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Background: RNA-binding proteins (RBPs) play essential roles in post-transcriptional control of gene expression. Dysregulation of RBPs is intensively implicated in development and progression of human diseases, including cancers. However, the roles of RBPs in nasopharyngeal carcinoma (NPC), which is a distinct subtype of head and neck cancer, remain elusive. Methods: NPC-related RBPs were explored by analyzing GEO database and high-throughput proteomic data obtained from crosslinking immunoprecipitation. The expression levels of Y box binding protein 1 (YBX1) protein in NPC samples were measured by immunohistochemistry (IHC) staining. The association of YBX1 protein levels with prognosis of NPC patients was analyzed by Kaplan-Meier Plotter. The expression levels of YBX1 in NPC cells were inhibited by RNA interference. Cell growth was measured by CCK-8 assay. Cell mobility and invasiveness were measured by transwell assays. Tumorigenicity was measured by using a xenograft tumor assay. The expression levels of mRNAs or proteins were determined by qPCR or western blot assays, respectively. The mRNAs binding to YBX1 were determined by RNA immunoprecipitation (RIP) and qPCR. The effect of YBX1 on mRNA translation was measured by luciferase reporter assay. Results: In the present study, we demonstrated a differentially expressed RBPs profile between NPC and its normal counterpart. Among these aberrantly expressed RBPs, YBX1 was overexpressed in NPC. We found that YBX1 is mainly localized in the cytoplasm of NPC cells. Loss of YBX1 led to reduced cell proliferation, migration and invasiveness in vitro, and reduced tumorigenicity in vivo. Overexpression of YBX1 associates with high expression of cell cycle G2/M checkpoint modulators. In addition, YBX1 promotes AURKA protein expression by directly binding to its mRNA. Loss of YBX1 leads to reduction of AURKA protein level. Forced expression of AURKA rescues cell proliferation and invasiveness in YBX1-silenced NPC cell. Conclusions: The current study indicated that YBX1 promotes NPC cell proliferation and invasiveness through enhancing protein synthesis of AURKA.

Rosai-Dorfman disease (RDD, also known as sinus histiocytosis with massive lymphadenopathy) is a rare and benign non-Langerhans cell histiocytosis. Skin biopsy usually shows nodular or diffuse dermatitis. Rosai-Dorfman cells (RDD cells) and emperipolesis are the key to diagnosis. RDD cells express S-100 antigen, CD68, CD163, α1-antitrypsin, α1-antichymotrypsin, and ham-56, whereas Langerhans cell markers such as CD1a and langerin are negative. We presented a case of a 55-year-old man with varying sizes of many dark red nodules and lumps over the face, trunk, and limbs for approximately 1 year but without systemic involvement. The results of the laboratory evaluations were notable for an increased level of serum IL-6 and serum IgG4. Histopathological examination showed a diffused dense nodular infiltration of "nude" epithelioid histiocytes with infiltration of minimal lymphocytes and plasm cells around the epithelioid nodules. Immunohistochemistry identified nodular histiocytes being stained strongly positive for S-100 and CD68 but negative for CD1a. Plasma cells showed focally positive for IgG, IgG4, and CD38 and with a ratio of IgG4/IgG >40%. Considering these findings, we believe that our case meets the diagnostic description of "cutaneous Rosai-Dorfman disease" and is, therefore, a rare case with clinical features of multiple tumor-like nodules, sarcoidosis-like histological features, and immunohistochemistry of IgG4-positive plasma cells.

Nasopharyngeal carcinoma (NPC) is notorious for its aggressiveness and high metastatic potential. NPC patients with distant metastasis have a particularly poor prognosis; however, evaluating metastatic potential by expression profiles of primary tumors is challenging. This study aimed to investigate the association between activation of epidermal growth factor receptor (EGFR) signaling and NPC metastasis and the underlying mechanisms. We found an association between EGFR protein overexpression and intense EGFR immunostaining in NPC samples with advanced tumor node metastasis stage, clinical stage, and distant metastasis in NPC patients. Exogenous EGF stimulates NPC mobility and invasiveness in vitro. Activation of EGFR signaling prompted PKM2 translocation to the nucleus. Silencing either EGFR or PKM2 attenuates NPC cell aggressiveness in vitro and in vivo. Blocking EGFR signaling with cetuximab suppressed NPC cell invasiveness in vitro and metastatic potential in vivo. Comprehensive analyses of transcriptome profiles indicated that the EGFR-PKM2 axis activates a number of novel metastasis promoters, including F3, FOSL1, EPHA2, ANTXR2, and AKR1C2. Finally, we found that the metastasis-promoting function of the EGFR-PKM2 axis is dependent on nuclear PKM2 regulation of the transcription of metastasis-related genes, including FOSL1 and ANTXR2. Our study indicates that EGFR-PKM2 signaling promotes NPC cell invasion and metastasis through induction of FOSL1 and ANTXR2 and identifies EGFR as a promising biomarker for predicting the risk of distant metastasis., This study revealed activation of EGFR signaling promotes NPC metastasis via nuclear PKM2 mediated induction of FOSL1 and ANTXR2.

Although the original purpose of the systemic lupus erythematosus (SLE) classification criteria was to distinguish SLE from other mimic diseases, and to facilitate sample selection in scientific research, they have become widely used as diagnostic criteria in clinical situations. It is not known yet if regarding classification criteria as diagnostic criteria, what problems might be encountered? This is the first study comparing the three sets of classification criteria for SLE, the 1997 American College of Rheumatology (ACR’97), 2012 Systemic Lupus International Collaborating Clinics (SLICC’12) and 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR’19), for their ability to distinguish patients with SLE from patients with pure mucocutaneous manifestations (isolated cutaneous lupus erythematosus without internal disease, i-CLE) in the lupus disease spectrum. 1,865 patients with SLE and 232 patients with i-CLE were recruited from a multicenter study. We found that, due to low specificity, none of the three criteria are adept at distinguishing patients with SLE from patients with i-CLE. SLICC’12 performed best among the original three criteria, but if a positive ANA was removed as an entry criterion, EULAR/ACR’19 would performed better. A review of previous studies that compared the three sets of criteria was presented in this work.

Patients with condylomata acuminata of the vulva usually have increased difficulty to achieve complete response to treatment and also have a higher risk for disease recurrence. Treatment for this disease varies, including surgical excision, cryotherapy, electrocautery, CO2 laser therapy, topical therapy, and photodynamic therapy (PDT), but none of these alone provides a satisfactory outcome, especially for giant condyloma acuminatum (GCA). We reported two cases of GCA successfully cured with surgical removal, electrocautery and photodynamic therapy.

Background: Poor communication of medication information to general practitioners when patients are discharged from hospital is a widely recognised problem. There has been little research exploring the accuracy of medication information in electronic discharge summaries (EDS) linked to hospital e-prescribing systems. Objective: To evaluate the accuracy of medication lists and medication change information in EDS produced using an integrated e-prescribing and EDS system (where EDS discharge medication lists were imported from discharge e-prescription records, medication change information was manually entered, and medications were dispensed from paper copies of the patients' e-prescriptions). Method: Retrospective audit of EDSs for a random sample, representative of adult patients ( n = 87) discharged from a major teaching hospital. EDS medication lists were compared to pharmacist-verified paper discharge prescriptions (considered to be the most accurate discharge medication list) to identify discrepancies. EDS medication change information was compared to medication changes identified by comparing pharmacist-verified “Medication History on Admission” forms with pharmacist-verified paper discharge prescriptions. Results: There were 85/87 (98%) EDSs that included a discharge medication list. Of these, 50/85 (59%) contained one or more medication list discrepancies (median 1, range 0–15). The most common discrepancy was omission of medication (58%); 84/131 (64%) discrepancies were considered clinically significant (risk of adverse outcome); 162/351 (46%) clinically significant medication changes were stated in the EDS; and 153/351 (44%) changes were both stated and included a reason. Conclusion: EDS discrepancies were common despite integration with e-prescribing. Eliminating paper prescriptions, enhancing e-prescribing/EDS functionality and involving pharmacists in EDS preparation may reduce discrepancies.

Epigenetic modifications affect the differentiation of T cell subsets and the pathogenesis of autoimmune diseases, but many mechanisms of epigenetic regulation of T cell differentiation are unclear. Here we show reduced expression of the transcription factor RFX1 in CD4+ T cells from patients with systemic lupus erythematosus, which leads to IL-17A overexpression through increased histone H3 acetylation and decreased DNA methylation and H3K9 tri-methylation. Conditional deletion of Rfx1 in mice exacerbates experimental autoimmune encephalomyelitis and pristane-induced lupus-like syndrome and increases induction of Th17 cells. In vitro, Rfx1 deficiency increases the differentiation of naive CD4+ T cells into Th17 cells, but this effect can be reversed by forced expression of Rfx1. Importantly, RFX1 functions downstream of STAT3 and phosphorylated STAT3 can inhibit RFX1 expression, highlighting a non-canonical pathway that regulates differentiation of Th17 cells. Collectively, our findings identify a unique role for RFX1 in Th17-related autoimmune diseases., Th17 cells are a common pathogenic effector cell in autoimmune inflammatory diseases. Here the authors show that the transcription factor RFX1 limits Th17 differentiation and is protective against the pathogenesis of Th17-driven autoimmune diseases.

Nasopharyngeal carcinoma (NPC) originates via malignant transformation of the pseudostratified nasopharyngeal epithelium, composed of basal and luminal cells. Super enhancers (SEs) are large clusters of cis-elements involved in the regulation of gene expression through epigenetic regulatory mechanisms. In this study, we demonstrated that basal cell-specific proteins are highly expressed, whereas luminal cell proteins are downregulated in NPC, implying a perturbation of basal-to-luminal differentiation during NPC development. We characterized NPC cell models according to different molecular signatures associated with their differentiation status and found that distinct SE landscapes are tightly associated with basal or luminal-like molecular signatures in NPC cells. Furthermore, the transcription of ΔNP63α, a prominent isoform of TP63, was found to be driven by SEs in NPC cells. Data from chromatin immunoprecipitation (ChIP)-sequencing showed that ΔNP63α largely occupied regions of SEs associated with basal cell-specific genes. Silencing of ΔNP63α led to a loss of H3K27ac occupancy at basal-type SEs and triggered a basal-to-luminal gene expression signature switch, suggesting that ΔNP63α is a master factor contributing to the perturbation of luminal differentiation. Integrative transcriptomics analysis also revealed that ΔNP63α acts as a core factor involved in the dysregulation of gene expression in NPC. Furthermore, ΔNP63α enhanced EGF-stimulated NF-κB activation in NPC cells by activating SE-mediated EGFR transcription. Finally, depletion of ΔNP63α in NPC cells induced robust growth inhibition of NPC cells in vitro and in vivo. Our data revealed that ΔNP63α-dependent SE reprogramming contributes to the blockade of luminal differentiation and uncontrolled proliferation in NPC.

Oxidored-nitro domain-containing protein 1 (NOR1) is a tumor suppressor downregulated in various human cancers, including nasopharyngeal carcinoma (NPC), lung cancer, and testicular cancer. NOR1 protein is highly expressed in the normal brain; however, its role in brain tumors remains unknown. In this study, we demonstrated that the NOR1 protein level was decreased in glioma tissue samples as compared to its normal counterpart. Exogenously expressed NOR1 protein in glioma U251 cells inhibits tumor cell proliferation, migration, and invasion. Re-expression of NOR1 induced cell cycle S to G2 phase arrest and suppressed its tumorigenicity in nude mice. Overexpression of NOR1 in U251 cells also led to a decrease of Ki67 expression in xenografts. Transcriptomic analysis revealed that NOR1 expression altered the expression of genes favored cell proliferation. Among the differentially expressed genes, FOXR2, a member of the FOX gene family, which promotes glioma progression, was decreased in NOR1 expressing cells. The downregulation of FOXR2 by NOR1 was validated in vitro and in vivo. Our findings suggest for the first time that NOR1 suppresses glioma progression via modulating the FOXR2 expression.

ObjectiveT cell receptor (TCR) diversity determines the autoimmune responses in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and is closely associated with autoimmune diseases prognosis and prevention. However, the characteristics of variations in TCR diversity and their clinical significance is still unknown. Large series of patients must be studied in order to elucidate the effects of these variations.MethodsPeripheral blood from 877 SLE patients, 206 RA patients and 439 healthy controls (HC) were amplified for the TCR repertoire and sequenced using a high-throughput sequencer. We have developed a statistical model to identify disease-associated TCR clones and diagnose autoimmune diseases.ResultsSignificant differences were identified in variable (V), joining (J) and V-J pairing between the SLE or RA and HC groups. These differences can be utilised to discriminate the three groups with perfect accuracy (V: area under receiver operating curve > 0.99). One hundred ninety-eight SLE-associated and 53 RA-associated TCRs were identified and used for diseases classification by cross validation with high specificity and sensitivity. Disease-associated clones showed common features and high similarity between both autoimmune diseases. SLE displayed higher TCR heterogeneity than RA with several organ specific properties. Furthermore, the association between clonal expansion and the concentration of disease-associated clones with disease severity were identified, and pathogen-related TCRs were enriched in both diseases.ConclusionsThese characteristics of the TCR repertoire, particularly the disease-associated clones, can potentially serve as biomarkers and provide novel insights for disease status and therapeutical targets in autoimmune diseases.

The autoantibody is an essential characteristic of inflammatory disorders, including autoimmune diseases. Although the exact pathogenic mechanisms of these diseases remain elusive, accumulated evidence has implicated that genetic factors play important roles in autoimmune inflammation. Among these factors, CD24 was first identified as a heat-stable antigen in 1978 and first successfully cloned in 1990. Thereafter, its functional roles have been intensively investigated in various human diseases, especially autoimmune diseases and cancers. It is currently known that CD24 serves as a costimulatory factor of T cells that regulate their homeostasis and proliferation, while in B cells, CD24 is functionally involved in cell activation and differentiation. CD24 can enhance autoimmune diseases in terms of its protective role in the clonal deletion of autoreactive thymocytes. Furthermore, CD24 deficiency has been linked to mouse experimental autoimmune encephalomyelitis. Finally, CD24 genetic variants, including single-nucleotide polymorphisms and deletions, are etiologically relevant to autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus. Therefore, CD24 is a promising biomarker and novel therapeutic target for autoimmune diseases.

Summary Background Pemphigus vulgaris (PV) is an autoimmune blistering disorder with a complex aetiology involving genetic and environmental factors, most of which remain unknown. It has become increasingly evident that aberrant epigenetic modifications are associated with the occurrence and development of autoimmune skin disorders. However, it is not known whether epigenetic modifications play a role in the development of PV. Objectives To analyse DNA methylation and histone modification patterns in peripheral blood mononuclear cells (PBMCs) of patients with PV. Methods PBMC samples were isolated from 24 patients with PV and 20 healthy controls. Skin lesion biopsies and control skin specimens were obtained from 25 patients with PV and 15 healthy controls. Global DNA methylcytosine levels, as well as histone acetylation and methylation levels, were measured by enzyme-linked immunosorbent assay. mRNA expression levels were determined using real-time reverse transcription–polymerase chain reaction. Results Genomic DNA methylation in PBMCs of patients with PV was increased relative to controls. DNMT1 expression levels were significantly higher in PV PBMCs than in controls. MBD3 expression was repressed in PV PBMCs compared with healthy controls. Global histone H3/H4 acetylation and H3K4/H3K27 methylation levels were significantly decreased in patient PBMCs compared with healthy controls. These changes were accompanied by increased HDAC1, HDAC2 and SUV39H2 and decreased SUV39H1 and EZH2 in PV PBMCs. Conclusions Aberrant DNA methylation and histone modifications occur in PBMCs of patients with PV, possibly due to the deregulation of epigenetic modifier genes. These changes may contribute to the pathological immune responses in PV.

The tumor suppressor candidate gene Ras association domain family 1, isoform A (RASSF1A) encodes a microtubule-associated protein that is implicated in the regulation of cell proliferation, migration, and apoptosis. Several studies indicate that down-regulation of RASSF1A resulting from promoter hypermethylation is a frequent epigenetic abnormality in malignant melanoma. In this study, we report that compared with melanocytes in normal skins or benign skin lesions, RASSF1A is down-regulated in melanoma tissues as well as cell lines, and its expression negatively correlates with lymph node metastasis. Following ectopic expression in RASSF1A-deficient melanoma A375 cell line, RASSF1A reduces cell viability, suppresses cell-cycle progression but enhances apoptotic cell death. In vivo, RASSF1A expression inhibits the tumorigenic potential of A375 cells in nude mice, which also correlates with decreased cell proliferation and increased apoptosis. On the molecular level, ectopic RASSF1A expression leads to differential expression of 209 genes, including 26 down-regulated and 183 up-regulated ones. Among different signaling pathways, activation of the apoptosis signal-regulating kinase 1 (ASK1)/p38 MAP kinase signaling is essential for RASSF1A-induced mitochondrial apoptosis, and the inhibition of the Akt/p70S6 kinase/eIF4E signaling is also important for RASSF1A-mediated apoptosis and cell-cycle arrest. This is the first study exploring the biological functions and the underlying mechanisms of RASSF1A during melanoma development. It also identifies potential targets for further diagnosis and clinical therapy.

Lactotransferrin (LTF) has been shown to regulate tumorogenesis. However, little is known about the role of LTF in regulating the development of human nasopharyngeal carcinoma (NPC). The aim of our study was to investigate whether LTF could regulate the development of NPC by characterizing the pattern of LTF expression in human NPC tissues using cDNA and tissue microarrays. Loss of LTF expression was observed in a significantly higher frequency of NPC tissues compared to that in nontumor nasopharyngeal epithelial tissues. While 61.25% of NPC tissues at the T1/T2 stage were positive for LTF expression, only 40.82% of NPC at the T3/T4 stage were stained by anti-LTF. Similarly, 41.58% of NPC with local lymph node metastasis displayed LTF expression, a value significantly lower than the 46.36% in primary tumors (p < 0.05). These findings suggest that LTF may negatively regulate the development and metastasis of NPC in vivo. Furthermore, overexpression of or treatment with LTF inhibited the proliferation of NPC cells and promoted cell cycle arrest at the G(0)/G(1) phase in vitro. While LTF treatment downregulated expression of cyclin D1 and phosphorylation of retinoblastoma protein (Rb), expression of p21 and p27 in 5-8F NPC cells was enhanced. Moreover, LTF treatment modulated the mitogen-activated protein kinase (MAPK) pathway, but did not affect p53 and STAT3 expression in 5-8F NPC cells. Thus LTF is likely to be a candidate tumor suppressor and downregulates the development of NPC by inhibiting NPC proliferation through induction of cell cycle arrest and modulation of the MAPK signaling pathway. Therefore, our findings provide new insights in understanding the mechanism(s) underlying the action of LTF in regulating the development of human NPC.

Systemic lupus erythematosus (SLE) is a female predominant autoimmune disease characterized by multi-organ dysfunctions. However, current available therapies control the disease at the cost of many potential adverse effects. The development of safer and more effective therapies for SLE is a critical unmet need. Icaritin (ICT) is an active monomer extracted from Chinese herbals named the Epimedium genus. In this study, we found that ICT exhibited the capacity of regulating Foxp3/IL17a balance, enhancing Treg cell suppressive activities, and inhibiting over-activation of CD4(+)T cells from SLE. We also observed that ICT regulated Foxp3/IL17a balance by increasing STAT5b expression and histone methylation modification. Subsequent experiments further confirmed that ICT-treated mice exhibited amelioration of renal damages and suggested that ICT may be a potential new drug for the treatment of SLE.

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease involving multiple organs and characterized by overproduction of autoantibodies and T and B cell abnormalities. The treatment for SLE has been restricted to immunosuppressants and corticosteroids. Mycophenolate mofetil (MMF), as a relatively new immunosuppressant, is now widely used in the treatment of SLE patients, particularly those with nephritis. However, it is unclear whether mycophenolic acid (MPA) could modulate the reported disorders of epigenetic status in CD4(+)T cells from SLE patients. In this study, we demonstrated that MPA can upregulate the histone H3/H4 global acetylation status by regulating HATs and HDACs in lupus CD4(+)T cells. Furthermore, we found that MPA also affected the histone H4 acetylation and histone H3K4 tri-methylation levels in CD40L promoter region that inhibited the expression of CD40L. These findings indicate the potential epigenetic mechanism of therapeutic effects of MPA in SLE.

Promoter hypermethylation-mediated silencing of tumor suppressor genes (TSGs) is a hallmark of oncogenesis. Oxidored-nitro domain-containing protein 1 (NOR1) is a candidate TSG that is downregulated in nasopharyngeal carcinoma (NPC). In the present study, we identified a functional NOR1 promoter that is regulated by heat shock factor 1 and nuclear respiratory factor 1. The promoter is located within a CpG island. Hypermethylation of this CpG island was found in NPC tissue samples and cancer cell lines, whereas no aberrant promoter methylation was detected in non-cancerous nasopharyngeal tissue samples or normal nasopharyngeal epithelial cells. Treatment of NPC 6-10B cells and leukemia HL60 cells with 5'-aza-2'-deoxycytidine increased endogenous levels of NOR1 messenger RNA. Ectopic expression of NOR1 in NPC HNE1 cells inhibited tumor cell colony formation and viability. These findings suggest that promoter hypermethylation may participate in transcriptional inactivation of the NOR1 gene in NPC. Frequent epigenetic inactivation of the NOR1 gene in NPC suggests that it may be a critical tumor suppressor involved in the development of NPC.

Background Nasopharyngeal carcinoma (NPC) is a head and neck malignancy with high occurrence in South-East Asia and Southern China. Recent findings suggest that epigenetic inactivation of multiple tumor suppressor genes plays an important role in the tumourigenesis of NPC. BRD7 is a NPC-associated bromodomain gene that exhibits a much higher-level of mRNA expression in normal than in NPC biopsies and cell lines. In this study, we explored the role of DNA methylation in regulation of BRD7 transcription. Methods The presence of CpG islands within BRD7 promoter was predicted by EMBOSS CpGplot and Softberry CpGFinder, respectively. Nested methylation-specific PCR and RT-PCR were employed to detect the methylation status of BRD7 promoter and the mRNA expression of BRD7 gene in tumor cell lines as well as clinical samples. Electrophoretic mobility shift assays (EMSA) and luciferase assay were used to detect the effects of cytosine methylation on the nuclear protein binding to BRD7 promoter. Results We found that DNA methylation suppresses BRD7 expression in NPC cells. In vitro DNA methylation in NPC cells silenced BRD7 promoter activity and inhibited the binding of the nuclear protein (possibly Sp1) to Sp1 binding sites in the BRD7 promoter. In contrast, inhibition of DNA methylation augments induction of endogenous BRD7 mRNA in NPC cells. We also found that methylation frequency of BRD7 promoter is much higher in the tumor and matched blood samples from NPC patients than in the blood samples from normal individuals. Conclusion BRD7 promoter demethylation is a prerequisite for high level induction of BRD7 gene expression. DNA methylation of BRD7 promoter might serve as a diagnostic marker in NPC.