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Comprehensive Analysis of lncRNA-Mediated ceRNA Crosstalk and Identification of Prognostic Biomarkers in Wilms’ Tumor
Wilms’ tumor (WT) is the most common type of childhood kidney cancer, and most cases present with favorable histology and respond well to standard treatment. However, a subset of patients with WT is diagnosed with bilateral, relapsed, and high-risk tumors which remain the leading cause of cancer-related death in children. Long noncoding RNAs (lncRNAs) and their aberrant expression have currently been attracting great attention as oncogenes or tumor suppressors during tumor initiation and progression. So far, their roles and related competitive endogenous RNA (ceRNA) network remain unelucidated in nephroblastoma pathogenesis. We comprehensively integrated lncRNA, microRNA (miRNA), and messenger RNA (mRNA) expression profiles from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and screened out differentially expressed mRNAs (DEMs), lncRNAs (DELs), and miRNAs (DEMis) to construct a ceRNA network based on the information generated from miRcode, miRTarBase, TargetScan, and miRDB. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to analyze the functional characteristics of DEMs in the ceRNA network. The interaction between protein molecules was also analyzed by establishing a protein-protein interaction network. Finally, prognosis-related biomarkers were identified via survival analysis. Initially, 1647 DELs, 115 DEMis, and 3280 DEMs (|log FC| > 2; FDR < 0.01) were obtained using the R package. Next, we constructed a lncRNA-miRNA-mRNA network (ceRNA network), in which 176 DELs, 24 DEMis, and 141 DEMs were identified. Furthermore, 148 functional enrichment terms from GO were identified and 29 KEGG pathways were found to be significantly enriched. We also integrated patient clinical information to analyze the association between DERNAs and patient prognosis. We found that high expression of 8 DELs (LINC00473, AL445228.2, DENND5B−AS1, DLEU2, AC123595.1, AC135178.1, LINC00535, and LMO7−AS1) and 4 DEMs (CEP55, DEPDC1, PHF19, and TRIM36) correlated with poor survival in a patient with WT, whereas high expression of 2 DELs (MEG3 and RMST), 1 DEM (KIAA0922), and 1 DEMi (hsa−mir−200a) could possibly lead to better clinical outcomes. For the first time, the present study provided a novel insight into lncRNA-related ceRNA networks and identified potential prognostic biomarkers in Wilms’ tumor.
MicroRNA-200a Promotes Phagocytosis of Macrophages and Suppresses Cell Proliferation, Migration, and Invasion in Nasopharyngeal Carcinoma by Targeting CD47
Nasopharyngeal carcinoma (NPC) causes severe oncogenic lesions in the nasopharynx. CD47, a transmembrane integrin-associated protein, plays a key role in the ability of tumor cells to escape phagocytosis, working as an immune checkpoint in the immune response. Besides this role, CD47 has been reported to regulate cell proliferation and migration. The present study addresses the relationship between CD47 and microRNA-200a and examines their regulatory mechanisms in NPC. Bioinformatics analyses and dual-luciferase reporter assays were used to confirm the putative relationship between miR-200a and CD47, and their interaction was further detected using western blotting and RT-PCR. Further, results showed that miR-200a affect NPC cell proliferation, migration, and invasion by regulating CD47. A cell phagocytosis assay showed that miR-200a and a CD47 monoclonal antibody increased the sensitivity of NPC cells to macrophage phagocytosis by inhibiting the functions of CD47. Additionally, miR-200a expression was suppressed and CD47 expression increased in both clinical NPC tissues and cell lines. Taken together, these results show the miR-200a/CD47 combination as a potential therapeutic for treatment of NPC.
Sulfonamide-Based Azaheterocyclic Schiff Base Derivatives as Potential Carbonic Anhydrase Inhibitors: Synthesis, Cytotoxicity, and Enzyme Inhibitory Kinetics
A series of sulfonamide-bearing azaheterocyclic Schiff base derivatives 3(a-j) were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides 1(a-d) were reacted with N2H4 to get aromatic sulfonyl hydrazides 2(a-d). The intermediate hydrazides 2(a-d) were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases 3(a-j). The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of 3(a-j) on carbonic anhydrase activity were determined, and it was found that derivative 3c exhibited the most potent activity with IC50 among all other derivatives and is also more active than standard acetazolamide (IC50). The enzyme inhibitory kinetics results determined by Lineweaver-Burk plots revealed that compound 3c inhibits the enzyme by noncompetitive mode of inhibition with value 8.6 μM. The molecular docking investigations of the synthesized analogues 3(a-j) were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF-7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose-dependent manner. Based on our investigations, it was suggested that analogue 3c may serve as core structure to project carbonic anhydrase inhibitors with greater potency.
A Functional Polymorphism in the Promoter Region of Interleukin-12B Increases the Risk of Colorectal Cancer
Objective. To investigate whether the polymorphisms of interleukin-12B (IL-12B) were associated with the risk of developing colorectal cancer (CRC). Patients and Methods. Genotypes of rs17860508 and rs3212227 were determined by polymerase chain reaction with a direct sequencing method in 329 CRC patients and 342 matched healthy control subjects. The expression of IL-12B mRNA was determined by RT-qPCR in 50 pairs of CRC tissues and their adjacent normal tissues. Results. Compared with TTAGAG/TTAGAG genotype of rs17860508, the GC/GC and TTAGAG/GC genotypes may significantly increase the risk of CRC (OR = 1.81, 95% CI = 1.18–2.78; OR = 1.46, 95% CI = 1.01–2.12, respectively). Furthermore, the mRNA levels of IL-12B were significantly higher in the CRC tissues from patients with the rs17860508 GC/GC genotype than those with the TTAGAG/GC () and TTAGAG/TTAGAG () genotypes. Conclusion. These data suggested that the rs17860508 GC/GC genotype might upregulate IL-12B expression at the transcriptional level and thus increase the risk of CRC.
Skull Abnormalities in Cadavers in the Gross Anatomy Lab
Background. The skull encompasses and houses one of the most important organs in the body—the brain—and like all tissues in the body, it is comprised of living cells that are constantly remodeling as this maintains the strength and homeostasis of the bone. In the present study, abnormal bone growth patterns were observed and the possible causes of said findings were investigated in multiple cadaver skulls dissected during head and neck anatomy courses at Detroit Mercy Dental over the past year. There are many factors, both intrinsic and extrinsic, with differences in stimulation to the skull resulting in skull abnormalities. Materials and Methods. For this study, skull abnormalities were examined from 65 formalin-embalmed cadaver heads, obtained from the Gross Anatomy Laboratory at the University of Detroit Mercy School of Dentistry between the years 2016 and 2019. We have recorded the age, sex, and previous chief medical issues of all lab specimens used in the study. Skulls were later evaluated for possible indications of bone disease such as hypertosis frontalis interna (HFI) or Paget’s disease. Results. Among the sixty-five specimens provided to the Detroit Mercy Dental cadaver lab, 19 specimens (29%) were found to present with irregular, undulating, thickening of the frontal bone internal surface. The findings located on the skulls closely resembled the gross anatomic appearance of HFI or Paget’s disease; however, a conclusive diagnosis of these skull abnormalities cannot be made without a pathologist biopsy and radiological examination. Twelve of the nineteen specimens that displayed possible bone disease, approximating 63% prevalence, were females; their ages ranged from 68 to 95 years old. Thus, seven of the nineteen specimens exhibiting features of skull abnormalities, approximating 36% prevalence, were males with ages ranging from 70 to 103 years old. In addition, five of these nineteen specimens collected (26% prevalence) had been diagnosed with neurological disorders, including Alzheimer’s, dementia, depression, and Parkinson’s disease. In the current study, the proportion of specimens exhibiting skull abnormalities was higher compared to the overall prevalence observed in previous studies. Conclusion. Possible causes of observed anatomical abnormalities in the skull of cadavers of a gross anatomy laboratory were investigated, and it was determined that hypertosis frontalis interna (HFI) may contribute to such abnormalities. This is a condition that affects bone growth in the frontal skull. Our numbers of skull abnormalities were higher than previous studies and might be due to the fact that HFI was predominately present as an incidental finding during imaging of postmenopausal females or observed postmortem in cadavers. In addition, Paget’s disease or hormonal imbalances could also result in similar features, and thus cannot be ruled out as a plausible cause. Paget’s disease causes the bone to deposit at a faster rate than normal, which will result in thick and brittle bone. Studies that will involve further examination of new cadavers for the presence of HFI is needed, either using biopsy specimens and/or radiological examination to explore possible causes for the abnormal bone growth in the frontal bone.
The Antiosteoporosis Effects of Yishen Bugu Ye Based on Its Regulation on the Differentiation of Osteoblast and Osteoclast
Yishen Bugu Ye (YSBGY), a traditional Chinese medicine comprising 12 types of medicinal herbs, is often prescribed in China to increase bone strength. In this study, the antiosteoporotic effects of YSBGY were investigated in C57BL/6 mice afflicted with dexamethasone- (Dex-) induced osteoporosis (OP). The results showed that YSBGY reduced the interstitial edema in the liver and kidney of mice with Dex-induced OP. It also increased the number of trabecular bone elements and chondrocytes in the femur, promoted cortical bone thickness and trabecular bone density, and modulated the OP-related indexes in the femur and tibia of OP mice. It also increased the serum concentrations of type I collagen, osteocalcin, osteopontin, bone morphogenetic protein-2, bone morphogenetic protein receptor type 2, C-terminal telopeptide of type I collagen, and runt-related transcription factor-2 and reduced those of tartrate-resistant acid phosphatase 5 and nuclear factor of activated T cells in these mice, suggesting that it improved osteoblast differentiation and suppressed osteoclast differentiation. The anti-inflammatory effect of YSBGY was confirmed by the increase in the serum concentrations of interleukin- (IL-) 33 and the decrease in concentrations of IL-1, IL-7, and tumor necrosis factor-α in OP mice. Furthermore, YSBGY enhanced the serum concentrations of superoxide dismutase and catalase in these mice, indicating that it also exerted antioxidative effects. This is the first study to confirm the antiosteoporotic effects of YSBGY in mice with Dex-induced OP, and it showed that these effects may be related to the YSBGY-induced modulation of the osteoblast/osteoclast balance and serum concentrations of inflammatory factors. These results provide experimental evidence supporting the use of YSBGY for supporting bone formation in the clinical setting.