TRAF3IP2-IL-17 Axis Strengthens the Gingival Defense against Pathogens.

Recent genome-wide association studies have suggested novel risk loci associated with periodontitis, which is initiated by dysbiosis in subgingival plaque and leads to destruction of teeth-supporting structures. One such genetic locus was the tumor necrosis factor receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a gene encoding the gate-keeping interleukin (IL)-17 receptor adaptor. In this study, we first determined that carriers of the lead exonic variant rs13190932 within the TRAF3IP2 locus combined with a high plaque microbial burden was associated with more severe periodontitis than noncarriers. We then demonstrated that TRAF3IP2 is essential in the IL-17-mediated CCL2 and IL-8 chemokine production in primary gingival epithelial cells. Further analysis suggested that rs13190932 may serve a surrogate variant for a genuine loss-of-function variant rs33980500 within the same gene. Traf3ip2 null mice (Traf3ip2-/-) were more susceptible than wild-type (WT) mice to the Porphyromonas gingivalis-induced periodontal alveolar bone loss. Such bone loss was associated with a delayed P. gingivalis clearance and an attenuated neutrophil recruitment in the gingiva of Traf3ip2-/- mice. Transcriptomic data showed decreased expression of antimicrobial genes, including Lcn2, S100a8, and Defb1, in the Traf3ip2-/- mouse gingiva in comparison to WT mice prior to or upon P. gingivalis oral challenge. Further 16S ribosomal RNA sequencing analysis identified a distinct microbial community in the Traf3ip2-/- mouse oral plaque, which was featured by a reduced microbial diversity and an overabundance of Streptococcus genus bacteria. More P. gingivalis was observed in the Traf3ip2-/- mouse gingiva than WT control animals in a ligature-promoted P. gingivalis invasion model. In agreement, neutrophil depletion resulted in more local gingival tissue invasion by P. gingivalis. Thus, we identified a homeostatic IL-17-TRAF3IP2-neutrophil axis underpinning host defense against a keystone periodontal pathogen.

[A case of autologous corneal stromal lenticule transplantation and vision function training in the correction of hyperopia].

Hypermetropic anisometropia is often accompanied by visual fatigue, and the higher hyperopia is prone to form amblyopia. To avoid Wear glasses fatigue, the higher hyperopia is often under corrected and regulative spasm. Pseudomyopia may occur in the early stage after refractive surgery. In this case, autologous corneal stromal lenticule transplantation was used to correct hyperopia. After standard visual cognitive training, the Uncorrected Distance Visual Acuity was rapidly improved, and the binocular vision was normal.

[Stimulatory and inhibitory signaling pathways of the T cell-APC interaction and the effect of TLR agonists on APCs]. / Stimulierende und inhibierende Signalwege der APZ- und T-Zell-Interaktion sowie Einfluss von TLR-Agonisten auf APZ.

BACKGROUND: CD8+ cells are key players in the identification and elimination of cancer cells. Cancers can escape an effective T cell response by inducing an exhausted cell state, which limits the cytotoxic capacity of the effector cells. Among other mechanisms, new checkpoint inhibitors reactivate exhausted, dysfunctional T cells. CD8+ T cells can eliminate tumor cells after presentation of tumor-specific antigens via antigen-presenting cells (APCs). APC-mediated tumor recognition is mainly stimulated by Toll-like receptors (TLRs). OBJECTIVE: This study investigates the effect of TLR agonists on APCs as well as stimulatory and inhibitory signaling pathways of the T cell-APC interaction. MATERIALS AND METHODS: Gene expression of interleukin (IL)12 and programmed death ligand 1 (PD-L1) was analyzed by quantitative polymerase chain reaction (qPCR) after 0, 8, 24, and 48 h of CD14+ cell stimulation with CpG. Protein expression of inhibitor of nuclear factor kappa B (IκBα) after CpG stimulation was investigated by western blot. CD8+ T cells were stimulated for 72 h with or without programmed cell death protein 1 (PD-1) checkpoint blockade and analyzed for expression of PD­1, Tim­3, CTLA4, and Lag3 by flow cytometry. RESULTS: TLR stimulation (by unmethylated CpG DNA) of APCs upregulates immunostimulatory signals such as IL12 expression but also activates immunoinhibitory signaling pathways such as PD-L1 expression. This signaling is NF-κB dependent. After blockade of the PD-1/PD-L1 signaling pathway, overexpression of other immune checkpoint inhibitory receptors was observed-a potential explanation for lacking therapeutic responses after TLR stimulation with PD­1 checkpoint blockade. CONCLUSION: TLR stimulation causes APCs in the tumor microenvironment to upregulate PD-L1 in an NF-κB-mediated fashion, thereby contributing to CD8+ T cell exhaustion. The effect of PD­1 blockade after TLR stimulation might be impaired due to upregulation of other checkpoint inhibitors.

[Knowledge, attitude and practice of echinococcosis prevention and control, and their influencing factors among residents living in Seda County, Sichuan Province].

OBJECTIVE: To understand the status of knowledge, attitude and practice on echinococcosis prevention and control and investigate their influencing factors among residents living in Seda County of Sichuan Province, so as to provide a scientific basis for the further implementation of health education interventions in the county. METHODS: A multi-stage stratified random sampling method was employed on September 2018. Ten townships were randomly sampled, and 2 to 3 administrative villages were randomly sampled from each township. Then, 20 to 40 households were randomly sampled from each village, and 1 to 2 villagers were investigated in each household. The knowledge, attitude and practice on echinococcosis prevention and control were investigated using a household questionnaire survey, and the factors affecting the qualification of echinococcosis prevention and control knowledge were identified using chi-square test and logistic regression analysis. RESULTS: A total of 760 questionnaires were assigned, and 748 effective questionnaires were recovered, with a recovery rate of 98.42%. The overall qualification rate of echinococcosis prevention and control knowledge was 56.42% (422/748) in residents living in Seda County, and the awareness of the question "How to get echinococcosis?" was only 48.40%. The proportion of subjects with a positive attitude towards echinococcosis prevention and control was 64.71% to 94.79%, and the rate of corrected echinococcosis prevention and control behaviors was 10.40% to 82.45%. Univariate analysis showed that factors affecting the qualification rate of echinococcosis prevention and control knowledge included gender, occupation, education level, frequency of echinococcosis screening and frequency of health education (all P < 0.05), and binary logistic regression analysis showed that women, herdsmen as the primary occupation, an education level of primary school and below, absence of echinococcosis screening and absence of health education were factors responsible for the unqualified awareness of echinococcosis prevention and control knowledge (all P < 0.05). CONCLUSIONS: There is a low awareness rate of echinococcosis prevention and control knowledge and a low proportion of corrected echinococcosis prevention and control behaviors in residents living in Seda County, Sichuan Province. Multiple forms of health education activities pertaining to echinococcosis prevention and control are needed with adaptation to local circumstance, and implementation of appropriate behavioral interventions is recommended.

Head and Neck Cancer Immunotherapy beyond the Checkpoint Blockade.

The success of immune checkpoint receptor blockade has brought exciting promises for the treatment of head and neck squamous cell carcinoma (HNSCC). While patients who respond to checkpoint inhibitors tend to develop a durable response, <15% of patients with HNSCC respond to immune checkpoint inhibitors, underscoring the critical need to alleviate cancer resistance to immunotherapy. Major advances have been made to elucidate the intrinsic and adaptive resistance mechanisms to immunotherapy. Central genomic events in HNSCC have been found to possess previously unknown roles in suppressing immune sensing. Such inhibitory function affects both the innate and adaptive arms of tumor-specific immunity. While checkpoint blockade effectively reinvigorates adaptive T-cell responses, additional targeting of the oncogenic inhibitors of innate immune sensing likely informs a novel and potent strategy for immune priming. This review discusses the recent advances on the identification of key HNSCC oncogenes that impair antitumor immunity and emerging immune-priming approaches that sensitize poorly immunogenic HNSCCs to checkpoint blockade. These approaches include but are not limited to cancer vaccine systems utilizing novel type I interferon agonists as immune adjuvants, radiation, DNA damage-inducing agents, and metabolic reprogramming. The goal of these multipronged approaches is to expand tumor-specific effector T-cells, break checkpoint receptor-mediated tolerance, and metabolically support sustained T-cell activation. The translation of therapeutics that reverses oncogenic inhibition of immune sensing requires thorough characterization of the HNSCC regulators of innate immune sensors, development of additional immunocompetent HNSCC mouse models, as well as engineering of more robust immune adjuvant delivery systems. Built on the success of checkpoint blockade, validation of novel immune-priming approaches holds key promises to expand the pool of responders to immunotherapy.

[Clinical analysis of 309 hospitalized children with pertussis-associated pneumonia].

Objective: To investigate the clinical characteristics of pertussis-associated pneumonia and analyze it's risk factors. Methods: Clinical data were taken from Shenzhen Children's Hospital with Bordetella pertussis infection and confirmed by culture or real-time polymerase chain reaction (PCR) of nasopharyngeal secretion from October 2013 to December 2015. Patients were divided into two groups, those with radiologically confirmed pneumonia in the course of their disease and those with not. Clinical data were retrospectively analyzed and compared. T test, Rank sum test or chi square test were used for comparison between groups. Risk factors were analyzed by unconditional Logistic regression analysis. Results: A total of 501 children hospitalized with Bordetella pertussis infection were included. Among them, 309 patients were diagnosed with pneumonia. The median age was 3 (2, 6) months. Symptoms were paroxysmal cough (n=252, 81.6%), tachypnea (n=69, 22.3%), and cyanosis (n=105, 34.0%). The time from onset of cough to radiologically confirmed pneumonia was between 1 and 66 days with a median of 9 (5.5, 15.0) days. The most common pathogen of coinfection was respiratory syncytial virus (RSV)(20 cases). Macrolides were used in 306 cases for (8.2±3.6) days. All cases showed significant improvement. There were more male children (62.1% (192/309) vs. 50.3% (95/189) , χ(2)=6.768, P=0.009), and more instances of comorbidities (13.3% (41/309) vs.5.8% (11/189) , χ(2)=6.957, P=0.008) in the pneumonia group than in the other. The age was younger (3 (2,6) vs.4 (2,6) months, Z=32.91, P=0.000) in pneumonia group than in the other. Male sex, younger age, and underlying disease were independent risk factors for pertussis-associated pneumonia (OR=1.648, 1.486, 2.695, P=0.008, 0.036, 0.005). Conclusions: Pneumonia, as a complication of pertussis, is very easy to see in hospitalized children. The duration of hospitalization is extensive. It is more likely to happen in children who are male, young, and having underlying diseases. Pneumonia is easy to occur in the first 2 weeks of the course of disease.

Precision Therapy of Head and Neck Squamous Cell Carcinoma.

Precision medicine is an approach to disease prevention and treatment that takes into account genetic variability and environmental and lifestyle influences that are unique to each patient. It facilitates stratification of patient populations that vary in their susceptibility to disease and response to therapy. Shared databases and the implementation of new technology systems designed to advance the integration of this information will enable health care providers to more accurately predict and customize prevention and treatment strategies for patients. Although precision medicine has had a limited impact in most areas of medicine, it has been shown to be an increasingly successful approach to cancer therapy. Despite early promising results targeting aberrant signaling pathways or inhibitors designed to block tumor-driven processes such as angiogenesis, limited success emphasizes the need to discover new biomarkers and treatment targets that are more reliable in predicting response to therapy and result in better health outcomes. Recent successes in the use of immunity-inducing antibodies have stimulated increased interest in the use of precision immunotherapy of head and neck squamous cell carcinoma. Using next-generation sequencing, the precise profiling of tumor-infiltrating lymphocytes has great promise to identify hypoimmunogenic cancer that would benefit from a rationally designed combinatorial approach. Continued interrogation of tumors will reveal new actionable targets with increasing therapeutic efficacy and fulfill the promise of precision therapy of head and neck cancer.

Engineering Vaccines to Reprogram Immunity against Head and Neck Cancer.

The recent Food and Drug Administration's approval of monoclonal antibodies targeting immune checkpoint receptors (ICRs) for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) offers exciting promise to improve patient outcome and reduce morbidities. A favorable response to ICR blockade relies on an extensive collection of preexisting tumor-specific T cells in the tumor microenvironment (TME). ICR blockade reinvigorates exhausted CD8+ T cells and enhances immune killing. However, resistance to ICR blockade is observed in about 85% of patients with HNSCC, therefore highlighting the importance of characterizing the mechanisms underlying HNSCC immune escape and exploring combinatorial strategies to sensitize hypoimmunogenic cold HNSCC to ICR inhibition. Cancer vaccines are designed to bypass the cold TME and directly deliver cancer antigens to antigen-presenting cells (APCs); these vaccines epitomize a priming strategy to synergize with ICR inhibitors. Cancer cells are ineffective antigen presenters, and poor APC infiltration as well as the M2-like polarization in the TME further dampens antigen uptake and processing, both of which render ineffective innate and adaptive immune detection. Cancer vaccines directly activate APC and expand the tumor-specific T-cell repertoire. In addition, cancer vaccines often contain an adjuvant, which further improves APC function, promotes epitope spreading, and augments host intrinsic antitumor immunity. Thus, the vaccine-induced immune priming generates a pool of effectors whose function can be enhanced by ICR inhibitors. In this review, we summarize the major HNSCC immune evasion strategies, the ongoing effort toward improving HNSCC vaccines, and the current challenges limiting the efficacy of cancer vaccines.

Remission effect of vitamin C on isoflurane-induced apoptosis and its mechanism.

This study aims to discuss the remission effect of vitamin C on isoflurane-induced apoptosis of rats and its possible mechanism of action, to provide a theoretical basis for postoperative cognitive impairment. Reactive oxygen species (ROS) detection, adenosine triphosphate (ATP) test, MTT method and Morris water maze were applied for detection tests. For data statistics, double factor analysis of variance (ANOVA) and post hoc Bonferroni test were adopted. It was found that vitamin C could slow down the isoflurane-induced accumulation of ROS in H4-APP cells; moreover, it could relieve the activation of caspase-3 and increase cell survival rate to inhibit the occurrence of apoptosis, indicating that ROS was the source of cell toxicity. On the other hand, vitamin C could protect the cells with its antioxidant effect. It was proved that vitamin C could remit isoflurane-induced apoptosis and relieve the decline in learning and memory ability of rats.