Toxicological effects of traffic-related air pollution on the lungs: Evidence, biomarkers and intervention.

BACKGROUND: Numerous epidemiological studies have recently observed that exposure to traffic-related air pollution (TRAP) is associated with increased risk of various respiratory diseases. Major gaps in knowledge remain regarding the toxicological effects. OBJECTIVES: We examined the toxicological effects of the gasoline exhaust particles (GEP), a paradigm of TRAP, in rats, with an objective to provide the evidence, obtain the biomarkers, and suggest effective intervention measure. METHODS: We measured the airway hyperresponsiveness (AHR), inflammatory cells in the bronchoalveolar lavage (BAL) fluid, histological changes in the lung tissues, and the biomarkers so as to systematically examine the toxicological effects of GEPs at different dose levels (0.5, 2.5, 5 mg/kg BW). The intervention of vitamin E (VE), a natural antioxidant, on the toxicological effects was investigated. RESULTS: The lung injury caused by GEP exposure was first indicated by the airway hyperresponsiveness (AHR). Compared with the control group, GEP exposure significantly increased the airway resistances and decreased the lung compliance; the higher the dose of GEP, the more serious the lung injury. Lung injury was also revealed by the increase of inflammatory cells, including the lymphocytes and neutrophils, in the BAL fluid. With the increase of GEP dose, histological changes in the lung tissues were further observed: inflammatory cell infiltration increased and alveolar wall thickened. The toxicology of GEP was demonstrated by the increase of the biomarkers of the oxidative stress, the pro-inflammatory cytokines and the apoptosis cytokine. However, administration of VE was found to be effective in restoring airway injury. CONCLUSION: The toxicological effects of traffic-related air pollution (TRAP) on rat lungs are supported by evidence and biomarkers, and vitamin E intervention is feasible.

Effect of conventional combined orthodontic-surgical treatment on oral health-related quality of life: A systematic review and meta-analysis.

INTRODUCTION: Although conventional combined orthodontic-surgical treatment is frequently applied in orthodontic clinic practice, its actual effect on oral health-related quality of life (OHRQoL) remains inconclusive. We aimed to appraise trials investigating the effect of conventional combined orthodontic-surgical treatment on OHRQoL in patients with dentofacial deformities. METHODS: Electronic searches of 6 databases and manual searches were conducted up to January 2019. Randomized controlled trials, controlled clinical trials, and prospective cohort studies that investigated the impact of combined orthodontic-surgical treatment on OHRQoL using validated instruments were included. The risk of bias within individual studies was assessed with the use of the Cochrane tool or the Newcastle-Ottawa Scale according to study designs. Meta-analysis was conducted, and OHRQoL at different time points during conventional combined orthodontic-surgical treatment were statistically pooled and compared. RESULTS: Of the 893 records initially identified, 24 studies were included in this review. Relative to pretreatment, the condition-specific OHRQoL was significantly improved 6 months after surgery, particularly in the perceptions to social aspects (mean difference [MD] 4.88, 95% confidence interval [CI] 2.45 to 7.32), facial appearance (MD 5.48, 95% CI 4.18 to 6.79), and oral function (MD 4.49, 95% CI 3.27 to 5.72). In terms of changes during combined orthodontic-surgical treatment, the condition-specific OHRQoL worsened in the presurgical orthodontic treatment (MD -7.25, 95% CI -13.29 to -1.22) and improved postsurgically compared with pretreatment (MD 16.59, 95% CI 10.41 to 22.77). Similar patterns were observed in the general OHRQoL changes. CONCLUSIONS: For patients undergoing combined orthodontic-surgical treatment, the OHRQoL seems to decrease temporarily in presurgical orthodontic treatment compared with pretreatment and to increase to a level better than it was before treatment during postsurgical orthodontic treatment. Based on the present review, combined orthodontic-surgical treatment could be an effective choice to improve OHRQoL for patients affected with severe dentofacial deformities.

The effectiveness of vibrational stimulus to accelerate orthodontic tooth movement: a systematic review.

BACKGROUND: In recent years, it has been a hot research topic to accelerate orthodontic tooth movement (OTM) through vibration. This review was therefore aimed to systematically evaluate the available evidences on the efficacy of vibrational stimulus to accelerate OTM. METHODS: Randomized controlled trials and controlled clinical trials that evaluated the efficacy of vibration on OTM acceleration were searched through electronic and manual search. Two review authors independently conducted the study inclusion, quality assessment and data extraction. The quality of synthesized evidence was assessed according to GRADE system. RESULTS: Eight clinical trials were included in this systematic review. Four studies found that vibration did not enhance the rate of OTM during alignment phase. Two studies revealed that the use of vibratory stimulation accelerated canine retraction. No deleterious effects including pain perceptions and root resorptions were reported. CONCLUSIONS: Within the limitations of this review, weak evidence indicates that vibrational stimulus is effective for accelerating canine retraction but not for alignment. The effects of vibration on pain intensity and root resorption during orthodontic treatment are inconclusive. Future high-quality clinical trials are needed before warranting recommendations to clinical application.

Natural Killer Cells: A Promising Kit in the Adoptive Cell Therapy Toolbox.

As an important component of the innate immune system, natural killer (NK) cells have gained increasing attention in adoptive cell therapy for their safety and efficacious tumor-killing effect. Unlike T cells which rely on the interaction between TCRs and specific peptide-MHC complexes, NK cells are more prone to be served as "off-the-shelf" cell therapy products due to their rapid recognition and killing of tumor cells without MHC restriction. In recent years, constantly emerging sources of therapeutic NK cells have provided flexible options for cancer immunotherapy. Advanced genetic engineering techniques, especially chimeric antigen receptor (CAR) modification, have yielded exciting effectiveness in enhancing NK cell specificity and cytotoxicity, improving in vivo persistence, and overcoming immunosuppressive factors derived from tumors. In this review, we highlight current advances in NK-based adoptive cell therapy, including alternative sources of NK cells for adoptive infusion, various CAR modifications that confer different targeting specificity to NK cells, multiple genetic engineering strategies to enhance NK cell function, as well as the latest clinical research on adoptive NK cell therapy.

Metformin suppresses the growth of colorectal cancer by targeting INHBA to inhibit TGF-ß/PI3K/AKT signaling transduction.

Multiple evidence shows that metformin serves as a potential agent for Colorectal Cancer (CRC) treatment, while its molecular mechanisms still require detailed investigation. Here, we revealed that metformin specifically suppressed the proliferation of CRC cells by causing G1/S arrest, and INHBA is a potential target for metformin to play an anti-proliferation effect in CRC. We verified the oncogene role of INHBA by knocking down and overexpressing INHBA in CRC cells. Silencing INHBA abrogated the cell growth, while overexpression INHBA promotes the proliferation of CRC cells. As an oncogene, INHBA was aberrant overexpression in CRC tissues and closely related to the poor prognosis of CRC patients. In mechanism, INHBA is an important ligand of TGF-ß signaling and metformin blocked the activation of TGF-ß signaling by targeting INHBA, and then down-regulated the activity of PI3K/Akt pathway, leading to the reduction of cyclinD1 and cell cycle arrest. Together, these findings indicate that metformin down-regulates the expression of INHBA, then attenuating TGF-ß/PI3K/Akt signaling transduction, thus inhibiting the proliferation of CRC. Our study elucidated a novel molecular mechanism for the anti-proliferation effect of metformin, providing a theoretical basis for the application of metformin in CRC therapy.

Wnt/ß-catenin signalling: function, biological mechanisms, and therapeutic opportunities.

The Wnt/ß-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis. The deregulation of Wnt/ß-catenin signalling often leads to various serious diseases, including cancer and non-cancer diseases. Although many articles have reviewed Wnt/ß-catenin from various aspects, a systematic review encompassing the origin, composition, function, and clinical trials of the Wnt/ß-catenin signalling pathway in tumour and diseases is lacking. In this article, we comprehensively review the Wnt/ß-catenin pathway from the above five aspects in combination with the latest research. Finally, we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment.

Transcriptome Analyses Identify a Metabolic Gene Signature Indicative of Antitumor Immunosuppression of EGFR Wild Type Lung Cancers With Low PD-L1 Expression.

PURPOSE: With the development and application of targeted therapies like tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), non-small cell lung cancer (NSCLC) patients have achieved remarkable survival benefits in recent years. However, epidermal growth factor receptor (EGFR) wild-type and low expression of programmed death-ligand 1 (PD-L1) NSCLCs remain unmanageable. Few treatments for these patients exist, and more side effects with combination therapies have been observed. We intended to generate a metabolic gene signature that could successfully identify high-risk patients and reveal its underlying molecular immunology characteristics. METHODS: By identifying the bottom 50% PD-L1 expression level as PD-L1 low expression and removing EGFR mutant samples, a total of 640 lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) tumor samples and 93 adjacent non-tumor samples were finally extracted from The Cancer Genome Atlas (TCGA). We identified differentially expressed metabolic genes (DEMGs) by R package limma and the prognostic genes by Univariate Cox proportional hazards regression analyses. The intersect genes between DEMGs and prognostic genes were put into the least absolute shrinkage and selection operator (LASSO) penalty Cox regression analysis. The metabolic gene signature contained 18 metabolic genes generated and successfully stratified LUAD and LUSC patients into the high-risk and low-risk groups, which was also validated by the Gene Expression Omnibus (GEO) database. Its accuracy was proved by the time-dependent Receiver Operating Characteristic (ROC) curve, Principal Components Analysis (PCA), and nomogram. Furthermore, the Single-sample Gene Set Enrichment Analysis (ssGSEA) and diverse acknowledged methods include XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT-ABS, and CIBERSORT revealed its underlying antitumor immunosuppressive status. Besides, its relationship with somatic copy number alterations (SCNAs) and tumor mutational burden (TMB) was also discussed. RESULTS: It is noteworthy that metabolism reprogramming is associated with the survival of the double-negative LUAD and LUSC patients. The SCNAs and TMB of critical metabolic genes can inhibit the antitumor immune process, which might be a promising therapeutic target.

Pan-Cancer Molecular Characterization of m6A Regulators and Immunogenomic Perspective on the Tumor Microenvironment.

PURPOSE: N6-methyladenosine (m6A) methylation plays a critical role in diverse biological processes. However, knowledge regarding the constitution of m6A on tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) across cancer types is still lacking. We performed comprehensive immuno-genomic analyses to reveal molecular characterization of the m6A regulators and immune-related genes (IRGs) across TME and TIL heterogeneity. METHODS: We comprehensively analyzed the properties of m6A regulators in genomic profiles from The Cancer Genome Atlas (TCGA) according to expression perturbations of crucial IRGs, CD274, CD8A, GZMA, and PRF1. The four IRGs were proved to be reliable biomarkers of TILs and TME via CIBERSORT and ESTIMATE analyses, and their co-expression relationship was certified by TIMER analysis. Based on their median values, the samples from the pan-cancer tissues (N = 11,057) were classified into eight TME types. The RNA expression levels of 13 m6A regulators were compared across TME subtypes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was also used to classify TME clusters, expression variants of IRGs and m6A regulators were verified among TME clusters. Meanwhile, the correlation between m6A regulators and tumor mutational burden (TMB) were tested. Finally, the impacts of IRGs and TME clusters in clinical characteristics and outcomes were revealed. RESULTS: CD274, CD8A, GZMA, and PRF1 showed similar TILs' characteristics, of which the level of T cells CD8 and T cells CD4 memory activated are consistent with the expression levels of the four IRGs and higher immune infiltration. Besides, CD274, CD8A, GZMA, and PRF1 were positively correlated with the stromal score or immune score in almost all 33 tumor types. All of four IRGs showed impact between tumor pathological stages or clinical outcomes. Among TME type I to type IV, m6A regulators' expression drift changed from high-level to low-level in ESCA, BLCA, HNSC, CESC, BRCA, and GBM. However among TME type V to type VIII, m6A regulators drew a shift from low-level to high-level expression in CESC, BLCA, ESCA, KIRP, HNSC, BRCA, KIRC, COAD, LAML, GBM, and KICH. In ssGSEA analyses, IRGs' expression levels were elevated with the immune infiltration degree and m6A regulators' expression level varied among three TIL subgroups. With different TMB levels, expression differences of m6A regulators were observed in BLCA, BRCA, COAD, LGG, LUAD, LUSC, STAD, THCA, and UCEC. CONCLUSION: We identified four crucial IRGs affecting TILs, TME characteristics and clinical parameters. Expression variants of m6A regulators among the subgroups of TME types and ssGSEA clusters suggested that m6A regulators may be essential factors for phenotypic modifications of IRGs and thus affecting TME characteristics across multiple tumor types.

Age-Related Immunoreactivity Profiles to Diverse Mycobacterial Antigens in BCG-Vaccinated Chinese Population.

Long-term immunoreactivity to mycobacterial antigens in Bovis Calmette-Guérin (BCG)-vaccinated population is not well investigated. Herein, 361 volunteer healthy donors (HDs) with neonatal BCG vaccination from Shanghai region (China) were enrolled. They were subdivided into ESAT-6/CFP10- (E6C10-) and ESAT-6/CFP10+ (E6C10+) groups based on gamma-interferon release assays (IGRAs). Three mycobacterial antigens, including Rv0934, Rv3006, and Rv3841, were subjected to the determination of immunoreactivity by ELISPOT assay. The immunoreactivities to three mycobacterial antigens were firstly compared among TB patients (N=39), E6C10+ HDs (N=78, 21.61% of HDs) and E6C10- HDs (N=283, 78.39% of HDs). It was revealed that Rv3006 was dominant upon M.tb infection, while Rv3841 was likely to be more responsive upon latent TB infection. In E6C10- population, the immunoreactivity to Rv3841 maintained along with aging, whereas those to Rv3006 and Rv0934 attenuated in E6C10- HDs older than 45 years old. Our study implies the shift of dominant antigens at different infection statuses, providing the clues for the selection of mycobacterial antigens in vaccine development and precision revaccination in the future.

Local extraction and detection of early stage breast cancers through a microneedle and nano-Ag/MBL film based painless and blood-free strategy.

Early diagnosis is the key to the good prognosis of breast cancer. At present, clinical tumor diagnosis is mainly through serum analysis, which is painful and can only detect relatively advanced tumors that have already metastasized from the glands into the blood circulation. Here, we developed an earlier diagnostic method (before tumor cells entering the blood) of breast cancers through a convenient and painless process with blood-free samples. The microneedles were utilized to insert into the animals' testing areas, while the tissue fluid was collected through our synthesized breathable thin film. The obtained tissue fluid sample was then incubated to form blue products. In the area where tumors occurred, the blue changes were more obvious than the healthy area, a semi-localization and semi-quantitative detection of the tumorous area thus could be realized. The results of corresponding animal experiments showed that, after the injection of tumor cells, the proposed nano-Ag based colorimetric method can detect the occurrence of breast cancers in 7 days. What is more, these early tumors could be effectively suppressed through classical DOX treatment. For comparison, the classical blood test needed 14 days to validate the occurrence of breast cancers. The subsequent human tests further demonstrated the feasibility of the present method. The development of this work could provide a more convenient, accurate and comfortable technology to support for the early screening and diagnosis of cancer patients, so as to fundamentally reduce the mortality of the breast cancers.

Epiregulin enhances odontoblastic differentiation of dental pulp stem cells via activating MAPK signalling pathway.

OBJECTIVES: The odontoblastic differentiation of dental pulp stem cells (DPSCs) contributes to tertiary dentin formation. Our previous study indicated that epiregulin (EREG) enhanced odontogenesis potential of dental pulp. Here, we explored the effects of EREG during DPSC odontoblastic differentiation. METHODS: The changes in EREG were detected during tertiary dentin formation. DPSCs were treated with recombinant human EREG (rhEREG), EREG receptor inhibitor gefitinib and short hairpin RNAs. The odontoblastic differentiation was assessed with ALP staining, ALP activity assay, alizarin red S staining and real-time RT-PCR of DSPP, OCN, RUNX2 and OSX. Western blot was conducted to examine the levels of p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (Erk1/2). The expression of EREG and odontoblastic differentiation-related markers was investigated in human dental pulp from teeth with deep caries and healthy teeth. RESULTS: Epiregulin was upregulated during tertiary dentin formation. rhEREG enhanced the odontoblastic differentiation of DPSCs following upregulated p38 MAPK and Erk1/2 phosphorylation, but not JNK, whereas depletion of EREG suppressed DPSC differentiation. Gefitinib decreased odontoblastic differentiation with decreased phosphorylation of p38 MAPK and Erk1/2. And suppression of p38 MAPK and Erk1/2 pathways attenuated DPSC differentiation. In human dental pulp tissue, EREG upregulation in deep caries correlates with odontoblastic differentiation enhancement. CONCLUSION: Epiregulin is released during tertiary dentin formation. And EREG enhanced DPSC odontoblastic differentiation via MAPK pathways.

External apical root resorption in non-extraction cases after clear aligner therapy or fixed orthodontic treatment.

BACKGROUND/PURPOSE: The application of removable aligner in orthodontic treatment has increased rapidly in recent years, while its effects on root resorption remains unclear. The aim of this study was to comparatively evaluate the amount of external apical root resorption (EARR) in non-extraction patients receiving clear aligner therapy (CAT) or fixed orthodontic treatment (FOT). MATERIALS AND METHODS: Eighty non-extraction patients treated with CAT or FOT exclusively were evaluated retrospectively. Panoramic radiographs were used to measure the length of crowns and roots of the incisors before and after treatment. The amount of EARR was determined by the relative change of root-crown ratio and compared between the two groups. The potential predictive factors of EARR were investigated using spearman correlation analysis. RESULTS: The overall EARR in the CAT patients was significantly less than the FOT. Similar results were observed in maxillary central incisors, maxillary lateral incisors, mandibular central incisors and mandibular lateral incisors. The duration of treatment positively correlated with the amount of EARR in both modalities. Gender, age, skeletal pattern or degree of malocclusion did not affect the occurrence of EARR. CONCLUSION: Clear aligner therapy may have a superiority of reducing external apical root resorption compared to fixed orthodontic treatment in non-extraction patients.

Mycobacterial Lipoprotein Z Triggers Efficient Innate and Adaptive Immunity for Protection Against Mycobacterium tuberculosis Infection.

Mycobacterial lipoproteins are considered to be involved in both virulence and immunoregulatory processes during Mycobacterium tuberculosis (M.tb) infection. In our previous investigations on the immunoreactivity of more than 30 M.tb proteins in active TB patients, we identified mycobacterial lipoprotein Z (LppZ) as one of the most immune dominant antigens. How LppZ triggers immune responses is still unclear. In this study, we analyzed LppZ-mediated innate and adaptive immunity using a murine air pouch model and an M.tb infection model, respectively. We found that LppZ could not only recruit inflammatory cells but also induce the production of proinflammatory cytokines inside the pouches. LppZ could also induce strong Th1 responses following immunization and confer protection against challenge with M.tb virulent strain H37Rv at a similar level to BCG vaccination but with less pathological damage in the lungs. Furthermore, we revealed the presence of LppZ-specific functional CD4+ T cells in the lungs of the challenged mice that were capable of secreting double or triple cytokines, including IFN-γ, IL-2, and TNF-α. Our study thus demonstrates that LppZ is of strong immunogenicity during M.tb infection in both humans and mice and has the ability to trigger effective innate and cellular immunity. Considering the limitations of candidate antigens in the pipeline of TB vaccine development, LppZ-mediated immune protection against M.tb challenge in the mouse model implies its potential application in vaccine development.

Efficacy of piezocision on accelerating orthodontic tooth movement: A systematic review.

OBJECTIVES: The aim of this systematic review was to evaluate the effect of piezocision as an adjunctive procedure to accelerate orthodontic tooth movement. MATERIALS AND METHODS: Randomized controlled trials and controlled clinical trials that investigated the effectiveness of piezocision on accelerating orthodontic tooth movement were identified through electronic and manual searches. The literature search, study inclusion, risk of bias assessment, and data extraction were performed by two reviewers independently. RESULTS: Four eligible studies were included in this review. All studies reported accelerated tooth movement after piezocision, and three reported a significant reduction of treatment duration in the piezocision group. No deleterious effects on periodontal status, pain perception, satisfaction, root resorption, or anchorage control were reported in any studies. CONCLUSION: Based on currently available information, weak evidence supports that piezocision is a safe adjunct to accelerate orthodontic tooth movement, at least in the short term. More high-quality clinical trials to determine the long-term effects and optimal protocol for piezocision are needed to draw more reliable conclusions.

Determination of Lipoprotein Z-Specific IgA in Tuberculosis and Latent Tuberculosis Infection.

Tuberculosis (TB) remains one of the most severe infectious diseases. It is still of paramount importance to establish more accurate, rapid, and efficient diagnostic methods. Since infection with Mycobacterium tuberculosis (M. tb) is largely mediated through the respiratory tract, IgA responses against mycobacterial proteins are worthy of investigation for their potential clinical utility. In this study, the IgA response targeting lipoprotein Z (LppZ) was determined by using a homemade ELISA with plasma of TB patients (N = 125), LTBI individuals (N = 92), healthy controls (HCs) (N = 165), as well as TB patients undergoing anti-TB treatment (N = 9). In parallel the antigen-specific IFN-γ release from PBMCs triggered by LppZ and M. tb-specific ESAT-6 or CFP-10 was detected by using an ELISPOT assay. It was found that the LppZ-specific IgA level was dramatically higher in TB patients than in HCs (p < 0.0001). Compared to that before anti-TB treatment, the LppZ-specific IgA level decreased substantially after 2 months of anti-TB treatment (p = 0.0297) and remained at low levels until the end of the treatment. What is more, pulmonary TB patients exhibited significantly higher LppZ-specific IgA-values than extra-pulmonary TB patients (p = 0.0296). Interestingly, the LppZ-specific IgA-values were negatively correlated to the amounts of IFN-γ released in response to LppZ with statistical significance (r = -0.5806, p = 0.0002). LppZ-specific IgA level was also higher in LTBI individuals than in HCs (p < 0.0001). Additionally there were some PPD+ HC individuals with high LppZ-specific IgA levels but the potential of this assay for identifying leaky LTBI in PPD+ HCs needs to be further investigated through follow-up studies. The sensitivity of detecting TB solely with ESAT-6 or CFP-10-specific IFN-γ release was increased by including the LppZ-specific IgA results, respectively, from 86.11 to 100% and 88.89 to 100%; the sensitivity of screening for LTBI was increased from 80.36 to 83.93% and 57.14 to 69.64%, respectively. The higher LppZ-specific IgA responses in TB and LTBI populations than in controls indicated high immunoreactivity to LppZ upon M. tb infection. Although the assay was not efficient enough for independent application in sero-diagnosis, LppZ-specific IgA might become a complementary biomarker for the improvement of TB and LTBI screening.