Family with sequence similarity 20-member C (FAM20C), a recently characterized Golgi kinase, performs numerous biological functions by phosphorylating more than 100 secreted proteins. However, the role of FAM20C in the salivary glands remains undefined. The present study demonstrated that FAM20C is mainly located in the cytoplasm of duct epithelial cells in the salivary glands. Fam20c f/f ; Mmtv-Cre mice were created in which Fam20c was inactivated in the salivary gland cells and observed that the number of ducts and the ductal cross-sectional area increased significantly, while the number of acinar cells was reduced. The granular convoluted tubules (GCTs) exhibited an accumulation of aberrant secretory granules, along with a reduced expression and altered distribution patterns of β nerve growth factor, α-amylase and bone morphogenetic protein (BMP) 4. This abnormality suggested that the GCT cells were immature and exhibited defects in developmental and secretory functions. In accordance with the morphological alterations and the reduced number of acinar cells, FAM20C deficiency in the salivary glands significantly decreased the salivary flow rate. The Na + , Cl − and K + concentrations in the saliva were all significantly increased due to dysfunction of the ducts. Furthermore, Fam20c deficiency significantly increased BMP2 and BMP7 expression, decreased BMP4 expression, and attenuated the canonical and noncanonical BMP signaling pathways in the salivary glands. Collectively, the results of the present study demonstrate that FAM20C is a key regulator of acinar and duct structure and duct maturation and provide a novel avenue for investigating novel therapeutic targets for oral diseases including xerostomia.
Metastasis of breast cancer represents the major reason for its poor prognosis, leading to high mortality. In breast cancer, a tumor suppressor gene TP53 is commonly mutated. TP53 mutation leads to an altered expression of various genes, an event that is associated with aggressive tumor and is a strong independent marker for survival. In this study, we identified a novel p53 target gene, immunoglobulin superfamily 9 (IGSF9). IGSF9 is generally down-regulated in breast cancer tissues. Loss of IGSF9 is associated with frequent metastasis and poor prognosis of breast cancer patients. Wild-type p53, but not R175H mutant, trans-activates the transcription of IGSF9 via binding to its promoter (−137 to −131 bp), inhibits epithelial-mesenchymal transition (EMT), consequently the inhibition of breast cancer cells migration and invasion. IGSF9 interacts with focal adhesion kinase (FAK) and inhibits FAK/AKT signaling activity. PND1186, FAK inhibitor, inhibits breast cancer metastasis induced by IGSF9 knockdown in vitro and in vivo. Taken together, IGSF9 is trans-activated by p53 and inhibits breast cancer metastasis by modulating FAK/AKT signaling pathway. IGSF9 could serve as a prognostic marker and potential therapeutic target for breast cancer.
Mounting evidence suggests that distinct microbial communities reside in tumors and play important roles in tumor physiology. Recently, Nejman et al. profiled the composition and localization of intratumoral bacteria using 16S DNA sequencing and histological visualization methods across seven tumor types, including human glioblastoma. However, considering potential contamination in their sample origins and processing, the results based on traditional histological methods need to be validated. Here, we propose a three-dimensional (3D) intratumoral microbiota visualization and quantification protocol to observe microbiota in intact tumor tissues on the premise of avoiding possible contamination in the surface of tissues, based on tissue clearing, immunofluorescent labeling, microscopy imaging, and image processing. For the first time, we have achieved 3D quantitative imaging of bacterial LPS fluorescent signals deep in gliomas in a contamination-free manner, which was founded mostly localized near nuclear membranes or in the intercellular space. Through an automated statistical algorithm, reliable signals can be distinguished for further analysis of their sizes, distribution, and fluorescence intensities. Combining two-dimensional images from multiple thin-section histological methods, including immunochemistry and fluorescence in situ hybridization, we provide a comprehensive histological investigation of the morphology and distribution of these signals on human glioma samples. We expect that this multi-evidence chain will provide supporting proof for the presence of intratumoral bacteria in human glioma and that the integrated pipeline can be applied to investigate the native bacteria within diverse tumors and contribute to the interpretation of their direct roles in the tumor microenvironment.
Backgrounds Controversy surrounding CpG island methylator phenotype (CIMP) in glioma exists with regard to its prognostic value.Methods PubMed, EMBASE, and Cochrane Library databases were searched for studies describing molecular and clinicopathological features, and overall survival of gliomas stratified by CIMP status. Associations of CIMP with outcome parameters were estimated using odds ratio (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) using a fixed or random effects model.Results A total of 12 studies involving 2386 gliomas (1051 CIMP-positive and 1335 CIMP-negative) were included. Molecular analysis showed that CIMP is more frequent in IDH1-mutated gliomas (OR 229.07; 95% CI 138.72–378.26) and 1p19q LOH gliomas (OR 5.65; 95% CI 2.66–12.01), though CIMP was not associated with EGFR mutation (OR 0.14; 95% CI 0.05–0.43) or MGMT promoter methylation (OR 3.01; 95% CI 0.79–11.48). Clinicopathological analysis showed that CIMP is more frequent in oligodendroglioma (OR 5.51; 95% CI 3.95–7.70), but less frequent in glioblastoma (OR 0.14; 95% CI 0.10–0.19). However, CIMP was not associated with anaplastic oligoastrocytomas (OR 1.57; 95% CI 1.24-2.00) or oligoastrocytoma (OR 0.79; 95% CI 0.35–1.76). We found that CIMP-positive glioma was associated with a longer overall survival (HR -0.57; 95% CI -0.97– -0.16).Conclusions A CIMP-positive glioma has better prognosis and its own molecular features (such as IDH1 and 1p19q LOH mutations) and clinicopathological features. These conditions suggest CIMP could be used as an independent prognostic marker for glioma.
Background: Glucose variability may contribute to macrovascular complications of diabetes but evidence for its association with diabetic retinopathy (DR) is limited. This study is aimed to investigate the correlation between incremental glucose peak (IGP) and diabetic retinopathy (DR) in Chinese population with type 2 diabetes.Methods: A hospital-registry, case-control study collecting data from Liaoning Diabetic Microvascular Complications Study (LD-MCS) during 2012-2018. 795 adults with DR were included and matched with two diabetic controls per case (n = 1590) by gender and age. IGP was defined as the peak minus baseline plasma glucose value during 5-point oral glucose tolerance test (OGTT). DR was diagnosed by two-field fundus photographs under Early Treatment Diabetic Retinopathy Study criteria and stratified into mild non-proliferative DR (NPDR), moderate NPDR, and vision-threatening DR (VTDR). Logistic regression analysis was applied to determine the relationships.Results: Among 2385 participants (age, 58.40±11.52 years; 57.11% men), higher IGP was independently associated with the presence of any DR (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02-1.07; P < 0.001), moderate NPDR (OR, 1.06; 95% CI, 1.01-1.12; P = 0.020) and VTDR (OR, 1.13; 95% CI, 1.07-1.19; P < 0.001), respectively. Moreover, estimated ratio for any DR and VTDR from low-quartile IPG increased by 1.33 (95% CI, 1.04-1.70; P for trend = 0.021) and 3.64 (95% CI, 1.97-6.72; P for trend < 0.001), respectively.Conclusions: OGTT-derived IGP was independently associated with DR severity scales in Chinese patients with type 2 diabetes. More attention by health care personnel needs to be paid to glucose variability of this population.
Background: Nitrous oxide (N 2 O), due to its euphoriant properties is often abused for recreational purpose. Case Report: A 38-year-old male who admitted to inhaling recreational nitrous oxide more than five months, presented with a progressive symmetrical tingling sensations and weakness of limbs. Serum vitamin B 12 was lower than normal. Magnetic resonance imaging (MRI) of the spine demonstrated hyperintensity of the posterior cord extending from C1-C5. Nerve conduction velocity test showed slowed motor conduction velocities and delayed or absent F-waves consistent with demyelinating neuropathy. The patient was managed with B 12 supplement and his nerve function basically returned to normal after three months. Conclusion: This is a rare case of subacute combing degeneration caused by excessive inhalation of nitrous oxide.
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