Biologics : Targets & Therapy最新文献

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.

Background and objectives: Stem cell therapy shows great promise for treating Alzheimer's disease (AD). Cholinesterase inhibitors (ChEIs) like donepezil are well-established for alleviating AD symptoms. This study aimed to determine if combining ChEI treatment with stem cell therapy could improve therapeutic outcomes.

Methods: Neural stem cells (NSCs) were injected into the hippocampus of the 5xFAD AD mice using a stereotactic technique. Following this, donepezil or a placebo was administered for one month. We assessed behavioral improvements, survival and health of the grafts, and changes in synaptic density.

Results: The AD mice demonstrated cognitive impairment in both the Morris water maze and novel object recognition tests. In groups receiving stem cell therapy, donepezil enhanced the survival and neuronal differentiation of grafted NSCs, promoting the establishment of synaptic connections with the host brain. The combined treatment with donepezil and NSC transplantation more effectively increased synaptic density and improved behavioral performance in AD mice compared to NSC transplantation alone.

Conclusion: Combining ChEIs with NSC transplantation produces synergistic effects in AD treatment. This approach highlights the potential of integrating these therapies to develop more effective strategies for managing Alzheimer's disease.

Introduction: Alterations in intestinal permeability and microbiota dysregulation have been linked to the development of multiple sclerosis (MS). Short-chain fatty acids (SCFA) and medium-chain fatty acids (MCFA) are products of gut bacteria fermentation which are involved in immune regulation processes. In MS, SCFA have important immunomodulatory properties both in the periphery and the central compartment. Interferon β (IFNβ) was the first disease-modifying therapy approved for the treatment of MS and its effects on the gut microbiota are not fully elucidated.

Patients and methods: We performed a prospective observational study aimed to assess peripheral levels of SCFA and MCFA in 23 newly diagnosed, treatment-naïve MS patients (nMS) before and after one year of IFNβ treatment and 23 healthy controls (HC). We investigated their associations with inflammation, interleukin-10 (IL-10), and blood-brain barrier permeability, matrix metalloproteinase 9 (MMP9).

Results: No significant differences in SCFA/MCFA levels were observed between baseline and after IFNβ treatment. Caproic acid levels were significantly higher in nMS compared to HC (1.64 vs 1.27 µM, p=0.005). The butyric acid/caproic acid ratio was higher in HC compared to nMS (5.47 vs 2.55, p=0.005). Correlation analysis revealed associations between SCFA/MCFA levels and inflammatory biomarkers.

Conclusion: nMS have a higher gut-inflammatory activity as seen by the caproic acid ratio as opposed to HC. In this cohort, IFNβ does not appear to modify the peripheral SCFA/MCFA levels after one year of treatment. The quantifications of peripheral SCFA/MCFA may prove to be a useful biomarker for gut-brain axis disruption in MS patients.

Purpose: To describe the effectiveness and persistence of treatment with three anti-TNFα drugs, Infliximab, Etanercept, and Adalimumab, in patients with Rheumatoid Arthritis (RA) in a rheumatology center.

Patients and methods: A longitudinal, retrospective cohort study was conducted. Data were obtained from the health records of patients with RA who were followed up in a rheumatology center between 2011 and 2019 under a multidisciplinary healthcare model (MCM). The drugs used in this study were indicated according to the treatment guidelines for prescription. In order to follow-up of disease activity, at least three DAS28 reports for every analyzed year were used. The chi-square test and Fisher's exact test were used for statistical analyses of categorical variables. For the analysis of treatment persistence, the Kaplan-Meier method was used based on the recorded follow-up time of disease activity.

Results: One hundred and eighty-three RA patients included (80% women, median age 60 years), who received adalimumab (n = 56) (30.6%), etanercept (n = 64) (34.9%), or infliximab (n = 63) (34.4%) during the 7-year study period. A higher proportion of patients had moderate or high disease activity for all three anti-TNFα. In first-year treatment, 67% to 87% of the cohort achieved disease activity control and disease response to treatment. For the first three years, 95% to 98% of patients continued with the medications. In years 5th and 7th, the proportion of patients on medication was 80% to 90% and 42% to 54%, respectively.

Conclusion: The efficacy and persistence of anti-TNF-α were similar among the three molecules. These findings regarding long-term persistence in treatment may be useful for therapeutic decision-making based on real-life cohort results.

Background: Long noncoding ribonucleic acids (lncRNAs), small noncoding RNAs known as microRNAs (miRNAs) as well as some cytokines are recently thought to have a role in many inflammatory and autoimmune disorders including Behçet's disease (BD). This chronic multisystem disease lacks the particular histological or laboratory findings that might aid in its diagnosis. Therefore, any association with such molecules may have an impact on understanding the disease pathogenesis and/or management. The current study compared the levels of NEAT1, miR-21 and IL17 levels in sera of Egyptian BD patients and healthy individuals. The expression levels of these molecules were further investigated for their association with BD manifestations and activity aiming to explore their potential application in disease management.

Results: NEAT1 & miR-21 showed down-regulation while IL-17 showed up-regulation among BD patients as compared to controls. IL-17 had significant correlation with major vessels involvement and cyclophosphamide intake. NEAT1 showed a significant negative correlation with colchicine intake. Disease activity did not correlate significantly with any of NEAT1, miR-21 or IL-17.

Conclusion: NEAT1, miR-21 and IL17 might have a role in Behçet's disease pathogenesis, so more research is needed to unveil that role and their potential usage as biomarkers for the diagnosis or therapeutic targets.

Objective: Anlotinib demonstrated encouraging therapeutic activity as third-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Programmed cell death protein 1 (PD-1) inhibitors also exhibited promising and durable response against previously-treated advanced NSCLC. Therefore, the present study aimed to determine the feasibility and safety of anlotinib plus PD-1 inhibitors for previously-treated NSCLC in clinical practice.

Methods: This retrospective study included 56 patients with advanced NSCLC treated with systemic treatment previously. Patients included were treated with anlotinib plus PD-1 inhibitors in clinical practice. Therapeutic outcomes of the patients were evaluated radiologically using target lesions, and the prognostic outcomes were generated by follow-up. Adverse reactions experienced throughout the treatment were documented and analyzed.

Results: Between August 2018 and November 2022, 56 patients with advanced NSCLC were eligible to participate in this study consecutively. Therapeutic outcomes resulted in an overall response rate of 28.6% [95% confidence interval (CI): 17.3%-42.2%] and a disease control rate of 91.1% (95% CI: 80.4%-97.0%). Furthermore, this combination regimen among the 56 patients yielded a median progression-free survival (PFS) of 6.5 months (95% CI: 4.81-8.19) and a median overall survival (OS) of 15.8 months (95% CI: 10.23-21.37), respectively. And the median duration of response (DoR) among patients who responded was 8.3 months (95% CI: 4.38-12.22). Additionally, adverse reactions of all grades throughout the treatment were observed in 50 patients (89.3%), and adverse reactions of grade ≥3 were detected in 23 patients (41.1%). Fatigue, hypertension, diarrhea, nausea, and vomiting were the most common adverse reactions. Association analysis between PFS and baseline characteristic subgroups indicated that ECOG score and number of metastatic lesions might be potential predictors of PFS in the exploratory analysis.

Conclusion: Anlotinib plus PD-1 inhibitors demonstrated a tolerable safety profile and encouraging therapeutic activity as subsequent-line therapy in patients with advanced NSCLC. This conclusion should be confirmed in prospective large-scale clinical trials subsequently.

In this case report, we describe a 21-year-old man with recurrent hemangiomas in his left eye socket and nasal cavity. Traditional surgeries were unsuccessful, so we used Bevacizumab, a drug that inhibits blood vessel growth. This approach significantly reduced the tumor size and stopped frequent nosebleeds. Over two years, the tumor remained controlled without major side effects, suggesting Bevacizumab as a promising non-surgical treatment for recurrent hemangiomas.

Objective: Tocilizumab (TCZ) is the only biologic drug approved for the treatment of giant cell arteritis (GCA), having clinical trials and real-life studies proved its efficacy and safety. However, the optimal duration of the treatment has yet to be determined, being its early interruption associated with an increased risk of relapse. Conversely, prolonged schemes of therapy may rise safety concerns. The aim of the study was to evaluate the incidence of adverse events (AEs) and remission/relapse rate in a cohort of GCA patients treated with TCZ and an accelerated steroid tapering scheme, followed for 24 months.

Methods: We retrospectively included patients referring to our clinic from January 2019 to November 2021 who were diagnosed with GCA and started subcutaneous TCZ treatment (162 mg/week). They also received up to 62,5 mg of prednisone (PDN), tapered following an accelerated six-month scheme.

Results: We collected 38 patients, with a mean age of 76,4 years, treated with TCZ for an average of 22,3 months. AEs occurred in 11 (29%) subjects, and only one serious AE was reported; 7 (18%) patients permanently discontinued TCZ. At the end of the follow-up, all the patients continuing treatment showed clinical remission, with a PDN dosage <5mg. We registered 3 (8%) minor relapses under TCZ, after an average of 15 months.

Conclusion: Our data support the evidence of a safe and effective long-term use of TCZ in GCA patients, especially when combined with moderate GCs doses for the shortest possible duration.