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Abstract Background Adenotonsillar hypertrophy (ATH) is a major cause of pediatric obstructive sleep apnea (OSA), potentially impacting craniofacial growth and development. Currently, whether children with ATH exhibit distinctive hyoid bone position and upper airway morphology remains uncertain. This research aimed to compare the hyoid bone position and upper airway morphology of children with and without ATH. Methods A total of 199 children aged 6–8 years were recruited for the study, and their pre-treatment lateral cephalograms were obtained. The size of the adenoids and tonsils on the lateral cephalogram was assessed based on Fujioka’s and Baroni’s methods for classification into groups: adenoid hypertrophy only (AHO) group, tonsillar hypertrophy only (THO) group, adenoid and tonsillar hypertrophy (AH + TH) group, and control group (CG). The position of the hyoid bone and upper airway morphology was analyzed using Dolphin Image Software. Results The distance between the hyoid bone and mentum was greater in the THO group compared to the AHO group (P = 0.005). Children in the AHO group exhibited a longer soft palate (SPL) compared to the THO group (P = 0.014), whereas the THO group displayed a reduced SPL in comparison to healthy controls (P = 0.008). The THO group showed a more inferior tongue position compared to children in the AHO group (P = 0.004). Subjects in the THO group exhibited significantly wider inferior airway space compared to healthy children (P

Protein kinase C α (PKCα) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms. In this study, we found that PKCα inhibition enhances CD8+ T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKCα as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation through β transducin repeat-containing protein. Notably, the efficacy of PKCα inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo. Clinical analysis revealed that PKCα expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKCα, identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKCα in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.

Angelica sinensis polysaccharides are important active ingredients and biological resources in traditional Chinese medicine. Properly changing the fermentation conditions of microorganisms may alter the yield of fermentation products. Based on single factor test results, three factors with great influence on the yield of Angelica sinensis polysaccharides produced by Aspergillus niger were optimized: initial pH value, fermentation time, and culture temperature. According to the box Behnken central combination principle, a response surface analysis scheme with three factors and three levels was designed, and the yields of active polysaccharide of Angelica sinensis were taken as the response value to optimize the fermentation process. The results of response surface analysis showed that under the optimized fermentation temperature of 30 °C, cultivation time of 8 days, and initial pH value of 5, the predicted yield of active polysaccharides from Angelica sinensis was 15.5%, while the actual value was 15.35%, which was 0.11% lower than the predicted value. This indicated that using response surface analysis to optimize the fermentation conditions of Angelica sinensis polysaccharides was reasonable and feasible. This method can effectively improve the biological resource utilization rate of Angelica sinensis polysaccharides.

Backgroud Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear.Case presentation We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free.Conclusion This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.

Introduction Orthodontic treatment using face mask protraction combined with an alternate rapid maxillary expansion and constriction/protraction face mask (Alt-RAMEC/PFM) protocol is effective in the early treatment of patients with class III malocclusion, but the stability of treatment outcomes represents a major concern. Previous studies have suggested that tonsillar hypertrophy can be a risk factor for class III malocclusion and tonsillectomy may prompt the normalisation of dentofacial growth. However, these studies had a low-to-moderate level of evidence. This study was designed to identify the impact of tonsillectomy before orthodontic treatment on the efficacy and stability of Alt-RAMEC/PFM protocols and the sleep quality and oral health in children with anterior crossbite and tonsillar hypertrophy.Methods and analysis This is a two-arm, parallel-group, superiority cluster randomised controlled trial, with four clinics randomly assigned to the surgery-first arm and the orthodontic-first arm in a 1:1 ratio. The Alt-RAMEC protocol involves alternate activation and deactivation of the expander’s jet screw over 6 weeks to stimulate maxillary suture distraction. Patients will be instructed to wear the PFM for a minimum of 14 hours per day. The primary outcomes are changes in Wits appraisal and the degree of maxillary advancement from baseline to the end of orthodontic treatment. Lateral cephalometric radiographs, polysomnography, Obstructive Sleep Apnoea-18 questionnaire and Oral Health Impact Profile-14 questionnaire will be traced, collected and measured. We will recruit 96 patients intofor the study. To assess differences, repeated multilevel linear mixed modelling analyses will be used.Ethics and dissemination This study has been granted ethical approval by the Ethics Committee of the School & Hospital of Stomatology, Wuhan University (approval No. 2023-D10). Written informed consent will be obtained from the participants and their guardians. The results of the trial will be disseminated through academic conferences and journal publications.Trial registration number ChiCTR2300078833.

ABSTRACTThere are a variety of bioactive components in rice bran oil (RBO), among which the richer ones include γ-oryzanol, α-tocopherol and sitosterol. The activity of these ingredients is affected by the vehicle and formulation, and there is a significant synergy between these antioxidants. At present, the content of antioxidants in physically refined RBO has reached a high level. Therefore, comparing the activity of physically refined RBO with γ-oryzanol, α-tocopherol, and sitosterol as single components and the above three ingredients dissolved in the same base oil as RBO can provide information for better application of these antioxidants. The results showed that the antioxidant and anti-senescence capacities of physically refined RBO were significantly higher than those of dissolved γ-oryzanol, α-tocopherol, and sitosterol and better than those of the mixture. This study illustrates that the antioxidant and anti-senescence effects of highly active physically refined RBO are superior to those antioxidants derived from RBO.

Type I interferons play a fundamental role in innate host defense against viral infections by eliciting the induction of an antiviral gene program that serves to inhibit viral replication. Activation of type I interferon is regulated by the IRF3 transcription factor, which undergoes phosphorylation-dependent activation by the upstream kinase, TBK1, during viral infection. However, the mechanisms by which TBK1 achieves activation to support signaling to IRF3 remain incompletely understood. Here we identified the E3 ubiquitin ligase, tripartite motif containing 28 (TRIM28), as a positive regulator of type I interferon activation by facilitating TBK1 signaling. Genetic deletion of TRIM28 via CRISPR-Cas9 editing resulted in impaired type I interferon activation upon both RNA and DNA virus challenge, corresponding with increased susceptibility to virus infections in TRIM28 knockout cells. Mechanistically, TRIM28 interacted with TBK1 and mediated the assembly of K63-linked ubiquitin chains onto TBK1, a post-translational modification shown to augment TBK1 signal transmission events. TRIM28 knockout cells further displayed defective TBK1 phosphorylation and complex assembly with IRF3, resulting in impaired IRF3 phosphorylation. Altogether, our data demonstrate TBK1 to be a novel substrate for TRIM28 and identify TRIM28 as an essential regulatory factor in controlling innate antiviral immune responses.

Abstract Background Abstracts provide readers a concise and readily accessible information of the trials. However, poor reporting quality and spin (misrepresentation of research findings) can lead to an overestimation in trial validity. This methodological study aimed to assess the reporting quality and spin among randomized controlled trial (RCT) abstracts in pediatric dentistry. Methods We hand-searched RCTs in five leading pediatric dental journals between 2015 and 2021. Reporting quality in each abstract was assessed using the original 16-item CONSORT for abstracts checklist. Linear regression analyses were performed to identify factors associated with reporting quality. We evaluated the presence and characteristics of spin only in abstracts of parallel-group RCTs with nonsignificant primary outcomes according to pre-determined spin strategies. Results One hundred eighty-two abstracts were included in reporting quality evaluation. The mean overall quality score was 4.57 (SD, 0.103; 95% CI, 4.36–4.77; score range, 1–10). Only interventions, objective, and conclusions were adequately reported. Use of flow diagram (P

Abstract Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8+ T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated SerpinB2 and CCL4 transcription, two secretory factors responsible for cancer stemness inhibition and CD8+ T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC.

ABSTRACTObjective The study was to investigate the possible mechanism of Lu'an GuaPian tea in treating heart failure (HF) via network pharmacology and molecular docking.Method The target of Lu'an GuaPian tea were screened. The GeneCards, NCBI, and DisGeNET databases were searched for HF targets. The GO and KEGG pathway analysis were used to obtain the targets and pathways. Molecular docking was used to verify the most likely targets and flavonoids.Results The Venn diagram revealed that AKT1, TNF, SRC, EGFR, ESR1, PTGS2, MMP9, and KDR were the top 8 target genes. GO and KEGG analysis suggested that Lu'an GuaPian tea could treat HF through PI3K-Akt pathway. Molecular docking predicted that compounds 1 and 7 have the highest binding affinity.Conclusion Lu'an GuaPian tea can be used to treat HF via PI3K-Akt signaling pathway, and the compound 1 and 7 were the most active lead compounds for regulating PI3K.

Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3–MDM2–SLUG–SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.

Antimicrobial mouthwashes are considered to reduce dental plaque biofilm and thus the potential to prevent plaque-induced oral diseases, particularly periodontal diseases. The effectiveness of mouthwashes relates to this antiplaque role, as well as, their tooth-whitening potential and ability to mask/mange malodour (halitosis). There is also a growing interest in the use of mouthwashes as an adjunctive measure in post surgical and post-dental care, while the COVID-19 pandemic has given a new lease of life to mouthwashes as an oral antispetic that may be useful in reducing the oral viral load. The mode of action of mouthwashes varies, depending on their active ingredients, concentrations, and mode and frequency of use, as does their potential effectiveness. This article aims to provide a narrative overview of the evidence of the effectiveness of the most widely used mouthwashes in managing oral diseases, oral conditions, and adjunctive care roles.

Urothelial carcinoma (UC) with deficient mismatch repair (dMMR) is a specific subtype of UC characterized by the loss of mismatch repair (MMR) proteins and its association with Lynch syndrome (LS). However, comprehensive real-world data on the incidence, clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in the Chinese patients with dMMR UC remains unknown. We analyzed 374 patients with bladder urothelial carcinoma (BUC) and 232 patients with upper tract urothelial carcinoma (UTUC) using tissue microarrays, immunohistochemistry, and targeted next-generation sequencing. Results showed the incidence of dMMR UC was higher in the upper urinary tract than in the bladder. Genomic analysis identified frequent mutations in KMT2D and KMT2C genes and LS was confirmed in 53.8% of dMMR UC cases. dMMR UC cases displayed microsatellite instability-high (MSI-H) (PCR method) in 91.7% and tumor mutational burden-high (TMB-H) in 40% of cases. The density of intratumoral CD8+ T cells correlated with better overall survival in dMMR UC patients. Positive PD-L1 expression was found in 20% cases, but some patients positively responded to immunotherapy despite negative PD-L1 expression. Our findings provide valuable insights into the characteristics of dMMR UC in the Chinese population and highlights the relevance of genetic testing and immunotherapy biomarkers for treatment decisions.

Abstract Background Toll-like receptor 3 (TLR3) plays an important role in the immune/inflammatory response in the nervous system and is a main pathological feature of Alzheimer’s disease (AD). This study investigates the role of early activation of TLR3 in the pathophysiological process of AD. Methods In the experiment, the agonist of TLR3, Poly(I:C), was intraperitoneally injected into the APP/PS1 mouse model of AD and wild-type control mice starting from the age of 4 to 9 months. At the age of 14 months, behavioral tests were conducted. Western blot and immunohistochemistry staining were used to evaluate the level of amyloid β-protein (Aβ), the activation of inflammatory cells, and neuron loss. In addition, the levels of inflammatory cytokines were measured using a quantitative polymerase chain reaction. Results The results demonstrated that the early activation of TLR3 attenuated neuronal loss and neurobehavioral dysfunction. Moreover, the early activation of TLR3 reduced Aβ deposition, inhibited the activation of microglia and astrocytes, and decreased the transcription of pro-inflammatory factors in the hippocampus. Conclusions The results indicated that the activation of TLR3 by Poly (I:C) in the early stage of development of AD in a mouse model attenuated neuron loss and improved neurobehavioral functions. The underlying mechanisms could be attributed to its role in Aβ clearance, the inhibition of glial cells, and the regulation of neuroinflammation in the hippocampus.

Abstract Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With the progress of metabonomics and proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or deacylases. Reciprocally, protein acylation is involved in key cellular processes relevant to physiology and diseases, such as protein stability, protein subcellular localization, enzyme activity, transcriptional activity, protein–protein interactions and protein–DNA interactions. Herein, we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several diseases. We also highlight the recent progress in the development of inhibitors for acyltransferase, deacylase, and acylation reader proteins for their potential applications in drug discovery.

BackgroundLynch syndrome (LS)-associated glioblastoma (GBM) is rare in clinical practice, and simultaneous occurrence with cutaneous porokeratosis is even rarer. In this study, we analyzed the clinicopathological and genetic characteristics of LS-associated GBMs and concurrent porokeratosis, as well as evaluated the tumor immune microenvironment (TIME) of LS-associated GBMs.MethodsImmunohistochemical staining was used to confirm the histopathological diagnosis, assess MMR and PD-1/PD-L1 status, and identify immune cell subsets. FISH was used to detect amplification of EGFR and PDGFRA, and deletion of 1p/19q and CDKN2A. Targeted NGS assay analyzed somatic variants, MSI, and TMB status, while whole-exome sequencing and Sanger sequencing were carried out to analyze the germline mutations.ResultsIn the LS family, three members (I:1, II:1 and II:4) were affected by GBM. GBMs with loss of MSH2 and MSH6 expression displayed giant and multinucleated bizarre cells, along with mutations in ARID1A, TP53, ATM, and NF1 genes. All GBMs had TMB-H but not MSI-H. CD8+ T cells and CD163+ macrophages were abundant in each GBM tissue. The primary and recurrent GBMs of II:1 showed mesenchymal characteristics with high PD-L1 expression. The family members harbored a novel heterozygous germline mutation in MSH2 and FDPS genes, confirming the diagnosis of LS and disseminated superficial actinic porokeratosis.ConclusionLS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive TIME. The presence of MMR deficiency and TMB-H may serve as predictive factors for the response to immune checkpoint inhibitor therapy in GBMs. The identification of LS-associated GBM can provide significant benefits to both patients and their family members, including accurate diagnosis, genetic counseling, and appropriate screening or surveillance protocols. Our study serves as a reminder to clinicians and pathologists to consider the possibility of concurrent genetic syndromes in individuals or families.

Abstract Ferroptosis is a newly discovered form of cell death that is characterized by the accumulation of iron‐dependent lipid peroxidation. Research on ferroptosis has seen exponential growth over the past few years. Tumor cells are strongly dependent on iron for their growth, which makes them develop mechanisms to increase iron uptake and inhibit iron output, thereby completing iron accumulation. Ferroptosis can be induced or inhibited by various stresses through multiple mechanisms, making it stands at the crossroads of stresses related cancer cell fate determination. In this review, we give a brief summary of ferroptosis hallmarks and provide a systematic analysis of the current molecular mechanisms and regulatory networks of diverse stress conditions on ferroptosis. We also discuss the relationships between ferroptosis and cancer therapy responses to further understand potential targets and therapeutic strategies for cancer treatment.

Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii, shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing PINK1 or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure.

The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury–repair process following lung injury. Pulmonary fibrosis (PF) is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells. In this study, we report that P21 expression was increased in alveolar epithelial type 2 cells (AEC2s) in a time-dependent manner following multiple bleomycin-induced PF. Repeated injury of AEC2s resulted in telomere shortening and triggered P21-dependent cell senescence. AEC2s with elevated expression of P21 lost their self-renewal and differentiation abilities. In particular, elevated P21 not only induced cell cycle arrest in AEC2s but also bound to P300 and β-catenin and inhibited AEC2 differentiation by disturbing the P300–β-catenin interaction. Meanwhile, senescent AEC2s triggered myofibroblast activation by releasing profibrotic cytokines. Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF. The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development, which suggests a potential strategy for the treatment of fibrotic lung diseases.

In the process of orthodontic treatment, the presence of orthodontic appliances makes it difficult to clean tooth surfaces. This can lead to an increased level of bacterial colonization, resulting in enamel demineralization and periodontal diseases. Considering the large surface area that orthodontic appliances usually have and that they can be in direct contact with bacteria throughout the treatment, modifications in the form of coatings on the surface of orthodontic appliances can be an effective and practical approach to reducing bacterial proliferation and preventing relevant adverse effects. In this mini-review, we discuss various antibacterial coatings which have been applied onto orthodontic appliances in recent 5 years, as well as their antibacterial mechanisms and methods for the preparation of these coatings. From this mini-review, both orthodontists and researchers can get the latest findings in the field of antibacterial coatings onto orthodontic appliances, which is helpful for the decision-making in clinical practice and research activities.

Pulmonary fibrosis (PF) is a chronic, progressive, fatal interstitial lung disease with limited available therapeutic strategies. We recently reported that the protein kinase glycogen synthase kinase-3β (GSK-3β) interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) in alveolar macrophages (AMs), resulting in a profibrotic phenotype of AMs and promoting the development of PF. Here, we showed that chronic lung injury upregulated the stress response protein tribbles homolog 3 (TRIB3), which interacted with GSK-3β and stabilized GSK-3β from ubiquitination and degradation. Elevated GSK-3β expression phosphorylated A20 to inhibit its ubiquitin-editing activity, causing the accumulation of C/EBPβ and the production of several profibrotic factors in AMs and promoting PF development. Activated C/EBPβ, in turn, increased the transcription of TRIB3 and GSK-3β, thereby establishing a positive feedback loop in AMs. The knockdown of TRIB3 expression or the pharmacologic disruption of the TRIB3‒GSK-3β interaction was an effective PF treatment. Our study reveals an intact profibrotic axis of TRIB3‒GSK-3β‒A20‒C/EBPβ in AMs, which represents a target that may provide a promising treatment strategy for PF.

Immune checkpoint inhibitors (ICIs) have shown encouraging outcomes against Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer with mismatch repair deficient/microsatellite instability–high (dMMR/MSI-H). However, there is as yet no clarity on the safety and efficacy of immunotherapy combined with chemotherapy in LS-associated urothelial carcinoma (UC). Here, we report a patient with recurrent and metastatic LS-associated UC who achieved sustained response to programmed death protein 1 (PD-1) inhibitor combined with chemotherapy over 31 months, during which the side effects of immunotherapy could be controlled and managed. Our findings indicate that the dMMR/MSI status and PD-1 expression in UC may have potential predictive value for the response to PD-1-targeted immunotherapy. Our case supports the inclusion of such combination and/or monotherapy for UC in clinical studies and using dMMR/MSI status and PD-1 expression as potential predictive biomarkers for assessment of the therapeutic response.

Mouth breathing is one of the most common deleterious oral habits in children. It often results from upper airway obstruction, making the air enter completely or partially through oral cavity. In addition to nasal obstruction caused by various kinds of nasal diseases, the pathological hypertrophy of adenoids and/or tonsils is often the main etiologic factor of mouth breathing in children. Uncorrected mouth breathing can result in abnormal dental and maxillofacial development and affect the health of dentofacial system. Mouth breathers may present various types of growth patterns and malocclusion, depending on the exact etiology of mouth breathing. Furthermore, breathing through the oral cavity can negatively affect oral health, increasing the risk of caries and periodontal diseases. This review aims to provide a summary of recent publications with regard to the impact of mouth breathing on dentofacial development, describe their consistencies and differences, and briefly discuss potential reasons behind inconsistent findings.

Abstract Background Enamel white spot lesions (WSLs), characterized by an opaque, matt, and chalky white appearance of enamel, are a sign of incipient caries. WSLs are common in orthodontic practice and can affect both the oral health and dental aesthetics of patients. Extensive studies have been conducted to evaluate the effectiveness of prevention or treatment for orthodontically induced enamel WSLs. However, substantial heterogeneity has been found in the outcomes used for the prevention and treatment of WSLs in literature, which prevents researchers from comparing and combining the results of different studies to draw more decisive conclusions. Therefore, we aim to develop a Core Outcome Set for trials on the prevention and treatment of Orthodontically induced enamel White Spot Lesions (COS-OWSL). Methods The development of COS-OWSL comprises four phases: (1) a scoping review to identify and summarize all existing outcomes that have been used in trials on the prevention or treatment of orthodontically induced WSLs; (2) qualitative interviews with orthodontic patients without (for prevention) and with WSL-affected teeth (for treatment) and relevant dental professionals to identify additional outcomes relevant to them; (3) Delphi surveys to collect opinions from key stakeholders including patients, dental professionals, and researchers and to reach a preliminary consensus; and (4) a consensus meeting to develop the final COS-OWSL. Discussion The COS-OWSL will be developed to facilitate the synthesis of evidence regarding the prevention and treatment of orthodontically induced WSLs and to promote the consistent use of relevant patient-important outcomes among future studies in this field. Trial registration Core Outcome Measures in Effectiveness Trials (COMET) initiative (the COS-WSL project) 1399

Lingyan Wang et al. report that the autophagy-associated protein FIP200 interacts with the RNA sensor RIG-I to trigger activation of the type I interferon pathway.

BackgroundSleep-disordered breathing (SDB) is a chronic sleep-related breathing disorder, considered associated with increased risk of cardiovascular disorders, metabolic disorders, cognitive dysfunction and behavior changes. Periodontal diseases are chronic infectious diseases that are also believed to be associated with cardiovascular diseases, metabolic syndrome and cognitive dysfunction. Several studies have indicated that SDB may be associated with periodontal diseases through certain mechanisms such as inflammation response, oxidative stress and oral dryness. The aim of this systematic review is to explore the association between SDB and periodontal diseases in an integrated approach.Materials and MethodsThis systematic review will include cohort studies, cross-sectional studies and case-control studies that are identified by electronic and manual searches. Electronic searches will be conducted in the following databases: PubMed, Embase, Scopus and Web of Science. Our search will cover articles published from inception of databases to March 2022 without restrictions in language and settings. Pre-determined eligibility criteria include: participants (participants without a history of respiratory diseases, history of periodontal treatment within the past 6 months and history of medication that is known to influence SDB or periodontal diseases); exposure (participants who have been diagnosed with SDB or at high-risk for SDB); comparison (participants without SDB); and outcome (periodontal parameters, such as probing depth, clinical attachment level, bleeding on probing, radiographic bone loss). Two authors will perform study screening and data extraction independently and in duplicate. All discrepancies will be solved by discussion. The methodological quality of included studies will be assessed using the Newcastle-Ottawa Scale.DiscussionThis systematic review will summarize the existing evidence on the association between SDB and periodontal diseases, a topic of controversy and clinical significance. Its findings can provide evidence for the development of relevant prevention and treatment strategies. The results will be disseminated through peer-reviewed journals.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022313024. Registered on March 28th 2022.

Thermal plasma process has been recognized as a clean technology to pyrolyze a wide variety of hydrocarbons to produce light gasses at extreme conditions. To tackle the engineering issues related with scale-up of such an ultra-high temperature reactor, we herein propose a novel design of thermal plasma array reactor (TPAR), which accommodates multiple arcs in staggered array mode inside the reactor with replaceable graphite-rod electrodes. The feed hydrocarbons flow through the arc-intertwined high-temperature zone with anticipated mixing and heat transfer intensification. To illustrate the essential features of the TPAR design, the computational fluid dynamics (CFD) simulations are carried out to reveal the influence of the reactor design on the mixing and reaction performance using the methane pyrolysis process as a case in the TPAR. It is demonstrated that the energy consumption for the methane to acetylene production can achieve satisfactory results in a rather simplified TPAR design.

c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.

Enamel demineralization, as a type of frequently-occurring dental problem that affects both the health and aesthetics of patients, is a concern for both dental professionals and patients. The main chemical composition of the enamel, hydroxyapatite, is easy to be dissolved under acid attack, resulting in the occurrence of enamel demineralization. Among agents for the preventing or treatment of enamel demineralization, amorphous calcium phosphate (ACP) has gradually become a focus of research. Based on the nonclassical crystallization theory, ACP can induce the formation of enamel-like hydroxyapatite and thereby achieve enamel remineralization. However, ACP has poor stability and tends to turn into hydroxyapatite in an aqueous solution resulting in the loss of remineralization ability. Therefore, ACP needs to be stabilized in an amorphous state before application. Herein, ACP stabilizers, including amelogenin and its analogs, casein phosphopeptides, polymers like chitosan derivatives, carboxymethylated PAMAM and polyelectrolytes, together with their mechanisms for stabilizing ACP are briefly reviewed. Scientific evidence supporting the remineralization ability of these ACP agents are introduced. Limitations of existing research and further prospects of ACP agents for clinical translation are also discussed.

Alzheimer’s disease (AD) has become the most common age-related dementia in the world and is currently incurable. Although many efforts have been made, the underlying mechanisms of AD remain unclear. Extracellular amyloid-beta deposition, intracellular tau hyperphosphorylation, neuronal death, glial cell activation, white matter damage, blood–brain barrier disruption, and other mechanisms all take part in this complicated disease, making it difficult to find an effective therapy. In the study of therapeutic methods, how to restore functional neurons and integrate myelin becomes the main point. In recent years, with the improvement and maturity of induced pluripotent stem cell technology and direct cell reprogramming technology, it has become possible to induce non-neuronal cells, such as fibroblasts or glial cells, directly into neuronal cells in vitro and in vivo. Remarkably, the induced neurons are functional and capable of entering the local neural net. These encouraging results provide a potential new approach for AD therapy. In this review, we summarized the characteristics of AD, the reprogramming technique, and the current research on the application of cellular reprogramming in AD. The existing problems regarding cellular reprogramming and its therapeutic potential for AD were also reviewed.

Depletion of tribbles pseudokinase 3 (TRIB3) is known to suppress the expression of several tumor-promoting factors, including EGFR. Here, the authors show that TRIB3 interacts with EGFR and regulates its stability and activity, and perturbing EGFR-TRIB3 interaction attenuates NSCLC progression by accelerating EGFR degradation.

Abstract Background Children aged 6–7 years are in the early mixed dentition, which is a period of high prevalence of dental caries and other dental diseases and a critical period for the formation of oral health behaviors. Therefore, good oral hygiene habits of children and oral health knowledge of parents are very important. This study sought to explore the relationship between children’s oral health behaviors, parental oral health knowledge, parental choices of pit and fissure sealants, and parents’ education levels based on a large-scale sample size for the first time, and to compare the influences of parental education levels between parents. Methods Families of the first and second graders of primary schools in Wuhan Hongshan District were included in this study. A total of 8446 questionnaires were collected to obtain comprehensive information on children’s oral health behaviors, parents’ oral health knowledge and parents’ pit and fissure sealants-related choices. The relationship between these outcome variables and parents’ education levels were studied using logistic regression analysis and chi-square test. Results Parents who reported good educational background had more favorable oral health knowledge than those of other parents, and their children had better oral hygiene behaviors. Four indicators of five measures to children’s oral health behaviors were significantly associated with mother’s education level (P

Objective: To systematically review in vitro studies that evaluated the effects of plant extracts on dentin bonding strength.Materials and Methods: Six electronic databases (PubMed, Embase, VIP, CNKI, Wanfang and The Cochrane Library) were searched from inception to September 2021 in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA). In vitro studies that compared the performance of dental adhesives with and without the plant extracts participation were included. The reference lists of the included studies were manually searched. Two researchers carried out study screening, data extraction and risk of bias assessment, independently and in duplicate. Meta-analysis was conducted using Review Manager 5.3.Results: A total of 62 studies were selected for full-text analysis. 25 articles used the plant extracts as primers, while five added the plant extracts into adhesives. The meta-analysis included 14 articles of in vitro studies investigating the effects of different plant extract primers on dentin bonding strength of etch-and-rinse and self-etch adhesives, respectively. The global analysis showed statistically significant difference between dental adhesives with and without plant extract primers. It showed that the immediate bond strength of dental adhesives was improved with the application of plant extract primers.Conclusion: The application of proanthocyanidin (PA) primers have positive effect on the in vitro immediate bonding strength of dental adhesives irrespective of etch-and-rinse or self-etch modes.

This report shows the contribution of metagenomic next-generation sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report two leukemia patients who developed severe infections due to carbapenem-resistant Klebsiella pneumoniae (CrKP). The mNGS can be strongly recommended as an alternative investigation for patients who are at high risk of infection without positivity on body fluid culture. This can provide the opportunity for adequate therapy.

Abstract Background White spot lesions (WSLs) are common adverse effects in fixed orthodontic treatment. Remineralising agents are widely used to prevent WSLs formation and are the first-line treatment for existing WSLs. Previous systematic reviews have evaluated the effectiveness of remineralisation agents in the management of WSLs. However, their conclusions were contradictory. The objective of this study will be to compare the effectiveness and safety of current remineralising agents used in the management of WSLs in patients treated with fixed orthodontic appliances in any orthodontic setting. Methods Literature searches will be conducted in several electronic databases (from inception onwards): MEDLINE (via Ovid), Scopus, Embase, the Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL), among others. Grey literature will be identified through searching clinical trials registries. Randomised controlled trials that compared the effectiveness of different remineralisation agents in the prevention and treatment of WSLs will be included. Two researchers will independently screen all citations, full-text articles, and abstract data. The study risk bias will be appraised using an appropriate tool. The primary outcomes will be WSLs incidence and severity of WSLs. Secondary outcomes will be subjective measures of WSLs and adverse effects. The mean difference (MD) and relative risk (RR) with corresponding 95% confidence intervals (CI) will be chosen as effect measures for continuous and binary outcomes, respectively. If feasible, fixed and random-effects pairwise meta-analyses and frequentist network meta-analyses will be conducted where appropriate. Discussion This network meta-analysis will compare the effectiveness of remineralising agents in the prevention and treatment of orthodontically induced WSLs. By integrating the evidence from direct and indirect comparisons and ranking all evaluated interventions, our findings have the potential to help clinicians make more accurate treatment decisions. Systematic review registration PROSPERO CRD42019116852, registered on March 15, 2019

Cancer stem cells contribute to breast cancer metastasis and recurrence. Here the authors show that TRIB3 enhances breast cancer stemness through interaction with AKT to promote FOXO1 stability, which then increases SOX2 activity.

Trichoderma rubrum (T. rubrum) is one of the important pathogens because it is the cause of most dermatomycosis. The treatment of Trichophyton rubrum infection is time-consuming and very expensive; it is easy for the infections to reoccur, leading to therapeutic failures, persistence, and chronic infection. These issues have inspired researchers to study natural alternative therapies instead. Cnidium monnieri (L.), as a kind of traditional Chinese medicine, has a variety of pharmacological activities and a wide range of applications, so it has a high potential for researching and economic value. We detected the effect of aqueous extract of C. monnieri (L.) on the activity of T. rubrum by Cell Count Kit-8 assay (CCK-8), and we found that 128 and 256 μg/ml of aqueous extracts of C. monnieri (L.) co-cultured with T. rubrum for 24 h showed the inhibitory effect on T. rubrum. The results of scanning electron microscopy (SEM) and transmission electron microscopy (TEM) confirmed that aqueous extract of C. monnieri (L.) damaged the T. rubrum. At the same time, mass spectrometry screening with T. rubrum before and after the treatment of 256 μg/ml of aqueous extracts of C. monnieri (L.) showed that 966 differentially expressed proteins were detected, including 524 upregulated differentially expressed genes (DEGs) and 442 downregulated DEGs. The most significantly downregulated protein was chitin synthase (CHS); and the results of qRT-PCR and Western blotting demonstrated that the expression level of CHS was downregulated in the 256 μg/ml group compared with the control group. The study showed that the aqueous extract of C. monnieri (L.) could destroy the morphology of mycelia and the internal structure of T. rubrum, and it could inhibit the growth of T. rubrum. The antifungal effect of aqueous extract of C. monnieri (L.) may be related to the downregulation of the expression of CHS in T. rubrum, and CHS may be one of the potential targets of its antifungal mechanism. We concluded that aqueous extract from C. monnieri (L.) may be a potential candidate for antifungal agents.

Abstract Background Toll-like receptor 4 (TLR4) is well known for activating the innate immune system; however, it is also highly expressed in adaptive immune cells, such as CD4+ T-helper 17 (Th17) cells, which play a key role in multiple sclerosis (MS) pathology. However, the function and governing mechanism of TLR4 in Th17 remain unclear. Methods The changes of TLR4 in CD4+ T cells from MS patients and experimental autoimmune encephalomyelitis (EAE) mice were tested. TLR4-deficient (TLR4−/−) naïve T cells were induced in vitro and transferred into Rag1−/− mice to measure Th17 differentiation and EAE pathology. DNA sequence analyses combining with deletion fragments and mutation analyses, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA) were used to explore the mechanism of TLR4 signaling pathway in regulating Th17 differentiation. Results The levels of TLR4 were increased in CD4+ Th17 cells both from MS patients and EAE mice, as well as during Th17 differentiation in vitro. TLR4−/− CD4+ naïve T cells inhibited their differentiation into Th17, and transfer of TLR4−/− CD4+ naïve T cells into Rag1−/− mice was defective in promoting EAE, characterized by less demyelination and Th17 infiltration in the spinal cord. TLR4 signal enhanced Th17 differentiation by activating RelA, downregulating the expression of miR-30a, a negative regulator of Th17 differentiation. Inhibition of RelA activity increased miR-30a level, but decreased Th17 differentiation rate. Furthermore, RelA directly regulated the expression of miR-30a via specific binding to a conserved element of miR-30a gene. Conclusions TLR4−/− CD4+ naïve T cells are inadequate in differentiating to Th17 cells both in vitro and in vivo. TLR4-RelA-miR-30a signal pathway regulates Th17 differentiation via direct binding of RelA to the regulatory element of miR-30a gene. Our results indicate modulating TLR4-RelA-miR-30a signal in Th17 may be a therapeutic target for Th17-mediated neurodegeneration in neuroinflammatory diseases.

Background: During the COVID-19 pandemic, many dental care services including orthodontic practice were suspended. Orthodontic patients turned to social media platforms to communicate, share experiences, and look for solutions. Our study aimed to investigate the attitudes and perspectives of orthodontic patients during the COVID-19 epidemic in China by analyzing orthodontics-related posts on Sina Weibo (a Chinese counterpart of Twitter).Materials and Methods: Potentially eligible posts on Sina Weibo platform were collected between December 30, 2019, and April 18, 2020. Posts related to both orthodontics and COVID-19 were included and then coded and classified into specific appliances and themes. Geographic and temporal distributions of the included posts were analyzed. In addition, time-lagged cross correlation was performed to explore the association between the number of daily posts and daily new COVID-19 cases/deaths in China. Chi-square tests were employed to compare the differences between fixed appliances and aligners in problems/difficulties and feelings during the epidemic.Results: Of the 28,911 posts identified, 4,484 were included in the analysis. The most frequently mentioned themes were appointments (n = 2,621, 58.5%), negative feelings (n = 2,189, 48.8%), and problems/difficulties (n = 1,155, 25.8%). A majority of posts were tweeted in regions with high levels of economic development and population density in eastern China and from February to March. The number of daily posts had a significantly positive correlation with daily new COVID-19 cases/deaths in China (P < 0.05). Compared with clear aligners, patients with fixed appliances reported more problems/difficulties (P < 0.001) and negative feelings (P < 0.001), but fewer positive feelings (P < 0.001).Conclusions: The analysis of Weibo posts provided a timely understanding of the impact of COVID-19 on orthodontic patients. Delayed appointments were their greatest concern, and negative feelings and untreated orthodontic problems increased during the suspension of dental care services. However, patients with clear aligners reported fewer negative feelings and problems than those with fixed appliances. The findings highlighted the need to consider both treatment- and psychology-related issues of orthodontic patients and how to handle them appropriately during the epidemic.

Introduction Regular toothbrushing with fluoride toothpaste is a fundamental intervention for caries prevention. Professional fluoride application (PFA) is widely considered a beneficial supplement to the routine use of fluoride toothpaste. However, some recent studies have failed to demonstrate the preventive effect of PFA. In addition, an increasing number of studies have highlighted the potential adverse effects of fluoride. However, little information exists on the effectiveness of additional PFA. The objective of this review is to systematically analyse the efficacy of PFA in addition to regular fluoride toothpaste among children under the age of 16.Method and analysis We will search the PubMed, Embase, Google Scholar and Cochrane Central Register of Controlled Trials databases for randomised controlled trials without language or publication date restrictions. Additional studies will be identified by manually searching the reference lists of the included studies and relevant reviews. At least two authors will carry out the selection of studies independently and in duplicate. The Cochrane Risk of Bias tool will be used to assess the risk of bias of the included studies. The random effects model will be used for meta-analyses. The data synthesis will be conducted using Review Manager software (RevMan V.5.3). The Grading of Recommendation, Assessment, Development and Evaluation will be used to assess the quality of supporting evidence for each major comparison.Ethics and dissemination There is no need for ethical approval. The results of this review will be disseminated through peer-reviewed publications and social networks.PROSPERO registration number CRD42020165270

Objectives: To assess the current COVID-19 related experiences, knowledge, attitudes, and behaviors among orthodontists, orthodontic residents, and orthodontic nurses in China, and to identify factors associated with their self-perceived and actual level of knowledge, as well as their willingness to treat/care for COVID-19 patients.Materials and Methods: A cross-sectional online survey was conducted in China using a 37-item questionnaire developed based on previous research. A professional online survey tool (www.wjx.cn) and a social media platform (WeChat) were used to display and distribute the questionnaire. Data were collected during April 11 to 13, 2020, when most regions of China had resumed dental practice except for high-risk regions such as Wuhan. Then the data were analyzed with multivariable generalized estimating equations.Results: A total of 2,669 valid questionnaires were collected. Orthodontic services were suspended for nearly all respondents (97.8%) during the epidemic, and 68.0% had resumed work by the time they completed the questionnaire. The majority of respondents (80.2%) were confident that they understood COVID-19 related knowledge, but most of them only correctly answered less than half of the questions testing their actual level of knowledge. About two-thirds (64.1%) were willing to treat/care for patients with confirmed or suspected COVID-19. The completion of relevant training programs was significantly associated with more confidence in knowledge mastery (P < 0.001) and a higher actual level of knowledge (P < 0.001), but did not increase their willingness to treat/care for patients with COVID-19 (P = 0.235).Conclusions: Before work resumption, COVID-19-related training programs are essential for the improvement of knowledge, confidence, and preparedness of orthodontic professionals. Sufficient and proper protection should also be provided to ensure safety and reduce the psychological burden on them.Clinical Relevance: The findings can provide evidence for policy-making related to the resumption of elective dental services.

Objective To study the characteristics of fatigue and the correlation between fatigue and other symptoms of Parkinson's disease (PD). Methods According to Fatigue Severity Scale (FSS), 100 PD patients enrolled in this study were divided into fatigue group (FSS > 4 score, N = 58) and non-fatigue group (FSS ≤ 4 score, N = 42). Unified Parkinson's Disease Rating Scale Ⅲ (UPDRS Ⅲ), revised Hoehn-Yahr stage and modified Webster score were used to investigate the severity of motor symptom. Non-Motor Symptoms Scale (NMSS), Mini-Mental State Examination (MMSE), Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were adopted to measure the severity of non-motor symptom. In addition, UPDRSⅡ was used to evaluate the activities of daily living and 39-Item Parkinson's Disease Questionnaire (PDQ-39) was used to measure life quality of PD patients, respectively. Results There were 58 out of 100 PD patients having fatigue symptom, namely the occurrence rate of fatigue was 58%. The occurrence rate of daytime nap (χ2= 16.256, P = 0.000), fatigue (χ2 = 84.639, P = 0.000), lack of interest (χ2 = 10.705, P = 0.001), lack of passion (χ2 = 9.350, P = 0.002), depression (χ2 = 9.350, P = 0.002), anxiety/panic (χ2 = 4.625, P = 0.032), emotional apathy (χ2 = 22.032, P = 0.000), anhedonia (χ2 = 18.247, P = 0.000), poor memory (χ2 = 4.366, P = 0.037), urgency of urination (χ2 = 5.774, P = 0.016), frequency of micturition (χ2 = 5.774, P = 0.016), hard in sex life (χ2 = 3.877, P = 0.049), and decreased sense of smell or taste (χ2 = 5.360, P = 0.021) were significantly higher in PD patients of fatigue group than those in non-fatigue group. UPDRSⅢ scores (t = 6.374, P = 0.000), revised Hoehn-Yahr stage (Z = -3.345, P = 0.001), modified Webster score (t = 6.819, P = 0.000), NMSS (t = 2.923, P = 0.011), HAMD (Z = - 2.451, P = 0.014), HAMA (t = 5.417, P = 0.000), ESS (Z = - 2.116, P = 0.034), UPDRS Ⅱ (Z = - 3.115, P = 0.002) and PDQ - 39 (Z = - 2.696, P = 0.007) were significantly higher in PD patients of fatigue group than those in non - fatigue group. Spearman rank correlation analysis indicated that FSS scores had high positive correlation with modified Webster score (rs = 0.622, P = 0.000) and NMSS (rs = 0.611, P = 0.000), moderate positive correlation with duration (rs = 0.582, P = 0.000), UPDRSⅢ (rs = 0.573, P = 0.000), revised Hoehn-Yahr stage (rs = 0.542, P = 0.000), HAMD (rs = 0.505, P = 0.000), HAMA (rs = 0.477, P = 0.000), ESS (rs = 0.474, P = 0.000), PSQI (rs = 0.410, P = 0.000), UPDRS Ⅱ (rs = 0.559, P = 0.000) and PDQ-39 (rs = 0.578, P = 0.000), and low negative correlation with MMSE (rs=- 0.258, P = 0.000). Conclusions The occurrence of fatigue in PD is high, which has interaction effect with other symptoms of PD, consequently affecting the life quality of PD patients.

Vitamin D3 has been found to produce therapeutic effects on obesity-associated insulin resistance and dyslipidemia through its potent anti-inflammatory activity, but the precise immunomodulatory mechanism remains poorly understood. In the present study we found that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D3, significantly attenuated monosodium glutamate (MSG)-induced obesity and insulin resistance as indicated by body weight reduction, oral glucose tolerance improvement, and a glucose infusion rate increase as detected with hyperinsulinemic-euglycemic clamp. Moreover, 1,25(OH)2D3 not only restored pancreatic islet functions but also improved lipid metabolism in insulin-targeted tissues. The protective effects of 1,25(OH)2D3 on glycolipid metabolism were attributed to its ability to inhibit an obesity-activated inflammatory response in insulin secretory and targeted tissues, as indicated by reduced infiltration of macrophages in pancreas islets and adipose tissue while enhancing the expression of Tgf-β1 in liver tissue, which was accompanied by increased infiltration of Treg cells in immune organs such as spleen and lymph node as well as in insulin-targeted tissues such as liver, adipose, and muscle. Together, our findings suggest that 1,25(OH)2D3 serves as a beneficial immunomodulator for the prevention and treatment of obesity or metabolic syndrome through its anti-inflammatory effects. KEY WORDS: Insulin resistance, Dyslipidemia, MSG-obese rat, Treg cell, Vitamin D3, 1,25-Dihydroxyvitamin D3

Abstract Background The reporting of randomised controlled trial (RCT) abstracts is of vital importance. The primary objective of this study was to investigate the association between structure format and RCT abstracts’ quality of methodology reporting, informed by the current requirement and usage of structure formats by leading general medical/internal medicine journals (secondary objective). Methods A two-part cross-sectional study. First, through hand searches, we identified all RCTs published in the top-50 high-impact general medical/internal medicine journals during July–December 2015 (n = 370), and retrieved the ‘instructions to authors’ of these journals. From these, we extracted the actual usage of structure formats and headings, as well as relevant journal policies. Then, after a pilot study and sample size calculation, we assessed the methodology reporting quality of 176 IMRaD (Introduction, Methods, Results, and Discussion) and 165 HS (Highly Structured) RCT abstracts sampled from 33 of the 50 selected journals, using a 9-item checklist developed based on the CONSORT for Abstracts guidelines (primary outcome: overall quality score, OQS; score range 0 to 9). Results 88% (324/370) of all identified RCT abstracts were structured, among which 66% (215/324) used the IMRaD format and 34% (109/324) used HS. According to journals’ ‘instructions to authors’, 48% (24/50) journals required IMRaD, 32% (16/50) required HS, 8% (4/50) required unstructured, while the rest did not state any requirement on structure format. According to generalised estimation equation analysis adjusting for potential confounders and clustering effects, the OQS of HS abstracts was 0.5 (95% CI 0.1 to 1.0, p = 0.028) higher than IMRaD abstracts. More HS abstracts reported study setting (adjusted odds ratio, 4.2; 95% CI: 1.7 to 10.0; p = 0.001), definition of the main outcome measure (2.5; 1.3 to 4.9; p = 0.006) and the time point for main outcome assessment (3.0; 1.5 to 6.2; p = 0.002), whereas more IMRaD abstracts described the unit of randomisation (0.4; 0.3 to 0.8; p = 0.004). Conclusions For RCT abstracts, the IMRaD format is more frequently used and required by leading general medical/internal medicine journals than the HS format. Abstracts in the HS format report trial methodology more completely than those in the IMRaD format.

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-κB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) were required for EGFR-mediated NF-κB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IκB phosphorylation and subsequent NF-κB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-κB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-κB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR and that perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy.