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Objective: The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) remain unclear. We examined the effect of intensively treating traditional risk factors for CAN, including hyperglycemia, hypertension, and dyslipidemia, in individuals with type 2 diabetes (T2D) and high cardiovascular risk participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.Research Design and Methods: CAN was defined as heart rate variability indices below the fifth percentile of the normal distribution. Of 10,251 ACCORD participants, 71% (n = 7,275) had a CAN evaluation at study entry and at least once after randomization. The effects of intensive interventions on CAN were analyzed among these subjects through generalized linear mixed models.Results: As compared with standard intervention, intensive glucose treatment reduced CAN risk by 16% (odds ratio [OR] 0.84, 95% CI 0.75-0.94, P = 0.003)-an effect driven by individuals without cardiovascular disease (CVD) at baseline (OR 0.73, 95% CI 0.63-0.85, P < 0.0001) rather than those with CVD (OR 1.10, 95% CI 0.91-1.34, P = 0.34) (Pinteraction = 0.001). Intensive blood pressure (BP) intervention decreased CAN risk by 25% (OR 0.75, 95% CI 0.63-0.89, P = 0.001), especially in patients ≥65 years old (OR 0.66, 95% CI 0.49-0.88, P = 0.005) (Pinteraction = 0.05). Fenofibrate did not have a significant effect on CAN (OR 0.91, 95% CI 0.78-1.07, P = 0.26).Conclusions: These data confirm a beneficial effect of intensive glycemic therapy and demonstrate, for the first time, a similar benefit of intensive BP control on CAN in T2D. A negative CVD history identifies T2D patients who especially benefit from intensive glycemic control for CAN prevention. [ABSTRACT FROM AUTHOR]

Genetic factors have been postulated to be involved in the etiology of diabetic peripheral neuropathy (DPN), but their identity remains mostly unknown. The aim of this study was to conduct a systematic search for genetic variants influencing DPN risk using two well-characterized cohorts. A genome-wide association study (GWAS) testing 6.8 million single nucleotide polymorphisms was conducted among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial. Included were 4,384 white case patients with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument clinical examination score >2.0) and 784 white control subjects with T2D and no evidence of DPN at baseline or during follow-up. Replication of significant loci was sought among white subjects with T2D (791 DPN-positive case subjects and 158 DPN-negative control subjects) from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the Genotype-Tissue Expression (GTEx) database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance (P < 5 × 10-8) in ACCORD. The minor allele of the lead SNP (rs13417783, minor allele frequency = 0.14) decreased DPN odds by 36% (odds ratio [OR] 0.64, 95% CI 0.55-0.74, P = 1.9 × 10-9). This effect was not influenced by ACCORD treatment assignments (P for interaction = 0.6) or mediated by an association with known DPN risk factors. This locus was successfully validated in BARI 2D (OR 0.57, 95% CI 0.42-0.80, P = 9 × 10-4; summary P = 7.9 × 10-12). In GTEx, the minor, protective allele at this locus was associated with higher tibial nerve expression of an adjacent gene (SCN2A) coding for human voltage-gated sodium channel NaV1.2 (P = 9 × 10-4). To conclude, we have identified and successfully validated a previously unknown locus with a powerful protective effect on the development of DPN in T2D. These results may provide novel insights into DPN pathogenesis and point to a potential target for novel interventions. [ABSTRACT FROM AUTHOR]

In this study, we studied the effect of liver X receptor (LXR) agonist T0901317 on Niemann-Pick C1 protein (NPC1) expression in apoE -/- mice. Male apoE -/- mice were randomized into 4 groups, baseline group ( n=10), control group ( n=14), treatment group ( n=14) and prevention group ( n=14). All of the mice were fed with a high-fat/high-cholesterol (HFHC) diet containing 15% fat and 0.25% cholesterol. The baseline group treated with vehicle was sacrificed after 8 weeks of the diet. The control group and the prevention group were treated with either vehicle or T0901317 daily by oral gavage for 14 weeks. The treatment group was treated with vehicle for 8 weeks, and then was treated with the agonist T0901317 for additional 6 weeks. Gene and protein expression was analyzed by real-time quantitative PCR, immunohistochemistry and Western blotting, respectively. Plasma lipid concentrations were measured by commercially enzymatic methods. We used RNA interference technology to silence NPC1 gene expression in THP-1 macrophage-derived foam cells and then detected the effect of LXR agonist T0901317 on cholesterol efflux. Plasma triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and apoA-I concentrations were markedly increased in T0901317-treated groups. T0901317 treatment reduced the aortic atherosclerotic lesion area by 64.2% in the prevention group and 58.3% in the treatment group. LXR agonist treatment increased NPC1 mRNA expression and protein levels in the small intestine, liver and aorta of apoE -/- mice. Compared with the normal cells, cholesterol efflux of siRNA THP-1 macrophage-derived foam cells was significantly decreased, whereas cholesterol efflux of LXR agonist T0901317-treated THP-1 macrophage-derived foam cells was significantly increased. Our results suggest that LXR agonist T0901317 inhibits atherosclerosis development in apoE -/- mice, which is related to up-regulating NPC1 expression. [ABSTRACT FROM AUTHOR]

Chondrosarcoma is extremely rare in maxillofacial soft tissue. A case diagnosed as well-differentiated chondrosarcoma in the left parotid region was reported. The clinic pathological features, diagnosis, treatment, and prognosis were discussed with the literature review. [ABSTRACT FROM AUTHOR]

Ossifying fibromyxoid tumor is an uncommon neoplasm with uncertain histogenesis. This tumor is usually characterized by a small, painless mass in the subcutaneous tissue or limb muscles. In this case, an ossifying fibromyxoid tumor of the mandible was reported, and relevant literature was reviewed. [ABSTRACT FROM AUTHOR]

Tongue osteocartilaginous choristoma is the disease that there are well-developed bone and cartilage in the tongue. This article reported a case of tongue osteocartilaginous choristoma in the oral-cavity,which is rare. [ABSTRACT FROM AUTHOR]

Cardiovascular autonomic neuropathy (CAN) is an independent predictor of cardiovascular disease (CVD) morbidity and all-cause and CVD mortality in diabetes. In light of its significant heritability, we aimed to identify genetic predictors of CAN through an unbiased genome-wide association study (GWAS) among whites in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohort, comprising individuals with type 2 diabetes (T2D) and high CVD risk. CAN was defined based on indices of heart rate variability derived from 10-s resting electrocardiograms, namely, as the lowest quartile of standard deviation of normally conducted R-R intervals (SDNN <7.813 ms) and highest quartile of QT index (QTI >104.32%). Applying logistic regression models, we conducted a GWAS testing 6.8 million common single nucleotide polymorphisms (SNPs), with cases (N=807) having CAN at baseline and/or during follow-up and controls (N=3,144) being without CAN at end of follow-up. The top signal, rs779142, on chromosome 1p36, was associated with 35% increased odds of CAN (OR=1.35 [1.20-1.51], P=1.9 ×10-7). Among incident cases (N=499), this SNP reached GWAS significance (OR=1.48 [1.29-1.69], P=1.7 ×10-8). In a time-to-event analysis, rs779142 was associated with increased risk of progression to CAN (HR=1.45 [1.28-1.64], P=6.9 ×10-9) - an effect that was independent of the glycemic control arm assignments within the trial (P for interaction = 0.40). Genes lying within 1Mb of the lead SNP included KCNAB2 - a potassium voltage-gated channel associated with fatal cardiac arrhythmia, and PER3 - period circadian clock 3, which is involved in the regulation of the cardiac sympathovagal balance. To conclude, we have identified a locus on 1p36 having a genome-wide significant effect on the development of incident CAN in T2D. Pending further studies, these findings may provide better mechanistic insights into CAN pathophysiology as well as potential new therapeutic targets against this complication. Disclosure: Y. Tang: None. H. Shah: None. X. Sun: None. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. M.J. Wagner: None. A. Motsinger-Reif: None. J.B. Buse: Consultant; Self; Neurimmune AG. Research Support; Self; AstraZeneca, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk A/S, Sanofi, vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg, Novo Nordisk A/S, Senseonics, vTv Therapeutics, Zafgen, Inc. J. Mychaleckyj: None. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. A. Doria: Research Support; Self; Sanofi-Aventis. Funding: National Institutes of Health [ABSTRACT FROM AUTHOR]

Background: Although the roles of PD-L1 in promoting tumor escape from immunosurveillance have been extensively addressed, its non-immune effects on tumor cells remain unclear., Methods: The spatial heterogeneity of PD-L1 staining in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) tissues was identified by immunohistochemistry. Three-dimensional (3D) specific cell-led invasion assay and 3D cancer spheroid model were used to investigate the roles of PD-L1 hi leader cells in collective invasion. The impact of M1 macrophages on specific PD-L1 expression in leader cells and its mechanisms were further studied. Finally, the effect of combination therapy of anti-PD-L1 and CDK4 inhibitor on HPV-positive tumors were evaluated on a mice model., Results: Here, we observed a distinctive marginal pattern of PD-L1 expression in HPV-positive HNSCC tissues. By mimicking this spatial pattern of PD-L1 expression in the 3D invasion assay, we found that PD-L1 hi cells led the tumor collective invasion. M1 macrophages induced specific PD-L1 expression in leader cells, and depletion of macrophages in tumor-bearing mice abrogated PD-L1 hi leader cells and collective invasion. Mechanistically, TNF-α secreted by M1 macrophages markedly increased the abundance of PD-L1 via CDK4/ubiquitin-specific peptidase 14-mediated deubiquitination of PD-L1. We also found that suppression of CDK4 enhanced the efficacy of anti-PD-L1 therapy in an E6/E7 murine model., Conclusions: Our study identified TNF-α/CDK4/ubiquitin-specific peptidase 14-mediated PD-L1 stability as a novel mechanism underlying M1 macrophage-induced PD-L1 hi leader cells and collective tumor invasion, and highlighted the potential of the combination therapy of anti-PD-L1 and CDK4 inhibitor for HPV-positive HNSCC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To analyze the clinicopathological features of maxillofacial granular cell tumors (GCT) with the aid of immunohistochemical staining., Methods: Seven cases of maxillofacial GCT were retrospectively collated, and the microscopic morphology of maxillofacial GCT was analyzed. The expression of S-100, neuron-specific enolase (NSE), SOX-10, CD68, actin, desmin, and Ki-67 in GCT was detected by immunohistochemical staining. The cases were observed in the follow-ups after clinical treatment., Results: All seven GCT tumors lacked envelopes and were poorly defined. Microscopically, the sizes of the tumor cells were large and appeared with inconspicuous cell membranes, forming a syncytium-like appearance. The cytoplasm was filled with characteristic eosinophilic granules. The immunohistochemical results showed that six cases were NSE-positive, five cases were S-100-positive, seven cases were CD68-positive, five cases were SOX-10-positive, one case was actin-positive, and seven cases were desmin-negative. The Ki-67 index did not exceed 5% in all cases. In the follow-up sessions, none of the six cases presented a recurrence., Conclusions: Maxillofacial GCT has a characteristic histological structure. Immunohistochemical S-100, CD68, and other indicators can assist in diagnosis, and the prognosis is good after clinical resection.

Malignant transformation arising in benign lymphoepithelial cysts is a complex and rare occurrence, and related research is limited. This study presents a case of the malignant degeneration of lymphoepithelial cyst in parapharyngeal space. Clinicopathological features and differential diagnosis are discussed with literature review to provide reference for clinical diagnosis and treatment management.

Odontogenic primary tumor is a rare benign odontogenic tumor in the maxillofacial area. A case of odontogenic primary basal tumor is reported. The clinicopathological features and treatment principles are discussed in the literature.

In histopathological analysis of radicular cysts (RCs), lesions in epithelium can provide pathologists with rich information on pathologic degree, which is helpful to determine the type of periapical lesions and make precise treatment planning. Automatic segmentation and localization of epithelium from whole slide images (WSIs) can assist pathologists to complete pathological diagnosis more quickly. However, the class imbalance problem caused by the small proportion of fragmented epithelium in RCs imposes challenge on the typical automatic one-stage segmentation method. In this paper, we proposed a classification-guided segmentation algorithm (CGSA) for accurate segmentation. Our method was a two-stage model, including a classification network for region of interest (ROI) location and a segmentation network guided by classification. The classification stage eliminated most irrelevant areas and alleviated the class imbalance problem faced by the segmentation model. The results of 5-fold cross validation demonstrated that CGSA outperformed the one-stage segmentation method which was lacking in prior epithelium localization information. The epithelium segmentation achieved an overall Dice's coefficient of 0.722, and intersection over union (IoU) of 0.593, which improved by 5.5% and 5.9% respectively compared with the one-stage segmentation method using UNet.Clinical Relevance- This work presents a framework for automatic epithelium segmentation in histopathological images of RCs. It can be applied to make up for the shortcomings of manual annotation which is labor-intensive, time-consuming and objective.

Accumulating evidence have emerged important roles for microRNAs (miRNAs) participating in epithelial-mesenchymal transition (EMT) process and are associated with metastasis in cervical cancer. We hypothesized that miR-223 played an important role in cell metastasis of cervical cancer. Here, we found miR-223 was downregulated in human cervical cancer cell lines and clinical tumor tissues. Result of wound healing and cell migration assays revealed that miR-223 inhibited cell migration, whereas miR-223-in showed the opposite effect. In terms of mechanism, miR-223 influenced the expression of the EMT-associated proteins by upregulating the epithelial markers E-cadherin and α-cadherin and downregulating the mesenchymal marker vimentin. In conclusion, miR-223 inhibited cell metastasis of human cervical cancer by modulating epithelial-mesenchymal transition.