Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study.

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Development of a Pathomics-Based Model for the Prediction of Malignant Transformation in Oral Leukoplakia.

Accurate prognostic stratification of oral leukoplakia (OLK) with risk of malignant transformation into oral squamous cell carcinoma is crucial. We developed an objective and powerful pathomics-based model for the prediction of malignant transformation in OLK using hematoxylin and eosin (H&E)-stained images. In total, 759 H&E-stained images from multicenter cohorts were included. A training set (n = 489), validation set (n = 196), and testing set (n = 74) were used for model development. Four deep learning methods were used to train and validate the model constructed using H&E-stained images. Pathomics features generated through deep learning combined with machine learning algorithms were used to develop a pathomics-based model. Immunohistochemical staining of Ki67, p53, and PD-L1 was used to interpret the black box of the model. Pathomics-based models predicted the malignant transformation of OLK (validation set area under curve [AUC], 0.899; testing set AUC, 0.813) and significantly identified high-risk and low-risk populations. The prediction performance of malignant transformation from dysplasia grading (validation set AUC, 0.743) was lower than that of the pathomics-based model. The expressions of Ki67, p53, and PD-L1 were correlated with various pathomics features. The pathomics-based model accurately predicted the malignant transformation of OLK and may be useful for the objective and rapid assessment of the prognosis of patients with OLK.

Differential Expression of α-Enolase in Clinical Gastric Tissues and Cultured Normal/Cancer Cells in Response to Helicobacter pylori Infection and cagA Transfection.

Background and Objectives: The role of α-enolase (ENO1) in Helicobacter pylori-related gastric lesions might be a critical factor in the pathogenesis, but remains undefined. Materials and Methods: This study investigated the differential expression of α-enolase in clinical gastric specimens and cultured normal/cancer cells in response to H. pylori (cagA+) infection and cagA transfection using qPCR, Western blots and histochemical methods. Results: A total of 172 gastric specimens were collected from 142 patients, the former comprising chronic superficial gastritis (CSG), precancerous diseases (PCDs, including atrophic gastritis, intestinal metaplasia and dysplasia) and gastric cancer (GC) cases. Among the CSG and PCD cases, the H. pylori-infected group had significantly elevated ENO1 mRNA levels compared with the uninfected group. In the GC cases, differential ENO1 expressions were detected between the cancer tissues and the paracancerous tissues. Notably, significant difference was first detected between the GC cell (AGS) and the normal cell (GES-1) as a response of ENO1 to H. pylori infection and cagA transfection. Conclusions: This report reveals that ENO1 expression is associated with H. pylori infection, cagA transfection, co-culture duration, multiplicity of infection, gastric normal/cancerous cell lines and cellular differentiation. The findings may be crucial bases for further ascertaining H. pylori pathogenic mechanism and formulating novel therapeutic and diagnostic strategies.

Effect of vitamin E and supragingival scaling on salivary gland function in patients with differentiated thyroid cancer treated with 131I.

OBJECTIVE: The aim of this study was to evaluate the effect of vitamin E and supragingival scaling with vitamin C on the salivary glands of patients with differentiated thyroid carcinoma after 131I treatment. METHODS: A total of 89 prospective patients with differentiated thyroid carcinoma were enrolled and randomly divided into the following groups: vitamin E group (n = 30, group A), vitamin C group (n = 30, group B) and supragingival scaling with vitamin C group (n = 29, group C). Using functional indices (e.g. maximum uptake fraction, uptake index, excretion fraction, secretion time and excretion rate), changes in the salivary gland functions before and a month after 131I treatment were assessed by dynamic imaging of salivary gland. RESULTS: We compared the before and after 131I therapy results of the three groups. In group A (P < 0.05), the excretion fraction and excretion rate of the left parotid gland were significantly higher, and the uptake index of the bilateral submandibular glands was significantly lower. No significant changes in salivary gland functional parameters were observed in group B (P > 0.05). The uptake index of the bilateral parotid glands and the excretion rate of the left parotid gland were significantly higher in group C (P < 0.05). The degree of serum amylase level reduction decreased significantly in group C (P < 0.05). CONCLUSION: Vitamin E showed a protective effect on parotid excretion function in patients with differentiated thyroid carcinoma who underwent 131I treatment. Supragingival scaling may be a promising radiation protector because it is associated with a protective effect on the salivary gland functions.

Periodontitis exacerbates endothelial dysfunctions partly via endothelial-mesenchymal transition in streptozotocin-induced diabetes rats.

OBJECTIVES: Periodontal infections are related to the expansion of diabetes cardiovascular problems. However, the pathological process and probable mechanism remain unexplained. This study investigated the impact of periodontitis on streptozotocin (STZ)-induced diabetes rats' carotid artery. METHODS: We randomized 24 Sprague-Dawley (SD) rats into four groups: control, chronic periodontitis (CP), diabetes mellitus (DM), and DM +CP groups. Fasting blood glucose (FBG) and hemoglobin A1c (HBA1c ) were measured to verify the establishment of the DM model. After euthanasia, the maxillary was collected for further studies like hematoxylin-eosin (HE), Masson staining, and micro-computed tomography (micro-CT) analysis. Immunofluorescence (IF) staining was used to detect endothelial-mesenchymal transition (EndMT)-related markers in carotid artery wall. We further used ELISA and quantitative real-time PCR to investigate the effect of high glucose (HG) and Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) on human umbilical vein endothelial cells (HUVECs). RESULTS: Compared with DM and CP groups, bone resorption and pathological changes of the vascular wall were the most serious in the DM+CP group. The vascular wall of the DM+CP group had a higher level of interleukin (IL)-6 and vascular cell adhesion molecule 1 (VCAM-1). The carotid artery vascular wall of the DM+CP group contained more cells that expressed both mesenchymal and endothelial cell markers, along with elevated transcription factor levels. Furthermore, P.g-LPS and HG upregulated the inflammatory cytokines expression and caused phenotypic changes of HUVECs in vitro. CONCLUSION: Periodontitis exacerbates endothelial dysfunctions partly via endothelial-mesenchymal transition in STZ-induced diabetes rats.

Evaluation of the prognostic value of CBXs in gastric cancer patients.

Chromobox (CBX) proteins were suggested to exert epigenetic regulatory and transcriptionally repressing effects on target genes and might play key roles in the carcinogenesis of a variety of carcinomas. Nevertheless, the functions and prognostic significance of CBXs in gastric cancer (GC) remain unclear. The current study investigated the roles of CBXs in the prognosis of GC using the Oncomine, The Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, The Cancer Genome Atlas (TCGA), and cBioPortal databases. CBX1/2/3/4/5 were significantly upregulated in GC tissues compared with normal tissues, and CBX7 was downregulated. Multivariate analysis showed that high mRNA expression levels of CBX3/8 were independent prognostic factors for prolonged OS in GC patients. In addition, the genetic mutation rate of CBXs was 37% in GC patients, and genetic alterations in CBXs showed no association with OS or disease-free survival (DFS) in GC patients. These results indicated that CBX3/8 can be prognostic biomarkers for the survival of GC patients.

Exosomes derived from human exfoliated deciduous teeth ameliorate adult bone loss in mice through promoting osteogenesis.

Cell-free based therapy is an effective strategy in regenerative medicine as it avoids controversial issues, such as immunomodulation and stability. Recently, exosomes have been explored as a favorable substitution for stem cell therapy as they exhibit multiple advantages, such as the ability to be endocytosed and innate biocompatibility. This study aimed to investigate the effects of stem cells from human exfoliated deciduous teeth (SHED)-derived exosomes (SHED-Exo) on bone marrow stromal cells (BMSCs) osteogenesis and bone recovery. SHED-Exo were isolated, characterized, and applied to the bone loss area caused by periodontitis in a mouse model. We found that the injection of SHED-Exo restored bone loss to the same extent as original stem cells. Without affecting BMSCs proliferation, SHED-Exo mildly inhibited apoptosis. Moreover, SHED-Exo specifically promoted BMSCs osteogenesis and inhibited adipogenesis compared with SHED-derived conditioned medium. The expression of osteogenic marker genes, alkaline phosphatase activity, and Alizarin Red S staining of BMSCs was significantly increased by co-culturing with SHED-Exo. Moreover, Western blot analysis showed that Runx2, a key transcriptional factor in osteogenic differentiation, and p-Smad5 were upregulated upon SHED-Exo stimulation. Expression of the adipogenic marker PPARγ and the amount of lipid droplets decreased when exosomes were present. Low doses of exosomes inhibited the expression of the inflammatory cytokines IL-6 and TNF-α. In conclusion, SHED-Exo directly promoted BMSCs osteogenesis, differentiation, and bone formation. Therefore, exosomes have the potential to be utilized in the treatment of periodontitis and other bone diseases.

TiO2/SnOx-Au nanocomposite catalyzed photochromic reaction for colorimetric immunoassay of tumor marker.

A simple colorimetric immunoassay based on visible light excitation for detection of carcinoembryonic antigen (CEA) was developed. Firstly, visible light photocatalysts of TiO2/SnOx-Au ternary heterostructures were prepared by in situ reduction method, which were characterized using transmission electron microscope (TEM), energy-dispersive X-ray spectroscopy (EDX), X-ray powder diffraction (XRD) and UV-vis diffuse reflectance spectroscopy (DRS). Then, a novel sandwich-type colorimetric immunoassay for quantitative analysis of CEA by using TiO2/SnOx-Au nanoparticle as signal tag was constructed. Under visible light irradiation (λ ≥ 420 nm), the color development of TMB was obtained. And the quantitative analysis was carried out in ABS buffer solution by ultraviolet spectrum scanning. Under optimal conditions, the absorbance values increased with the increasing of CEA levels in samples, which presented linear relationship in the range of 5 pg mL-1-2.5 ng mL-1 with a detection limit of 5 pg mL-1. Meanwhile, the colorimetric immunosensor owned acceptable specificity, stability and reproducibility.

Vitamin D/VDR signaling inhibits LPS-induced IFNγ and IL-1ß in Oral epithelia by regulating hypoxia-inducible factor-1α signaling pathway.

BACKGROUND: Oral lichen planus (OLP) is known as a chronic inflammatory disease. Our recent studies have suggested that vitamin D/vitamin D receptor (VDR) signaling exerts its protective effects on oral keratinocyte apoptosis by regulating microRNA-802 and p53-upregulated modulator of apoptosis (PUMA), but its roles in oral epithelial inflammatory responses in OLP are still unknown. Herein, we identify lipopolysaccharide (LPS) is able to enhance interferon gamma (IFNγ) and interleukin-1 beta (IL-1ß) productions in human oral keratinocytes (HOKs) dependent on hypoxia-inducible factor-1α (HIF-1α). METHODS: HIF-1α and cytokines levels in HOKs were investigated by real-time PCR and western blotting after LPS challenge. The effects of 1,25(OH)2D3 on LPS-induced HIF-1α and cytokines were tested by real-time PCR, western blotting, siRNA-interference and plasmids transfection techniques. The roles of 1,25(OH)2D3 in regulating HIF-1α levels were investigated using western blotting, siRNA-interference, plasmids transfection and Chromatin Immunoprecipitation (ChIP) assays. Finally, HIF-1α, IFNγ and IL-1ß expressions in oral epithelia derived from mice and individuals were measured by real-time PCR, western blotting and immunohistochemical staining. RESULTS: As a critical regulator, vitamin D suppresses LPS-induced HIF-1α to block IFNγ and IL-1ß productions. Mechanistically, vitamin D inactivates nuclear factor-κB (NF-κB) pathway and up-regulates von Hippel-Lindau (VHL) levels, leading to HIF-1α reduction. Moreover, HIF-1α status of oral epithelia is elevated in VDR-/- mie as well as in VDR-deficient human biopsies, accompanied with increased IFNγ and IL-1ß. CONCLUSION: Collectively, this study uncovers an unrecognized roles of vitamin D/VDR signaling in regulating cytokines in oral keratinocytes and reveals the molecular basis of it.

Role of mammary serine protease inhibitor on the inflammatory response in oral lichen planus.

OBJECTIVES: Oral lichen planus (OLP) is a chronic inflammatory condition with an unclear pathological mechanism. IκB kinase α (IKKα)-regulated mammary serine protease inhibitor (MASPIN) has been shown to mediate inflammation, particularly in cancers. Here, we explored the expression of MASPIN in OLP and its role in the inflammatory response. MATERIALS AND METHODS: Immunohistochemistry staining and reverse transcription-polymerase chain reaction assays were used to detect the subcellular localization and expression of MASPIN and IKKα in OLP and healthy control tissues. Levels of the inflammatory factors were compared with enzyme-linked immunosorbent assays. MASPIN and IKKα were overexpressed and silenced, respectively, in an inflammation model of human oral keratinocytes (HOKs) stimulated with lipopolysaccharide (LPS). RESULTS: Mammary serine protease inhibitor expression was down-regulated, whereas IKKα expression was up-regulated in OLP tissues (p < 0.01). The levels of tumour necrosis factor-alpha and interleukin-6 in OLP tissues were increased compared to those of healthy controls (p < 0.01). MASPIN overexpression in LPS-stimulated HOK cells inhibited the levels of IKKα and the secretion of inflammatory cytokines. By contrast, IKKα silencing promoted the expression of MASPIN and inhibited the secretion of inflammatory cytokines. CONCLUSION: Both MASPIN and IKKα are involved in the inflammatory process of OLP, suggesting potential therapeutic targets.

[Recent Progress of Molecular Genetic Characteristics and Prognosis of Non-Hodgkin's Lymphoma--Review].

Lymphomas are traditionally divided into Hodgkin's lymphoma and non-Hodgkin's lymphoma(NHL), the NHL is a common hematological cancer, which represents a wide spectrum of illnesses from the most indolent to the most aggressive malignancies, and the detection of related molecular targets will be needed for diagosing each subtype of NHL. Advances in understanding the pathogenesis of NHL have improved the precision of diagnosis and the prognosis evaluation of patients with this disorder, such as chromosomal translocation leading to the up-regulation of oncogene expression. Besides, the deletion of several tumor suppressor genes may cause excessive proliferation in tumor cells, and the single nucleotide polymorphism (SNP) determines the differences of susceptibility, drug-resistance and prognosis of NHL. In addition, DNA methylation, histone modification, non-coding RNA and other epigenetic phenomena play an increasingly important role in the diagnosis, selection of clinical drugs and evaluation of prognosis of NHL. In this review, the recent progress of researches on chromosome translocation, deletion of tumor suppression genes, gene poly-morphism and epigenetics are summarized.

Vitamin D/VDR signaling suppresses microRNA-802-induced apoptosis of keratinocytes in oral lichen planus.

Vitamin D is known to play a protective role in inflammatory diseases. Although the suppressive effect of vitamin D/vitamin D receptor (VDR) signaling has been shown in the context of oral lichen planus (OLP), the molecular basis of its regulatory function remains poorly understood. Herein, we reported that miR-802 overexpression in OLP could aggravate apoptosis of oral keratinocytes by targeting B-cell lymphoma 2 mRNA. In addition, vitamin D/VDR signaling was able to suppress miR-802 expression in LPS-treated or activated CD4+ T cell-stimulated human oral keratinocytes by blocking NF-κB pathways, thereby inhibiting OLP apoptosis. Consistent with the results in vitro, we showed that miR-802 expression was enhanced in oral keratinocytes from VDR-/- mice, and an inverse correlation between VDR and miR-802 was found in human biopsy specimens of OLP. Collectively, our data suggest that vitamin D/VDR signaling suppresses oral keratinocyte apoptosis by targeting miR-802.-Zhao, B., Xu, N., Li, R., Yu, F., Zhang, F., Yang, F., Ge, X., Li, Y. C., Du, J. Vitamin D/VDR signaling suppresses microRNA-802-induced apoptosis of keratinocytes in oral lichen planus.

Successful treatment of isolated oral lichen planus on lower lip with traditional Chinese medicine and topical wet dressing: A case report.

RATIONALE: Biopsy is very important for the diagnosis of oral lichen planus (OLP) on the lips. Traditional Chinese medicine (TCM) can be used to coordinate the whole body, soften and eliminate swellings and masses, and regulate the functions of qi and blood. Therefore, TCM could be an effective and safe treatment for OLP. Wet dressing is particularly important for the treatment of lip diseases. We report on a rare case of OLP on the lower lip. PATIENT CONCERNS: A 38-year-old female patient presenting with a history of recurrent erosion, bleeding, and pain on her lower lip for 10 years. DIAGNOSES: Erosive OLP of the lower lip. INTERVENTIONS: The patient was treated for 4 months using TCM comprising "Qingwen Jiedu Kouyankang granules," total Paeonia glucosides, and a combination of hormones and anti-inflammatory agents applied locally using a wet dressing. OUTCOMES: Lip erosion was improved remarkably after 1 month, and there was no recurrence or aggravation of the condition. The duration of the follow-up period was 5 months. LESSONS: The therapeutics used here were effective and safe for the treatment of OLP and could improve the quality of life in patients with lip erosion. The therapeutics provide new insight into the treatment of OLP on the lip.

LPS-induced Vitamin D Receptor Decrease in Oral Keratinocytes Is Associated With Oral Lichen Planus.

The suppressive function of vitamin D on oral lichen planus (OLP) have been documented previously. Vitamin D receptor (VDR) expression is down-regulated in OLP, but the molecular mechanism of its decrease and the related anti-inflammatory contributor of epithelial VDR signaling is unclear. Herein, we demonstrated that lipopolysaccharide (LPS) remarkedly down-regulated VDR expression of keratinocytes, and the reduced regulation was dependent on tumor necrosis factor alpha (TNFα)-miR-346 pathway. In human specimen studies, VDR levels of oral mucosal epithelia from OLP patients decreased substantially accompanied with robust TNFα and miR-346 induction, compared to the normal tissues. In addition, vitamin D/VDR signaling inhibited LPS-induced p53-upregulated modulator of apoptosis (PUMA) induction in keratinocytes via impeding nuclear factor-κB (NF-κB) activation, resulting in keratinocytes apoptosis reduction. Importantly, PUMA activity was up-regulated strongly in diseased epithelium, reversely correlated with VDR expression. Totally, our data indicate that LPS is responsible for VDR downregulation in oral keratinocytes, which is associated with OLP development.

A Comparison between splenic fossa and subhepatic fossa auxiliary partial heterotopic liver transplantation in a porcine model.

To test the alternative possible locations for the placement of a liver graft and the relevant surgical technique issues, we developed a porcine model of auxiliary partial heterotopic liver transplantation (APHLT) and evaluated the difference between 2 styles of liver transplantation, either subhepatic fossa or splenic fossa APHLT, by comparing survival and biochemical indexes. Thirty-eight miniature pigs were randomly divided into 2 groups. A left hemihepatic graft without the middle hepatic vein (HV) was procured from the living donor. In group A (n = 9), an 8 mm diameter polytetrafluoroethylene (PTFE) graft approximately 2.5 cm long was connected to the left HV while another PTFE graft of the same size was connected to the left portal vein (PV). The liver graft was implanted in the right subhepatic fossa following splenectomy and right nephrectomy. In group B (n = 10), a PTFE graft of the same size was connected to the left HV while the liver graft was implanted in the splenic fossa following splenectomy and left nephrectomy. Survival rate and complications were observed at 2 weeks after transplantation. Data were collected from 5 animals in group A and 6 animals in group B that survived longer than 2 weeks. The liver function and renal function of the recipients returned to normal at 1 week after surgery in both groups. Eighty-eight percent (14/16) of the PTFE grafts remained patent at 2 weeks after surgery, but 44% of the PTFE grafts (7/16) developed mural thrombus. No significant differences in the survival rate and biochemistry were found between the 2 groups. In conclusion, the splenic fossa APHLT can achieve beneficial outcomes similar to the subhepatic fossa APHLT in miniature pigs, although it also has a high morbidity rate due to hepatic artery thrombosis, PV thrombosis, and PTEF graft mural thrombus formation. Liver Transplantation 22 812-821 2016 AASLD.

Underestimated PTCH1 mutation rate in sporadic keratocystic odontogenic tumors.

OBJECTIVES: Keratocystic odontogenic tumors (KCOTs) are benign cystic lesions of the jaws that occur sporadically in isolation or in association with nevoid basal cell carcinoma syndrome (NBCCS). The protein patched homolog 1 gene (PTCH1) is associated with NBCCS development and tumor genesis associated with this syndrome. However, previous studies have revealed that more than 85% of syndromic KCOTs and less than 30% of sporadic KCOTs harbor PTCH1 mutations. The significantly lower PTCH1 mutation rates observed in sporadic KCOTs suggest that they serve a minor role in pathogenesis. We aimed to discern the importance of PTCH1 mutations in sporadic KCOTs. MATERIALS AND METHODS: PTCH1 mutational analysis was performed with 19 new sporadic KCOT cases by direct sequencing of epithelial lining samples separated from fibrous capsules. Using this approach, we further reexamined 9 sporadic KCOTs that were previously reported to lack PTCH1 mutations by our group. RESULTS: Nineteen PTCH1 mutations were detected in patient samples from 16/19 new cases (84%) all these mutations were absent in fibrous tissues and peripheral blood specimens from the same patients. We also identified four PTCH1 mutations in 3/9 patients (33%) that were previously undetected. DISCUSSION: These data indicated that PTCH1 mutations occur in sporadic KCOTs at a higher rate than previously suspected, owing to the masking effects of the attached stromal tissues in the test samples. These results suggest that the PTCH1 gene plays a significant role in the pathogenesis of sporadic KCOTs, which is comparable to that observed in NBCCS patients.

The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome.

Mutations in the transmembrane receptor patched homolog 1 (Homo sapiens) (ptch1) are responsible for nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder that causes developmental abnormalities and predisposes the affected individuals to cancer. Many of these mutations, including mutations in the C-terminus of the large intracellular loop (ICL) of ptch1 (p.C727VfsX745 and p.S733IfsX736), result in the premature truncation of the protein. The ptch1­C727VfsX745 and ptch1-S733IfsX736 mutations have been identified in patients with NBCCS­associated keratocystic odontogenic tumors (KCOTs). In the present study, we found that the molecular mechanisms regulated by the non-canonical Hedgehog (Hh) signaling pathway through cyclin B1 are involved in the pathogenesis of NBCCS-associated KCOTs. In contrast to wild-type ptch1, ptch1-C727VfsX745 and ptch1­S733IfsX736 clearly exhibited reduced binding to cyclin B1. Moreover, the cells expressing these two mutations demonstrated an increase in cell cycle progression and these two mutation constructs failed to inhibit cell proliferation. In addition, the mutants enhanced the activity of glioma-associated oncogene family zinc finger 1 (GLI1), a downstream reporter of Hh signaling. Thus, our data suggest that the non-canonical Hh pathway mediated through ptch1 and cyclin B1 is involved in the pathogenesis of NBCCS-associated KCOTs. The C-terminus of ICL in ptch1 may also be a potential therapeutic target in the treatment of this disease.