FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain via m6A-dependent stabilization of 5-HT3A mRNA in sensory neurons.

The N6-methyladenosine (m6A) modification of RNA is an emerging epigenetic regulatory mechanism that has been shown to participate in various pathophysiological processes. However, its involvement in modulating neuropathic pain is still poorly understood. In this study, we elucidate a functional role of the m6A demethylase alkylation repair homolog 5 (ALKBH5) in modulating trigeminal-mediated neuropathic pain. Peripheral nerve injury selectively upregulated the expression level of ALKBH5 in the injured trigeminal ganglion (TG) of rats. Blocking this upregulation in injured TGs alleviated trigeminal neuropathic pain, while mimicking the upregulation of ALKBH5 in intact TG neurons sufficiently induced pain-related behaviors. Mechanistically, histone deacetylase 11 downregulation induced by nerve injury increases histone H3 lysine 27 acetylation (H3K27ac), facilitating the binding of the transcription factor forkhead box protein D3 (FOXD3) to the Alkbh5 promoter and promoting Alkbh5 transcription. The increased ALKBH5 erases m6A sites in Htr3a messenger RNA (mRNA), resulting in an inability of YT521-B homology domain 2 (YTHDF2) to bind to Htr3a mRNA, thus causing an increase in 5-HT3A protein expression and 5-HT3 channel currents. Conversely, blocking the increased expression of ALKBH5 in the injured TG destabilizes nerve injury-induced 5-HT3A upregulation and reverses mechanical allodynia, and the effect can be blocked by 5-HT3A knockdown. Together, FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain through m6A-dependent stabilization of Htr3a mRNA in TG neurons. This mechanistic understanding may advance the discovery of new therapeutic targets for neuropathic pain management.

Mandible-First Sequencing Increase Surgical Accuracy for Patients With Skeletal Class II Malocclusion Concomitant With Unstable Condyle-Fossa Relation.

The aim of this study was to explore whether mandible-first sequencing increases the surgical accuracy in bimaxillary orthognathic surgery for patients with skeletal class II malocclusion concomitant with the unstable condyle-fossa relation. A retrospective evaluation of 19 patients who had undergone virtually planned double-splint orthognathic surgery with different operation sequences was performed: maxilla-first (n=9) or mandible-first (n=10) surgery. The centroid position, translational, and rotational differences in the maxilla were evaluated by comparing the virtual plans with actual results. The stability was assessed by comparing the actual results with the follow-up outcomes 6 months postoperatively. The accuracy of the maxilla centroid position was improved in mandible-first sequencing surgery: mandible-first 1.87±0.94 mm versus maxilla-first 2.70±0.75 mm (P<0.05). Moreover, no significant difference was detected in the translational and orientational discrepancies between the 2 groups. Neither sequencing procedure differed in the overall stability: maxilla-first (1.48±1.13 mm) versus mandible-first (1.57±0.90 mm). This study indicated that the mandible-first surgery leads to a more accurate maxilla position than the maxilla-first surgery for patients with skeletal class II malocclusion concomitant with the unstable condyle-fossa relation.

A simple liposome-based bionic bacterium for tumor treatment by re-education of tumor-associated microphages in combination with chemotherapy.

Re-education of tumor-associated macrophages (TAMs) into M1-like macrophages (Mφ1) has become one of the aims of tumor immunotherapy. Injection of live bacteria has been applied for this purpose; however, an acute innate immune response might be caused in this progress, and therefore a bacteria-based strategy with great security is needed. In this study, the bacterial walls of Staphylococcus aureus were inserted into the bilayer of liposome to construct liposome-based bionic bacteria (Bio-Bac), and doxorubicin (DOX) was encapsulated to form DOX@Bio-Bac. DOX@Bio-Bac re-educated the THP-1-derived TAMs into Mφ1 in vitro, and subsequently inhibited the migration and invasion of CAL27 cells. In a mouse model of hepatocellular carcinoma with lymphatic metastasis, the re-education of TAMs was proved, and an effective inhibition of tumor growth and metastasis in mice was observed. The liposome-based bionic bacteria constructed in this study provide a new strategy for re-education of TAMs, replacing the bacterial therapy reported previously, and a more effective anti-tumor effect can be obtained by combining the chemotherapy drugs with this bionic bacterium.

Evaluation of Related Factors of Maxillary Sinusitis After Le Fort I Osteotomy Based on Computed Tomography: A Retrospective Case-Control Study.

ABSTRACT: Maxillary sinusitis is 1 of the postoperative complications of the Le Fort I osteotomy, this study investigated the related factors of maxillary sinusitis after Le Fort I osteotomy. A total of 23 cases, 92 controls, and 11 related factors were included in this case-control study with a 1:4 case-control ratio. The risk factors for maxillary sinusitis after Le Fort I were examined by least absolute shrinkage and selection operator multivariate conditional logistic regression and least absolute shrinkage and selection operator multivariate linear regression. The patency of maxillary sinus ostium at 6 months after surgery was significantly associated with maxillary sinusitis after Le Fort I osteotomy. Compared with the obstructed maxillary sinus ostium, the percentage of the volume of the healthy air cavity in the complete sinus cavity increased 70.7% when the maxillary sinus ostium was unobstructed, and 95% confidence interval was 0.610 to 0.805. Similarly, when the maxillary sinus ostium was wide, the percentage increased 6.0% compared with the narrow 1, and 95% confidence interval was 0.013 to 0.107. This study indicated that the patency of maxillary sinus ostium has an important impact on maxillary sinusitis after Le Fort I osteotomy. Close attention should be paid to maintain the maxillary sinus ostium and the drainage of maxillary sinuses unobstructed in a clinical setting.

Effects of autologous concentrated growth factor on gingival thickness in periodontal accelerated osteogenic orthodontics: a 6-month randomized controlled trial.

BACKGROUND: Earlier studies have not given clear results of concentrated growth factor (CGF) on gingival thickness (GT) in periodontal accelerated osteogenic orthodontics (PAOO). This randomized controlled trial aimed to evaluate the effects of CGF on GT in patients with thin gingival phenotype undergoing PAOO. METHODS: Forty four patients presenting 264 anterior mandibular teeth were recruited and randomly allocated to one of the groups: test-positioning of autologous CGF after PAOO or control-positioning of a collagen membrane after PAOO. GT, gingival height (GH), buccal alveolar bone thickness (BT), and buccal alveolar bone height (BH) were evaluated depending on cross-sectional CBCT images at t0 (before surgery) and t1(6 months after surgery). RESULTS: GT were increased in both groups at t1 compared to t0. Yet, higher values were observed in the test group (from 0.94 ± 0.23 to 1.31 ± 0.33 mm) compared to the control group (from 0.94 ± 0.19 to 1.02 ± 0.16 mm) (p < 0.05). Moreover, in the intergroup comparison, GT at t1 in the test group was significantly higher compared to the control group (p < 0.01). Furthermore, the GT of central incisors, lateral incisors and canine teeth all showed significantly changes compared with baseline and the test group showed higher increase (p < 0.01). No statistically significant difference were found in GH, BT, BH and all clinical parameters between two groups at t1 (p > 0.05). CONCLUSIONS: Within the limitation of this study, gingival thickness could be increased by using CGF in PAOO for the patients with thin gingival phenotype. Trial registration The study was registered in Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ) under the number ChiCTRINR17013346, Registered 11 November 2017.

miR­142­3p targets AC9 to regulate sciatic nerve injury­induced neuropathic pain by regulating the cAMP/AMPK signalling pathway.

The aim of the present study was to investigate the effects of microRNA (miR)­142­3p on neuropathic pain caused by sciatic nerve injury in chronic compression injury (CCI) rats, and further investigate its mechanism. Rat experiments were divided into four parts in the study. In the first part, the rats were divided into the Sham and CCI groups. The expression of miR­142­3p, AC9 and cAMP were detected. In the second part, the rats were divided into the Sham, CCI, miR­142­3p mimic, mimic­negative control (NC), miR­142­3p small interfering RNA (siRNA) and siRNA­NC groups. The expression of cAMP and the levels of AMPK pathway­related proteins were detected. In the third part, the rats were randomly divided into Sham, CCI, AC9 mimic, mi­NC, AC9 siRNA and si­NC groups. Double luciferase reporter assay was used to analyse the targeting relationship between miR­142­3p and AC9. In the fourth part, the rats were divided into the Sham, CCI, miR­142­3p siRNA, AC9 mimic, miR­142­3p siRNA + AC9 siRNA, cAMP activator (Forskolin) and miR­142­3p siRNA + cAMP inhibitor groups. The expression of miR­142­3p was significantly increased while AC9 and cAMP expression significantly decreased in CCI rats. However, AC9 overexpression significantly increased the levels of cAMP protein. Luciferase reporter assay also proved that AC9 is the target gene of miR­142­3p. Moreover, miR­142­3p silencing was found to reduce neuropathic pain in CCI rats by upregulating the expression of AC9. It was also found that cAMP activation can relieve neuropathic pain and promote the expression of AMPK­related proteins in CCI rats. Silencing miR­142­3p can target AC9 to reduce the expression of inflammatory factors and neuropathic pain in CCI rats by increasing the expression of cAMP/AMPK pathway­related proteins.

[Expression and clinical significance of HIST1H2BH in head and neck squamous cell carcinoma].

PURPOSE: The purpose of this study was to investigate the expression of HIST1H2BH in head and neck squamous cell carcinoma (HNSCC) and to analyze its clinical significance. METHODS: The expression of HIST1H2BH in different tumors and HNSCC were analyzed based on the Oncomine and GEPIA database, and its relationship with clinicopathological parameters and prognostic value of HNSCC patients were also analyzed. The expression of HIST1H2BH in clinical specimens were detected by immunohistochemical staining. The variation of HIST1H2BH in HNSCC and its relationship with prognosis were analyzed based on the cBioPortal database. The interaction proteins and molecular mechanism of HIST1H2BH were preliminarily predicted using the String database. SPSS 24.0 software package was used for statistical analysis of the data. RESULTS: Analysis of Oncomine database and GEPIA database showed that HIST1H2BH was highly expressed in variety of tumors, and was significantly highly expressed in HNSCC. The expression level of HIST1H2BH was closely related to the pathological stage and prognosis of HNSCC patients, the prognosis of patients with high HIST1H2BH expression was poor. Immunohistochemical results of clinical specimens showed that the expression of HIST1H2BH in the cancerous tissue of HNSCC patients was significantly higher than that in the adjacent tissues. cBioPortal database analysis showed that the variation rate of HIST1H2BH in HNSCC patients was not high, but it was related to the disease-free survival rate. String database analysis showed that there were many genes associated with HIST1H2BH, and the signal pathways involved in biological processes were also complex. CONCLUSIONS: The expression of HIST1H2BH is elevated in HNSCC tissues, and its high expression is associated with poor prognosis. HIST1H2BH could be served as a marker for diagnosis and prognosis of HNSCC.

Framing Effect in the Trolley Problem and Footbridge Dilemma.

The present study investigated the effect of dilemma type, framing, and number of saved lives on moral decision making. A total of 591 undergraduates, with a mean age of 20.56 (SD = 1.37) were randomly assigned to 12 groups on the basis of a grid of two dilemma types (the trolley problem or the footbridge dilemma) by three frames (positive, neutral, or negative frame) by two different numbers of workers (5 or 15 people). The main effects of dilemma type, frame, and number of saved workers were all significant. The interaction of dilemma type and number of saved workers and the interaction of the three independent factors were significant. Results indicated that moral judgment is affected by framing. Specifically, people were more inclined to utilitarianism in the positive or neutral frame and more inclined to intuitionism in the negative frame. Furthermore, this effect can be moderated by dilemma type and number of saved lives. Implications of our results are discussed.