Biologics : Targets & Therapy最新文献

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.

Introduction: This study aims to systematically assess the anticancer potential of distinct Lactobacillus strains on Human Colorectal Tumor (HCT) 115 cancer cells, with a primary focus on the apoptotic mechanisms involved. Lactobacillus strains were isolated from sheep milk and underwent a meticulous microbial isolation process. Previous research indicates that certain probiotic bacteria, including Lactobacillus species, may exhibit anticancer properties through mechanisms such as apoptosis induction. However, there is limited understanding of how different Lactobacillus strains exert these effects on cancer cells and the underlying molecular pathways involved.

Methods: Cytotoxicity was evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and exposure durations of Lactobacillus cell-free lyophilized filtrates. Additional apoptotic features were characterized using 4.6-diamidino-2-phenylindole (DAPI) analysis for nuclear fragmentation and Annexin V/PI analysis for apoptosis quantification. Genetic analysis explored the modulation of apoptotic proteins (Bax and Bcl₂) in response to Lactobacillus treatment. Whole-genome sequencing (WGS) was performed to understand the genetic makeup of the Lactobacillus strains used in the study.

Results: The study demonstrated a significant reduction in HCT 115 cell viability, particularly with L. plantarum, as evidenced by Sulforhodamine B (SRB) and MTT assays. DAPI analysis revealed nuclear fragmentation, emphasizing an apoptotic cell death mechanism. Annexin V/PI analysis supported this, showing a higher percentage of early and late apoptosis in L. plantarum-treated cells. Genetic analysis uncovered up-regulation of pro-apoptotic protein Bax and down-regulation of anti-apoptotic protein Bcl₂ in response to Lactobacillus treatment. WGS study revealed a strain reported to NCBI PRJNA439183.

Discussion: L. plantarum emerged as a potent antiproliferative agent against HCT 115 cancer cells, inducing apoptosis through intricate molecular mechanisms. This study underscores the scientific basis for L. plantarum's potential role in cancer therapeutics, highlighting its impact on antiproliferation, adhesion, and gene-protein regulation. Further research is warranted to elucidate the specific molecular pathways involved and to evaluate the therapeutic potential of L. plantarum in preclinical and clinical settings.

Background: It has been established that Spalt-Like Transcription Factor 4 (SALL4) promotes Colorectal Cancer (CRC) cell proliferation. Furthermore, Amphiregulin (AREG) is crucially involved in cancer cell proliferation and therapeutic resistance regulation. In this regard, this study aimed to establish whether SALL4 affects the radiosensitization of CRC cells via AREG expression regulation.

Methods: Transcriptome sequencing and the Human Transcription Factor Database (HumanTFDB) were used to identify the potential SALL4 targets. The dual-luciferase reporter analysis was used to confirm the SALL4-induced AREG activation. Western Blot (WB) and Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) assays were used to examine the effect of X-ray irradiation on SALL4 and AREG expression. The AREG-KD (Knockdown) stable cell lines were created through lentiviral infection. Cell proliferation was tracked using Cell Counting Kit 8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU)-incorporation assays. Cell cycle and apoptosis were examined through flow cytometry. The cells were exposed to a controlled X-ray radiation dose (6 Gy) for imaging purposes.

Results: SALL4 could bound to the AREG promoter, enhancing AREG expression. Furthermore, irradiation upregulated SALL4 and AREG in CRC cells. Additionally, AREG knockdown in CRC cells led to reduced DNA replication efficiency, suppressed cell proliferation, increased DNA damage, and enhanced G1 phase arrest and apoptosis following irradiation. On the other hand, AREG overexpression reversed the inhibitory effects of SALL4 downregulation on AREG expression.

Conclusion: In CRC cells, SALL4 downregulation suppressed AREG expression, regulating CRC cell radiosensitivity via the PI3K-AKT pathway, thus presenting a potential therapeutic pathway for CRC treatment using Radiotherapy (RT).

Purpose: The study aimed to develop and characterize Indikizumab, a novel humanized anti-IL-17A monoclonal antibody (mAb), for potential therapeutic use in inflammatory indications such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis.

Methods: The research involved the purification of IL-17 isoforms, epitope mapping, affinity ranking, and comparative binding assessment of anti-IL-17 antibodies. The study also included cell-based neutralization assays and in vivo studies using mouse models to evaluate the efficacy of Indikizumab.

Results: Indikizumab demonstrated a high binding affinity (K_D=27.2 pM) and specificity for IL-17A, with comparable potency to Secukinumab. In cell-based neutralization assays, Indikizumab effectively neutralized the effects of IL-17A and demonstrated a statistically significant reduction in plasma KC (Keratinocyte) levels in a mouse model. In imiquimod-induced psoriasis mouse model, Indikizumab showed potential in reducing the psoriasis index.

Conclusion: Indikizumab represents a promising therapeutic option for inflammatory indications with its high binding affinity, specificity for IL-17A, and effectiveness in neutralizing IL-17A effects in vivo.

Natural products have proven to be promising anti-cancer agents due to their diverse chemical structures and bioactivity. This review examines their central role in cancer treatment, focusing on their mechanisms of action and therapeutic benefits. Medicinal plants contain bioactive compounds, such as flavonoids, alkaloids, terpenoids and polyphenols, which exhibit various anticancer properties. These compounds induce apoptosis, inhibit cell proliferation and cell cycle progression, interfere with microtubule formation, act on topoisomerase targets, inhibit angiogenesis, modulate key signaling pathways, improve the tumor microenvironment, reverse drug resistance and activate immune cells. Herbal anti-cancer drugs offer therapeutic advantages, particularly selective toxicity against cancer cells, reducing the adverse side effects associated with conventional chemotherapy. Recent studies and clinical trials highlight the benefits of herbal medicines in alleviating side effects, improving tolerance to chemotherapy and the occurrence of synergistic effects with conventional treatments. For example, the herbal medicine SH003 was found to be safe and potentially effective in the treatment of solid cancers, while Fucoidan showed anti-inflammatory properties that are beneficial for patients with advanced cancer. The current research landscape on herbal anticancer agents is extensive. Numerous studies and clinical trials are investigating their efficacy, safety and mechanisms of action in various cancers such as lung, prostate, breast and hepatocellular carcinoma. Promising developments include the polypharmacological approach, combination therapies, immunomodulation and the improvement of quality of life. However, there are still challenges in the development and use of natural products as anti-cancer drugs, such as the need for further research into their mechanisms of action, possible drug interactions and optimal dosage. Standardizing herbal extracts, improving bioavailability and delivery, and overcoming regulatory and acceptance hurdles are critical issues that need to be addressed. Nonetheless, the promising anticancer effects and therapeutic benefits of natural products warrant further investigation and development. Multidisciplinary collaboration is essential to advance herbal cancer therapy and integrate these agents into mainstream cancer treatment.