Esophageal squamous cell carcinoma (ESCC), the major histologic form of esophageal cancer, is a heterogeneous tumor displaying a complex variety of genetic and epigenetic changes. Aberrant RNA editing of adenosine-to-inosine (A-to-I), as it is catalyzed by adenosine deaminases acting on RNA (ADAR), represents a common posttranscriptional modification in certain human diseases. In this study, we investigated the status and role of ADARs and altered A-to-I RNA editing in ESCC tumorigenesis. Among the three ADAR enzymes expressed in human cells, only ADAR1 was overexpressed in primary ESCC tumors. ADAR1 overexpression was due to gene amplification. Patients with ESCC with tumoral overexpression of ADAR1 displayed a poor prognosis. In vitro and in vivo functional assays established that ADAR1 functions as an oncogene during ESCC progression. Differential expression of ADAR1 resulted in altered gene-specific editing activities, as reflected by hyperediting of FLNB and AZIN1 messages in primary ESCC. Notably, the edited form of AZIN1 conferred a gain-of-function phenotype associated with aggressive tumor behavior. Our findings reveal that altered gene-specific A-to-I editing events mediated by ADAR1 drive the development of ESCC, with potential implications in diagnosis, prognosis, and treatment of this disease. Cancer Res; 74(3); 840-51. Ó2013 AACR.

BackgroundIn 2009, severe fever with thrombocytopenia syndrome virus (SFTSV) was identified as a novel member of the genus phlebovirus in the Bunyaviridae family in China. The detailed clinical features of cases with SFTSV infection have not been well described, and the risk factors for severity among patients and fatality among severe patients remain to be determined.Methodology/Principal FindingsClinical and laboratory features of 115 hospitalized patients with SFTSV infection during the period from June 2010 to December 2011 in Northeast China were retrospectively reviewed. We assessed the risk factors associated with severity in confirmed cases and fatality in severe cases by multivariate analysis. One hundred and three (89.6%) of 115 patients presented with multiple organ dysfunction, and 22 (19.1%) of 115 proceeded to the stage of life threatening multiple organ failure. Of the 115 patients, 14 fatalities (12.2%) were reported. Multivariate analysis demonstrated that the independent predictors of risk for severity were: albumin ≤30 g/l (OR, 8.09; 95% CI, 2.58-25.32), APTT ≥ 66 seconds (OR, 14.28; 95% CI, 3.28-62.24), sodium ≤130 mmol/l (OR, 5.44; 95% CI, 1.38-21.40), and presence of neurological manifestations (OR, 7.70; 95% CI, 1.91-31.12). Among patients with severe disease, presence of acute lung injury/acute respiratory distress syndrome (HR, 4.59; 95% CI, 1.48–14.19) and disseminated intravascular coagulation (HR, 4.24; 95% CI, 1.38–13.03) were independently associated with fatality.Conclusions/SignificanceSFTSV infection may present with more severe symptoms and laboratory abnormalities than hitherto reported. Due to infection with a novel bunyavirus, the patients may sufferer multiple organ dysfunction and die of multiple organ failure. In the clinical assessment of any case of SFTS, independent factors relating to prognosis need to be taken into account by clinicians.

Background and aims We aim to assess the safety and immunogenicity of inactivated whole-virion SARS-CoV-2 vaccines in patients with chronic liver diseases (CLD) in this study. Methods This was a prospective, multi-center, open-label study. Participants aged over 18 years with confirmed CLD and healthy volunteers were enrolled. All participants received 2 doses of inactivated whole-virion SARS-CoV-2 vaccines. Adverse reactions were recorded within 14 days after any dose of SARS-CoV-2 vaccine, laboratory testing results were collected after the second dose, and serum samples of enrolled subjects were collected and tested for SARS-CoV-2 neutralizing antibodies at least 14 days after the second dose. Results A total of 581 participants (437 patients with CLD and 144 healthy volunteers) were enrolled from 15 sites in China. Most adverse reactions were mild and transient, and injection site pain (36 [8.2%]) was the most frequently reported adverse event. Three participants had Grade 3 aminopherase elevation (defined as alanine aminopherase>5 upper limits of normal) after the second dose of inactivated whole-virion SARS-CoV-2 vaccination, and only one of them was judged as severe adverse event potentially related to SARS-CoV-2 vaccination. The positive rates of SARS-CoV-2 neutralizing antibodies were 76.8% in non-cirrhotic CLD group, 78.9% in compensated cirrhotic group, 76.7% in decompensated cirrhotic group (P=0.894 among CLD subgroups) and 90.3% in healthy controls (P=0.008 versus CLD group). Conclusion Inactivated whole-virion SARS-CoV-2 vaccines are safe in patients with CLD. Patients with CLD had lower immunological response to SARS-CoV-2 vaccines than healthy population. The immunogenicity is similarly low in non-cirrhotic CLD, compensated cirrhosis and decompensated cirrhosis.

Liposomes, which are biodegradable and essentially non-toxic vehicles, can encapsulate both hydrophilic and hydrophobic materials, and are utilized as drug carriers in drug delivery systems. In addition, liposomes can be used to carry radioactive compounds as radiotracers can be linked to multiple locations in liposomes. One option is the hydrated compartment inside the liposome, another the lipid core into which especially hydrophobic conjugates can be attached, and the third option is the outer lipid leaflet where molecules can be bound by covalent linkage. Delivery of agents to the reticuloendothelial system (RES) is easily achieved, since most conventional liposomes are trapped by the RES. For the purpose of delivery of agents to target organs other than RES, long-circulating liposomes have been developed by modifying the liposomal surface. Understanding of the in vivo dynamics of liposome-carried agents is required for the evaluation of the bioavailability of drugs encapsulated in liposomes. In this review, we focus on the in vivo trafficking of liposomes visualized by positron emission tomography (PET) and discuss the characteristics of liposomes that affect the targeting of drugs in vivo.

The lysyl oxidase (LOX) family is comprised of five members, and some members have recently emerged as important regulators of tumor progression. Among these, at present, LOX‑like (LOXL)2 is the prototypical LOX and the most comprehensively studied member. A growing body of evidence has implicated LOXL2 in the promotion of cancer cell invasion, metastasis and angiogenesis, as well as in the malignant transformation of solid tumors. Moreover, a high expression of LOXL2 is associated with a poor prognosis. These data have piqued the interest of a number of researchers and research groups, who have identified LOXL2 as a strong target candidate in the development of inhibitors for use as functional and efficacious tumor therapeutics. In the present study, we summarize the recent progress made regarding LOXL2, mainly focusing on its function and mechanisms of action in tumor progression and metastasis. In this review, we note that LOXL2 promotes tumor progression possibly by activating multiple signal pathways through a variety of mechanisms, both biochemical and biomechanical. The data presented herein may open new avenues for the therapeutic utility of LOXL2.

The serine ⁄ threonine kinase UNC-51-like kinase 1 (ULK1) plays an essential role in autophagosome formation, although the exact molecular mechanism is unknown. The present study was first to investigate the clinical and prognostic significance of ULK1 in esophageal squamous cell carcinoma (ESCC). Protein and mRNA levels of ULK1 in normal esophageal epithelial cells, ESCC cell lines, paired ESCC lesions and the adjacent noncancerous tissues were examined using western blot and real-time RT-PCR. The results showed that only the ULK1 protein level was upregulated in ESCC samples compared with normal esophageal cells and tissues. Also, we found that protein stabilization of ULK1 was higher in ESCC cell lines. Furthermore, immunohistochemical staining of ULK1 was performed on the tissue microarray containing 248 ESCC and 51 normal esophageal tissues. A total of 70.2% ESCC specimens showed intensive expression of ULK1 in contrast to the undetectable expression of ULK1 in normal esophageal tissues. Statistical analysis revealed that ULK1 expression was significantly correlated with T status (P = 0.048). Moreover, patients with higher ULK1 expression were associated with shorter overall survival time. Multivariate analysis suggested that ULK1 expression and N status (P < 0.001) were independent prognostic indicators for the survival of patients. Functional studies showed that suppression of ULK1 expression in ESCC cell lines by specific small interfering RNA resulted in inhibition of cell proliferation and induction of apoptosis under starvation conditions. These findings provide evidence that ULK1 represents a novel and clinically useful biomarker for ESCC patients and plays an important role during the progression of ESCC. (Cancer Sci 2011; 102: 1568-1575 E sophageal carcinoma has been reported as the eighth most occurring cancer and the sixth leading cause of cancer death in the world.(1,2) Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal carcinoma in Asia, (3) especially in north central China.(4) Great advances have been achieved in surgical techniques and perioperative management in recent years; however, the mortality of this disease has not been significantly decreased. The main reason for poor prognosis of ESCC is that most early cases are asymptomatic, therefore patients are usually diagnosed at an advanced stage when the cancer has displayed local invasion and lymph node metastasis. Currently, only the stage based on the tumornode-metastasis (TNM) classification is widely accepted as a prognostic factor, which is not as precise as desired. Therefore, there is urgency to identify sensitive and specific biological markers that could accurately evaluate the prognosis of ESCC clinically.Macroautophagy (herein referred to as autophagy) is a dynamic process that intracellular double-membrane structures called autophagosomes sequester cytoplasmic contents, then fuse with lysosomes for breakdown and turn over these metabolic materials. (5,6) In normal cells, autophagy h...

BackgroundDying tumor cells after irradiation could promote the proliferation of living tumor cells might cause tumor relapse and treatment failure. Our previous study showed that activated caspase-3 after irradiation probably participates in tumor repopulation. In this study, we investigated whether high mobility group box 1(HMGB1) is also involved in tumor repopulation.MethodsColorectal tumor cells were irradiated. The cleaved caspase-3 (CC3) in irradiated tumor cells and HMGB1 in the supernatant of irradiated tumor cells were detected by Western blot. A large number of irradiated colorectal tumor cells (feeder cells) were then co-cultured with a small number of luciferase-labeled living colorectal tumor cells (reporter cells) and proliferation of reporter cells was measured by bioluminescence imaging. The CC3 and HMGB1 protein expression in colorectal tumor and peritumoral tissues were detected by immunohistochemistry and their correlation with prognosis were analyzed.ResultsThe irradiated colorectal tumor cells underwent apoptosis and necrosis and produced CC3 in tumor cells and HMGB1 in the supernatant of cultured cells. The increased expression of secretory HMGB1 correlated with CC3 level and proliferating cell nuclear antigen (PCNA) after irradiation in vitro. The irradiated dying cells remarkably stimulated living tumor cell proliferation. Interestedly, immunohistochemistry staining showed that positive HMGB1, CC3, and Ki67 expression were significantly higher in colorectal tumor tissues than in peritumoral tissues (p <0.01). The Kaplan-Meier survival analysis revealed that high HMGB1, CC3, and Ki67 levels were significantly associated with poor prognosis (p <0.05, p <0.01). Multivariate analysis using Cox proportional hazards model showed that TNM staging and HMGB1 were independent prognostic factors in patients with colorectal cancer (CRC) (p <0.01, p <0.001).ConclusionBoth apoptotic and necrotic cells could stimulate proliferation of living tumor cells, and the increased expression of CC3 and HMGB1 in tumor cells could be new markers for poor prognosis in colorectal cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0166-1) contains supplementary material, which is available to authorized users.

Metabolomics as the new omics technique develops after genomics, transcriptomics, and proteomics and has rapid development at present. Liver diseases are worldwide public health problems. In China, chronic hepatitis B and its secondary diseases are the common liver diseases. They can be diagnosed by the combination of history, virology, liver function, and medical imaging. However, some patients seldom have relevant physical examination, so the diagnosis may be delayed. Many other liver diseases, such as drug-induced liver injury (DILI), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases, still do not have definite diagnostic markers; the diagnosis consists of history, medical imaging, and the relevant score. As a result, the clinical work becomes very complex. So it has broad prospects to explore the specific and sensitive biomarkers of liver diseases with metabolomics. In this paper, there are several summaries which are related to the current research progress and application of metabolomics on biomarkers of liver diseases.