Background: Cancer stem cells (CSCs) are highly tumorigenic, chemotherapy-resistant, tumor growth-sustaining, and are implicated in tumor recurrence. Previous studies have shown that lysine-specific histone demethylase 1A (KDM1A) is highly expressed in several human malignancies and CSCs. However, the role of KDM1A in CSCs and the therapeutic potential of KDM1A inhibitors for the treatment of the advanced thyroid cancer are poorly understood. Methods: Firstly, KDM1A was identified as an important epigenetic modifier that maintained the stemness of thyroid cancer through a mini histone methylation modifier screen and confirmed in thyroid cancer tissues and cell lines. RNA sequence was performed to discover the downstream genes of KDM1A. The underlying mechanisms were further investigated by ChIP, IP and dual luciferase reporter assays, gain and loss of function assays. Results: Here we report that KDM1A regulates the stemness of thyroid cancer and promotes thyroid cancer progression via the Wnt/β-catenin pathway. Mechanistically, KDM1A down-regulates two antagonists of the canonical Wnt pathway, APC2 and DKK1, by demethylating H3K4me1/2 of the APC2 promoter region and the nonhistone substrate HIF-1α, resulting in the inhibition of APC2 transcription and the activation of the HIF-1α/microRNA-146a/DKK1 axis. Importantly, we also demonstrate that GSK-LSD1, a highly selective inhibitor of KDM1A, significantly inhibits thyroid cancer progression and enhances the sensitivity of thyroid cancer to chemotherapy. Conclusions: KDM1A plays an important role in thyroid cancer progression and maintains stemness, our study provides a new strategy for the therapy of advanced thyroid cancer.

The BRAFV600E mutation is the most common oncogenic mutation in thyroid cancer, suggesting an aggressive subtype of thyroid cancer and poor prognosis. Vemurafenib, a selective inhibitor of BRAFV600E, may provide therapeutic benefit in various cancers including thyroid cancer. However, the prevalence of drug resistance remains a challenge because of the feedback activation of the MAPK/ERK and PI3K/AKT pathways. In treating thyroid cancer cells with vemurafenib, we have detected reactivation of the MAPK/ERK signaling pathway as a result of the release of multiple receptor tyrosine kinases (RTKs) from the negative feedback of ERK phosphorylation. SHP2 is an important target protein downstream of the RTK signaling pathway. Decreasing it through SHP2 knockdown or the use of an inhibitor of SHP2 (SHP099) was found to significantly increase the early sensitivity and reverse the late resistance to vemurafenib in BRAFV600E mutant thyroid cancer cells. Overall, our findings suggest that blocking SHP2 reverses the reactivation of the MAPK/ERK signaling pathway caused by the activation of RTKs and improves the sensitivity of thyroid cancer to vemurafenib, which has potential implications for mechanism-based early combination strategies to treat thyroid cancer.

The use of the BRAF inhibitor vemurafenib exhibits drug resistance in the treatment of thyroid cancer (TC), and finding more effective multitarget combination therapies may be an important solution. In the present study, we found strong correlations between Ref-1 high expression and BRAF mutation, lymph node metastasis, and TNM stage. The oxidative stress environment induced by structural activation of BRAF upregulates the expression of Ref-1, which caused intrinsic resistance of PTC to vemurafenib. Combination inhibition of the Ref-1 redox function and BRAF could enhance the antitumor effects of vemurafenib, which was achieved by blocking the action of Ref-1 on BRAF proteins. Furthermore, combination treatment could cause an overload of autophagic flux via excessive AMPK protein activation, causing cell senescence and cell death in vitro. And combined administration of Ref-1 and vemurafenib in vivo suppressed PTC cell growth and metastasis in a cell-based lung metastatic tumor model and xenogeneic subcutaneous tumor model. Collectively, our study provides evidence that Ref-1 upregulation via constitutive activation of BRAF in PTC contributes to intrinsic resistance to vemurafenib. Combined treatment with a Ref-1 redox inhibitor and a BRAF inhibitor could make PTC more sensitive to vemurafenib and enhance the antitumor effects of vemurafenib by further inhibiting the MAPK pathway and activating the excessive autophagy and related senescence process.

Objective To summarize the clinical features of primary nephrotic syndrome (PNS) complicated by plastic bronchitis (PB) in children to provide guidance for treatment. Methods We conducted a retrospective review of the clinical data of 25 children hospitalized with NS complicated by PB in our Hospital between 10/2016 and 03/2019, and summarized the clinical manifestations, imaging and fiberoptic bronchoscopy (FOB) examinations, treatment course and outcome of them. Results 1). The 25 children, with a nephrotic syndrome (NS) course of one to 36 months, were all diagnosed with PB after FOB, among which 8 cases (32%) had respiratory failure and required ventilatory support. All of them started with respiratory symptoms such as fever and cough, and then suffered from dyspnea and progressive aggravation after 1–3 day(s) of onset, with rapid occurrence of bidirectional dyspnea and even respiratory failure in severe cases. 2). Laboratory test for pathogens: influenza A virus H1N1 (11 cases), influenza B virus (9 cases), adenovirus (3 cases) and mycoplasma pneumoniae (2 cases). There was no statistically significant difference (P>0.05) between children with common NS complicated by influenza virus (IV) infection (not accompanied by dyspnea) and those with kidney disease who developed PB in the white blood cell count, lymphocyte count, the inflammatory biomarkers C-reactive protein (CRP), procalcitonin (PCT) and humoral immunity (IgG level), yet the total IgG level was found significantly higher and the blood albumin level lower in the latter (P<0.05). 3). The 25 children were all examined with the FOB and treated with lavage, 15 of which had typical bronchial tree-like casts and 10 broken and stringy casts. Based on histopathological classification, all children were of Type I. 4). Twenty children (80%) with influenza were administered the antiviral drug Oseltamivir, 20 (80%) were treated with antibiotics, oral hormones were replaced with the same dosage of intravenous Methylprednisolone for 5 cases (20%), and 20 (80%) were intravenously administered gamma globulins (400–500 mg/kg x 3 days). These children showed a remarkable improvement after treatment and there were no deaths. Conclusion NS children are at high risk of influenza virus infection. Children with a severe case of NS are more susceptible to PB. If symptoms like shortness of breath, wheezing and progressive bidirectional dyspnea occur, FOB examination and lavage treatment should be performed as early as possible. Hyper-IgE-emia and hypoproteinemia may be the high risk factors for PNS complicated by PB in children.

CpG island methylator phenotype (CIMP), characterized by the concurrent and widespread hypermethylation of a cluster of CpGs, has been reported to play an important role in carcinogenesis. Limited studies have explored the role of CIMP in papillary thyroid carcinomas (PTCs). Here, in genome-wide DNA methylation analysis of 350 primary PTCs from the Cancer Genome Atlas database that were assessed using the Illumina HumanMethylation450K platform, our study helps to identify two subtypes displayed markedly distinct DNA methylation levels, termed CIMP (high levels of DNA methylation) and nCIMP subgroup (low levels of DNA methylation). Interestingly, PTCs with CIMP tend to have a higher degree of malignancy, since this subtype was tightly associated with older age, advanced pathological stage, and lymph node metastasis (all P &lt; 0.05). Differential methylation analysis showed a broad methylation gain in CIMP and subsequent generalized gene set testing analysis based on the significantly methylated probes in CIMP showed remarkable enrichment in epithelial mesenchymal transition and angiogenesis hallmark pathways, confirming that the CIMP phenotype may promote the tumor progression from another perspective. Analysis of tumor microenvironment showed that CIMP PTCs are in an immune-depletion status, which may affect the effectiveness of immunotherapy. Genetically, the significantly higher tumor mutation burden and copy number alteration both at the genome and focal level confirmed the genomic heterogeneity and chromosomal instability of CIMP. tumor Corresponding to the above findings, PTC patients with CIMP showed remarkable poor clinical outcome as compared to nCIMP regarding overall survival and progression-free survival. More importantly, CIMP was associated with worse survival independent of known prognostic factors.

Papillary thyroid cancer (PTC) is one of the most common malignant tumors in female, and estrogen can affect its progression. However, the targets and mechanisms of estrogen action in PTC remain unclear. Therefore, this study focuses on the relationship between estrogen-related genes (ERGs) expression and prognosis in PTC, particularly neuropeptide U (NMU), and its important role in tumor progression. Based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, differentially expressed genes (DEGs) predominantly enriched in ERGs were identified between PTC and normal tissue. Then, we identified ERGs that contributed most to PTC prognosis, including Transducer of ERBB2 1 (TOB1), trefoil factor 1 (TFF1), phospholipase A and acyltransferase 3 (PLAAT3), NMU, kinesin family member 20A (KIF20A), DNA topoisomerase II alpha (TOP2A), tetraspanin 13 (TSPAN13), and carboxypeptidase E (CPE). In addition, we confirmed that NMU was highly expressed in PTC and explored the effect of NMU on PTC cells proliferation in vitro and in vivo . The results showed that the proliferative capacity of PTC cells was significantly reduced with NMU knockdown. Moreover, the phosphorylation levels of the Kirsten rat sarcoma virus (KRAS) signaling pathway were significantly lower with NMU knockdown. These results suggest that ERGs, especially NMU, may be novel prognostic indicators in PTC.

Background: Celastrol, a triterpene present in the traditional Chinese medicine (TCM) Triptergium wilfordii, has been demonstrated to have remarkable anticancer activity. However, its specific mechanism on papillary thyroid carcinoma (PTC) remains to be elucidated.Methods: Potential targets of celastrol were screened from public databases. Through the Gene Expression Omnibus (GEO) online database, we obtained the bioinformatics analysis profile of PTC, GSE33630, and analyzed the differentially expressed genes (DEGs). Then, a protein-protein interaction (PPI) network was constructed by utilizing the STRING database. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. Finally, drug interactions between hub genes and celastrol were verified by molecular docking.Results: Four core nodes (MMP9, JUN, ICAM1, and VCAM1) were discerned via constructing a PPI network of 47 common targets. Through functional enrichment analysis, it was confirmed that the above target genes were basically enriched in the interleukin-17 (IL-17), nuclear factor kappa-B (NF-κB), and tumor necrosis factor (TNF) signaling pathways, which are involved in the inflammatory microenvironment to inhibit the development and progression of tumors. Molecular docking results demonstrated that celastrol has a strong binding efficiency with the 4 key proteins. Conclusions:In this research, it was demonstrated that celastrol can regulate a variety of proteins and signaling pathways against PTC, providing a theoretical basis for future clinical applications.

Background Myiasis is caused by dipterous larvae, and rarely affects the mouth. Diagnosis by traditional means is easy to be confused with other similar species. Here, we report a case of oral myiasis, in a 5-month-old infant who was diagnosed by morphological examination and molecular biological methods. Case presentation A 5-month old infant with acute myeloid leukemia was admitted due to recurrent skin masses for more than 4 months. The infant had lip swelling, which prevented him from closing the mouth and membranes were present in his mouth and there were also oral ulcers and erosions. Ten maggots were found in the mouth and one in the ear canal with pus flowing out and were confirmed as the third stage larvae of Sarcophaga ruficornis by morphological examination and a comparison of sequence of cytochrome oxidase subunit 1 (COX1) gene. After removal of the maggots and chemotherapy, the infant ’s condition was gradually improved. Conclusions To the best of our our knowledge, this is the first neonatal oral myiasis case reported in China and its diagnosis requires a high index of suspicion. Microscopy combined with specific DNA sequence analysis is an effective technological tool to provide rapid diagnoses of the larva specimen and cases of rare diseases, as illustrated in the current case.