A positive feedback loop between Periostin and TGFß1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation.

BACKGROUND: Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms. METHODS: Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-ß1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting. RESULTS: The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvß3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFß1 from the extracellular matrix and initiated POSTN/TGFß1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model. CONCLUSIONS: The POSTN/TGFß1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.

Contributions of HOTAIR polymorphisms to the susceptibility of cancer.

OBJECTIVE: Hox transcript antisense intergenic RNA (HOTAIR), a lncRNA, functions as a critical regulator in cancer development. A plenty of case-control studies were conducted to assess the actual relationship of HOTAIR gene generic variants on cancer susceptibility, yet conflicting conclusions remain. Herein, we carried out this up-to-date meta-analysis to get a better understanding of such relationship by incorporating all eligible case-control studies. MATERIALS AND METHODS: Six widely investigated polymorphisms were included in this meta-analysis: rs920778, rs4759314, rs7958904, rs874945, rs1899663, and rs12826786. We retrieved relevant studies from databases PubMed, EMBASE, Medline, CNKI and Wanfang update to June 2020. We applied odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the relationship strengths. RESULTS: Our findings indicate that rs920778, rs4759314, rs874945, rs12826786 polymorphism significantly increased with susceptibility to overall cancer. However, rs7958904, rs1899663 under any five genetic models could not impact susceptibility to overall cancer. Furthermore, altered cancer risk was detected when the data were stratified by cancer type, ethnicity, the source of controls, and HWE in all the SNPs. CONCLUSIONS: These findings of the meta-analysis suggest that HOTAIR polymorphisms may predispose to cancer susceptibility.

Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China.

Since December 2019, COVID-19 has occurred unexpectedly and emerged as a health problem worldwide. Despite the rapidly increasing number of cases in subsequent weeks, the clinical characteristics of pediatric cases are rarely described. A cross-sectional multicenter study was carried out in 10 hospitals across Hubei province. A total of 25 confirmed pediatric cases of COVID-19 were collected. The demographic data, epidemiological history, underlying diseases, clinical manifestations, laboratory and radiological data, treatments, and outcomes were analyzed. Of 25 hospitalized patients with COVID-19, the boy to girl ratio was 1.27:1. The median age was 3 years. COVID-19 cases in children aged <3 years, 3.6 years, and ≥6-years patients were 10 (40%), 6 (24%), and 9 (36%), respectively. The most common symptoms at onset of illness were fever (13 [52%]), and dry cough (11 [44%]). Chest CT images showed essential normal in 8 cases (33.3%), unilateral involvement of lungs in 5 cases (20.8%), and bilateral involvement in 11 cases (45.8%). Clinical diagnoses included upper respiratory tract infection (n=8), mild pneumonia (n=15), and critical cases (n=2). Two critical cases (8%) were given invasive mechanical ventilation, corticosteroids, and immunoglobulin. The symptoms in 24 (96%) of 25 patients were alleviated and one patient had been discharged. It was concluded that children were susceptible to COVID-19 like adults, while the clinical presentations and outcomes were more favorable in children. However, children less than 3 years old accounted for majority cases and critical cases lied in this age group, which demanded extra attentions during home caring and hospitalization treatment.

The impact of endoscopic ultrasound in preoperative evaluation for ampullary adenomas.

OBJECTIVE: We aimed to evaluate the efficacy of endoscopic ultrasonography (EUS) in assessing locoregionally and determining therapeutic options for ampullary adenomas and the related factors. METHODS: Patients undergoing EUS and surgical or endoscopic resection for biopsy-proven ampullary adenomas between 2009 and 2016 were retrospectively analyzed. The depth of tumor invasion, intraductal extension, and regional lymph node staging evaluated by EUS were compared with post-treatment pathological findings. RESULTS: Altogether 120 patients were enrolled in this study. The overall accuracy for EUS in T staging was 81.7%. The sensitivity and specificity of EUS for T staging were 93.9%, 45.5% for adenoma and T1, 50.0% and 96.5% for T2, 66.7% and 97.4% for T3, 50.0% and 97.5% for T4 lesions, respectively. The sensitivity, specificity, and accuracy of EUS for the diagnosis of any intraductal extension were 89.5%, 86.1%, and 86.7%, respectively. The overall accuracy of EUS for regional lymph node staging was 75.0%. The sensitivity and specificity of EUS for diagnosing N1 were 62.5% and 87.5%. By multivariate analysis no factors were found to be independently associated with EUS accuracy for tumor invasive depth. However, small lesion size (≤15 mm) and dilated duct were associated with an overestimation in intraductal extension. CONCLUSION: EUS may be a useful diagnostic tool for selecting endoscopic or surgical treatment for ampullary adenomas.

A model predicting short-term mortality in patients with advanced liver cirrhosis and concomitant infection.

Infection is a common cause of death in patients with advanced cirrhosis. We aimed to develop a predictive model in Child-Turcotte-Pugh (CTP) class C cirrhotics hospitalized with infection for optimizing treatment and improving outcomes.Clinical information was retrospectively abstracted from 244 patients at Tianjin Third Central Hospital, China (cohort 1). Factors associated with mortality were determined using logistic regression. The model for predicting 90-day mortality was then constructed by decision tree analysis. The model was further validated in 91 patients at Mayo Clinic, Rochester, MN (cohort 2) and 82 patients at Seoul St. Mary's Hospital, Korea (cohort 3). The predictive performance of the model was compared with that of the CTP, model for end-stage liver disease (MELD), MELD-Na, Chronic Liver Failure-Sequential Organ Failure Assessment, and the North American consortium for the Study of End-stage Liver Disease (NACSELD) models.The 3-month mortality was 58%, 58%, and 54% in cohort 1, 2, and 3, respectively. In cohort 1, respiratory failure, renal failure, international normalized ratio, total bilirubin, and neutrophil percentage were determinants of 3-month mortality, with odds ratios of 16.6, 3.3, 2.0, 1.1, and 1.03, respectively (P < .05). These parameters were incorporated into the decision tree model, yielding area under receiver operating characteristic (AUROC) of 0.804. The model had excellent reproducibility in the U.S. (AUROC 0.808) and Korea cohort (AUROC 0.809). The proposed model has the highest AUROC and best Youden index of 0.488 and greatest overall correctness of 75%, compared with other models evaluated.The proposed model reliably predicts survival of advanced cirrhotics with infection in both Asian and U.S.

Low-level clonal FGFR2 amplification defines a unique molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population.

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer rarely curable by surgery that is increasing rapidly in incidence. Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several kinds of tumors including ICC, but their incidence has not been assessed in Chinese patients. Using break-apart probes and by determining the ratios of FGFR2/chromosome enumeration probe (CEP) 10 double-color probes, we evaluated 122 ICCs for the presence of FGFR2 translocations and amplifications, respectively, by fluorescence in situ hybridization. We further determined FGFR2 protein expression by immunohistochemistry and analyzed the clinicopathologic records of the patients. Eight tumors (6.6%) had FGFR2 translocations, whereas 15 (12.3%) had low-level FGFR2 amplification. Interestingly, the tumors that showed both translocation and low-level amplification frequently were of the mass-forming type. Compared with the ICCs with normal FGFR2s, tumors with amplifications secreted less mucus (P = .017) and typically were accompanied by hepatitis B virus infection (P = .004). Tumors with low-level amplification generally were of lower stage (P = .013) and associated with better overall survival (P = .017). As tumors with FGFR2 amplification exhibit different biology from lesions with a normal gene, low-level amplification of FGFR2 may play an important role in tumor progression and may be a marker for targeted therapy.

Comparison of sequential pancreatic duct guidewire placement technique and needle knife precut sphincterotomy for difficult biliary cannulation.

OBJECTIVE: Pancreatic duct guidewire placement (PDGP) includes double guidewire technique (DGT) and transpancreatic sphincterotomy (TPS). DGT can be switched to TPS with ease due to the existing guidewire in the pancreatic duct. In this study, we aimed to combine DGT and TPS as a single technique, named sequential PDGP, and to compare its performance with needle knife precut sphincterotomy (NKPS) in treating difficult biliary cannulation (BC). METHODS: A total of 83 patients with difficult BC were enrolled in this study. Of these, 63 underwent sequential PDGP and 20 underwent NKPS. Cannulation success rate, cannulation time and endoscopic retrograde cholangiopancreatography (ERCP)-related complications were prospectively recorded and compared between the two groups. RESULTS: Successful BC was achieved in 88.9% (56/63) of the patients in the sequential PDGP group compared with 70.0% (14/20) in the NKPS group (P = 0.095). Cannulation time was 7.49 ± 5.03 min in the sequential PDGP group and 10.60 ± 7.24 min in the NKPS group (P = 0.086). Post-ERCP pancreatitis occurred in 12.7% of patients in the sequential PDGP group and 10.0% in the NKPS group (P = 1.000). There was no significant difference in the rates of other complications (bleeding, perforation and cholangitis) between the two groups. CONCLUSIONS: Sequential PDGP is a safe and effective alternative method to NKPS in cases of difficult BC. In those with failed standard cannulation, sequential PDGP can be considered when the guidewire is inadvertently inserted into the pancreatic duct or can be placed in the pancreatic duct without difficulty.

The Effects of HSP27 on Gemcitabine-Resistant Pancreatic Cancer Cell Line Through Snail.

OBJECTIVES: To evaluate the regulation mechanism of heat shock protein 27 (HSP27) on gemcitabine (GEM) resistance of pancreatic cancer cell. METHODS: The expression vectors pEGFP-C1-HSP27 and the vectors of MicroRNA targeting Snail were introduced into GEM-sensitive pancreatic cancer SW1990 cells, and the vectors of small hairpin RNA targeting HSP27 were transfected into SW1990 and GEM-resistant SW1990/GEM cells. The expressions of HSP27, p-HSP27 (Ser82), Snail, ERCC1, and E-cadherin were evaluated by Western blotting. The sensitivity of transfected cells to GEM was detected by CCK-8 assay and Annexin V-FITC apoptosis assay. RESULTS: As compared to SW1990, SW1990/GEM showed significantly increased expressions of HSP27, p-HSP27, Snail and ERCC1 with decreased expression of E-cadherin. By increasing HSP27 expression, we found increase of Snail and ERCC1 with reduction of E-cadherin expressions, while reduction of HSP27 expression caused reduction of Snail and ERCC1 but increase of E-cadherin expressions. Downregulation of Snail resulted in the reduction of ERCC1 expression and increase of E-cadherin. Furthermore, downregulation of HSP27 or snail caused increased GEM sensitivity of pancreatic cancer cells, and upregulation of HSP27 showed the opposite results. CONCLUSIONS: There is an inverse correlation between HSP27 expression and GEM sensitivity of SW1990 cells, which might be realized by regulating E-cadherin and ERCC1 expressions through Snail.

Circulating microRNAs: potential biomarkers for cancer.

Cancer is the leading cause of death in the world. Development of minimally invasive biomarkers for early detection of cancer is urgently needed to reduce high morbidity and mortality associated with malignancy. MicroRNAs (miRNAs) are small regulatory RNAs that modulate the activity of specific mRNA targets and play important roles in a wide range of physiologic and pathologic processes. Recently, miRNAs were found to be dysregulated in a variety of diseases including cancer. Emerging evidence suggests that miRNAs are involved in tumor initiation and progression. Together, the different expression profiles of miRNAs in cancer, and the stability of circulating miRNAs, make them new potentially clinical biomarkers for cancer diagnosis, classification, therapeutic decisions, and prognosis.

ABCG2: a potential marker of stem cells and novel target in stem cell and cancer therapy.

ABCG2 is a member of the ATP binding cassette (ABC) transporters, which can pump a wide variety of endogenous and exogenous compounds out of cells. Widely expressed in stem cells, ABCG2 is also found to confer the side population phenotype and is recognized as a universal marker of stem cells. Although the precise physiological role of ABCG2 in stem cells is still unclear, existing data strongly suggest that ABCG2 plays an important role in promoting stem cell proliferation and the maintenance of the stem cell phenotype. In addition, ABCG2 is also found to be expressed in a number of cancer cells and appears to be a marker of cancer stem cells. Moreover, ABCG2 expression in tumors may contribute to their formation and progression. Thus, ABCG2 has potential applications in stem cell and tumor therapy.