Rare Recurrent EWSR1-PLAGL1 Rearranged Intracranial Tumor With Biphasic Epithelioid Differentiation: One Case Report With Literature Review.

EWSR1-rearranged tumors encompass a rare and heterogeneous group of entities with features of the central nervous system (CNS) mesenchymal and primary glial/neuronal tumors. EWSR1-PLAGL1 gene fusion is a particularly rare form of rearrangement. We presented a recurrent intracranial EWSR1-PLAGL1 rearranged tumor and reviewed the relevant literature. In this case, histopathology and immunohistochemistry (IHC) were evaluated for both the primary and relapsed tumors. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were performed for the relapsed tumor. We compared the morphology, IHC results and molecular features with the previously reported EWSR1-PLAGL1 rearranged CNS tumors. Our case exhibited a unique feature with a variable biphasic pattern of epithelioid differentiation, which differed from the two reported groups. The primary and relapsed tumors both expressed cytokeratin of the focal area with epithelioid differentiation. The recurrent tumor showed an increased proliferation index (average Ki-67 index of 15%) compared with the primary tumor (average Ki-67 index of 5%). NGS showed that TERT promoter mutation was the only molecular change besides EWSR1-PLAGL1 fusion. Our study provides further insight into intracranial tumors with EWSR1-PLAGL1 fusion, representing a distinct CNS tumor with no-reported histological and immunohistochemical features. Future studies, particularly for the biphasic differentiation and the role of TERT promoter mutation were needed to clarify this unusual chromosomal rearrangement in the CNS tumor.

Metabolomic Analysis Reveals that SPHK1 Promotes Oral Squamous Cell Carcinoma Progression through NF-κB Activation.

BACKGROUND: Metabolic disorders are significant in the occurrence and development of malignant tumors. Changes of specific metabolites and metabolic pathways are molecular therapeutic targets. This study aims to determine the metabolic differences between oral squamous cell carcinoma (OSCC) tissues and paired adjacent noncancerous tissues (ANT) through liquid chromatography-mass spectrometry (LC-MS). SPHK1 is a key enzyme in sphingolipid metabolism. This study also investigates the potential role of SPHK1 in OSCC. MATERIALS AND METHODS: This study used LC-MS to analyze metabolic differences between OSCC tissues and paired ANT. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) were applied to explain the significance of phospholipid metabolism pathways in the occurrence and development of OSCC. Through further experiments, we confirmed the oncogenic phenotypes of SPHK1 in vitro and in vivo, including proliferation, migration, and invasion. RESULTS: The sphingolipid metabolic pathway was significantly activated in OSCC, and the key enzyme SPHK1 was significantly upregulated in oral cancer tissues, predicting poor OSCC prognosis. In this study, SPHK1 overexpression was associated with high-grade malignancy and poor OSCC prognosis. SPHK1 targeted NF-κB by facilitating p65 expression to regulate OSCC tumor progression and promote metastasis. CONCLUSIONS: This study identified metabolic differences between OSCC and paired ANT, explored the carcinogenic role of overexpressed SPHK1, and revealed the association of SPHK1 with poor OSCC prognosis. SPHK1 targets NF-κB signaling by facilitating p65 expression to regulate tumor progression and promote tumor metastasis, providing potential therapeutic targets for diagnosing and treating oral tumors.

Exosomal microRNA-23b-3p promotes tumor angiogenesis and metastasis by targeting PTEN in salivary adenoid cystic carcinoma.

MicroRNA (miR)-23b-3p is known to target various genes that are involved in cancer-related pathways. Exosomes are emerging intercellular communication agents. Exosomes secreted by cancer cells can deliver active molecules to the surrounding stromal cells, thereby influencing the recipient cells and promoting the development of cancers. However, the role of exosomal miR-23b-3p in salivary adenoid cystic carcinoma (SACC) is not yet clear. In this study, we set out to investigate the potential role of cancer-derived exosomal miR-23b-3p-related phosphatase and tensin homolog deleted on chromosome 10 in the alteration of angiogenesis and vascular permeability in SACC. We investigated the effect of exosomal miR-23b-3p on the progression of SACC. In vitro experiments indicated that exosomal miR-23b-3p led to an upregulation of vascular permeability, and reduced expression of tight junction proteins. In addition, exosomal miR-23b-3p also enhanced angiogenesis and migration. Next, the angiogenic effect of exosomal miR-23b-3p was validated in vivo, as it led to an increase in the tumor microvasculature. Furthermore, the growth rate of SACC was faster after injection of exosomes loaded with cholesterol-modified miR-23b-3p in mice. In conclusion, these results revealed that SACC cell-derived exosomes play an important role in promoting angiogenesis and local vascular microleakage of SACC by transporting miR-23b-3p, which suggests that miR-23b-3p in the exosomes may be a potential biomarker for distant metastasis of SACC. This suggests the potential of a novel therapeutic target by delivering anti-miR-23b-3p that focuses on exosomes.

Follistatin-like 1 suppresses osteoblast differentiation of bone marrow mesenchymal cells during inflammation.

OBJECTIVE: The current study aimed to explore the effect of Follistatin-like 1 (FSTL1) on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in an inflammatory environment. DESIGN: Animal models of FSTL1-deficiency and wild-type mice were used, and the micro-CT images of the femoral head were evaluated. Mouse bone marrow mesenchymal stem cells were treated with various concentrations of recombinant FSTL1 (rFSTL1) in an inflammatory environment in vitro. Meanwhile, overexpression or knockdown of FSTL1 through lentiviral transfection was performed. Alkaline phosphatase (ALP) activity was tested, and Alizarin Red staining (ARS) was performed to evaluate osteogenic differentiation ability. The mRNA expression level of osteogenesis-related genes was detected by RT-qPCR. RESULTS: In vivo experiments revealed a higher number of femoral skulls, higher trabecular thickness, smaller trabecular space, and less osteoporosis in FSTL1-knockdown mice than in the wild-type mice. The BMSCs with overexpression of FSTL1 or those treated with recombinant FSTL1 (rFSTL1) showed suppression of ALP activity, calcium nodule formation, and expression of osteogenesis-related genes osteopontin (OPN), osteocalcin (OCN), collagen type I alpha 1 (Col1α1), and more importantly, rFSTL1 functions in a dose-dependent manner. In contrast, FSTL1 knockdown promoted the osteogenesis activity and the expression of these osteogenesis-related genes in vitro. CONCLUSIONS: FSTL1 is an osteogenic suppressor that inhibits the osteogenic differentiation of BMSCs during inflammation and it can be a new target for bone regeneration.

Identification of pivotal microRNAs involved in the development and progression of salivary adenoid cystic carcinoma.

BACKGROUND: miRNAs and mRNAs have been significantly implicated in tumorigenesis and served as promising prognostic biomarkers for human cancer. Hence, this study was aimed to develop the pivotal miRNA biomarkers-based prognostic signature for salivary adenoid cystic carcinoma. METHODS: The miRNA and mRNA expression data were integrated from the gene expression omnibus database to study their involvement in salivary adenoid cystic carcinoma development and progression. Gene ontology and kyoto encyclopedia of genes and genomes were conducted to analyze the biological pathways. Reverse transcription-quantitative PCR was used to verify the expression of selected miRNAs in salivary adenoid cystic carcinoma and corresponding normal tissues. RESULTS: There were 386 differentially expressed genes: 158 upregulated and 228 downregulated genes and 102 differentially expressed miRNAs: 78 upregulated and 24 downregulated miRNAs in the salivary adenoid cystic carcinoma samples. A miRNA-mRNA network containing 11 miRNAs and 199 genes was subsequently constructed. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis revealed that the genes targeted by the 11 miRNAs were mostly involved in tumor-related pathways and processes, such as miRNAs in cancer, focal adhesion, neurotrophin signaling pathway, and the PI3K-Akt signaling pathway. Among them, 4 miRNAs (miR-375, miR-494, miR-34c-5p, and miR-331-3p) were selected to verify by reverse transcription-quantitative PCR in 36 pairs of collected salivary adenoid cystic carcinoma and adjacent nontumor samples. Overall survival analysis revealed that the higher expression of miR-331-3p was significantly associated with a worst overall survival and multivariate Cox regression analysis suggested that hsa-miR-331-3p could be an independent prognostic factor for salivary adenoid cystic carcinoma. CONCLUSION: Our results revealed that 4-miRNAs signature was a powerful prognostic biomarker for salivary adenoid cystic carcinoma, which provide a basis for exploring deeper mechanisms regarding the progression of salivary adenoid cystic carcinoma, and leading to the development of potential therapeutic strategies.

Sphk1 promotes salivary adenoid cystic carcinoma progression via PI3K/Akt signaling.

The progression of salivary adenoid cystic carcinoma (SACC) is closely related to abnormal gene expression. Herein, the role of Sphk1 in SACC was explored. Sphk1 was overexpressed in SACC tissues. In SACC cell lines, Sphk1 induced cell proliferation, inhibited apoptosis, and promoted cell migration. Moreover, Sphk1 overexpression induced up-regulation of the PI3K protein level and AKT phosphorylation level. Rescue assays further showed that activation of the Sphk1 /PI3K/Akt pathway affected various biological functions of SACC cells. Together, these findings suggested that Sphk1 promotes salivary tumorigenesis by activating the PI3K/ Akt pathway, which may provide novel intervention targets for SACC treatment.

Multicenter analysis and a rapid screening model to predict early novel coronavirus pneumonia using a random forest algorithm.

ABSTRACT: Early determination of coronavirus disease 2019 (COVID-19) pneumonia from numerous suspected cases is critical for the early isolation and treatment of patients.The purpose of the study was to develop and validate a rapid screening model to predict early COVID-19 pneumonia from suspected cases using a random forest algorithm in China.A total of 914 initially suspected COVID-19 pneumonia in multiple centers were prospectively included. The computer-assisted embedding method was used to screen the variables. The random forest algorithm was adopted to build a rapid screening model based on the training set. The screening model was evaluated by the confusion matrix and receiver operating characteristic (ROC) analysis in the validation.The rapid screening model was set up based on 4 epidemiological features, 3 clinical manifestations, decreased white blood cell count and lymphocytes, and imaging changes on chest X-ray or computed tomography. The area under the ROC curve was 0.956, and the model had a sensitivity of 83.82% and a specificity of 89.57%. The confusion matrix revealed that the prospective screening model had an accuracy of 87.0% for predicting early COVID-19 pneumonia.Here, we developed and validated a rapid screening model that could predict early COVID-19 pneumonia with high sensitivity and specificity. The use of this model to screen for COVID-19 pneumonia have epidemiological and clinical significance.

Risk factors analysis of COVID-19 patients with ARDS and prediction based on machine learning.

COVID-19 is a newly emerging infectious disease, which is generally susceptible to human beings and has caused huge losses to people's health. Acute respiratory distress syndrome (ARDS) is one of the common clinical manifestations of severe COVID-19 and it is also responsible for the current shortage of ventilators worldwide. This study aims to analyze the clinical characteristics of COVID-19 ARDS patients and establish a diagnostic system based on artificial intelligence (AI) method to predict the probability of ARDS in COVID-19 patients. We collected clinical data of 659 COVID-19 patients from 11 regions in China. The clinical characteristics of the ARDS group and no-ARDS group of COVID-19 patients were elaborately compared and both traditional machine learning algorithms and deep learning-based method were used to build the prediction models. Results indicated that the median age of ARDS patients was 56.5 years old, which was significantly older than those with non-ARDS by 7.5 years. Male and patients with BMI > 25 were more likely to develop ARDS. The clinical features of ARDS patients included cough (80.3%), polypnea (59.2%), lung consolidation (53.9%), secondary bacterial infection (30.3%), and comorbidities such as hypertension (48.7%). Abnormal biochemical indicators such as lymphocyte count, CK, NLR, AST, LDH, and CRP were all strongly related to the aggravation of ARDS. Furthermore, through various AI methods for modeling and prediction effect evaluation based on the above risk factors, decision tree achieved the best AUC, accuracy, sensitivity and specificity in identifying the mild patients who were easy to develop ARDS, which undoubtedly helped to deliver proper care and optimize use of limited resources.

A rapid screening model for early predicting novel coronavirus pneumonia in Zhejiang Province of China: a multicenter study.

Novel coronavirus pneumonia (NCP) has been widely spread in China and several other countries. Early finding of this pneumonia from huge numbers of suspects gives clinicians a big challenge. The aim of the study was to develop a rapid screening model for early predicting NCP in a Zhejiang population, as well as its utility in other areas. A total of 880 participants who were initially suspected of NCP from January 17 to February 19 were included. Potential predictors were selected via stepwise logistic regression analysis. The model was established based on epidemiological features, clinical manifestations, white blood cell count, and pulmonary imaging changes, with the area under receiver operating characteristic (AUROC) curve of 0.920. At a cut-off value of 1.0, the model could determine NCP with a sensitivity of 85% and a specificity of 82.3%. We further developed a simplified model by combining the geographical regions and rounding the coefficients, with the AUROC of 0.909, as well as a model without epidemiological factors with the AUROC of 0.859. The study demonstrated that the screening model was a helpful and cost-effective tool for early predicting NCP and had great clinical significance given the high activity of NCP.

Hepatic progenitor cell activation is induced by the depletion of the gut microbiome in mice.

The homeostasis of the gut microbiome is crucial for human health and for liver function. However, it has not been established whether the gut microbiome influence hepatic progenitor cells (HPCs). HPCs are capable of self-renewal and differentiate into hepatocytes and cholangiocytes; however, HPCs are normally quiescent and are rare in adults. After sustained liver damage, a ductular reaction occurs, and the number of HPCs is substantially increased. Here, we administered five broad-spectrum antibiotics for 14 days to deplete the gut microbiomes of male C57BL/6 mice, and we measured the plasma aminotransferases and other biochemical indices. The expression levels of two HPC markers, SRY-related high mobility group-box gene 9 (Sox9) and cytokeratin (CK), were also measured. The plasma aminotransferase activities were not affected, but the triglyceride, lactate dehydrogenase, low-density lipoprotein, and high-density lipoprotein concentrations were significantly altered; this suggests that liver function is affected by the composition of the gut microbiome. The mRNA expression of Sox9 was significantly higher in the treated mice than it was in the control mice (p < 0.0001), and a substantial expression of Sox9 and CK was observed around the bile ducts. The mRNA expression levels of proinflammatory factors (interleukin [IL]-1ß, IL-6, tumor necrosis factor [TNF]-α, and TNF-like weak inducer of apoptosis [Tweak]) were also significantly higher in the antibiotic-treated mice than the levels in the control mice. These data imply that the depletion of the gut microbiome leads to liver damage, negatively impacts the hepatic metabolism and function, and activates HPCs. However, the underlying mechanisms remain to be determined.

Transitions of the Understanding and Definition of Primary Glaucoma.

OBJECTIVE: In previous decades, glaucoma has been primarily attributed to elevated intraocular pressure (IOP), but this has gradually been replaced by the development of optic neuropathy as the central concept of glaucoma in developed countries. However, there still remain strong controversies in the definition of glaucoma in China. In this current review, we are going to discuss these controversies and elaborate on the historical transitions of the definition of glaucoma both in China and developed countries. Furthermore, we will briefly describe the "ocular-cranial pressure gradient" theory and discuss the relationship between glaucoma and degenerative diseases of the central nervous system (CNS) in order to show the complex pathogenesis of glaucoma and the importance for the modification to the definition of glaucoma. DATA SOURCES: We performed a comprehensive search in both PubMed and SinoMed using the following keywords: (a) "primary glaucoma" and "guideline," (b) "ocular-cranial pressure gradient," and (c) "glaucoma," "Alzheimer's disease," and "Parkinson's disease." The literature search included the related articles with no restrictions on publication date. STUDY SELECTION: The primary references were Chinese and English articles including (a) original guidelines and expert consensuses of primary glaucoma, (b) reviews focusing on the differences between various versions of these guidelines and consensuses, and (c) papers about ocular-cranial pressure gradient theory and the relationship between glaucoma and CNS degenerative diseases. RESULTS: The definitions and classifications of both primary open-angle glaucoma and primary angle-closure glaucoma differ between Chinese glaucoma consensuses and international primary glaucoma guidelines. Chinese definitions and classifications put more emphasis on the IOP, while international guidelines put more emphasis on the presence of optic neuropathy. The ocular-cranial pressure gradient theory and the research on the relationship between glaucoma and CNS degenerative diseases have provided new directions for exploring the pathogenesis of glaucoma. CONCLUSIONS: As regards the definition and classification of primary glaucoma, we find that there are still some discrepancies between Chinese expert consensuses and international guidelines. Glaucoma is a disease with complex etiologies, while its common characteristic is a specific optic neuropathy. The current definition and understanding of glaucoma is an ongoing and evolving process, reflecting our latest available evidence on its pathogenesis. Chinese ophthalmology community may need to update our guidelines, accommodating these latest developments.

Lentivirus-mediated angiopoietin-2 gene silencing decreases TNF-α induced apoptosis of alveolar epithelium cells.

OBJECTIVE: To investigate the role of angiopoietin-2 (Ang-2) in tumor necrosis factor-α (TNF-α) induced apoptosis of alveolar epithelium cells (AECs). METHODS: TNF-α was used to induce human alveolar epithelial HPAEpiC cells, and Ang-2 siRNA vector was transfected to the HPAEpiC cells. RT-PCR and Western blot were used. TUNEL staining was applied to observe apoptosis, and annexin V-FITC-PI staining was used to calculate apoptosis rate. RESULTS: mRNA and protein expressions of Ang-2, activated Bax, and cleaved caspase-3 in HPAEpiC cells were up-regulated, but the expression level of Bcl-2 decreased (P < 0.05). After transfection of Ang-2 siRNA, mRNA and protein expressions of Ang-2, activated Bax, and cleaved caspase-3 in HPAEpiC cells were down-regulated, but the expression level of Bcl-2 increased (P < 0.05). The number of apoptotic cells increased after TNF-α treatment; however, the number decreased after Ang-2 siRNA transfection. Annexin V-FITC-PI staining verified that the total number of apoptotic cells was elevated with TNF-α treatment, but declined after transfection of Ang-2 siRNA. CONCLUSIONS: The expression level of Ang-2 increased during TNF-α-induced apoptosis. Inhibiting Ang-2 expression may suppress the early stages of cell apoptosis and the degree of TNF-α-induced apoptosis.

A TET2 rs3733609 C/T genotype is associated with predisposition to the myeloproliferative neoplasms harboring JAK2(V617F) and confers a proliferative potential on erythroid lineages.

Common germline single-nucleotide polymorphisms (SNPs) at JAK2 locus have been associated with Myeloproliferative neoplasms (MPN). And, the germline sequence variant rs2736100 C in TERT is related to risk of MPN, suggesting a complex association between SNPs and the pathogenesis of MPN. Our previous study (unpublished data) showed that there was a high frequency distribution in rs3733609 C/T genotype at Ten-Eleven Translocation 2 (TET2) locus in one Chinese familial primary myelofibrosis. In the present study, we evaluate the role and clinical significance of rs3733609 C/T genotype in JAK2V617F-positive sporadic MPN (n = 181). TET2 rs3733609 C/T genotype had a higher incidence (13.81%; 25/181) in JAK2V617F-positive sporadic MPN patients than that in normal controls (n = 236) (6.35%; 15/236), which was predisposing to MPN (odds ratio(OR) = 2.361; P = 0.01). MPN patients with rs3733609 C/T genotype had increased leukocyte and platelets counts, elevated hemoglobin concentration in comparison with T/T genotype. Thrombotic events were more common in MPN patients with rs3733609 C/T than those with T/T genotype (P < 0.01). We confirmed that rs3733609 C/T genotype downregulated TET2 mRNA transcription, and the mechanism may be involved in a disruption of the interaction between CCAAT/enhancer binding protein alpha (C/EBPA) and TET2 rs3733609 C/T locus.TET2 rs3733609 C/T genotype stimulated the erythroid hematopoiesis in MPN patients. Altogether, we found a novel hereditary susceptible factor-TET2 rs3733609 C/T variant for the development of MPN, suggesting the variant may be partially responsible for the pathogenesis and accumulation of MPN.

[Dynamically monitoring minimal residual disease in acute leukemia after complete remission by multiparameter flow cytometry and its relation with prognosis].

This study was purposed to investigate the dynamically monitoring minimal residual disease (MRD) by flow cytometry (FCM) in patients with acute leukemia (AL) after complete remission and its relation with prognosis. From October 2010 to May 2012, 58 cases of AL (including 45 cases of AML and 13 cases of ALL) were regularly monitored for MRD in bone marrow by FCM and their bone marrow morphology was observed by light microscopy at the same time which continued to relapse or to follow-up deadline in the Department of Hematology, the First Affiliated Hospital of Zhengzhou University. Through average follow-up for 9 months (3 - 21 months), the average MRD level of patients with CR was got. And the prognostic value of MRD level at different time points in AL patients after CR was analysed and summarized. MRD ≥ 1% was defined as positive, otherwise, as negative. The results showed that the maximum and minimum MRD levels of 45 AML patients were 9.57% and 0.01% respectively, the average was 0.67%; the maximum and minimum MRD levels of 13 cases of ALL patients were 7.9% and 0.0016% respectively, the average was 0.99%. Among 44 cases after induction therapy, the relapse rate of MRD(+) group was 53.3% (8/15), the relapse rate of MRD(-) group was 10.3% (3/29), and the relapse rate of MRD(+) group was higher than that of MRD(-) group (χ(2) = 7.58, P = 0.006). Among 58 cases after the first consolidatory therapy, the relapse rate of MRD(+) group was 62.5% (5/8), the relapse rate of MRD(-) group was 16.0% (8/50), and the relapse rate of MRD(+) group was higher than that of MRD(-) group (χ(2) = 6.11, P = 0.013). It is concluded that MRD detected by FCM has a large range (10(-6) - 10(-2)), which can not be used as a single indicator of complete remission. When MRD ≥ 1% after induction therapy and the first consolidatory therapy, the relapse rate significantly increases, MRD can be used as a sensitive indicator for prognosis.

Chronic ethanol consumption up-regulates protein-tyrosine phosphatase-1B (PTP1B) expression in rat skeletal muscle.

AIM: to investigate the potential effects of chronic ethanol intake on protein-tyrosine phosphatase-1B (PTP1B) and the insulin receptor signaling pathway in rat skeletal muscle. METHODS: rats received ethanol treatment at a daily dose of 0 (control), 0.5 (group L), 2.5 (group M) or 5 gxkg(-1) (group H) via gastric gavage for 22 weeks. In vivo insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Expression of PTP1B in skeletal muscles was examined at both the mRNA (real-time PCR) and protein (Western blot) levels. PTP1B activity was assayed with a p-nitrophenol phosphate (PNPP) hydrolysis method. Changes of insulin signaling in skeletal muscle were analyzed with Western blotting. RESULTS: the activity and expression of PTP1B were dose-dependently elevated 1.6 and 2.0 fold in the skeletal muscle by ethanol, resepctively, at the doses of 2.5 and 5 gxkg(-1)xd(-1). Total IRß and IRS-1, as well as their phosphorylated forms, were decreased by ethanol at the two higher doses. Moreover, chronic ethanol consumption resulted in a significant inhibition of the association between IRS-1 and the p85 subunit of phosphatidylinositol 3-kinase, inhibition of Akt phosphorylation and reduced levels of mitogen-activated protein kinase phosphorylation. CONCLUSION: chronic ethanol intake at 2.5 and 5 xkg(-1)xd(-1) sufficient doses can down-regulate the expression of IRß, P-IRß, and IRS-1, as well as the phosphorylated forms of IRS-1 and Akt, in rat skeletal muscle, possibly through increased PTP1B activity.