Supplementary Figures 1-3 from Celecoxib Inhibits Interleukin-6/Interleukin-6 Receptor–Induced JAK2/STAT3 Phosphorylation in Human Hepatocellular Carcinoma Cells

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Additional file 1: of Whole-exome sequencing identifies a novel missense variant within LOXHD1 causing rare hearing loss in a Chinese family

Supplementary Materials and Tables. (a) The process of whole-exome sequencing (WES) analysis. (b) Table S1. Filtering process of WES analysis in our study. (c) Table S2. Candidate gene and variant identified by trio-WES. (d) Table S3. Variants validated by Sanger sequencing. (DOC 59 kb

Table1_Case Report: Hemophagocytic Lymphohistiocytosis Prior to the Onset of Leukemia in a Boy With CDK13-Related Disorder.DOCX

Cardinal features of CDK13-related disorders are characterized by intellectual disability, developmental delay, dysmorphic facial features, structural heart defect and structural brain abnormality. A 9-year-old boy presented with intellectual disability, development delay, characteristic craniofacial features, brain malformation, cryptorchidism, autism spectrum disorder, and recently, recurrent hemophagocytic lymphohistiocytosis (HLH) in a half year period. Further investigation revealed the diagnosis of CDK13-related disorder. Finally, we found the underlying cause of HLH is acute lymphoblastic leukemia. Probably leukemia was a coincidental finding in this boy with CDK13-related disorder, but the case herein suggests that individuals with CDK13-related disorder also face risk of developing cancers. Further detailed information could enable us to clarify this presentation because of only limited investigation in affected cases.</p

Supplementary Figure Legends 1-3 from Celecoxib Inhibits Interleukin-6/Interleukin-6 Receptor–Induced JAK2/STAT3 Phosphorylation in Human Hepatocellular Carcinoma Cells

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Table1_Case report: Genetic analysis of a novel intronic inversion variant in the SPTB gene associated with hereditary spherocytosis.pdf

Background: Hereditary spherocytosis (HS) is a congenital haemolytic anaemia attributed to dysregulation or abnormal quantities of erythrocyte membrane proteins. Currently, the most common erythrocytic gene, spectrin β (SPTB), variants are located in exons and give rise to mRNA defects. However, the genetic characteristics and pathogenic mechanisms of SPTB intronic variants are not completely understood. This study aimed to analyse a rare intronic inversion variant in the SPTB gene associated with HS, and explore the impact of the variant on SPTB mRNA splicing.Method: The clinical manifestations of the patient were summarised and analysed for spherocytosis phenotype diagnosis. The pathogenic variant was identified in the proband using targeted next-generation and Sanger sequencing. RNA sequencing was performed to analyse whether SPTB gene splicing and expression were affected.Results: Targeted next-generation sequencing identified a novel disease-associated intronic inversion variant of the SPTB gene in the proband. The inversion variant was located between intron 19 and 20, and contained the entire exon 20 and partial sequences of adjacent introns. Sanger sequencing confirmed that the intronic inversion variant only appeared in the genome of the proband, not in his parents. RNA sequencing revealed that the variant could result in the skipping of exon 20 and reduced expression of SPTB mRNA.Conclusion: This study identifies a rare intronic inversion variant in the SPTB gene associated with hereditary spherocytosis. The pathogenic variant can lead to exon 20 skipping and decreased SPTB gene expression. This finding has not been previously reported in any literature. This study can expand the intronic variant spectrum of the SPTB gene, deepen our understanding of HS pathogenesis, and contribute to the genetic diagnosis and clinical management of patients.</p

Product Identification and Distribution from Hydrothermal Conversion of Walnut Shells

Agricultural byproducts are a major source of biomass for biofuel/bioenergy conversion. The southeastern U.S. produces a great amount of nutshells from pecan, walnut, and peanut processing. In this study, walnut shells were selected as a representative agricultural byproduct, and a hydrothermal process catalyzed by both bases and acid was applied to convert the walnut shells into liquefied organic compounds. Conversion rate, major organic products, and their distribution were measured under different concentration of bases (0−1.0 M) and reaction temperature (200−300 °C, corresponding to a pressure range of 1.5−8.6 MPa). An increase in base concentration (KOH and Na2CO3 ) or reaction temperature generally resulted in higher conversation rates and was more favorable to the generation of organic compounds of lower molecular weights. HCl as a catalyst promoted the generation of levulinic acid, but the conversion rates were very low. Major compounds from hydrothermal process catalyzed by bases were phenol derivatives. Small amounts of cyclopenten derivatives and C12−18 fatty acids were detected. The effects of reaction conditions on the distribution of products were characterized by the relative abundance of each compound group categorized based on the GC retention time

Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma

Cholesteatoma is a common disease of the middle ear. Currently, surgical removal is the only treatment option and patients face a high risk of relapse. The molecular basis of cholesteatoma remains largely unknown. Here, we show that Osteopontin (OPN), a predominantly secreted protein, plays a crucial role in the development of middle ear cholesteatoma. Global transcriptome analysis revealed the loss of epithelial features and an enhanced immune response in human cholesteatoma tissues. Quantitative RT-PCR and immunohistochemical staining of middle ear cholesteatoma validated the reduced expression of epithelial markers, as well as the elevated expression of mesenchymal markers including Vimentin and Fibronectin, but not N-Cadherin, α-smooth muscle actin (α-SMA) or ferroptosis suppressor protein 1 (FSP1), indicating a partial epithelial-mesenchymal transition (EMT) state. Besides, the expression of OPN was significantly elevated in human cholesteatoma tissues. Treatment with OPN promoted cell proliferation, survival and migration and led to a partial EMT in immortalized human keratinocyte cells. Importantly, blockade of OPN signaling could remarkably improve the cholesteatoma-like symptoms in SD rats. Our mechanistic study demonstrated that the AKT-zinc finger E-box binding homeobox 2 (ZEB2) axis mediated the effects of OPN. Overall, these findings suggest that targeting the OPN signaling represents a promising strategy for the treatment of middle ear cholesteatoma.</p

Fragment-Based Drug Design and Drug Repositioning Using Multiple Ligand Simultaneous Docking (MLSD): Identifying Celecoxib and Template Compounds as Novel Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3)

We describe a novel method of drug discovery using MLSD and drug repositioning, with cancer target STAT3 being used as a test case. Multiple drug scaffolds were simultaneously docked into hot spots of STAT3 by MLSD, followed by tethering to generate virtual template compounds. Similarity search of virtual hits on drug database identified celecoxib as a novel inhibitor of STAT3. Furthermore, we designed two novel lead inhibitors based on one of the lead templates and celecoxib

XZH-5 Inhibits STAT3 Phosphorylation and Enhances the Cytotoxicity of Chemotherapeutic Drugs in Human Breast and Pancreatic Cancer Cells

<div><p>Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in breast and pancreatic cancer. Inhibiting constitutive STAT3 signaling represents a promising molecular target for therapeutic approach. Using structure-based design, we developed a non-peptide cell-permeable, small molecule, termed as XZH-5, which targeted STAT3 phosphorylation. XZH-5 was found to inhibit STAT3 phosphorylation (Tyr705) and induce apoptosis in human breast and pancreatic cancer cell lines expressing elevated levels of phosphorylated STAT3. XZH-5 could also inhibit interleukin-6-induced STAT3 phosphorylation in cancer cell lines expressing low phosphorylated STAT3. Inhibition of STAT3 signaling by XZH-5 was confirmed by the down-regulation of downstream targets of STAT3, such as Cyclin D1, Bcl-2, and Survivin at mRNA level. In addition, XZH-5 inhibited colony formation, cell migration, and enhanced the cytotoxicity of chemotherapeutic drugs when combined with Doxorubicin or Gemcitabine. Our results indicate that XZH-5 may be a potential therapeutic agent for breast and pancreatic cancers with constitutive STAT3 signaling.</p> </div

XZH-5 induces apoptosis.

<p>(A) MDA-MB-231, SUM 159, PANC-1 and SW1990 cells were treated with XZH-5 for 8 hours. Cleaved PARP and Cleaved Caspase-3 were analyzed by western blot. (B) Caspase-3/7 activity was measured in XZH-5 treated MDA-MB-231, SUM 159, PANC-1 and SW1990 cells. The data represented three independent results.</p