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Background The generation of subclonal (low-frequency) mutations is driven by tumor mutations and the relationship between the heterogeneity of tumor mutation abundance and non-small cell lung cancer (NSCLC) remains unknown. We investigate the role of allele frequency heterogeneity (AFH) defined by circulating tumor DNA (ctDNA) profiling in predicting prognosis in advanced NSCLC patients. Methods Publicly available data set of POPLAR (N=211) and OAK (N=642) trials were used for analyzing. A low ratio of allele frequency (AF) of a mutation to the maximum-somatic-allele-frequency (MSAF) was used to define the presence of AFH. The prognostic value of AF/MSAF ratio that was below a defined cutoff point in overall survival (OS) was evaluated using Cox-proportional hazards regression; and the structural break point was determined by LOESS regression and Chow test. The derived AFH was also explored in an independent cohort (N=259) of advanced NSCLC receiving first-line EGFR-TKIs from the First Affiliated Hospital of Guangzhou Medical University. Results In the POPLAR and OAK cohort, low AF/MSAF ratio was found to be significantly associated with unfavorable OS in univariate and multivariate analysis. The structural break point analysis demonstrated that AF/MSAF

Highlights • Initial blood urea nitrogen (BUN) and D-dimer levels were associated with mortality in COVID-19 patients. • Combination of BUN ≥ 4.6 mmol/L and D-dimer ≥ 0.845 μg/mL can identify patients at high risk of in-hospital mortality. • Development of a nomogram model based on initial BUN and D-dimer levels. • The nomogram could be a suitable and useful individualised tool to predict mortality in COVID-19 patients., The crude mortality rate in critical pneumonia cases with coronavirus disease 2019 (COVID-19) reaches 49%. This study aimed to test whether levels of blood urea nitrogen (BUN) in combination with D-dimer were predictors of in-hospital mortality in COVID-19 patients. The clinical characteristics of 305 COVID-19 patients were analysed and were compared between the survivor and non-survivor groups. Of the 305 patients, 85 (27.9%) died and 220 (72.1%) were discharged from hospital. Compared with discharged cases, non-survivor cases were older and their BUN and D-dimer levels were significantly higher (P < 0.0001). Least absolute shrinkage and selection operator (LASSO) and multivariable Cox regression analyses identified BUN and D-dimer levels as independent risk factors for poor prognosis. Kaplan–Meier analysis showed that elevated levels of BUN and D-dimer were associated with increased mortality (log-rank, P < 0.0001). The area under the curve for BUN combined with D-dimer was 0.94 (95% CI 0.90–0.97), with a sensitivity of 85% and specificity of 91%. Based on BUN and D-dimer levels on admission, a nomogram model was developed that showed good discrimination, with a concordance index of 0.94. Together, initial BUN and D-dimer levels were associated with mortality in COVID-19 patients. The combination of BUN ≥ 4.6 mmol/L and D-dimer ≥ 0.845 μg/mL appears to identify patients at high risk of in-hospital mortality, therefore it may prove to be a powerful risk assessment tool for severe COVID-19 patients.

COVID-19, the disease caused by SARS-CoV-2, is a highly contagious disease. The World Health Organization has declared the ongoing outbreak to be a global public health emergency. Currently, the research on SARS-CoV-2 is in its primary stages. Based on current published evidence, this review systematically summarizes the epidemiology, clinical characteristics, diagnosis, treatment and prevention of COVID-19. It is hoped that this review will help the public to recognize and deal with SARS-CoV-2, and provide a reference for future studies.

// Hengyi Gao 1,2,4 , Feng Zhu 2 , Min Wang 2 , Hang Zhang 2 , Dawei Ye 3 , Jiayin Yang 4 , Li Jiang 5 , Chang Liu 5 , Renyi Qin 2 , Lunan Yan 4 and Guangqin Xiao 2,4 1 Department of General Surgery, Guizhou Provincial People’s Hospital, Guiyang, China 2 Department of Hepato-Pancreato-Biliary Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 3 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 4 Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China 5 Department of State Key Laboratory of Biotherapy and Pathology, West China Hospital of Sichuan University, Chengdu, China Correspondence to: Guangqin Xiao, email: // Keywords : hepatocellular carcinoma, liver fibrosis, hepatitis B virus, preoperatively, noninvasive Received : June 03, 2016 Accepted : December 05, 2016 Published : December 19, 2016 Abstract Background: Advanced liver fibrosis can result in serious complications (even patient’s death) after partial hepatectomy. Preoperatively percutaneous liver biopsy is an invasive and expensive method to assess liver fibrosis. We aim to establish a noninvasive model, on the basis of preoperative biomarkers, to predict liver fibrosis in hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection. Methods: The HBV-infected liver cancer patients who had received hepatectomy were retrospectively and prospectively enrolled in this study. Univariate analysis was used to compare the variables of the patients with mild to moderate liver fibrosis and with severe liver fibrosis. The significant factors were selected into binary logistic regression analysis. Factors determined to be significant were used to establish a noninvasive model. Then the diagnostic accuracy of this novel model was examined based on sensitivity, specificity and area under the receiver-operating characteristic curve (AUC). Results: This study included 2,176 HBV-infected HCC patients who had undergone partial hepatectomy (1,682 retrospective subjects and 494 prospective subjects). Regression analysis indicated that total bilirubin and prothrombin time had positive correlation with liver fibrosis. It also demonstrated that blood platelet count and fibrinogen had negative correlation with liver fibrosis. The AUC values of the model based on these four factors for predicting significant fibrosis, advanced fibrosis and cirrhosis were 0.79-0.83, 0.83-0.85 and 0.85-0.88, respectively. Conclusion: The results showed that this novel preoperative model was an excellent noninvasive method for assessing liver fibrosis in HBV-infected HCC patients.

Purpose: We sought to find new immune-based treatments for pancreatic cancer. Experimental Design: We detected IL18 expression in plasma and specimens from patients with pancreatic cancer. We then investigated whether IL18 had a therapeutic effect for pancreatic cancer in vitro and in vivo and any underlying mechanisms. Results: Higher plasma IL18 was associated with longer overall survival (OS), but higher IL18 in pancreatic cancer tissues was associated with shorter OS and increased invasion and metastasis. Recombinant IL18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral blood and lymph nodes. However, IL18 promoted the proliferation and invasion of pancreatic cancer cells, in vitro and in vivo, through the NF-κB pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-κB inhibitor, we were able to prevent the procancerous effects of IL18 and prolong the survival time of the mice. Conclusions: IL18 has both cancer-promoting and cancer-suppressing functions. Although its single-agent treatment has no therapeutic effect on pancreatic cancer, when combined with the NF-κB pathway inhibitor, IL18 improved survival in a murine pancreatic cancer model. Our study implies the possibility of a combinational immunotherapy that uses IL18 and targets NF-κB pathway. Clin Cancer Res; 22(23); 5939–50. ©2016 AACR.

Single nucleotide polymorphisms (SNPs) in MicroRNAs (miRNAs) are involved in the mechanism of carcinogenesis. Several studies have evaluated the association of rs4919510 SNP in miR-608 with cancer susceptibility in different types of cancer, with inconclusive outcomes. To obtain a more precise estimation, we carried out this meta-analysis through systematic retrieval from the PubMed and Embase database. A total of 10 case-control studies were analyzed with 6,000 cases and 7,664 controls. The results showed that 4919510 SNP in miR-608 was significantly associated with decreased cancer risk only in recessive model (CC vs. GG+GC: OR=0.89, 95% CI: 0.82-0.97, P=0.009). By further stratified analysis, we found that rs4919510 SNP had some relationship with decreased cancer risk in both homozygote model (CC vs. GG: OR=0.59, 95% CI: 0.36-0.96, P=0.034) and dominant model (CG+ CC vs. GG: OR=0.60, 95% CI: 0.37-0.98, P=0.042) in Caucasians but no relationship in any genetic model in Asians. These results indicated that miR-608 rs4919510 polymorphism may contribute to the decreased cancer susceptibility and could be a promising target to forecast cancer risk for clinical practice. However, to further confirm these results, well-designed large scale case-control studies are needed in the future.

Parkinson's disease (PD) is one of the most common forms of neurodegenerative disease in the elderly population and is typically manifested by motor symptoms and nonmotor symptoms and signs. Nonmotor symptoms, such as sensory symptoms, have been regarded as the significant features of this disease. These symptoms often occur in early stages of PD and influence quality of life. However, researchers suggest that the sensory symptoms of PD are frequently unrecognized by clinicians and remain untreated. The disorders include pain, olfactory disturbance, and visual dysfunction input on the underlying sensory abnormality. This Review focuses on the clinical features, pathophysiological mechanisms, and treatment strategies for sensory symptoms of PD from both clinical studies and basic research, providing a comprehensive overview of the sensory symptoms in PD. © 2016 Wiley Periodicals, Inc.

Background This study attempted to examine the discordance between family caregivers and cancer patients in their poor-prognosis disclosure preferences in mainland China and then ascertained the associations between quality of life (QoL), perceived stress, and poor-prognosis disclosure preferences. Methods Six hundred fifty-one pairs of inpatients and their matched caregivers (participation rate = 92.2%) were recruited in this cross-sectional survey. A set of paired self-administered questionnaires were completed independently by patient–caregiver dyads. Results Fewer family caregivers than cancer patients felt that poor prognosis should be disclosed to patients (61.2% vs. 90.0%, p

Cancer cachexia is a devastating, multifactorial, and irreversible syndrome characterized by skeletal muscle reduction with or without fat loss. Although much attention has been focused on muscle wasting, fat loss may occur earlier and accelerate muscle wasting in cachexia. The cause of 20% of cancer related death makes it urgent to discover molecular mechanisms behind cancer cachexia. Here we applied weighted gene co-expression network analysis (WGCNA) to identify cachexia related gene modules using differentially expressed 3289 genes and 59 long non-coding RNAs based on microarray data of cachectic and non-cachectic subcutaneous adipose tissue. Subsequently, 16 independent modules were acquired and GSAASeqSP Toolset confirmed that black module was significantly associated with fat loss in cancer cachexia. Top 50 hub-genes in black module contained only one lncRNA, VLDLR antisense RNA 1 (VLDLR-AS1). We then explored the function of black module from the view of VLDLR-AS1-connected genes in the network. GO enrichment and KEGG pathways analysis revealed LDLR-AS1-connected genes were involved in Wnt signaling pathway, small GTPase mediated signal transduction, epithelial-mesenchymal transition and so on. Through construction of competing endogenous RNAs (ceRNAs) regulation network, we showed that VLDLR-AS1 may function with hsa-miR-600 to regulate gene GOLGA3, DUSP14, and UCHL1, or interact with hsa-miR-1224-3p to modulate the expression of gene GOLGA3, ZNF219, RNF141, and CALU. After literature validation, we predicted that VLDLR-AS1 most likely interacted with miR-600 to regulate UCH-L1 through Wnt/β-catenin signaling pathway. However, further experiments are still required to validate mechanisms of VLDLR-AS1 in fat reduction of cancer cachexia.

Background Aspartate aminotransferase to platelet ratio index (APRI) and the fibrosis index based on four factors (FIB-4) are the two most focused non-invasive models to assess liver fibrosis. Aims We aimed to examine the validity of these two models for predicting hepatitis B virus (HBV)-related liver fibrosis accompanied with hepatocellular carcinoma (HCC). Methods We enrolled HBV-infected patients with liver cancer who had received hepatectomy. The accuracy of APRI and FIB-4 for diagnosing liver fibrosis was assessed based on their sensitivity, specificity, diagnostic efficiency, positive predictive value (PPV), negative predictive value (NPV), kappa ( κ ) value and area under the receiver-operating characteristic curve (AUC). Results Finally 2176 patients were included, with 1682 retrospective subjects and 494 prospective subjects. APRI ( r s = 0.310) and FIB-4 ( r s = 0.278) were positively correlated with liver fibrosis. And χ 2 analysis demonstrated that APRI and FIB-4 values correlated with different levels of liver fibrosis with all P values less than 0.01. The AUC values for APRI and FIB-4 were 0.685 and 0.626 ( P = 0.73) for predicting significant fibrosis, 0.681 and 0.648 ( P = 0.81) for differentiation of advanced fibrosis and 0.676 and 0.652 ( P = 0.77) for diagnosing cirrhosis. Conclusion APRI and FIB-4 correlate with liver fibrosis. However these two models have low accuracy for predicting HBV-related liver fibrosis in HCC patients.

// Tao Lu 2, * , Yanmei Zou 1, * , Guogang Xu 3 , Jane A. Potter 4 , Garry L. Taylor 4 , Qiuhong Duan 2 , Qin Yang 5 , Huihua Xiong 1 , Hong Qiu 1 , Dawei Ye 1 , Peng Zhang 1 , Shiying Yu 1 , Xianglin Yuan 1 , Feng Zhu 2 , Yihua Wang 6 , Hua Xiong 1 1 Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China 2 Department of Biochemistry and molecular biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China 3 Nanlou Respiratory Department, Chinese PLA General Hospital, Beijing, 10083, China 4 BioMedical Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK 5 Department of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China 6 Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK * These authors have contributed equally to this work Correspondence to: Hua Xiong, email: cnhxiong@163.com Keywords: PRIMA-1 Met , MEK, p53, colorectal cancer, tumorigenesis Received: October 17, 2015 Accepted: October 10, 2016 Published: October 27, 2016 ABSTRACT PRIMA-1 Met is the methylated PRIMA-1 (p53 reactivation and induction of massive apoptosis) and could restore tumor suppressor function of mutant p53 and induce p53 dependent apoptosis in cancer cells harboring mutant p53. However, p53 independent activity of PRIMA-1 Met remains elusive. Here we reported that PRIMA-1 Met attenuated colorectal cancer cell growth irrespective of p53 status. Kinase profiling revealed that mitogen-activated or extracellular signal-related protein kinase (MEK) might be a potential target of PRIMA-1 Met . Pull-down binding and ATP competitive assay showed that PRIMA-1 Met directly bound MEK in vitro and in cells. Furthermore, the direct binding sites of PRIMA-1 Met were explored by using a computational docking model. Treatment of colorectal cancer cells with PRIMA-1 Met inhibited p53-independent phosphorylation of MEK, which in turn impaired anchorage-independent cell growth in vitro. Moreover, PRIMA-1 Met suppressed colorectal cancer growth in xenograft mouse model by inhibiting MEK1 activity. Taken together, our findings demonstrate a novel p53-independent activity of PRIMA-1 Met to inhibit MEK and suppress colorectal cancer growth.

Bladder cancer is a relatively common urinary tract carcinoma. There are in general two categories of bladder cancer, low grade and high grade, which develop through distinct molecular pathways, have different clinical presentations and therefore require different management schemes. Regardless of tumor grade, most bladder cancers have high recurrence rate. Conventional treatments such as surgery, radiotherapy, and chemotherapy, though quite effective in managing the tumor burden itself, may not be effective enough to cure the disease. Herbal medicines, such as Zhuling, garlic, green tea, astragalus, triptolide, and Ganoderma lucidum, provide potential alternatives for the management of this disease. This chapter provides an overview of the scientific research studying the efficacy and potential mechanisms of action of these herbal remedies in the treatment of bladder cancer. Some of the active ingredients in the herbs have been shown to be effective in inhibiting tumor growth in vitro and in vivo. Animal models and cell line studies provide experimental evidence demonstrating the potential therapeutic effects of these herbs. Obviously, definitive clinical trials are needed to evaluate the safety and efficacy of herbal ­management of bladder cancer. In this chapter, we also discuss the relationship of nutrition and diet with bladder cancer.