. This approach provides a pathway for integrating TCM into evidence-based practices, contributing to the modernization of traditional medical systems.

The successful progression of therapeutic antibodies and other biologics from the laboratory to the clinic depends on their possession of "drug-like" biophysical properties. The techniques and the resultant biophysical and biochemical parameters used to characterize their ease of manufacture can be broadly defined as developability. Focusing on antibodies, this review firstly discusses established and emerging biophysical techniques used to probe the early-stage developability of biologics, aimed towards those new to the field. Secondly, we describe the inter-relationships and redundancies amongst developability assays and how in silico methods aid the efficient deployment of developability to bring a new generation of cost-effective therapeutic proteins from bench to bedside more quickly and sustainably.

Purpose: Emerging literature links the role of the renin-angiotensin-aldosterone system (RAAS) to the progression of cancers. However, the function of RAAS has not been verified in Clear-cell renal cell carcinoma (ccRCC).

Methods: ACE expression in ccRCC tissues was determined using RT-PCR, Western blot, and immunohistochemistry staining. The clinical significance of ACE was evaluated through Cox regression analysis. To assess the impact of ACE expression on ccRCC cell growth, metastasis, and glucose activity, CCK-8 assays, transwell assays, Seahorse detection, and xenograft models were utilized. The mechanisms of ACE and its upstream and downstream regulatory factors were investigated using RNA-seq, chromatin immunoprecipitation (ChIP), and luciferase reporter assays.

Results: RAAS-related gene Angiotensin-Converting Enzyme (ACE) was significantly under expressed in ccRCC cells and tissues. High ACE expression was positively associated with a favorable prognosis in ccRCC patients. Functional studies showed that ACE overexpression suppressed ccRCC cell line OS-RC-2 and A498 growth, metastasis, and glycolysis activities, while its knockdown had the opposite effect. Mechanistically, ACE inhibited ccRCC progression and epithelial-mesenchymal transition (EMT) by disrupting the AKT-FOXO1 signaling pathway. Furthermore, we provide evidence that ACE could enhance everolimus (approved agent for ccRCC) antitumor effect and ACE expression is transcriptionally regulated by ZBTB26.

Conclusion: Our findings investigated the roles and mechanisms of ACE in ccRCC. ACE inhibits the growth and metastasis of ccRCC cells in vitro and in vivo by promoting FOXO1 expression, which is the downstream target of PI3K-AKT pathway. Thus, this research suggests that ACE may be a promising target for new therapeutic strategy in ccRCC.

Introduction: Atrial fibrillation (AFib) is a common disorder featured by an irregular and fast heartbeat. The etiology of AFib is complex and involves genetic and environmental factors. The rs2200733 single nucleotide polymorphism (SNP) is located in close proximity to the promoter of paired-like homeodomain transcription factor 2 (PITX2) which plays a role in heart development.

Objective: In this study, the association between the rs2200733 SNP and AFib was examined in the Jordanian population.

Methods: The study included 450 subjects (274 controls and 176 patients with AFib). Patients were recruited from King Abdullah University Hospital based on the European Society of Cardiology criteria. The rs2200733 SNP was genotyped using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) technique.

Results: The mutant T allele of the rs2200733 SNP was common in the studied population with a frequency of 19%. The T allele and CT/TT genotypes were prevalent among patients with AFib compared with the controls (P<0.05, OR [CI]: 1.65 [1.12-2.43]). In addition, body mass index, diabetes, and hypertension were found to be associated with AFib risk.

Conclusion: The rs2200733 SNP was associated with AFib among Jordanian patients. The mutant T allele of the rs2200733 SNP might increase the risk of AFib.

For assessment of biosimilar drug products, if there are multiple-reference products (eg, a US-licensed product and an EU-approved product), a biosimilar bridging study with a 3-way pairwise comparison is often conducted. In our paper, two innovative methods in biosimilar bridging study are compared with the conventional method of pairwise comparisons. For parallel study design, the simultaneous confidence interval (CI) method is compared to the convention method. For crossover study design, the multiplicity-adjusted Schuirmann's two one-sided tests (MATOST) is considered. This paper conclude that the simultaneous CI method achieves the similar statistical power to the conventional approach in biosimilarity assessment. However, the MATOST method using the conservative Holm and Bonferroni approaches is not favorable since it leads to a large sample size although it controls the type I error rate.