Musculoskeletal adverse events induced by immune checkpoint inhibitors: a large-scale pharmacovigilance study.

Background: The musculoskeletal toxicity of immune checkpoint inhibitors (ICIs) is receiving increasing attention with clinical experience. Nevertheless, the absence of a systematic investigation into the musculoskeletal toxicity profile of ICIs currently results in the under-recognition of associated adverse events. Further and more comprehensive investigations are warranted to delineate the musculoskeletal toxicity profile of ICIs and characterize these adverse events. Material and methods: The present study employed the FDA Adverse Event Reporting System database to collect adverse events between January 2010 and March 2021. We utilized both the reporting odds ratio and the Bayesian confidence propagation neural network algorithms to identify suspected musculoskeletal adverse events induced by ICIs. Subsequently, the clinical characteristics and comorbidities of the major musculoskeletal adverse events were analyzed. The risk of causing these events with combination therapy versus monotherapy was compared using logistic regression model and Ω shrinkage measure model. Results: The musculoskeletal toxicity induced by ICIs primarily involves muscle tissue, including neuromuscular junctions, fascia, tendons, and tendon sheaths, as well as joints, spine, and bones, including cartilage. The toxicity profile of PD-1/PD-L1 and CTLA-4 inhibitors varies, wherein the PD-1 inhibitor pembrolizumab exhibits a heightened overall risk of inducing musculoskeletal adverse events. The major ICIs-induce musculoskeletal adverse events, encompassing conditions such as myositis, neuromyopathy (including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Guillain-Barré syndrome, and Chronic inflammatory demyelinating polyradiculoneuropathy), arthritis, fractures, myelitis, spinal stenosis, Sjogren's syndrome, fasciitis, tenosynovitis, rhabdomyolysis, rheumatoid myalgia, and chondrocalcinosis. Our study provides clinical characteristics and comorbidities of the major ICIs-induced musculoskeletal adverse events. Furthermore, the combination therapy of nivolumab and ipilimumab does not result in a statistically significant escalation of the risk associated with the major musculoskeletal adverse events. Conclusion: Immune checkpoint inhibitors administration triggers a range of musculoskeletal adverse events, warranting the optimization of their management during clinical practice.

A Study Based on Network Pharmacology Decoding the Multi-Target Mechanism of Duhuo Jisheng Decoction for the Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) poses a grim public health impact. Duhuo Jisheng Decoction (DJD), a traditional Chinese medicine formula, has recently received significant attention for its efficacy and safety in treating IDD. However, the pathological processes of IDD in which DJD interferes and molecular mechanism involved are poorly understood, which brings difficulties to the clinical practice of DJD for the treatment of IDD. This study systematically investigated the underlying mechanism of DJD treatment of IDD. Network pharmacology approaches were employed, integrating molecular docking and random walk with restart (RWR) algorithm, to identify key compounds and targets for DJD in the treatment of IDD. Bioinformatics approaches were used to further explore the biological insights in DJD treatment of IDD. The analysis identifies AKT1, PIK3R1, CHUK, ALB, TP53, MYC, NR3C1, IL1B, ERBB2, CAV1, CTNNB1, AR, IGF2, and ESR1 as key targets. Responses to mechanical stress, oxidative stress, cellular inflammatory responses, autophagy, and apoptosis are identified as the critical biological processes involved in DJD treatment of IDD. The regulation of DJD targets in extracellular matrix components, ion channel regulation, transcriptional regulation, synthesis and metabolic regulation of reactive oxygen products in the respiratory chain and mitochondria, fatty acid oxidation, the metabolism of Arachidonic acid, and regulation of Rho and Ras protein activation are found to be potential mechanisms in disc tissue response to mechanical stress and oxidative stress. MAPK, PI3K/AKT, and NF-κB signaling pathways are identified as vital signaling pathways for DJD to treat IDD. Quercetin and Kaempferol are assigned a central position in the treatment of IDD. This study contributes to a more comprehensive understanding of the mechanism of DJD in treating IDD. It provides a reference for applying natural products to delay the pathological process of IDD.

Stability simulation analysis of targeted puncture in L4/5 intervertebral space for PELD surgery.

Introduction: The application prospects of percutaneous endoscopic lumbar discectomy (PELD) as a minimally invasive spinal surgery method in the treatment of lumbar disc herniation are extensive. This study aims to find the optimal entry angle for the trephine at the L4/5 intervertebral space, which causes less lumbar damage and has greater postoperative stability. To achieve this, we conduct a three-dimensional simulated analysis of the degree of damage caused by targeted puncture-based trephine osteotomy on the lumbar spine. Methods: We gathered clinical CT data from patients to construct a lumbar model. This model was used to simulate and analyze the variations in trephine osteotomy volume resulting from targeted punctures at the L4/5 interspace. Furthermore, according to these variations in osteotomy volume, we created Finite Element Analysis (FEA) models specifically for the trephine osteotomy procedure. We then applied mechanical loads to conduct range of motion and von Mises stress analyses on the lumbar motion unit. Results: In percutaneous endoscopic interlaminar discectomy, the smallest osteotomy volume occurred with a 20° entry angle, close to the base of the spinous process. The volume increased at 30° and reached its largest at 40°. In percutaneous transforaminal endoscopic discectomy, the largest osteotomy volume was observed with a 50° entry angle, passing through the facet joints, with smaller volumes at 60° and the smallest at 70°. In FEA, M6 exhibited the most notable biomechanical decline, particularly during posterior extension and right rotation. M2 and M3 showed significant differences primarily in rotation, whereas the differences between M3 and M4 were most evident in posterior extension and right rotation. M5 displayed their highest stress levels primarily in posterior extension, with significant variations observed in right rotation alongside M4. Conclusion: The appropriate selection of entry sites can reduce lumbar damage and increase stability. We suggest employing targeted punctures at a 30° angle for PEID and at a 60° angle for PTED at the L4/5 intervertebral space. Additionally, reducing the degree of facet joint damage is crucial to enhance postoperative stability in lumbar vertebral motion units.

The application of biomaterials in osteogenesis: A bibliometric and visualized analysis.

Osteogenesis serves an important role in bone tissue repairing. Novel biomaterials are widely prevalent as materials for orthopedic implants due to their biocompatibility and osteogenetic ability. The purpose of this study was to comprehensively analyze hotspots and future trend of biomaterials research in osteogenesis based on bibliometric and visualized analysis. A total of 1,523 papers about biomaterials research in osteogenesis between 2000 and 2021 were included in this study. During the above 20 years, China's leading position in the global biomaterials research in osteogenesis was obvious, and it was also the country that most frequently participates in international cooperation. Chinese Academy of Sciences was the most productive institution and the leader of research cooperation. Acta Biomaterialia and Biomaterials have published the largest number of articles in the field of biomaterials research in osteogenesis. Meanwhile, Acta Biomaterialia and Biomaterials were also the two journals with the highest total citation frequency. Wu CT, Chang J, Kaplan DL, and Xiao Y all made important contributions in the field of biomaterials research in osteogenesis. At present, there are five research hotspots in the field of biomaterials research in osteogenesis: 1) the immunomodulatory role of biomaterial-related inflammatory; 2) mechanisms of osteogenesis in biomaterials; 3) 3D printing and clinical application of biomaterials; 4) bone tissue engineering for biomaterial osteogenesis; and 5) regenerative medicine for biomaterial osteogenesis. The results of this study showed that mechanisms of osteogenesis in biomaterials, bone tissue engineering for biomaterial osteogenesis, and regenerative medicine for biomaterial osteogenesis will remain research hotspots in the future. International cooperation was also expected to expand and deepen the field of biomaterials research in osteogenesis.

Striatal D1 Dopamine Neuronal Population Dynamics in a Rat Model of Levodopa-Induced Dyskinesia.

BACKGROUND: The pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) is not well understood. Experimental data from numerous investigations support the idea that aberrant activity of D1 dopamine receptor-positive medium spiny neurons in the striatal direct pathway is associated with LID. However, a direct link between the real-time activity of these striatal neurons and dyskinetic symptoms remains to be established. METHODS: We examined the effect of acute levodopa treatment on striatal c-Fos expression in LID using D1-Cre PD rats with dyskinetic symptoms induced by chronic levodopa administration. We studied the real-time dynamics of striatal D1 + neurons during dyskinetic behavior using GCaMP6-based in vivo fiber photometry. We also examined the effects of striatal D1 + neuronal deactivation on dyskinesia in LID rats using optogenetics and chemogenetic methods. RESULTS: Striatal D1 + neurons in LID rats showed increased expression of c-Fos, a widely used marker for neuronal activation, following levodopa injection. Fiber photometry revealed synchronized overactivity of striatal D1 + neurons during dyskinetic behavior in LID rats following levodopa administration. Consistent with these observations, optogenetic deactivation of striatal D1 + neurons was sufficient to inhibit most of the dyskinetic behaviors of LID animals. Moreover, chemogenetic inhibition of striatal D1 + neurons delayed the onset of dyskinetic behavior after levodopa administration. CONCLUSION: Our data demonstrated that aberrant activity of striatal D1 + neuronal population was causally linked with real-time dyskinetic symptoms in LID rats.

Inhibition of striatal dopamine D5 receptor attenuates levodopa-induced dyskinesia in a rat model of Parkinson's disease.

Levodopa-induced dyskinesia (LID) is experienced by most patients of Parkinson's disease (PD) upon the long-term use of the dopamine precursor levodopa. Striatal dopaminergic signaling plays a critical role in the pathogenesis of LID through its interactions with dopamine receptors. The specific roles of striatal dopaminergic D5 receptors in the pathophysiological process of LID are still poorly established. In the study, we investigated the role of striatal dopamine D5 receptor in LID by using PD rats with or without dyskinetic symptoms after chronic levodopa administration. The experimental results showed that the expression level of D5 receptors in the sensorimotor striatum of dyskinetic rats is significantly higher than that of the non-dyskinetic controls. The administration of levodopa increased c-Fos expression in a subpopulation of sensorimotor striatum neurons of dyskinetic rats, but not in non-dyskinetic rats. The majority of the c-Fos+ neurons activated by levodopa in the striatum are positive for D5 receptor staining. Intrastriatal injection of D1-like (D1 and D5) dopamine receptor antagonist, SCH-23390, significantly inhibited dyskinetic behavior in dyskinetic rats after the injection of levodopa, meanwhile, intrastriatal administration of SKF-83959, a partial D5 receptor agonist, yielded significant dyskinetic movements in dyskinetic rats without levodopa. In contrast, intrastriatal perfusion of small interfering RNA directed against DRD5 downregulated D5 receptors expression and moderately inhibited dyskinetic behavior of dyskinetic animals. Our data suggested that the striatal dopamine D5 receptor might play a novel role in the pathophysiology of LID.