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OBJECTIVE To characterize the pattern of positive conversion of interferon gamma release assay (IGRA) in patients with Crohn's disease (CD) during infliximab therapy in China, which has a high burden of tuberculosis. METHODS Eligible patients with CD who received serial IGRA screening during infliximab therapy from January 2015 to March 2020 were retrospectively included. The positive conversion rate of IGRA and the risk of subsequent tuberculosis of the patients were analyzed. RESULTS A total of 128 patients with CD were included, and the median time from the initiation of IFX treatment to positive conversion or the last follow-up test of IGRA was 43.6 weeks. At baseline 3.9% of the patients were positive for IGRA and received prophylactic anti-tuberculosis treatment. In the other 123 patients with negative IGRA at baseline, 6.5% had IGRA positive conversion during infliximab treatment, and one (12.5%) who was exposed to Mycobacterium tuberculosis was diagnosed as having active tuberculosis. The conversion rate at 40 weeks, 2 years and 3 years after treatment were 10.0% (6/60), 2.2% (1/46) and 5.9% (1/17), respectively. Age, sex, history of smoking and alcohol consumption, disease severity (Crohn's disease activity index score) and immunosuppressive therapy were not significantly associated with latent tuberculosis test conversion. CONCLUSIONS Positive conversion of IGRA occurs early during treatment with infliximab for CD and the monitoring frequency of IGRA should be appropriately increased at the early stage of treatment. Physicians should pay attention to patient's history of tuberculosis exposure and carry out surveillance in a timely fashion.

Multiple myeloma (MM) is a hematologic tumor with monoclonal proliferation of malignant plasma cells in the bone marrow. Fascin (FSCN) is an actin-binding protein that plays a crucial role in cell migration and invasion, contributing to tumor metastasis. There are three members (FSCN1-3) in FSCN family. However, the prognostic role of FSCN family in MM remains unclear. In this study, we used four independent Gene Expression Omnibus (GEO) datasets to explore the relationships between FSCN1-3 expression profiles and patient survival in MM. We found that FSCN1 was dramatically down-regulated in MM compared to normal donors (p < 0.001) and monoclonal gammopathy of undetermined significance (MGUS) (p = 0.032). Patients with high expression of FSCN1 and FSCN2 had significantly longer OS (p = 0.023 and 0.028, respectively). Univariate and multivariate analysis showed that FSCN1 (p = 0.003, 0.002) and FSCN2 (p = 0.018, 0.013) were independent favorable prognostic factors for OS in MM. Moreover, the combination of high expression of FSCN1 and FSCN2 could effectively predict both longer EFS (p = 0.046) and OS (p = 0.015). Our study suggested that FSCN1 and FSCN2 can be used as favorable biomarkers for predicting clinical outcomes in MM.

Deltacoronavirus is the last identified Coronaviridae subfamily genus. Differing from other coronavirus (CoV) genera, which mainly infect birds or mammals, deltacoronaviruses (δ‐CoVs) reportedly infect both animal types. Recent studies show that a novel δ‐CoV, porcine deltacoronavirus (PDCoV), can also infect calves and chickens with the potential to infect humans, raising the possibility of cross‐species transmission of δ‐CoVs. Here, we explored the deep phylogenetic history and cross‐species transmission of δ‐CoVs. Virus–host co‐phylogenetic analyses showed that δ‐CoVs have undergone frequent host switches in birds, and sparrows may serve as the unappreciated hubs for avian to mammal transmission. Our molecular clock analyses show that PDCoV possibly originated in Southeast Asia in the 1990s, and that the PDCoV cluster shares a common ancestor with Sparrow‐CoV of around 1810. Our findings contribute valuable insights into the diversification, evolution, and interspecies transmission of δ‐CoVs and the origin of PDCoV, providing a model for exploring the relationships of δ‐CoVs in birds and mammals.

Acute myeloid leukemia (AML) is a malignant disease of myeloid hematopoietic stem or progenitor cells characterized by abnormal proliferation of primary and immature myeloid cells in bone marrow and peripheral blood. Gene mutation and expression profiles can be used as prognosis predictors for different prognostic subgroups. Secretory carrier-associated membrane proteins (SCAMPs) are a multigenic family with five members and act as cell surface vectors in the post-Golgi recycling pathways in mammals. Nevertheless, the prognostic and clinical influence of SCAMP family has hardly ever been illustrated in AML. In our study, expression patterns of SCAMP family (SCAMP1-5) were analyzed in 155 AML patients which were extracted from the Cancer Genome Atlas database. In chemotherapy, only subgroup, higher SCAMP1 level was significantly associated with longer EFS and OS (all P = 0.002), and SCAMP1 was confirmed to be an independent favorable factor in un-transplanted patients by Multivariate analysis (all P

The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and the median DDIT4 expression levels. High DDIT4 expressers had shorter overall survival (OS) and event-free survival (EFS) than the low expressers among the chemotherapy-only group (all P

Background: Multiple myeloma (MM) is the second most common hematologic malignancy worldwide and does not have sufficient prognostic indicators. FCER1G (Fc fragment Of IgE receptor Ig) is located on chromosome 1q23.3 and is involved in the innate immunity. Early studies have shown that FCER1G participates in many immune-related pathways encompassing multiple cell types. Meanwhile, it is associated with many malignancies. However, the relationship between MM and FCER1G has not been studied.Methods: In this study, we integrated nine independent gene expression omnibus (GEO) datasets and analyzed the associations of FCER1G expression and myeloma progression, ISS stage, 1q21 amplification and survival in 2296 myeloma patients and 48 healthy donors.Results: The expression of FCER1G showed a decreasing trend with the advance of myeloma. As ISS stage and 1q21 amplification level increased, the expression of FCER1G decreased (P = 0.0012 and 0.0036, respectively). MM patients with high FCER1G expression consistently had longer EFS and OS across three large sample datasets (EFS: P = 0.0057, 0.0049, OS: P = 0.0014, 0.00065, 0.0019 and 0.0029, respectively). Meanwhile, univariate and multivariate analysis indicated that high FCER1G expression was an independent favorable prognostic factor for EFS and OS in MM patients (EFS: P = 0.006, 0.027, OS: P =0.002,0.025, respectively).Conclusions: The expression level of FCER1G negatively correlated with myeloma progression, and high FCER1G expression may be applied as a favorable biomarker in MM patients.

Acute myeloid leukemia (AML) is a clonal and heterogeneous disease characterized by proliferation of immature myeloid cells, with impaired differentiation and maturation. Spinster homolog (SPNS) is a widely distributed transmembrane transporter, which assists sphingolipids in playing their roles through the cell membrane. However, the expression and clinical implication of the SPNS family has not been investigated in AML. From the Cancer Genome Atlas database, a total of 155 AML patients with complete clinical characteristics and SPNS1-3 expression data were contained in our study. In patients who received chemotherapy only, high expressions of SPNS2 and SPNS3 had adverse effects on event-free survival (EFS) and overall survival (OS) (all P＜0.05). However, in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) group, we only found a significant difference in OS between the high and low SPNS3 expression groups (P=0.001), while other SPNS members showed no effect on survival. Multivariate analysis indicated that high SPNS2 expression was an independent risk factor for both EFS and OS in chemotherapy patients. The results confirmed that high expression of SPNS2 and SPNS3 were poor prognostic factors, and the effect of SPNS2 can be neutralized by allo-HSCT.

Background DNA mismatch repair (MMR) genes play an important role in cancer development. Deficiencies in these genes may cause microsatellite instability (MSI), which can cause colorectal cancer (CRC). Therefore, we evaluate the relationship between MMR status and the clinicopathological and molecular features of Chinese patients with sporadic CRC. Methods We evaluated 1,405 patients who had undergone primary tumour resection, and divided them into MMR deficiency (dMMR) and MMR proficiency (pMMR) groups, according to their MMR gene expressions. All clinicopathological and molecular features were obtained from pathology reports. Results The dMMR group contained 125 patients and the pMMR group contained 1 280 patients. Patients with dMMR were more likely to be younger (P

A Cyprinid herpesvirus 2 (CyHV-2) strain YZ01 was isolated from an apparently healthy goldfish with history of exposure to CyHV-2 when the water temperature was heated from 3-6□ to 25□. Brain, kidney, spleen (referred to as BKS) and intestine of sick and dead fish as well as crucian carp (CrCB) or goldfish brain cell (GFB) suspensions inoculated with above tissue homogenate were collected for PCR assay.Infected cell layers were prepared into ultrathin sections for transmission electron microscopy. Virus DNA were purified from cell suspensions for whole genome sequencing and analysis. Intestine and mixed brain, kidney and spleen fluid (BKS) of dead goldfish and BKS-infected CrCB suspensions as well as their subsequent passages were tested positive by PCR. Nucleus deformation, lattice-like arrangement of inclusion bodies and various forms of immature and mature virions in the nucleus, cytoplasm and outside of cell membranes were observed. Whole genome analysis of 7 CyHV-2 strains available in GeneBank showed that all strains’ genomes share very high homology while YZ01 was more close to CyHV-2 CNDF-TB2015 and SY-C1 which are classified as C genotype.

The congenital intellectual disability (ID)-causing gene mutations remain largely unclear, although many genetic variations might relate to ID. We screened gene mutations in Chinese Han children suffering from severe ID and found a single-nucleotide polymorphism (SNP) in the 5′-untranslated region (5′-UTR) of fibroblast growth factor 13 (FGF13) mRNA (NM_001139500.1:c.-32c>G) shared by three male children. In both HEK293 cells and patient-derived induced pluripotent stem cells, this SNP reduced the translation of FGF13, which stabilizes microtubules in developing neurons. Mice carrying the homologous point mutation in 5′-UTR of Fgf13 showed delayed neuronal migration during cortical development, and weakened learning and memory. Furthermore, this SNP reduced the interaction between FGF13 5′-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for FGF13 translation in cortical neurons. Thus, this 5′-UTR SNP of FGF13 interferes with the translational process of FGF13 and causes deficits in brain development and cognitive functions.

Epithelial growth factor-like 7 (EGFL7) is a secretory protein with a well-characterized role in angiogenesis and the oncogenesis of certain solid tumors. Overexpression of EGFL7 is associated with adverse prognosis in patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, whether this association persists after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. To further clarify the prognostic role of EGFL7, seventy-one AML patients with EGFL7 expression data who underwent allo-HSCT from The Cancer Genome Atlas database were included and divided into either EGFL7(high) or EGFL7(low) group based on the median EGFL7 expression level. Two groups had similar clinical and molecular characteristics except that the EGFL7(high) group had less frequent NPM1 mutations (P= .001). Kaplan-Meier survival curves showed that high EGFL7 expressers had shorter OS than the low expressers (P= .040). Univariate analysis showed that high EGFL7 expression, MLL-PTD, RUNX1 and TP53 mutations were associated with short OS (all P

Aldo‐keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time‐resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha‐fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early‐stage HCC and AFP‐negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion: AKR1B10 is a potent serum marker for detection of HCC and early‐stage HCC, with better diagnostic performance than AFP.

Acute myeloid leukemia (AML) is a malignancy caused by the uncontrolled and dysregulated clonal expansion of abnormal myeloid primordial cells. In general, the prognosis of AML remains poor despite new discoveries in its pathogenesis and treatment. It is crucial to find early and sensitive biomarkers and continue to explore active targeted treatments. Interferon-induced transmembrane protein (IFITM) family is an important part of the interferon signaling pathway and participate in the regulation of immune cell signaling, adhesion, cancer, and liver cell migration. However, the clinical and prognostic value of the IFITM family in AML has rarely been studied. We screened The Cancer Genome Atlas database and found 155 AML patients with IFITM family (IFITM1-5) expression data. In patients who only received chemotherapy, those with high IFITM3 expression had significantly shorter event-free survival (EFS) and overall survival (OS) than patients with low expression (all P

Background Recent studies reveal lncRNAs are associated with tumor progression or metastasis in colorectal cancer (CRC). However, the functional roles of lncRNAs in colorectal liver metastases (CRLM) are still poorly understood. In this study, we performed an integrative analysis of long noncoding RNAs (lncRNAs) of CRLM in Chinese population. Methods We first applied RNA-seq and Short Time-series Expression Miner (STEM) to identify differentially expressed lncRNAs in normal tissues, tumor tissues and matched liver metastasis tissues in discovery cohort including four patients with CRLM, and subsequently differentially expressed lncRNAs were checked in the validation cohort consisting of 21 patients with CRLM by qRT-PCR. Then we analyzed the association between lncRNAs and overall survival (OS) in the third cohort with 108 CRC patients. Finally, we investigated the function of lncRNAs in HCT-116 and LoVo cell lines. Results RNA-seq and STEM analysis identified four lncRNAs (HL-5, HL-20, HL-38, and HL-59) according with the expression trend of N (normal tissues) < T (tumor tissues) < M (matched liver metastasis tissue), which may be associated with CRLM. Univariate analyses showed that high CASC19 expression was associated with poorer prognosis (P=0.013). CASC19 knockdown inhibited cell migration more than 50% in LoVo cells and HCT-116 cells (P

In this study, silver nanowires (AgNWs) were prepared by the polyol method using silver nitrate (AgNO3) as the silver source and polyvinylpyrrolidone (PVP) as the structure-directing agent under different reaction conditions. In order to obtain AgNWs with good uniformity and electrical conductivity, the orthogonal experiment method was adopted to design an experimental scheme. The scanning electron microscope, energy-dispersive X-ray spectrometer, X-ray diffraction, UV-2550 UV–Visible spectrophotometer, transmission electron microscope, Fourier transform infrared and Raman spectra were combined to characterize synthesized AgNWs. It can be concluded from experimental data that when the reaction temperature is 150°C, the ratio of AgNO3 to PVP is 1:3, the drop rate of PVP is 65 ml h–1, with the existence of ferric chloride (FeCl3), and the AgNWs exhibit optimal morphology with the diameter ranging from 60 to 200 nm. The results in this study will provide experimental guide for controllable formation of AgNWs.

Introduction Preeclampsia (PE) remains a leading cause of maternal and perinatal morbidity. At present, the treatments of preeclampsia are limited, and many patients need to terminate the pregnancy to relieve the disease. Soluble fms-like tyrosine kinase-1 (sFlt-1) is a decoy receptor of placental growth factor (PIGF) and vascular endothelial growth factor which can promote angiogenesis. Its level increases throughout pregnancy with preeclampsia and umbilical cord blood of their newborns. Material and methods In this experiment, we constructed zebrafish with high expression levels of sFlt-1 and explored their changes of nervous system developments and behaviors. Results Comparing with the WT group and the casRx group, the cerebral vascular developments at 72 h in the F1、F2 group were significantly decreased, the ratios of brain volume area to whole body area at 96 h were significantly decreased, and the behavioral trajectory distances and movement speeds at 6th day were shortened and slowed down. Conclusions The increased expression levels of sFlt-1 in zebrafish can inhibit the developments of cerebral blood vessels, brain volumes and the behavioral activities. It is speculated that elevated sFlt-1 in the pathological state of PE can inhibit the developments of nervous system in offspring.

Background: UPF1 is proved to dysregulate in multiple tumors and influence carcinogenesis. However, the role of UPF1 on oxaliplatin resistance in colorectal cancer (CRC) remains unknown.Methods: Firstly, we investigated the clinical relevance of UPF1 in CRC patients. Then, we explored the influence of UPF1 on chemoresistance to oxaliplatin in vitro and in vivo. Finally, we disclosed the underlying mechanisms of oxaliplatin resistance induced by UPF1.Results: UPF1 is upregulated in CRC and overexpression of UPF1 more likely results in recurrence in CRC patients and predicts a poorer overall survival (OS). UPF1 maintains stemness in CRC cell lines and promotes chemoresistance to oxaliplatin in CRC. UPF1-induced oxaliplatin resistance can be associated with interaction with TOP2A and increasing phosphorylated TOP2A.Conclusions: UPF1 was overexpressed and predicted a poor prognosis in CRC. UPF1 enhanced the stemness and chemoresistance to oxaliplatin by interaction with TOP2A and increase of phosphorylated TOP2A in CRC, which may provide a new therapy strategy for chemoresistance to oxaliplatin in CRC patients.

Genetic abnormalities are more frequently viewed as prognostic markers in acute myeloid leukemia (AML) in recent years. Fucosylation, catalyzed by fucosyltransferases (FUTs), is a post-translational modification that widely exists in cancer cells. However, the expression and clinical implication of the FUT family (FUT1-11) in AML has not been investigated. From the Cancer Genome Atlas database, a total of 155 AML patients with complete clinical characteristics and FUT1-11 expression data were included in our study. In patients who received chemotherapy alone showed that high expression levels of FUT3, FUT6, and FUT7 had adverse effects on event-free survival (EFS) and overall survival (OS) (all P

Circular RNAs (circRNAs) have been found to be important mediators of many biological processes in the growth and metastasis of various cancers. However, the potential roles of most circRNAs in the progression of bladder cancer remain unclear. In this research, we investigate the role of circKIF4A (hsa_circ_0007255) in the development and progression of bladder cancer. Detected by qRT-PCR analysis, circKIF4A was significantly upregulated in bladder cancer tissues and cell lines. We conducted CCK-8, colony-formation, transwell and mouse xenograft assays to explore the function of circKIF4A in bladder cancer. Functionally, knockdown of circKIF4A inhibited the proliferation and colony-formation ability of bladder cancer cells. Migration and metastatic ability were dramatically decreased after transfection with small interfering RNA targeting circKIF4A in both in vitro and in vivo assays. Mechanically, luciferase reporter assays and RNA immunoprecipitation assays were carried out to elucidate the underlying molecular mechanism of circKIF4A. The results revealed that circKIF4A sponges miR-375/1231 to promote bladder cancer progression by upregulating NOTCH2. Generally, our research unveils the essential role of circKIF4A-miR-375/1231-NOTCH2 axis in bladder cancer progression possibly via the competing endogenous RNA mechanism.

One of the key features of acute myeloid leukemia (AML), a group of very aggressive myeloid malignancies, is their strikingly heterogenous outcomes. Accurate biomarkers are needed to improve prognostic assessment. Glutamate oxaloacetate transaminase 1 (GOT1) is essential for cell proliferation and apoptosis by regulating cell's metabolic dependency on glucose. It is unclear whether the expression level of GOT1 has clinical implications in AML. Therefore, we analyzed the data of 155 AML patients with GOT1 expression information from The Cancer Genome Atlas (TCGA) database. Among them, 84 patients were treated with chemotherapy alone, while 71 received allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both treatment groups, high GOT1 expression was associated with shorter event-free survival (EFS) and overall survival (OS) (all P = 60 years, white blood cell count >= 15 x 10(9)/L, bone marrow blasts >= 70%, and DNMT3A, RUNX1 or TP53 mutations (all P

The prognosis role of CCT3 in MM and the possible pathways it involved were studied in our research. By analyzing ten independent datasets (including 48 healthy donors, 2220 MM, 73 MGUS, and 6 PCL), CCT3 was found to express higher in MM than healthy donors, and the expression level was gradually increased from MGUS, SMM, MM to PCL (all P

A series of injectable in situ cross-linking hyaluronic acid/carboxymethyl cellulose based hydrogels (HA/CMC) was prepared via disulfide bonds by the oxidation of dissolved oxygen. The results showed that HA/CMC hydrogels exhibited tunable gelling time, appropriate rheology properties, high swelling ratio, good stability, and sustained drug release ability. The gelling time of HA/CMC hydrogels ranged from 1.4 to 7.0 min, and the values of the storage modulus, complex shear modulus, dynamic viscosity, and yield stress of HA3/CMC3 hydrogel were about 5869 Pa, 5870 Pa, 587 Pa·s, and 1969 Pa, respectively. The degradation percentage of HA1/CMC1, HA2/CMC2, and HA3/CMC3 hydrogels were about 60, 49, and 41% after incubating 42 days, and the in vitro cumulative release percentage of BSA from HA1/CMC1, HA2/CMC2, and HA3/CMC3 drug-loaded hydrogels were about 99, 91, and 82% after 30 days. The series of injectable in situ cross-linking HA/CMC hydrogels exhibited good comprehensive performance, signifying that these hydrogels could be potentially used in the fields of short- and medium-term controlled drug release, cell encapsulation, regenerative medicine, and tissue engineering.

Primary immune thrombocytopenia (ITP) is a bleeding disorder commonly encountered in clinical practice. The International Working Group (IWG) on ITP has published several landmark papers on terminology, definitions, outcome criteria, bleeding assessment, diagnosis, and management of ITP. The Chinese consensus reports for diagnosis and management of adult ITP have been updated to the 4th edition. Based on current consensus positions and new emerging clinical evidence, the thrombosis and hemostasis group of the Chinese Society of Hematology issued Chinese guidelines for management of adult ITP, which aim to provide evidence-based recommendations for clinical decision making.

The incidence and mortality of colorectal cancer (CRC) are increasing in China. Although surgery is the initially preferred intervention, systematic and individualized treatment has become far more important, on account of the considerable developments in radiotherapy and chemotherapy. Nowadays, treatment decisions are usually made following multidisciplinary team (MDT) meetings, especially in Fudan University Shanghai Cancer Center (FUSCC). With precise and specific imaging examinations, effective preoperative staging and restaging after neoadjuvant therapy have been the routine, resulting in individualized treatments guided by MDT. These advantages also result in less invasive and function-preserving surgery. Based on clinical evidence of targeted therapy compared with traditional chemotherapy, effective treatment of CRC with metastasis, especially liver and peritoneal metastasis (PM), became more effective. Screening of patients with hereditary CRC, special consultant for surgical procedure and surveillance of hereditary CRC families are routinely performed.

Introduction The PI3Kδ inhibitor, linperlisib, is a structurally distinctive oral agent demonstrated to be clinically efficacious with a favorable safety profile in follicular lymphoma (FL) and peripheral T-cell lymphoma (PTCL). Here we report initial results of a phase1b study (NCT04279405) evaluating the activity and safety of linperlisib across B-cell lymphoma types, namely DLBCL, MCL, MZL, FL and SLL/CLL. Methods Enrollment initiated in Jan 2020 at 11 clinical sites in China for patients (pts) of DLBCL, MCL, MZL, FL and SLL/CLL having received at least one standard anti-tumor systemic therapy and at least 2 cycles of each prior treatment. Linperlisib tablets were administered orally, 80mg once daily under fasted conditions for 28 days as a cycle, until disease progression, unacceptable toxicity or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was evaluated every 2 cycles using the IWG 2007 criteria. Results As of Jul 22, 2021, 43 r/r lymphoma patients were enrolled, including DLBCL (20 pts), MCL (9 pts), FL (8 pts), MZL (3 pts) and SLL/CLL (3 pts). With a median of 2 prior therapies, the majority (93%) of pts previously received first line immunochemotherapy including anti-CD20 targeted therapies. One pts withdrew consent before study treatment began. Three pts withdrew consent in first cycle without post baseline imaging assessment. Forty two pts and 39 patients were evaluable for safety and efficacy, respectively. Linperlisib was well-tolerated in this study. The safety profile observed was consistent to that observed in the clinical studies with FL and PTCL patients, with no new toxicities reported. The most frequent TRAE (all Grade >10%) were neutropenia (54.8%), lymphopenia (40.5%), thrombocytopenia (28.6%), anemia (23.8%), alanine aminotransferase increased (21.4%), aspartate aminotransferase increased (21.4%), blood triglycerides increased (16.7%), blood uric acid increased (14.3%), diarrhoea (11.9%), proteinuria (11.9%) and rash (11.9%). The most frequent Grade ≥3 TRAEs were neutropenia (26.2%) and lymphopenia (9.5%). Thirteen (31.0%) pts experienced SAE considered to be drug related, including pneumonia, thrombocytopenia, pancreatitis, and febrile neutropenia. SAE leading discontinuation from study occurred in 7 pts .Three pts experienced AE that lead to dose modification. No death happened due to any TRAE. No specific associations were observed between B-cell lymphoma types and adverse events on linperlisib treatment. An overall response rate (ORR) and overall disease control rate (DCR) of 53.8% and 79.5% were observed in the evaluable patients. Table1 The 17 evaluable DLBCL pts contained 1 unconfirmed CR (GCB) and 3 PR (GCB, N-GCB, and DLBCL transformed from MZL). The DOR for the 4 DLBCL responders were 56 days, 56 days, 56 days and 196 days. The 8 evaluable FL pts were 3 unconfirmed CR plus 5 PR, and a median DOR of 112days. The 8 evaluable MCL pts contained 2 unconfirmed CR, 3 PR, and 2 SD. The median DOR of the 5 MCL responders were 56 days. The 3 evaluable MZL pts and 3 evaluable SLL/CLL pts were both consisted of 1 unconfirmed CR, 1 PR and 1 SD .The DOR for the 2 MZL responders were 196 days and 56 days, the DOR for the 2 SLL/CLL responders were both 196 days. At the data cutoff date, 16 pts were still treatment ongoing, 19 pts had received exceeding 6 months of treatment, and 1 pt had received exceeding 12 months of treatment, supporting a durable benefit of linperlisib monotherapy. Conclusions Linperlisib demonstrated broad anti-tumor activities in several r/r B -cell malignancies, including DLBC, MCL, MZL, FL and SLL/CLL. Furthermore, linperlisib showed a favorable safety profile with respect to the previously reported information from approved agents in the class of PI3K inhibitors. Further clinical studies of linperlisib in B-cell malignancies and in combination therapies are warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-125b in NPC radioresistance, one of upregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-125b was frequently upregulated in the radioresistant NPCs, and its increment was significantly correlated with NPC radioresistance, and was an independent predictor for poor patient survival. In vitro radioresponse assays showed that miR-125b inhibitor decreased, whereas miR-125b mimic increased NPC cell radioresistance. In a mouse model, therapeutic administration of miR-125b antagomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we confirmed that A20 was a direct target of miR-125b and found that miR-125b regulated NPC cell radioresponse by targeting A20/NF-κB signaling. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 overexpression decreased while A20 knockdown increased NPC cell radioresistance both in vitro and in vivo. Moreover, A20 was significantly downregulated while p-p65 (RelA) significantly upregulated in the radioresistant NPCs relative to radiosensitive NPCs, and miR-125b expression level was negatively associated with A20 expression level, whereas positively associated with p-p65 (RelA) level. Our data demonstrate that miR-125b and A20 are critical regulators of NPC radioresponse, and high miR-125b expression enhances NPC radioresistance through targeting A20 and then activating the NF-κB signaling pathway, highlighting the therapeutic potential of the miR-125b/A20/NF-κB axis in clinical NPC radiosensitization. Mol Cancer Ther; 16(10); 2094–106. ©2017 AACR.

Hepatitis A is an acute infection caused by Hepatitis A virus (HAV), which is widely distributed throughout the world. The HAV 3C cysteine protease (3Cpro), an important nonstructural protein, is responsible for most cleavage within the viral polyprotein and is critical for the processes of viral replication. Our group has previously demonstrated that HAV 3Cpro cleaves human NF-κB essential modulator (NEMO), a kinase required in interferon signaling. Based on this finding, we generated four luciferase-based biosensors containing the NEMO sequence (PVLKAQ↓ADIYKA) that is cleaved by HAV 3Cpro and/or the Nostoc punctiforme DnaE intein, to monitor the activity of HAV 3Cpro in human embryonic kidney cells (HEK-293T). Western blotting showed that HAV 3Cpro recognized and cleaved the NEMO cleavage sequence incorporated in the four biosensors, whereas only one cyclized luciferase-based biosensor (233-DnaE-HAV, 233DH) showed a measurable and reliable increase in firefly luciferase activity, with very low background, in the presence of HAV 3Cpro. With this biosensor (233DH), we monitored HAV 3Cpro activity in HEK-293T cells, and tested it against a catalytically deficient mutant HAV 3Cpro and other virus-encoded proteases. The results showed that the activity of this luciferase biosensor is specifically dependent on HAV 3Cpro. Collectively, our data demonstrate that the luciferase biosensor developed here might provide a rapid, sensitive, and efficient evaluation of HAV 3Cpro activity, and should extend our better understanding of the biological relevance of HAV 3Cpro., Highlights • Four luciferase-based biosensors were generated to monitor the activity of HAV 3Cpro. • The cyclized luciferase-based biosensor 233DH showed measurable and reliable data. • Luciferase activity of 233DH was specifically dependent on HAV 3Cpro activity. • 233DH was only recognized and cleaved by HAV 3Cpro but by no other viral 3CLpro.

Background: Acute myeloid leukemia (AML) is a highly heterogenous hematological malignancy and its prognostication depends on the genetic mutation and expression profile of each patient. Pantothenate kinase ( PANK ) is a regulatory enzyme that controls coenzyme A (CoA) biosynthesis. It has four isoforms encoded by PANK1-4 , respectively. Whether the expression of the PANK family has prognostic significance in AML remains unclear. Methods: We screened The Cancer Genome Atlas database for AML patients with complete PANK1-4 expression data. Eighty-four AML patients met the criteria and were included in this study. Clinical characteristics at diagnosis, including peripheral blood (PB) white blood cell counts (WBC), blast percentages in PB and bone marrow (BM), French-American-British (FAB) subtypes and the frequencies of common genetic mutations were described. Survival was estimated using the Kaplan-Meier method and the log-rank test. Multivariate Cox proportional hazard models were constructed for event-free survival (EFS) and overall survival (OS), using a limited backward elimination procedure. Results: Patients with high PANK2 expression had significantly longer event-free survival (EFS) and overall survival (OS) than patients with low PANK2 expression (P=0.007, P=0.016, respectively), whereas patients with high PANK4 expression had shorter EFS and OS than patients with low PANK4 expression (P=0.022, P=0.015, respectively). Multivariate analysis confirmed that high PANK4 expression was an independent risk factor for EFS and OS (both P Conclusions: Our study suggested that high PANK2 expression might have favorable effects on AML, while high PANK4 expression was indicative of poor prognosis.

Relapsed and refractory acute myeloid leukemia (R/R AML) has complicated pathogenesis. Its treatment is complicated, and the prognosis is poor. So far, there is no consensus on what is the optimal treatment strategy. With the deepening of research, new chemotherapy regimens, new small molecule inhibitors, and immunotherapy have been increasingly applied to clinical trials, providing more possibilities for the treatment of R/R AML. The most effective treatment for patients who achieve complete remission after recurrence is still sequential conditioning therapy followed by allogeneic hematopoietic cell transplantation. Finding the best combination of treatments is still an important goal for the future.

Background Since air pollution is only one of many environmental stressors that can affect skin, it has been challenging to identify skin appearance or functional features profoundly affected by chronic exposure to traffic-derived air pollution. Aims The current population study focused on taxi drivers working in urban and rural areas in order to take advantage of difference in occupational exposure. Methods The skin conditions of 100 middle-aged male taxi drivers from urban Shanghai and 66 from rural Chongming were measured with facial tape strips were collected for biomarker analyses. Results Trans-epidermal water loss (TEWL) values before and after tape stripping were considerably higher in urban taxi drivers from Shanghai. Contrary to previous studies, there was no apparent detrimental effect on skin wrinkle or pigmentation from traffic pollution, which might be attributed to the higher than general public level of photo-exposure in this population. At the same time, pollution exposure especially the heavy traffic pollution exposure was found to associate with lower stratum corneum trypsin-like enzyme activity (SCTE), reduced catalase activity and total antioxidant capacity (TAOC) in tape strips. Conclusion The evidence suggests that traffic-derived air pollution could deteriorate skin's physical and antioxidant barrier, whereas factors like photo-exposure can be overwhelming against appearance aging. Therefore, in addition to photoprotection, skin barrier care should be considered for people with high air pollution exposure.

pH and redox dual stimuli-responsive injectable hydrogels were prepared by cross-linking oxidized carboxymethyl cellulose (oxi-CMC) with 3,3′-dithiobis (propionohydrazide) (DTP) via Schiff base reaction under physiological condition. The hydrogels showed good performance such as tunable gelling time, appropriate rheology properties, high swelling ratio and low degradation rate. In vitro release studies confirmed that bovine serum albumin (BSA) as a model drug exhibited a sustainable release at pH 7.4 and an accelerated release under a lower pH 5.0 and/or reducing environments. The results signified that oxi-CMC/DTP hydrogels could be an attractive candidate for drug delivery system, tissue engineering or cell scaffold materials.

Background: Ibrutinib, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for the treatment of relapsed/refractory (R/R) Mantle cell lymphoma (MCL). Both single-agent ibrutinib and combination of ibrutinib with rituximab have achieved great efficacy with manageable toxicity (Wang,NEJM2013; Wang,Lancet Oncol2015; Dreyling,Lancet2015). This study, for the first time, analyzed the real-world effectiveness and tolerability of ibrutinib for MCL patients in China. Methods: This multi-center, retrospective cohort study enrolled adult patients (pts) with pathologically confirmed MCL who initiated ibrutinib-containing treatment between November 2017 (date of commercialization) and April 2020. Eligible patients were retrospectively divided into 3 subgroups to receive ibrutinib-containing treatments for different purposes: R/R MCL group, newly diagnosed MCL group and maintenance therapy group. This analysis reports the baseline characteristics, efficacy and safety profiles in R/R MCL patients. Results: A total of 67 R/R MCL pts receiving ibrutinib-containing treatment from 9 medical centers in China were included in this analysis. At ibrutinib initiation, the median age was 61.0 (range 39-81) years, 68.7% were male and 81.8% had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Approximately three-quarters of pts (72.3%) had 1 previous line of therapy before ibrutinib. Baseline characteristics are summarized in Table 1. Of all patients enrolled, 53.7% (36/67) of pts received ibrutinib monotherapy and 46.3% (31/67) received ibrutinib-containing combination therapy. IR (ibrutinib and rituximab) (16/31, 51.6%) and IR2 (ibrutinib, rituximab and lenalidomide) (5/31, 16.1%) were the two most common combination regimens. Nine patients (29.0%) received ibrutinib plus R-chemotherapy. Although no statistically significant difference was found in listed baseline characteristics between these two groups, a larger percentage of pts with bone marrow involvement (58.1% vs 35.7%) and bulky mass (largest diameter) ≥5 cm (46.4% vs 27.3%) were observed in combination therapy group. Best overall response rate (ORR) was 65.7% (20.9% complete remission [CR]). Median time to response (TTR) was 4.1 months and median duration of response (DOR) was 18.4 months. With a median follow-up of 10.2 months, median progression-free survival (PFS) was 21.3 months (95% confidence interval [CI], 15.2 - not available [NA]) (Figure 1A). PFS rates were 86.0%, 69.8% and 47.6% at 6 months, 1 year and 2 years. With a median follow-up of 11.2 months, median overall survival (OS) was not reached with OS rates of 98.5%, 87.9% and 76.3% at 6 months, 1 year and 2 years (Figure 1B). Compared with ibrutinib monotherapy, combination therapy showed higher ORR (50.0% vs 83.9%), CR rate (8.3% vs 35.5%) and shorter TTR (median TTR, 6.0 vs 2.2 months; Logrank,p=0.0012) (Figure 2A). Although the combination therapy had a trend for better PFS, no statistically significant benefit in PFS or OS was observed (Figure 2B, C). Safety analysis focused on 55 R/R MCL pts from 3 centers with adequate adverse events information. The most common treatment emergent adverse events (TEAEs) of interest were infection (8/55, 14.6%), rash (8/55, 14.6%), bleeding (5/55, 9.1%; 1/5 was major bleeding [subdural hemorrhage]) and atrial fibrillation (3/55, 5.5%). Four pts (7.3%) experienced grade 3-4 TEAE (neutropenia, n=2; neutropenia and lung infection, n=1; subdural hemorrhage, n=1). Six pts (10.9%) had ≥1 temporary ibrutinib discontinuation due to TEAE (infection, n=3; neutropenia, n=1; rash, n=1; vomiting, n=1). One patient discontinued ibrutinib permanently due to TEAE (subdural hemorrhage). Combination therapy group showed a higher incidence of hematological TEAE (60.9% vs 39.1%) and infection (20.7% vs 7.7%). No TEAE-related death or new safety signals was recorded. Conclusion: This real-world analysis demonstrates that ibrutinib is effective and tolerable for R/R MCL in China. Ibrutinib-containing combination therapy outperformed ibrutinib monotherapy in response rate and TTR, but showed no survival benefits. The response rate data of ibrutinib monotherapy obtained from our study was different to existing clinical trial data, which may be mainly due to the short follow-up time of our study. Further analysis with longer follow-up is needed to validate these findings. Disclosures No relevant conflicts of interest to declare.

Background Although the prognosis of patients with bladder cancer (BC) has improved significantly with the use of multimodal therapy, reliable prognostic biomarkers are still urgently needed due to the heterogeneity of tumors. Our aim was to develop an individualized immune-related gene pair (IRGP) signature that could precisely predict prognosis in BC patients. Methods Gene expression profiles and corresponding clinical information were collected from eight microarray data sets and one RNA-Seq data set. Results Among 1,811 immune genes, a 30-IRGP signature consisting of 52 unique genes was generated in the training cohort, which significantly stratified patients into low- and high-risk groups in terms of overall survival. In the testing and validation cohorts, the IRGP signature was also associated with patient prognosis in the univariate and multivariate Cox regression analyses. Several biological processes, including the immune response, chemotaxis, and the inflammatory response, were enriched among genes in the IRGP signature. When the signature was integrated with the TNM stage, an IRGP nomogram was developed and showed improved prognostic accuracy relative to the IRGP signature alone. Conclusions In short, we identified a robust IRGP signature for estimating overall survival in BC patients that could also be used as a promising biomarker for identifying high-risk patients for individualized therapy.

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-23a in NPC radioresistance, one of downregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-23a was frequently downregulated in the radioresistant NPC tissues, and its decrement correlated with NPC radioresistance and poor patient survival, and was an independent predictor for reduced patient survival. In vitro radioresponse assays showed that restoration of miR-23a expression markedly increased NPC cell radiosensitivity. In a mouse model, therapeutic administration of miR-23a agomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we found that reduced miR-23a promoted NPC cell radioresistance by activating IL-8/Stat3 signaling. Moreover, the levels of IL-8 and phospho-Stat3 were increased in the radioresistance NPC tissues, and negatively associated with miR-23a level. Our data demonstrate that miR-23a is a critical determinant of NPC radioresponse and prognostic predictor for NPC patients, and its decrement enhances NPC radioresistance through activating IL-8/Stat3 signaling, highlighting the therapeutic potential of miR-23a/IL-8/Stat3 signaling axis in NPC radiosensitization.

We investigated the effects ofHericium erinaceus(HEE) on alloxan induced diabetic neuropathic pain in laboratory rats. Alloxan induced diabetic rats were administered orally HEE. After 6 weeks of treatments, treatment with HEE 40 mg/kg in diabetic animals showed significant increase in pain threshold and paw withdrawal threshold and significant decrease in serum glucose and urine glucose. We also observed a significant increase in lactate dehydrogenase (LDH), Lipid peroxidation (LPO), glutathione peroxidase (GPx) activity, glutathione reductase (GR) activity, catalase (CAT) activity, Na+K+ATPase activity, and glutathione S transferase (GST) activity along with significant decreased levels of glutathione (GSH) content in diabetic rats. The total antioxidant status (TAOS) in the HEE-treated groups was significantly lower than that in the alloxan-treated group. HEE can offer pain relief in diabetic neuropathic pain. The improvement in diabetic state after HEE treatment along with the antioxidant activity could be the probable way by which it had alleviated diabetic neuropathy.

Toll‑like receptors (TLRs) are expressed in human bone marrow‑derived mesenchymal stromal cells (BM‑MSCs). The activation of TLRs is important in the proliferation, differ-entiation, migration and hematopoiesis‑supporting functions of BM‑MSCs. MicroRNAs (miRNAs) are involved in various biological functions by mediating mRNA degradation or inhibiting the translation of target genes. Our previous study confirmed that TLRs regulate the migration ability of BM‑MSCs. It was also identified that multiple miRNAs were regulated by TLRs. In view of this, it was hypothesized that TLR‑regulated miRNAs may be important in regulating the migration of BM‑MSCs. The migration ability of BM‑MSCs was evaluated following transfection of the cells with the mimics or antagonists of miRNA (miR)‑27b, miR‑146a, miR‑155 and miR‑154. miR‑155 significantly inhibited cell migration. Myosin light chain kinase (MYLK) was identified as the direct target of miR‑155 in BM‑MSCs, which was further investigated using the luciferase reporter assay. However, miR‑155 did not affect the expression of upstream proteins of the RhoA pathway controlling the activity of MYLK, suggesting that miR‑155 directly suppressed the expression of MYLK without affecting the RhoA pathway. These results may facilitate the development and clinical use of BM‑MSCs in terms of their migration.

// Xu Ye 1, 2, 3 , Hongyu Deng 3 , Min Su 3 , Qianjin Liao 3 , Dan Huang 4 , Duan-Fang Liao 4 , Zhi-Qiang Xiao 1, 2 and Deliang Cao 3, 4 1 Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 2 The Higher Educational Key Laboratory For Cancer Proteomics and Translational Medicine of Hunan province, Xiangya Hospital, Central South University, Changsha, Hunan 410005, China 3 Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China 4 Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (incubation), Hunan University of Chinese Medicine, Changsha, Hunan 410208, China Correspondence to: Deliang Cao, email: dlcao1998@gmail.com Zhi-Qiang Xiao, email: zqxiao2001@hotmail.com Keywords: colorectal cancer, microsatellite, polymorphisms, survival, prognostic marker Received: April 18, 2017 Accepted: June 28, 2017 Published: September 16, 2017 ABSTRACT Disease-specific markers are critical for early diagnosis, targeted therapy and prognostic prediction of diseases. Current study reports a complex microsatellite as a new prognostic marker of sporadic colorectal cancer. This microsatellite located at Chromosome 7q33 is composed of three tetranucleotide tandem repeats, (TTCC) 2 (TCCC) 5 (TCCT) 7 , flanked by a CT-rich sequence. We analyzed polymorphisms of this microsatellite in 158 sporadic colorectal cancer, 143 matched normal adjacent tissues (NAT) and 150 health donors. Our results showed that this complex microsatellite was instable with polymorphic frequency of 77.2% in colorectal cancer, 52.4% in NAT and 54.7% in health donors (p

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus. The first outbreak of PDCoV was announced from the United States in 2014, followed by reports in Asia. The nonstructural protein nsp5 is a 3C-like protease of coronavirus, and our previous study showed that PDCoV nsp5 inhibits type I interferon (IFN) production. In this study, we found that PDCoV nsp5 significantly inhibited IFN-stimulated response element (ISRE) promoter activity and transcription of IFN-stimulated genes (ISGs), suggesting that PDCoV nsp5 also suppresses IFN signaling. Detailed analysis showed that nsp5 cleaved signal transducer and activator of transcription 2 (STAT2) but not Janus kinase 1 (JAK1), tyrosine kinase 2 (TYK2), STAT1, and interferon regulatory factor 9 (IRF9), key molecules of the JAK-STAT pathway. STAT2 cleavage was dependent on the protease activity of nsp5. Interestingly, nsp5 cleaved STAT2 at two sites, glutamine 685 (Q685) and Q758, and similar cleavage was observed in PDCoV-infected cells. As expected, cleaved STAT2 impaired the ability to induce ISGs, demonstrating that STAT2 cleavage is an important mechanism utilized by PDCoV nsp5 to antagonize IFN signaling. We also discussed the substrate selection and binding mode of PDCoV nsp5 by homologous modeling of PDCoV nsp5 with the two cleaved peptide substrates. The results of our study demonstrate that PDCoV nsp5 antagonizes type I IFN signaling by cleaving STAT2 and provides structural insights for comprehending the cleavage mechanism of PDCoV nsp5, revealing a potential new function for PDCoV nsp5 in type I IFN signaling. IMPORTANCE The 3C-like protease encoded by nsp5 is a major protease of coronaviruses; thus, it is an attractive target for development of anticoronavirus drugs. Previous studies have revealed that the 3C-like protease of coronaviruses, including PDCoV and porcine epidemic diarrhea virus (PEDV), antagonizes type I IFN production by targeting the NF-κB essential modulator (NEMO). Here, for the first time, we demonstrate that overexpression of PDCoV nsp5 also antagonizes IFN signaling by cleaving STAT2, an essential component of transcription factor complex ISGF3, and that PDCoV infection reduces the levels of STAT2, which may affect the innate immune response.

MiR-125b is aberrantly expressed and has a role in the various types of tumors. However, the role and mechanism of miR-125b in nasopharyngeal carcinoma (NPC) are unclear. In this study, we investigated the role and mechanism of miR-125b in NPC. We observed that miR-125b was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa (NNM), and its increment was correlated with poor patient survival, and was an independent predictor for reduced patient survival; miR-125b promoted NPC cell proliferation and inhibited NPC cell apoptosis; in a mouse model, administration of miR-125b antagomir significantly reduced the growth of NPC xenograft tumors. Mechanistically, we confirmed that A20 was a direct target of miR-125b, and found that activation of nuclear factor κB (NF-κB) signaling pathway by A20 mediated miR-125b-promoting NPC cell proliferation and -inhibiting NPC cell apoptosis. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 inhibited NPC cell proliferation, induced NPC cell apoptosis, and reduced the growth of NPC xenograft tumors. Moreover, A20 was significantly downregulated, whereas p-p65(RelA) was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa, and miR-125b level was negatively associated with A20 level, whereas positively associated with p-p65 level. Our data demonstrate that miR-125b regulates NPC cell proliferation and apoptosis by targeting A20/NF-κB signaling pathway, and miR-125b acts as oncogene, whereas A20 functions as tumor suppressor in NPC, highlighting the therapeutic potential of miR-125b/A20/NF-κB signaling axis in the NPC.

Introduction Antithrombin (AT) deficiency is associated with an increasing risk of thrombosis. Materials and methods 15 unrelated patients with AT deficiency defined by thrombophilic assays were recruited and detailed clinical information about patients, focusing on the personal and family history of thromboembolism (TE), were recorded. Mutation analysis was performed by direct sequencing of an AT gene (SERPINC1) in the patients and their family members. Results A total of 15 heterozygous causative mutations, each being identified in one family, were identified. Five mutations (33.3%) were reported here for the first time, including three null mutations (Ser36X, Lys70X and Try307X) and two missense mutations (Phe123Cys and Leu340Phe) probably impairing the structural integrity and stability of protein based on the AT structural analysis. Of the 15 patients, 33.3% (5/15) had additional risk factors and only one patient presented with additional genetic alteration causing an early onset of thrombosis. Fourteen patients (93.9%) suffered from multisite recurrent thrombotic episodes after a first episode of thrombosis. 93.3% of the patients experienced deep vein thrombosis (DVT) and 40.0% presented with mesenteric venous thrombosis (MVT). In addition, both venous and arterial thrombosis was present in two unrelated patients. 51.0% subjects with AT deficiency in the 15 unrelated pedigrees experienced TE events. Conclusions Prophylactic anticoagulation may be suggested in AT-deficient patients to avoid the recurrent and multisite thrombosis. The association of primary MVT and AT deficiency is highlighted.

Background: In May 2012, an outbreak of viral hepatitis A was reported to the Guangxi Center for Disease Control and Prevention from a middle school in Liujiang County. An investigation was conducted to identify the cause and mode of transmission and to recommend control and prevention measures.Methods: A case was defined as any person from the middle school with onset of fatigue, anorexia, abdominal pain, diarrhoea or jaundice from 20 February to 20 May 2012. We compared attack rates (AR) between boys and girls, assuming that only boys used well water and girls used pipeline water. We then selected 133 students from three classes in each of the three grades to compare AR by reported water source and drinking history.Results: There were 22 cases, an AR of 3.8% (21/553) for students and 1.5% for teachers (1/65). Those who used well water were 8.7 (95% confidence interval [CI] = 2.1–37.2) times more likely to be ill than those using pipeline water. The cohort study showed that students who reported using well water daily were 5.2 (95% CI = 0.7–41.8) times more likely to be ill than those that reported using the pipeline water daily. Eighteen cases were confirmed as hepatitis A.Conclusion: This hepatitis A outbreak was potentially caused by a contaminated school well. We recommended that the school discontinue using the well and that the students should drink boiled water. As there is a vaccine for hepatitis A, we recommended that several doses of the vaccine be stored for controlling outbreaks and for immunizing susceptible populations in future outbreaks.

To identify a novel lung adenocarcinoma (AdC) biomarker, iTRAQ-tagging combined with 2D LC-MS/MS analysis was used to identify differentially expressed plasma membrane (PM) proteins in primary lung AdCs and paraneoplastic normal lung tissues (PNLTs). As a result, 36 differentially expressed membrane proteins were identified. Two differential PM proteins flotillin-1 and caveolin-1 were selectively validated by Western blotting. As there has been no report on the association of flotillin-1 with lung AdC, immunohistochemistry was further performed to detect the expression of flotillin-1 in the archival tissue specimens including 42 cases of PNLTs, 62 cases of primary lung AdCs with lymph node metastasis (LNM AdCs), and 46 cases of primary lung AdCs without lymph node metastasis (non-LNM AdCs), and the correlation of flotillin-1 expression levels in lung AdCs with clinicopathological features and clinical outcomes were evaluated. The results showed that up-regulation of flotillin-1 expression in lung AdCs was significantly correlated with advanced clinical stage, lymph node metastasis, increased postoperative relapse and decreased overall survival. Cox regression analysis revealed that the expressional level of flotillin-1 was an independent prognostic factor. The data suggest that flotillin-1 is a potential novel biomarker for lymph node metastasis and prognosis of lung AdC, and flotillin-1 up-regulation might play an important role in the pathogenesis of lung AdC.

Porcine deltacoronavirus (PDCoV) causes acute enteric disease and mortality in seronegative neonatal piglets. Previously we have demonstrated that PDCoV infection suppresses the production of interferon-beta (IFN-β), while the detailed mechanisms are poorly understood. Here, we demonstrate that nonstructural protein 5 (nsp5) of PDCoV, the 3C-like protease, significantly inhibits Sendai virus (SEV)-induced IFN-β production by targeting the NF-κB essential modulator (NEMO), confirmed by the diminished function of NEMO cleaved by PDCoV. The PDCoV nsp5 cleavage site in the NEMO protein was identified as glutamine 231, and was identical to the porcine epidemic diarrhea virus nsp5 cleavage site, revealing the likelihood of a common target in NEMO for coronaviruses. Furthermore, this cleavage impaired the ability of NEMO to activate the IFN response and downstream signaling. Taken together, our findings reveal PDCoV nsp5 to be a newly identified IFN antagonist and enhance the understanding of immune evasion by deltacoronaviruses., Highlights • PDCoV nsp5 inhibits type I IFN production by means of its protease activity. • PDCoV nsp5 cleaves NEMO to disrupt RIG-I/MDA5 signaling. • PDCoV nsp5 recognizes Q231 of NEMO as the P1 position for cleavage. • The cleaved NEMO products fail to induce the transcription of ISGs.

At present, the diagnosis of sleep apnea syndrome requires patients to wear the PSG sensors all night long in hospital, which is so inconvenient and expensive that millions of sleep apnea patients can't receive diagnosis and treatment. We propose a low-cost sleep monitoring device to be used at the comfort of home based on photoplethysmography (PPG) with only single photoelectric sensor, which can simultaneously obtain oxygen saturation, pulse rate, respiration rate, heart rate variability analysis and body motions to realize the basic monitoring of circulatory, respiratory, nervous system and motor system. The device consists of two light emitting diodes, a probe-drive module, an optical - frequency converter, a microcontroller MSP430F5438A, a wireless transceiver module and a Micro SD card module. The evaluations by commercial BIOPAC systems demonstrate the feasibility of our proposed device.