Exosomes as drug delivery systems in glioma immunotherapy.

Recently, the significant benefits of cancer immunotherapy for most cancers have been demonstrated in clinical and preclinical studies. However, the efficacy of these immunotherapies for gliomas is limited, owing to restricted drug delivery and insufficient immune activation. As drug carriers, exosomes offer the advantages of low toxicity, good biocompatibility, and intrinsic cell targeting, which could enhance glioma immunotherapy efficacy. However, a review of exosome-based drug delivery systems for glioma immunotherapy has not been presented. This review introduces the current problems in glioma immunotherapy and the role of exosomes in addressing these issues. Meanwhile, preparation and application strategies of exosome-based drug delivery systems for glioma immunotherapy are discussed, especially for enhancing immunogenicity and reversing the immunosuppressive tumor microenvironment. Finally, we briefly describe the challenges of exosome-based drug delivery systems in clinical translation. We anticipate that this review will guide the use of exosomes as drug carriers for glioma immunotherapy.

Survival in patients with Parkinson's disease: a ten-year follow-up study in northern China.

BACKGROUND: A thorough understanding of the factors that influence patient survival in Parkinson's disease (PD) will aid in prognosis prediction and provide a new direction for disease modification treatment. Currently, there are no standardized mortality ratio (SMR) data for PD patients in the northern Chinese mainland. The main focus of this study was to determine which factors in the prospectively collected baseline characteristics can affect the survival of PD patients. In addition, for the first time, we investigated the SMR of PD patients in northern China. METHODS: Between 2009 and 2012, 218 PD patients were continuously recruited from the movement disorder clinic of the First Affiliated Hospital of Dalian Medical University and followed up until death or May 31, 2021. The prespecified prognostic variables were demographics, clinical features, lifestyle factors, and drug dose prospectively collected at baseline. To determine the independent predictors of survival during follow-up, the Cox proportional hazards model was used. Kaplan-Meier analysis was applied to estimate the overall survival curve and to compare survival between layers based on statistically significant predictors. The SMR of this northern Chinese mainland PD cohort was calculated. RESULTS: After a mean follow-up of 9.58 ± 2.27 years, 50 patients (22.90%) died. Factors that could individually predict shortened survival during follow-up included older age at onset (hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.06-1.15), Hoehn and Yahr (H&Y) stage ≥ 3 (HR 9.36, 95% CI 2.82-31.03) and severe cognitive impairment (HR 6.18, 95% CI 2.75-13.88). Univariate Cox regression revealed that a certain amount of physical activity was associated with better survival (HR 0.41, 95% CI 0.22-0.74), while fatigue was associated with an increased risk of death (HR 2.54, 95% CI 1.37-4.70). The overall SMR was 1.32 (95% CI 0.98-1.74). CONCLUSIONS: Older age at onset, higher baseline H&Y stage, and severe cognitive impairment have a negative impact on survival. The 10-year survival of PD patients is not significantly different from that of the general population in China.

Colorimetric detection of Salmonella typhimurium based on hexadecyl trimethyl ammonium bromide-induced supramolecular assembly of ß-cyclodextrin-capped gold nanoparticles.

We developed an effective and specific colorimetric strategy to detect Salmonella typhimurium (S. typhimurium) based on hexadecyl trimethyl ammonium bromide (CTAB)-induced supramolecular assembly of ß-cyclodextrin-capped gold nanoparticles (ß-CD-AuNPs). In this study, ssDNA aptamer of S. typhimurium could combine with CTAB to form the supramolecular ssDNA-CTAB composite, so the ssDNA aptamer was applied to control the concentration of CTAB. In the presence of S. typhimurium, ssDNA aptamers selectively bound to S. typhimurium but not to CTAB, leading to the host-guest chemistry reaction of CTAB and ß-CD resulting in ß-CD-AuNP supramolecular assembly aggregation with an obvious color change. The ratio of absorption at 650 and 520 nm (A650nm/A520nm) has a linear correlation to the log scale of the concentration of the bacteria (1 × 102-1 × 107 CFU/mL) with a low limit of detection (LOD) of 13 CFU/mL. In addition, this optical sensor has good selectivity and practicability. In milk samples, the recovery was 93.55-111.32%, which suggested its potential application in real samples.

Acvr1 deletion in osteoblasts impaired mandibular bone mass through compromised osteoblast differentiation and enhanced sRANKL-induced osteoclastogenesis.

Bone morphogenetic protein (BMP) signaling is well known in bone homeostasis. However, the physiological effects of BMP signaling on mandibles are largely unknown, as the mandible has distinct functions and characteristics from other bones. In this study, we investigated the roles of BMP signaling in bone homeostasis of the mandibles by deleting BMP type I receptor Acvr1 in osteoblast lineage cells with Osterix-Cre. We found mandibular bone loss in conditional knockout mice at the ages of postnatal day 21 and 42 in an age-dependent manner. The decreased bone mass was related to compromised osteoblast differentiation together with enhanced osteoclastogenesis, which was secondary to the changes in osteoblasts in vivo. In vitro study revealed that deletion of Acvr1 in the mandibular bone marrow stromal cells (BMSCs) significantly compromised osteoblast differentiation. When wild type bone marrow macrophages were cocultured with BMSCs lacking Acvr1 both directly and indirectly, both proliferation and differentiation of osteoclasts were induced as evidenced by an increase of multinucleated cells, compared with cocultured with control BMSCs. Furthermore, we demonstrated that the increased osteoclastogenesis in vitro was at least partially due to the secretion of soluble receptor activator of nuclear factor-κB ligand (sRANKL), which is probably the reason for the mandibular bone loss in vivo. Overall, our results proposed that ACVR1 played essential roles in maintaining mandibular bone homeostasis through osteoblast differentiation and osteoblast-osteoclast communication via sRANKL.

A survey of power density of light-curing units used in private dental offices in Changchun City, China.

This study investigated power density and relevant information related to light-curing units used in private dental offices in Changchun City, China. The power density of 196 light-curing units used in private dental offices in Changchun City was measured using a simple random sampling method. Relevant information included the brand, type, years of operation, frequency of use, model numbers and types of light guide, resin buildup on the light guides, damage caused by the light guides, required maintenance of the curing lights, and ratio of the unit and chair number. There were 132 quartz tungsten halogen (QTH) units and 64 light-emitting diode units. The power density range was defined as 0-1,730 mW/cm(2). The mean power density was 453.1 mW/cm(2). The mean years of operation of the light-curing units were 3.96. The majority of dentists never tested the power density of the light-curing units and a considerable number of light guide surfaces showed resin buildup and damage. In Changchun City, the majority of light-curing units were QTH. Some units needed to be replaced due to aging. The majority of dentists were not aware that the light-curing units require periodic testing and maintenance. The data herein indicate the importance of periodic testing of the power density of light-curing units and timely replacement of the components and then guarantee the quality of medical services and their benefits to patients.

Elucidation of the mechanism underlying impaired sensorimotor gating in patients with primary blepharospasm using prepulse inhibition.

Objective: We aimed to analyze prepulse inhibition (PPI) impairment of the blink reflex in patients with primary blepharospasm (BSP). Methods: We recruited 30 BSP patients and 20 gender- and age-matched healthy controls (HCs). Weak electrical stimulation was applied to the right index finger at interstimulus intervals (ISIs) of 120, 200, and 300 ms before the supraorbital nerve stimulation to investigate PPI size [PPI size = (1 - R2 area at prepulse trials/R2 area at baseline trials) × 100%]. Results: The prepulse stimulus significantly inhibited the R 2 component at the three ISIs in both groups, but less inhibition was shown in the BSP group (p < 0.05). In HCs, the prepulse stimulus induced prolonged R 2 and R 2c latencies at the three ISIs and increased the R 1 amplitude at ISIs of 120 ms; these changes were absent in BSP patients. In the BSP group, patients with sensory tricks showed better PPI than patients without sensory tricks. Disease duration and motor symptom severity showed no significant correlation with PPI size. Conclusion: In BSP patients, PPI was impaired while R 1 facilitation was absent. PPI size did not correlate with the motor symptom severity and disease duration. Patients with sensory tricks showed better PPI than those without sensory tricks.

Corrigendum: Elucidation of the mechanism underlying impaired sensorimotor gating in patients with primary blepharospasm using prepulse inhibition.

[This corrects the article DOI: 10.3389/fneur.2023.1105483.].

Functional connectivity alterations in the frontoparietal network and sensorimotor network are associated with behavioral heterogeneity in blepharospasm.

Objective: Primary blepharospasm (BSP) is a clinically heterogeneous disease that manifests not only as spasmodic closure of the eyelids but also sometimes with apraxia of eyelid opening (AEO). This cross-sectional study aimed to investigate differences in the neural mechanisms of isolated BSP and BSP-associated AEO subtypes, which may reveal the pathophysiology underlying different phenotypes. Methods: A total of 29 patients manifested as isolated BSP, 17 patients manifested as BSP associated with AEO, and 28 healthy controls underwent resting-state functional near-infrared spectroscopy (fNIRS). We assessed functional connectivity (FC) between regions of interest (ROIs) in the fronto-parietal control network (PFCN) and sensorimotor network (SMN). We also examined the relationship between altered FC and behavioral data. Results: In the FPCN, ROI- analyses showed decreased FC between the left premotor cortex and supramarginal gyrus in the BSP with AEO group compared to the isolated BSP group. In the SMN, both subgroups showed hypoconnectivity of the left premotor cortex with the right primary motor cortex, primary sensory cortex, and somatosensory association cortex. This hypoconnectivity was positively correlated with the total number of botulinum toxin A treatments, which suggests that long-term botulinum toxin A treatment may modulate motor sequence planning and coordination. Conclusion: These findings showed different connectivity alterations in neural networks associated with motor and cognitive control among different behavioral phenotypes of BSP. The identification of specific alterations in various networks that correspond to clinical heterogeneity may inform the identification of potential biomarkers for early diagnosis and personalized neuromodulation targets for treating different BSP subphenotypes.

Correlation and underlying brain mechanisms between rapid eye movement sleep behavior disorder and executive functions in Parkinson's disease: an fNIRS study.

Purpose: Rapid eye movement sleep behavior disorder (RBD) affects 30%-40% of patients with Parkinson's disease (PD) and has been linked to a higher risk of cognitive impairment, especially executive dysfunction. The aim of this study was to investigate the brain activation patterns in PD patients with RBD (PD-RBD+) compared to those without RBD (PD-RBD-) and healthy controls (HCs), and to analyze the correlation between changes in cerebral cortex activity and the severity of RBD. Methods: We recruited 50 PD patients, including 30 PD-RBD+, 20 PD-RBD-, and 20 HCs. We used functional near infrared spectroscopy during a verbal fluency task (VFT-fNIRS) and clinical neuropsychological assessment to explore the correlation between PD-RBD+ and executive function and changes in neural activity. Results: The VFT-fNIRS analysis revealed a significant reduction in activation among PD-RBD+ patients across multiple channels when compared to both the PD-RBD- and HC groups. Specifically, PD-RBD+ patients exhibited diminished activation in the bilateral dorsolateral prefrontal cortex (DLPFC) and the right ventrolateral prefrontal cortex (VLPFC) relative to their PD-RBD- counterparts. Furthermore, compared to the HC group, PD-RBD+ patients displayed reduced activation specifically in the right DLPFC. Significantly, a noteworthy negative correlation was identified between the average change in oxygenated hemoglobin concentration (ΔHbO2) in the right DLPFC of PD-RBD+ patients and the severity of their RBD. Conclusion: Our study offers compelling evidence that RBD exacerbates cognitive impairment in PD, manifested as executive dysfunction, primarily attributed to reduced prefrontal activation. These aberrations in brain activation may potentially correlate with the severity of RBD.

Effects of trihexyphenidyl on prefrontal executive function and spontaneous neural activity in patients with tremor-dominant Parkinson's disease: An fNIRS study.

INTRODUCTION: The use of the anti-parkinsonian drug trihexyphenidyl (THP) to treat patients with Parkinson's disease (PD), particularly those with tremor-dominant PD (tdPD), has been well documented. Despite growing concerns about THP causing cognitive decline in tdPD patients, the underlying neural correlates remain unclear. Therefore, we investigated the effects of THP on prefrontal executive function and spontaneous neural activity in patients with tdPD by utilizing functional near-infrared spectroscopy (fNIRS). METHODS: We recruited 30 patients with tdPD, including 15 patients receiving THP and 15 patients not receiving THP. We performed comprehensive neuropsychological and clinical assessments to evaluate each patient's cognitive function, mental status, and clinical symptoms. We measured brain activation elicited from the verbal fluency task (VFT) and changes in amplitude of low-frequency fluctuations (ALFF) at rest to investigate executive function and spontaneous neural activity, respectively. In addition, we examined the relationship between altered activation during task and resting state and neuropsychological and clinical data. RESULTS: Compared with tdPD patients not taking THP, tdPD patients taking THP showed no differences on neuropsychological tests. However, there was insufficient activity of the dorsolateral prefrontal cortex (DLPFC) during VFT and reduced ALFF values for the DLPFC, ventrolateral prefrontal cortex (VLPFC), and the orbitofrontal cortex (OFC) related to the frontoparietal network (FPN) at rest. Furthermore, ALFF values of the VLPFC were positively correlated with scores of multiple cognitive domain functions. CONCLUSION: These findings suggest that THP treatment may lead to prefrontal dysfunction in tdPD patients, attenuating brain activation in executive function and cognition-related spontaneous neural activity.

Construction of hollow polydopamine nanoparticle based drug sustainable release system and its application in bone regeneration.

Nanomaterial-based drug sustainable release systems have been tentatively applied to bone regeneration. They, however, still face disadvantages of high toxicity, low biocompatibility, and low drug-load capacity. In view of the low toxicity and high biocompatibility of polymer nanomaterials and the excellent load capacity of hollow nanomaterials with high specific surface area, we evaluated the hollow polydopamine nanoparticles (HPDA NPs), in order to find an optimal system to effectively deliver the osteogenic drugs to improve treatment of bone defect. Data demonstrated that the HPDA NPs synthesized herein could efficiently load four types of osteogenic drugs and the drugs can effectively release from the HPDA NPs for a relatively longer time in vitro and in vivo with low toxicity and high biocompatibility. Results of qRT-PCR, ALP, and alizarin red S staining showed that drugs released from the HPDA NPs could promote osteogenic differentiation and proliferation of rat bone marrow mesenchymal stem cells (rBMSCs) in vitro. Image data from micro-CT and H&E staining showed that all four osteogenic drugs released from the HPDA NPs effectively promoted bone regeneration in the defect of tooth extraction fossa in vivo, especially tacrolimus. These results suggest that the HPDA NPs, the biodegradable hollow polymer nanoparticles with high drug load rate and sustainable release ability, have good prospect to treat the bone defect in future clinical practice.

Metformin Carbon Dots for Promoting Periodontal Bone Regeneration via Activation of ERK/AMPK Pathway.

The osteogenic potential of mesenchymal stem cells (MSCs) is severely impaired under persistent inflammation of periodontitis. A highly efficient way to promote or rescue osteogenic potential of MSCs under inflammation remains an unmet goal. Herein, metformin carbon dots (MCDs) with excellent biocompatibility are prepared from metformin hydrochloride and citric acid via a hydrothermal method. The MCDs can more effectively enhance the alkaline phosphatase (ALP) activity, calcium deposition nodules formation, expression of osteogenic genes and proteins in rat bone marrow mesenchymal stem cells (rBMSCs) than metformin under both inflammatory and normal conditions. Moreover, a novel pathway of extracellular signal-regulated kinases (ERK)/AMP-activated protein kinase (AMPK) signaling is involved in the MCDs-induced osteogenesis. In periodontitis rats, MCDs can effectively regenerate the lost alveolar bone, but not the metformin. Taken together, MCDs can be the promising candidate nanomaterial for periodontitis treatment. This work may provide a new pharmacological target of ERK/AMPK pathway for treating bone loss and also give additional insights into developing nanodrugs from the numerous medications.

[Polarity of ameloblasts and odontoblasts and their related regulators].

The polarity of ameloblasts and odontoblasts is crucial for their differentiation and function. Polarity-related molecules play an important role in this process. This review summarizes the process of polarity formation of ameloblasts and odontoblasts and their related regulators.

Distinctive role of ACVR1 in dentin formation: requirement for dentin thickness in molars and prevention of osteodentin formation in incisors of mice.

Dentin is a major component of teeth that protects dental pulp and maintains tooth health. Bone morphogenetic protein (BMP) signaling is required for the formation of dentin. Mice lacking a BMP type I receptor, activin A receptor type 1 (ACVR1), in the neural crest display a deformed mandible. Acvr1 is known to be expressed in the dental mesenchyme. However, little is known about how BMP signaling mediated by ACVR1 regulates dentinogenesis. To explore the role of ACVR1 in dentin formation in molars and incisors in mice, Acvr1 was conditionally disrupted in Osterix-expressing cells (designated as cKO). We found that loss of Acvr1 in the dental mesenchyme led to dentin dysplasia in molars and osteodentin formation in incisors. Specifically, the cKO mice exhibited remarkable tooth phenotypes characterized by thinner dentin and thicker predentin, as well as compromised differentiation of odontoblasts in molars. We also found osteodentin formation in the coronal part of the cKO mandibular incisors, which was associated with a reduction in the expression of odontogenic gene Dsp and an increase in the expression of osteogenic gene Bsp, leading to an alteration of cell fate from odontoblasts to osteoblasts. In addition, the expressions of WNT antagonists, Dkk1 and Sost, were downregulated and B-catenin was up-regulated in the cKO incisors, while the expression levels were not changed in the cKO molars, compared with the corresponding controls. Our results indicate the distinct and critical roles of ACVR1 between incisors and molars, which is associated with alterations in the WNT signaling related molecules. This study demonstrates for the first time the physiological roles of ACVR1 during dentinogenesis.

[The role of bone morphogenetic protein signaling pathway in tooth root development].

The bone morphogenetic protein (BMP) family is an important factor in the regulation of cell ular life activities and in the development of almost all tissues. BMP-mediated signaling plays an important role in tooth root development, which is a part of tooth development. Epithelial and mesenchymal interactions are involved in tooth root development, but the BMP signaling pathway has a different effect on tooth root development in epithelial and mesenchymal. This review summarizes the advances of BMP signaling in tooth root development.

[A survey of power density of clinical curing-light units used in Changchun].

OBJECTIVES: To investigate the power density and other relevant data of clinical curing-light units used in Changchun, and to provide practice recommendations to clinical dentists about maintaining of cuing-light units. METHODS: Stomatology hospitals, departments of stomatology in general hospitals, and private dental offices in Changchun were randomly selected to participate in the Survey. The investigation analyzed 270 curing-light units. The following data of curing-light units were gathered: brand, type, operation ages, numbers and types of light guide, resin build-ups on light guides, damages of light guides, use frequency, monitor and maintenance of curing lights, and unit numbers/chair numbers. RESULTS: There were 174 QTH and 96 LED units. The distribution of power density was from 0 to 1702 mW/cm(2). The mean power density was 413.2 mW/cm(2). The power densities of 73 lights were less than 200 mW/cm(2) and could not polymerize resin composites adequately. The mean number of operation age of the light units was 4.74 years. Most of clinical dentists didn't monitor the light-curing units and the situation of build-up from composite resin or damages on light guides was very severe. CONCLUSIONS: Most of the light-curing units used in Changchun were QTH. Some QTH units degenerate severely and need to be replaced with the new ones. Most of the clinical doctors lack the knowledge of how to properly monitor and maintain the light-curing units.