Tert-expressing cells contribute to salivary gland homeostasis and tissue regeneration after radiation therapy.

Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (TertHigh) cell population located in the ductal region of the adult SMG. These TertHigh cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. TertHigh cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of "cell cycling" and "oxidative stress response" pathways in TertHigh cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of TertHigh cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy.

Screening of Cross-Reactive Aptamers for the Detection of 24 Quinolones by Using a Liebig's Law-Guided Parallel-Series Strategy.

Quinolones, a widely used class of antibiotics, present significant environmental and health concerns if they excessively remain in the environment and in food. Aptamers specific to quinolones can be applied as bioreceptors for the detection of quinolone residues in the environment and food. The quinolone family contains dozens of different individuals that share the same core structure coupled with various substituents at six different positions. The diversity and complexity of the substitution sites make it a challenge to choose a set of representative molecules that encompass all the desired sites and preserve the core molecular framework for the screening of quinolone-specific aptamers via systematic evolution of ligands by exponential enrichment (SELEX). To address this challenge, we introduce a novel parallel-series strategy guided by Liebig's law for isolating quinolone-specific cross-reactive aptamers by using the library-immobilized SELEX method. Through this approach, we successfully identified 5 aptamers (Apt.AQ01-Apt.AQ05) with high binding affinity and excellent specificity to 24 different quinolone individuals. Among them, Apt.AQ03 showcased optimal performance with affinities ranging from 0.14 to 1.07 µM across the comprehensive set of 24 quinolones, exhibiting excellent specificity against nontarget interferents. The binding performance of Apt.AQ03 was further characterized with microscale thermophoresis, circular dichroism spectra, and an exonuclease digestion assay. By using Apt.AQ03 as a bioreceptor, a fluorescence resonance energy transfer (FRET) aptasensor was developed for the detection of 24 quinolones in milk, achieving a remarkable detection limit of 14.5-21.8 ng/mL. This work not only establishes a robust and effective strategy for selecting cross-reactive aptamers applicable to other small-molecule families but also provides high-quality aptamers for developing various high-throughput and reliable methods for the detection of multiple quinolone residues in food.

Three-Component Reaction for the Synthesis of Spiro-Heterocycles from Isatins, Substituted Ureas, and Cyclic Ketones.

We reported an efficient three-component reaction to access new spiro heterocycles through the annulation reactions of isatins, substituted ureas, and cyclic ketones under normal laboratory conditions, which is another example of isatins being used to build spiro compounds by the ring-opening and recyclization processes. The wide range of substrates, simple operation, normal experimental conditions, and high yields make the approach of high practical value.

Silica-magnesium coupling in lignin-based biochar: A promising remediation for composite heavy metal pollution in environment.

Lignin hydrothermal silica-carbon material served as a backbone for MgCl2 activation to prepare lignin-based silicon/magnesia biochar (ALB/Si-Mg) for Cd2+, Pb2+, Cu2+, and Zn2+ removal from water and soil environment. Characterization studies revealed a 1017.71-fold increase in the specific surface area of ALB/Si-Mg compared to the original lignin biochar (ALB), producing abundant oxygen functional groups (OC-O, Si-O, Mg-O), and mineral matter (Mg2SiO4 and MgO). Crucially, batch adsorption experiments demonstrated that the adsorption capacity of ALB/Si-Mg for Cd2+, Pb2+, Cu2+, and Zn2+ was 848.17, 665.07, 151.84, and 245.78 mg/g, which were 29.09-140.45 times of the ALB. Soil remediation experiments showed that applying ALB/Si-Mg increased soil effective silicon (109.04%-450.2%) and soil exchangeable magnesium (276.41%-878.66%), enhanced plant photosynthesis, and notably reduced the bioavailability of heavy metals in soil as well as the content of heavy metals in Pakchoi, thereby promoting Pakchoi growth and development. The presence of oxygen-containing functional groups on ALB/Si-Mg, along with Mg2SiO4 and MgO nanoparticles, enhanced the adsorption capacity for heavy metals through the promotion of heavy metal precipitation, ion exchange, and complexation mechanisms. This study establishes the groundwork for the coupling of silica and magnesium elements in biochar and the remediation of composite heavy metal environmental pollution.

Estimation of potential wildfire behavior characteristics to assess wildfire danger in southwest China using deep learning schemes.

Accurate estimation of potential wildfire behavior characteristics (PWBC) can improve wildfire danger assessment. However, wildfire behavior has been estimated by most fire spread models with immeasurable uncertainties and difficulties in large-scale applications. In this study, a PWBC estimation model (named PWBC-QR-BiLSTM) was proposed by coupling the Bi-directional Long Short-Term Memory (BiLSTM) and quantile regression (QR) methods. Multi-source data, including fuel, weather, topography, infrastructure, and landscape variables, were input into the PWBC-QR-BiLSTM model to estimate the potential rate of spread (ROS) and fire radiative power (FRP) over western Sichuan of China, and then to estimate the probability density of ROS and FRP. Daily ROS and FRP were extracted from the Global Fire Atlas and the MOD14A1/MYD14A1 product. The optimal PWBC-QR-BiLSTM model was determined using the Non-dominated Sorting Genetic Algorithm Ⅱ (NAGA-Ⅱ). Results showed that the PWBC-QR-BiLSTM performed well in estimating potential ROS and FRP with high accuracy (ROS: R2 > 0.7 and MAPE<30%, FRP: R2 > 0.8 and MAPE<25%). The modal PWBC values extracted from the estimated probability density were closer to the observed values, which can be regarded as a good indicator for wildfire danger assessment. The variable importance analysis also verified that fuel and infrastructure variables played an important role in driving wildfire behavior. This study suggests the potential of utilizing artificial intelligence to estimate PWBC and its probability density to improve the guidance on wildfire management.

Combining a machine-learning derived 4-lncRNA signature with AFP and TNM stages in predicting early recurrence of hepatocellular carcinoma.

BACKGROUND: Near 70% of hepatocellular carcinoma (HCC) recurrence is early recurrence within 2-year post surgery. Long non-coding RNAs (lncRNAs) are intensively involved in HCC progression and serve as biomarkers for HCC prognosis. The aim of this study is to construct a lncRNA-based signature for predicting HCC early recurrence. METHODS: Data of RNA expression and associated clinical information were accessed from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) database. Recurrence associated differentially expressed lncRNAs (DELncs) were determined by three DEG methods and two survival analyses methods. DELncs involved in the signature were selected by three machine learning methods and multivariate Cox analysis. Additionally, the signature was validated in a cohort of HCC patients from an external source. In order to gain insight into the biological functions of this signature, gene sets enrichment analyses, immune infiltration analyses, as well as immune and drug therapy prediction analyses were conducted. RESULTS: A 4-lncRNA signature consisting of AC108463.1, AF131217.1, CMB9-22P13.1, TMCC1-AS1 was constructed. Patients in the high-risk group showed significantly higher early recurrence rate compared to those in the low-risk group. Combination of the signature, AFP and TNM further improved the early HCC recurrence predictive performance. Several molecular pathways and gene sets associated with HCC pathogenesis are enriched in the high-risk group. Antitumor immune cells, such as activated B cell, type 1 T helper cell, natural killer cell and effective memory CD8 T cell are enriched in patients with low-risk HCCs. HCC patients in the low- and high-risk group had differential sensitivities to various antitumor drugs. Finally, predictive performance of this signature was validated in an external cohort of patients with HCC. CONCLUSION: Combined with TNM and AFP, the 4-lncRNA signature presents excellent predictability of HCC early recurrence.

Advances in MicroRNA Therapy for Heart Failure: Clinical Trials, Preclinical Studies, and Controversies.

Heart failure (HF) is a rapidly growing public health issue with more than 37.7 million patients worldwide and an annual healthcare cost of $108 billion. However, HF-related drugs have not changed significantly for decades, and it is essential to find biological drugs to provide better treatment for HF patients. MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) with a length of approximately 21 nucleotides and play an important role in the onset and progression of cardiovascular diseases. Increasing studies have shown that miRNAs are widely involved in the pathophysiology of HF, and the regulation of miRNAs has promising therapeutic effects. Among them, there is great interest in miRNA-132, since the encouraging success of anti-miRNA-132 therapy in a phase 1b clinical trial in 2020. However, it is worth noting that the multi-target effect of miRNA may produce side effects such as thrombocytopenia, revascularization dysfunction, severe immune response, and even death. Advances in drug delivery modalities, delivery vehicles, chemical modifications, and plant-derived miRNAs are expected to address safety concerns and further improve miRNA therapy. Here, we reviewed the preclinical studies and clinical trials of HF-related miRNAs (especially miRNA-132) in the past 5 years and summarized the controversies of miRNA therapy.

RDD-YOLOv5: Road Defect Detection Algorithm with Self-Attention Based on Unmanned Aerial Vehicle Inspection.

Road defect detection is a crucial aspect of road maintenance projects, but traditional manual methods are time-consuming, labor-intensive, and lack accuracy. Leveraging deep learning frameworks for object detection offers a promising solution to these challenges. However, the complexity of backgrounds, low resolution, and similarity of cracks make detecting road cracks with high accuracy challenging. To address these issues, a novel road crack detection algorithm, termed Road Defect Detection YOLOv5 (RDD-YOLOv5), was proposed. Firstly, a model was proposed to integrate the transformer structure and explicit vision center to capture the long-distance dependency and aggregate key characteristics. Additionally, the Sigmoid-weighted linear activations in YOLOv5 were replaced with the Gaussian Error Linear Units to enhance the model's nonlinear fitting capability. To evaluate the algorithm's performance, a UAV flight platform was constructed, and experimental freebies were provided to boost inspection efficiency. The experimental results demonstrate the effectiveness of RDD-YOLOv5, achieving a mean average precision of 91.48%, surpassing the original YOLOv5 by 2.5%. The proposed model proves its ability to accurately identify road cracks, even under challenging and complex traffic backgrounds. This advancement in road crack detection technology has significant implications for improving road maintenance and safety.

Diagnostic value of mesenteric CTA combined with D-dimer level and inflammatory factor changes in severity of mesenteric artery embolism.

Objective: To investigate the value of mesenteric CTA combined with D-dimer (DD) level and inflammatory factor changes in evaluating the severity of mesenteric artery embolism. Methods: This is a retrospective study. The imaging data of mesenteric CTA and the levels of plasma DD and inflammatory factors in 120 patients with mesenteric artery embolism confirmed by DSA or surgery in Baoding No.1 Central Hospital were analyzed retrospectively from January 2021 to December 2022. The coincidence rate of CTA alone and CTA combined with DD and inflammatory factors with the results of surgery or DSA was compared and analyzed. The specificity, sensitivity and accuracy of CTA alone and CTA combined with DD and inflammatory factors in diagnosing superior mesenteric artery embolism were compared. The correlations of different severity of mesenteric artery embolism with DD and inflammatory factor levels were compared and analyzed. Results: There was a significant difference in the coincidence rate between CTA diagnosis and CTA combined with DD and inflammatory factors diagnosis (p= 0.01). And the sensitivity and accuracy of the latter were significantly higher than those of the former (sensitivity, p= 0.01; accuracy, p= 0.00). The levels of plasma DD, TNF-a, CRP and IL-6 in the intestinal wall thinning group were significantly higher than those in the thickening group (p= 0.00). The above indexes increased significantly in the decreased intestinal wall enhancement group compared with the increased intestinal wall enhancement group (p= 0.00). DD, TNF-ɑ, CRP and IL-6 levels increased with the increase in stenosis severity. Conclusion: Mesenteric CTA combined with plasma DD and inflammatory factor levels can effectively determine the severity of mesenteric arterial embolism, and provide a scientific basis for early clinical diagnosis and treatment.

High-Definition Survey of Architectural Heritage Fusing Multisensors-The Case of Beamless Hall at Linggu Temple in Nanjing, China.

Following the development of digital measurement technology in recent years, the information contained in the measurement outcomes have become increasingly rich. However, the traditional graphical representation method based on vector graph needs to be updated. In this study, we use the Beamless Hall of Linggu Temple as an example. Measurements are conducted by using digital techniques, including three-dimensional (3D) laser scanning, close-range photogrammetry, and infrared thermal imaging. The pseudocolours that express spatial information and moisture distribution are calculated and generated through point clouds, which are used to express the land subsidence, wall deformation, moisture distribution, and other effects of the Beamless Hall. Furthermore, combining it with two-dimensional (2D) graphical representation, such as the plan, elevation, and section, damage-related information can be expressed intuitively and efficiently. This method can combine the advantages of graphics and images to provide a comprehensive and intuitive representation of the digital measurement results of brick architecture heritage. It can also provide a reference for surveying similar monuments and buildings of our architectural heritage.

NRF2 Dysregulation in Hepatocellular Carcinoma and Ischemia: A Cohort Study and Laboratory Investigation.

Background Intermediate stage hepatocellular carcinomas (HCCs) are treated by inducing ischemic cell death with transarterial embolization (TAE) or transarterial chemoembolization (TACE). A subset of HCCs harbor nuclear factor E2-related factor 2 (NRF2), a major regulator of the oxidative stress response implicated in cell survival after ischemia. NRF2-mutated HCC response to TAE and/or TACE is unknown. Purpose To test whether ischemia resistance is present in individuals with NRF2-mutated HCC and if this resistance can be overcome by means of NRF2 inhibition in HCC cell lines. Materials and Methods This was a combined retrospective review of an institutional database (from January 2011 to December 2018) and prospective study (from January 2014 to December 2018) of participants with HCC who underwent TAE and a laboratory investigation of HCC cell lines. Imaging follow-up included liver CT or MRI at 1 month after the procedure followed by 3-month interval scans. Tumor radiologic response was assessed on the basis of follow-up imaging. The time to local progression after TAE for individuals with and individuals without NRF2 pathway alterations was estimated by using competing risk analysis (Gray test). The in vitro response to ischemia in four HCC cell lines with and without NRF2 overexpression was evaluated, and the combination of ischemia with NRF2 knockdown by means of short hairpin RNA or an NRF2 inhibitor was tested. Doubling time estimates, dose response curve regression, and comparison analyses were performed. Results Sixty-five individuals (median age, 69 years [range, 19-84 years]; 53 men) were evaluated. HCCs with NRF2 pathway mutation had a shorter time to local progression after TAE compared to those without mutation (6-month cumulative incidence of local progression, 56% [range, 19%-91%] vs 22% [range, 12%-34%], respectively; P < .001) and confirmed ischemia resistance in NRF2-overexpressing HCC cell lines. However, ischemia and NRF2 knock-down worked synergistically to decrease proliferation of NRF2-overexpressing HCC cell lines. Dose response curves of ML385, an NRF2 inhibitor, showed that ischemia induces addiction to NRF2 in cells with NRF2 alterations. Conclusion Hepatocellular carcinoma with nuclear factor E2-related factor 2 (NRF2) alterations showed resistance to ischemia, but ischemia simultaneously induced sensitivity to NRF2 inhibition. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Weiss and Nezami in this issue.

In Situ Monitoring Apoptosis Process by a Self-Reporting Photosensitizer.

Although photodynamic therapy (PDT) has thrived as a promising treatment, highly active photosensitizers (PSs) and intense light power can cause treatment overdose. However, extra therapeutic response probes make the monitoring process complicated, ex situ and delayed. Now, this challenge is addressed by a self-reporting cationic PS, named TPE-4EP+, with aggregation-induced emission characteristic. The molecule undergoes mitochondria-to-nucleus translocation during apoptosis induced by PDT, thus enabling the in situ real-time monitoring via fluorescence migration. Moreover, by molecular charge engineering, we prove that the in situ translocation of TPE-4EP+ is mainly attributed to the enhanced interaction with DNA imposed by its multivalent positive charge. The ability of PS to provide PDT with real-time diagnosis help control the treatment dose that can avoid excessive phototoxicity and minimize potential side effect. Future development of new generation of PS is envisioned.

Identification of volatile compounds and odour activity values in quinoa porridge by gas chromatography-mass spectrometry.

BACKGROUND: Quinoa porridge is becoming popular among Asian for its nutritional values; hence, it is important to understand its aroma characteristics. RESULTS: Volatile compounds in porridge of 30 quinoa varieties were determined by gas chromatography-mass spectrometry combined with headspace-solid phase micro-extraction. In total, 53 volatile compounds were detected and grouped into 14 alkanals, four alcohols, seven ketones, 10 alkanes, 10 acids and esters, and eight heterocycles. The relative content of alkanes (22.97%), acids and esters (44.33%) was comparatively high, although alkanals (11.75%) may dominate the aroma. Most of the compounds were similar with respect to types and numbers, although they varied in amount, whereas 11 compounds varied significantly among different varieties. The 30 varieties could be divided into eight groups based on the concentrations of volatile compounds, although the same varieties would be divided into four groups if based on the relative odour activity values of twelve variable aroma compounds. CONCLUSION: Nine compounds were identified as the main contributors to the quinoa porridge aroma, including hexanal, 1-octen-3-ol, 2-pentylfuran, nonanal, (E,E)-2,4-decadienal and 6,10-dimethyl-5,9-undecadien-2-one. Heptanal, benzeneacetaldehyde and decanal may play roles in harmonizing the overall aroma. It is also interesting to note that 6,10,14-trimethyl-2-pentadecanone, with a slightly fatty aroma, showed a high content in all varieties. © 2019 Society of Chemical Industry.

Lower antioxidant capacity in the prefrontal cortex of individuals with schizophrenia.

OBJECTIVE: The glutathione (GSH) pathway is the main antioxidant system to protect against oxidative stress in the human brain. In this study, we tested whether molecular components of the GSH antioxidant system are changed in dorsolateral prefrontal cortex tissue from people with schizophrenia compared to controls. METHOD: The levels of total glutathione and reduced GSH were determined by fluorometric assay via quantifying thiols in extracts from frontal cortex of 68 people. Immunoblotting was used to measure levels of enzymes responsible for maintaining GSH, the glutamyl-cysteine ligase (GCL) catalytic subunit (GCLC) and the GSH peroxidase (GPx)-like protein ( n = 74). Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to measure GCLC messenger RNA (mRNA) expression. RESULTS: Both total glutathione ( t(66) = 2.467, p = 0.016) and reduced GSH ( t(66) = 3.001, p = 0.004) levels were significantly less in people with schizophrenia than in controls. However, there were no significant differences in either GCLC-like protein ( t(72) = -1.077, p = 0.285) or GCLC mRNA expression ( t(71) = -0.376, p = 0.708) between people with schizophrenia and control subjects. There was also no significant difference of GPx-like protein levels between schizophrenia and controls ( t(72) = -0.060, p = 0.952). Moreover, no significant correlations of putative confounding factors with GSH changes were detected. DISCUSSION: These results suggest that people with schizophrenia have impaired GSH antioxidant capacity, alongside normal levels of key regulatory proteins.

[A Maternal Health Care System Based on Mobile Health Care].

Wearable devices are used in the new design of the maternal health care system to detect electrocardiogram and oxygen saturation signal while smart terminals are used to achieve assessments and input maternal clinical information. All the results combined with biochemical analysis from hospital are uploaded to cloud server by mobile Internet. Machine learning algorithms are used for data mining of all information of subjects. This system can achieve the assessment and care of maternal physical health as well as mental health. Moreover, the system can send the results and health guidance to smart terminals.

Regulation of cell cycle progression by forkhead transcription factor FOXO3 through its binding partner DNA replication factor Cdt1.

To ensure genome stability, DNA must be replicated once and only once during each cell cycle. Cdt1 is tightly regulated to make sure that cells do not rereplicate their DNA. Multiple regulatory mechanisms operate to ensure degradation of Cdt1 in S phase. However, little is known about the positive regulators of Cdt1 under physiological conditions. Here we identify FOXO3 as a binding partner of Cdt1. FOXO3 forms a protein complex with Cdt1, which in turn blocks its interaction with DDB1 and PCNA. Conversely, FOXO3 depletion facilitated the proteolysis of Cdt1 in unperturbed cells. Intriguingly, FOXO3 deficiency resulted in impaired S-phase entry and reduced cell proliferation. We provide data that FOXO3 knockdown mimics Cdt1 down-regulation and affects G1/S transitions. Our results demonstrate a unique role of FOXO3 in binding to Cdt1 and maintaining its level required for cell cycle progression.

Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRA.

Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial early event in neuroblastoma pathogenesis is arrested differentiation of neuroblasts at various stages. Treatment of neuroblastoma with TPA and PDGF-BB leads to terminal differentiation of neuroblastoma cells. However, the signaling pathways that are involved in this process remain largely unknown. Here, we report that inhibition of endogenous FOXO proteins attenuated TPA/PDGF-BB mediated differentiation of neuroblastoma cells. Activated FOXO transcription factors acted on PDGFRA promoter to direct its basal mRNA expression as well as its induction upon serum deprivation. Depletion of endogenous PDGFRA in neuroblastoma cells significantly diminished neurite formation and extension under TPA/PDGF-BB treatment. Furthermore, ectopic expression of PDGFRA abolished the blockage of neuroblastoma differentiation by FOXOs inhibition. These findings define the FOXO-PDGFRA axis as crucial mechanistic components that govern TPA-induced neuroblastoma differentiation.

Safety Stressors and Coal Miners' Safety Performance: The Mediating Role of Resilience and Coping Styles.

Purpose: This study aimed to investigate the effects of three different safety stressors (safety role ambiguity, safety role conflicts, and safety interpersonal conflicts) on safety performance of coal miners under the mediating role of resilience and coping styles. Patients and Methods: The study is cross-sectional. To collect data to analyze the hypothesized relationships in the present study, a total of 450 questionnaires were distributed to coal miners in Shannxi Province of China. Regression analysis was employed as the main statistical technique in analyzing the data using SPSS 22.0 and Process 4.1. Results: The results of regression analysis indicate that the three kind of safety stressors have a negative predictive effect on coal miners' safety performance. Resilience and coping styles both were the mediating variables between the safety stressors (safety role ambiguity, safety role conflicts, and safety interpersonal conflicts) and coal miners' safety performance, and resilience and coping styles play a chain mediating role between the safety stressors (safety role ambiguity, safety role conflicts, and safety interpersonal conflicts) and safety performance of coal miners. Conclusion: This study further explores the mechanism between safety stressors and safety performance, providing theoretical guidance for improving the safety performance of coal mines. It emphasizes the importance of coal miner's resilience intervention, positive coping styles promotion, and negative coping styles prevention in coal mine safety production.

Endocytosis: the match point of nanoparticle-based cancer therapy.

Nanomedicine has inspired a ground-breaking strategy for cancer therapy. By intelligently assembling diverse moieties to form nanoparticles, numerous functionalities such as controlled release, synergistic efficiency, and in situ killing can be achieved. The emerging nanoparticles have been designed with elevated targeting efficiency as targeting cancer cells is the primary requirement for nanoparticles. However, effective targeting does not guarantee therapeutic effects as endocytosis is a prerequisite for nanoparticles to exert effects. The recent decade has witnessed the rapid development of endocytosis-oriented nanoparticles, and this review subtly analyzes, categorizes, and exemplifies these nanoparticles according to their biological internalization patterns, and the correlation between the endocytosis mechanism and the property of nanoparticles is bridged. Based on the interdisciplinary vision, the present challenges and future perspectives of nanoparticle design for successful endocytosis are discussed, highlighting the potential strategies for the future development of endocytosis-oriented nanoparticles, thus facilitating the endocytosis-oriented strategy from bench to bedside. The undeniable fact is that endocytosis-oriented nanoparticles will definitely bring new blood to the next generation of advanced cancer therapies.

AP-2α decreases TMZ resistance of recurrent GBM by downregulating MGMT expression and improving DNA damage.

AIMS: The incidence of recurrent gliomas is high, exerting low survival rates and poor prognoses. Transcription factor AP-2α has been reported to regulate the progression of primary glioblastoma (GBM). However, the function of AP-2α in recurrent gliomas is largely unclear. METHODS: The expression of AP-2α and O6-methylguanine DNA-methyltransferase (MGMT) was detected in recurrent glioma tissues and cell lines by Western blots, the regulation mechanisms between AP-2α/MGMT promoter and RA/AP-2α promoter were studied by luciferase reporter assays, EMSA, and chIP assays. The effects of AP-2α and TMZ/RA treatment on cell viability in vitro and in vivo were investigated by MTT assays, γH2AX staining, comet assays and intracranial injection. KEY FINDINGS: AP-2α expression negatively correlates with the expression of MGMT in glioma samples. AP-2α could directly bind with the promoter of the MGMT gene, suppresses transcriptional levels of MGMT and downregulate MGMT expression in TMZ-resistant U87MG-R and T98G cells, but TMZ treatment decreases AP-2α expression and increases MGMT expression. The extended TMZ treatment and increased TMZ concentrations reversed these effects. Moreover, AP-2α overexpression combines with TMZ to decrease cell viability, concurrently with improved DNA damage marker γH2AX. Furthermore, retinoic acid (RA) activates RAR/RXR heterodimers, which bind to RA-responsive elements (RAREs) of the AP-2α promoter, and activates AP-2α expression in recurrent glioma cells. Finally, in intracranial relapsed glioma mouse model, both RA and TMZ could retard tumor development and prolong the mouse survival. SIGNIFICANCE: AP-2α activation by gene overexpression or RA treatment reveals the suppressive effects on glioma relapse, providing a novel therapeutic strategy against malignant refractory gliomas.