Factors predicting occurrence and prognosis of hepatitis-B-virus-related hepatocellular carcinoma

Primary liver cancer is an important cause of cancer death, and hepatocellular carcinoma （HCC） accounts for 70%-85% of total liver cancer worldwide. Chronic hepatitis B virus （HBV） infection contributes to 〉 75% of HCC cases. High serum viral load is the most reliable indicator of viral replication in predicting development of HCC. HBV genotype C is closely associated with HCC in cirrhotic patients aged 〉 50 years, whereas genotype B is associated with development of HCC in non-cirrhotic young patients and postoperative relapse of HCC. Different HBV subgenotypes have distinct patterns of mutations, which are clearly associated with increased risk of HCC. Mutations accumulate during chronic HBV infection and predict occurrence of HCC. Chronic inflammation leads to increased frequency of viral mutation via cellular cytidine deaminase induction. Mutations are negatively selected by host immunity, whereas some immuno-escaped HBV mutants are active in hepatocarcinogenesis. Inflammatory pathways contribute to the inflammation-necrosis-regeneration process, ultimately HCC. Their hallmark molecules can predict malignancy in HBV-infected subjects. Continuing inflammation is involved in hepatocarcinogenesis and closely related to recurrence and metastasis. HBV load, genotype C, viral mutations and expression of inflammatory molecules in HBV-related HCC tissues are significantly associated with poor prognosis. Imbalance between intratumoral CD8^＋T cells and regulatory T cells or Thl and Th2 cytokines in peritumoral tissues can predict prognosis of HBV-related HCC. These factors are important for developing active prevention and surveillance of HBV-infected subjects who are more likely to develop HCC, or for tailoring suitable treatment to improve survival or postpone postoperative recurrence of HCC.

Clinical relevance and public health significance of hepatitis B virus genomic variations

Ten hepatitis B virus （HBV） genotypes （A-J） and 34 HBV subgenotypes have been identified so far. HBV genotypes and subgenotypes have distinct geographical distributions, and have been shown to differ with regard to clinical outcome, prognosis, and response to interferon treatment. Infection with subgenotype A2 is frequently associated with high viral load, resulting in acute infection via horizontal transmission. Genotypes A and B are more sensitive to interferon treatment than genotypes D and C, respectively. Genotype B is more frequent in acute hepatitis than genotype C, whereas genotype C （C2） is more frequently associated with an increased risk of hepatocellular carcinoma （HCC）, mostly cirrhotic, as compared with genotype B （B2）. Genotype mixture is associated with high viral load and worse outcome of HBV infection. HBV mutations in the S genes, especially amino acids substitution at position 145 （G145R）, are associated with immune escape, whereas mutations in the PreS or S genes which impair HBsAg secretion could present a risk to blood safety. HBV variants harboring mutations in the viral polymerase gene that confer resistance to nucleoside analogs may be selected during antiviral therapy. Different genotypes have distinct mutation patterns in the PreS and EnhH/BCP/Precore regions. PreS deletions, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. HCC- associated HBV mutants may not transmit via motherto-child transmission, and are likely generated during HBV-induced pathogenesis. Examination of HBV mutations alone or in combination and host genetic suscep-tibility will be helpful in classifying the HBV-infected subjects who will develop HCC and need active antiviral treatments.

Cancer incidence and patient survival rates among the residents in the Pudong New Area of Shanghai between 2002 and 2006

With the growing threat of malignancy to health,it is necessary to analyze cancer incidence and patient survival rates among the residents in Pudong New Area of Shanghai to formulate better cancer prevention strategies.A total of 43,613 cancer patients diagnosed between 2002 and 2006 were recruited from the Pudong New Area Cancer Registry.The incidence,observed survival rate,and relative survival rate of patients grouped by sex,age,geographic area,and TNM stage were calculated using the Kaplan-Meier,life table,and Ederer II methods,respectively.Between 2002 and 2006,cancer incidence in Pudong New Area was 349.99 per 100,000 person-years,and the 10 most frequently diseased sites were the lung,stomach,colon and rectum,liver,breast,esophagus,pancreas,brain and central nervous system,thyroid,and bladder.For patients with cancers of the colon and rectum,breast,thyroid,brain and central nervous system,and bladder,the 5-year relative survival rate was greater than 40%,whereas patients with cancers of the liver and pancreas had a 5-year relative survival rate of less than 10%.The 1-year to 5-year survival rates for patients grouped by sex,age,geographic area,and TNM stage differed significantly(all P<0.001).Our results indicate that cancer incidence and patient survival in Pudong New Area vary by tumor type,sex,age,geographic area,and TNM stage.

Inflammation-related factors predicting prognosis of gastric cancer

Gastric cancer(GC),which is mainly induced by Helicobacter pylori(H.pylori)infection,is one of the leading causes of cancer-related death in the developing world.Active inflammation initiated by H.pylori infection and maintained by inherent immune disorders promotes carcinogenesis and postoperative recurrence.However,the presence with H.pylori in tumors has been linked to a better prognosis,possibly due to the induction of antitumor immunity.Tumor infiltrations of tumorassociated macrophages,myeloid-derived suppressor cells,neutrophils,Foxp3+regulatory T cells are correlated with poor prognosis.Tumor infiltrating CD8+cytotoxic T lymphocytes,dendritic cells,and CD45RO T cells are generally associated with good prognosis of GC,although some subsets of these immune cells have inverse prognosis prediction values.High ratios of Foxp3+/CD4+and Foxp3+/CD8+in tumors are associated with a poor prognosis;whereas high Th1/Th2ratio in tumors predicts a good prognosis.High levels of interleukin(IL)-6,IL-10,IL-32,and chemokine C-C motif ligands(CCL)7 and CCL21 in circulation,high expression of CXC chemokine receptor 4,chemokine C-C motif receptor(CCR)3,CCR4,CCR5,CCR7,hypoxiainducible factor-1α,signal transducer activator of transcription-3,cyclooxygenase-2,and orphan nuclear receptor 4A2 in tumors are associated with an unfavorable prognosis.Increased serum levels of matrix metalloproteinases(MMP)-3,MMP-7,and MMP-11 and increased levels of MMP-9,MMP-12,and MMP-21 in tumors are consistently associated with poor survival of GC.Further emphasis should be put on the integration of these biomarkers and validation in large cohorts for personalized prediction of GC postoperative prognosis.

Virus-related liver cirrhosis: Molecular basis and therapeutic options

Chronic infections with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) are the major causes of cirrhosis globally. It takes 10-20 years to progress from viral hepatitis to cirrhosis. Intermediately active hepatic inflammation caused by the infections contributes to the inflammation-necrosis-regeneration process, ultimately cirrhosis. CD8+ T cells and NK cells cause liver damage via targeting the infected hepatocytes directly and releasing pro-inflammatory cytokine/chemokines. Hepatic stellate cells play an active role in fibrogenesis via secreting fibrosis-related factors. Under the inflammatory microenvironment, the viruses experience mutation-selection-adaptation to evade immune clearance. However, immune selection of some HBV mutations in the evolution towards cirrhosis seems different from that towards hepatocellular carcinoma. As viral replication is an important driving force of cirrhosis pathogenesis, antiviral treatment with nucleos(t)ide analogs is generally effective in halting the progression of cirrhosis, improving liver function and reducing the morbidity of decompensated cirrhosis caused by chronic HBV infection. Interferon-α plus ribavirin and/or the direct acting antivirals such as Vaniprevir are effective for compensated cirrhosis caused by chronic HCV infection. The standard of care for the treatment of HCV-related cirrhosis with interferon-α plus ribavirin should consider the genotypes of IL-28B. Understanding the mechanism of fibrogenesis and hepatocyte regeneration will facilitate the development of novel therapies for decompensated cirrhosis.

Prognostic value of preoperative carcinoembryonic antigen/tumor size in rectal cancer

BACKGROUND Carcinoembryonic antigen(CEA)is a commonly used biomarker in colorectal cancer.However,controversy exists regarding the insufficient prognostic value of preoperative serum CEA alone in rectal cancer.Here,we combined preoperative serum CEA and the maximum tumor diameter to correct the CEA level,which may better reflect the malignancy of rectal cancer.AIM To assess the prognostic impact of preoperative CEA/tumor size in rectal cancer.METHODS We retrospectively reviewed 696 stage I to III rectal cancer patients who underwent curative tumor resection from 2007 to 2012.These patients were randomly divided into two cohorts for cross-validation:training cohort and validation cohort.The training cohort was used to generate an optimal cutoff point and the validation cohort was used to further validate the model.Maximally selected rank statistics were used to identify the optimum cutoff for CEA/tumor size.The Kaplan-Meier method and log-rank test were used to plot the survival curve and to compare the survival data.Univariate and multivariate Cox regression analyses were used to determine the prognostic value of CEA/tumor size.The primary and secondary outcomes were overall survival(OS)and disease-free survival(DFS),respectively.RESULTS In all,556 patients who satisfied both the inclusion and exclusion criteria were included and randomly divided into the training cohort(2/3 of 556,n=371)and the validation cohort(1/3 of 556,n=185).The cutoff was 2.429 ng/mL per cm.Comparison of the baseline data showed that high CEA/tumor size was correlated with older age,high TNM stage,the presence of perineural invasion,high CEA,and high carbohydrate antigen 19-9(CA 19-9).Kaplan-Meier curves showed a manifest reduction in 5-year OS(training cohort:56.7%vs 81.1%,P<0.001;validation cohort:58.8%vs 85.6%,P<0.001)and DFS(training cohort:52.5%vs 71.9%,P=0.02;validation cohort:50.3%vs 79.3%,P=0.002)in the high CEA/tumor size group compared with the low CEA/tumor size group.Univariate and multivariate analyses identified CEA/tumor size as an independent prognostic factor for OS(training cohort:hazard ratio(HR)=2.18,95%confidence interval(CI):1.28-3.73,P=0.004;validation cohort:HR=4.83,95%CI:2.21-10.52,P<0.001)as well as DFS(training cohort:HR=1.47,95%CI:0.93-2.33,P=0.096;validation cohort:HR=2.61,95%CI:1.38-4.95,P=0.003).CONCLUSION Preoperative CEA/tumor size is an independent prognostic factor for patients with stage I-III rectal cancer.Higher CEA/tumor size is associated with worse OS and DFS.

Strategy and technology to prevent hospital-acquired infections:Lessons from SARS,Ebola,and MERS in Asia and West Africa

Hospital-acquired infections(HAIs) are serious problems for healthcare systems, especially in developing countries where public health infrastructure and technology for infection preventions remain undeveloped. Here, we characterized how strategy and technology could be mobilized to improve the effectiveness of infection prevention and control in hospitals during the outbreaks of Ebola, Middle East respiratory syndrome(MERS), and severe acute respiratory syndrome(SARS) in Asia and West Africa. Published literature on the hospital-borne outbreaks of SARS, Ebola, and MERS in Asia and West Africa was comprehensively reviewed. The results showed that healthcare systems and hospital management in affected healthcare facilities had poor strategies and inadequate technologies and human resources for the prevention and control of HAIs, which led to increased morbidity, mortality, and unnecessary costs. We recommend that governments worldwide enforce disaster risk management, even when no outbreaks are imminent. Quarantine and ventilation functions should be taken into consideration in architectural design of hospitals and healthcare facilities. We also recommend that health authorities invest in training healthcare workers for disease outbreak response, as their preparedness is essential to reducing disaster risk.

Role of nuclear receptor NR4A2 in gastrointestinal inflammation and cancers

NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily.It was originally considered to be essential in the generation and maintenance of dopaminergic neurons,and associated with neurological disorders such as Parkinson's disease.Recently,NR4A2 has been found to play a critical role in some inflammatory diseases and cancer.NR4A2 can be efficiently trans-activated by some proinflammatory cytokines,such as tumor necrosis factor-α,interleukin-1β,and vascular endothelial growth factor(VEGF).The nuclear factor-κB signaling pathway serves as a principal regulator of inducible NR4A expression in immune cells.NR4A2 can trans-activate Foxp3,a hallmark specifically expressed in regulatory T(Treg) cells,and plays a critical role in the differentiation,maintenance,and function of Treg cells.NR4A2 in T lymphocytes is pivotal for Treg cell induction and suppression of aberrant induction of Th1 under physiological and pathological conditions.High density of Foxp3 + Treg cells is significantly associated with gastrointestinal inflammation,tumor immune escape,and disease progression.NR4A2 is produced at high levels in CD133 + colorectal carcinoma(CRC) cells and significantly upregulated by cyclooxygenase-2-derived prostaglandin E 2 in a cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)-dependent manner in CRC cells.The cAMP/PKA signaling pathway is the common pathway of NR4A2-related inflammation and cancer.NR4A2 trans-activates osteopontin,a direct target of the Wnt/β-catenin pathway associated with CRC invasion,metastasis,and poor prognosis.Knockdown of endogenous NR4A2 expression attenuates VEGF-induced endothelial cell proliferation,migration and in vivo angiogenesis.Taken together,NR4A2 emerges as an important nuclear factor linking gastrointestinal inflammation and cancer,especially CRC,and should serve as a candidate therapeutic target for inflammation-related gastrointestinal cancer.

The prevalence rates of major chronic diseases in retired and in-service Chinese military officers(2000-2016): a meta-analysis

Background:Chronic diseases cause a tremendous burden to the military medical system.However,the prevalence rates of major chronic diseases among military officers remain unclear in China.Methods:China National Knowledge Infrastructure(CNKI),Wanfang Database,VIP Database for Chinese Technical Periodicals(VIP),Pub Med and Web of Science were searched for studies(from 2000 to 2016)concerning 6 major chronic diseases:hypertension,hyperlipidemia,diabetes mellitus,heart diseases,cerebrovascular diseases,and chronic obstructive pulmonary diseases(COPD)in Chinese military officers following strict inclusion and exclusion criteria.Three researchers independently extracted data from the included studies,and a fourth researcher reviewed and solved every disagreement.Statistical analysis was performed with STATA 14.0 and R 3.3.2.Heterogeneity was evaluated by the I^2 value.A random effect model was performed to combine the heterogeneous data.The Egger test was performed to test the publication bias.Results:A total of 90,758 military officers derived from 75 articles were pooled together.Publication bias was only observed in 37 studies reporting heart disease(P_(Egger test)=0.01).The overall prevalence rates of hypertension,hyperlipidemia,diabetes mellitus,heart diseases,cerebrovascular diseases,and COPD were 46.6%(95%CI 41.8%–51.5%),30.9%(26.4%–35.7%),20.7%(16.5%–25.7%),48.2%(41.7%–54.9%),20.2%(14.8%–26.9%)and 16.6%(12.9%–21.0%),respectively.The prevalence rates of hypertension,diabetes,heart disease,cerebrovascular disease,and COPD,rather than hyperlipidemia,increased with age in Chinese military officers.Heart diseases(P_(Q-test)<0.001)and hypertension(P_(Q-test)<0.001)increased sharply in retired officers compared with officers in service.Cerebrovascular disease was more frequent in Northern Theater Command than in any other theater command(P_(Q-test)<0.001).Conclusion:Major chronic diseases heavily affect Chinese military officers,especially retirees.Medical intervention should be enforced on the prevention of cerebrovascular diseases in those working in cold areas in the north,as well as hypertension and heart diseases in retirees.

Prediction and prophylaxis of hepatocellular carcinoma occurrence and postoperative recurrence in chronic hepatitis B virus-infected subjects

Hepatocellular carcinoma(HCC) is one of the most common and highly fatal malignancies worldwide. Chronic infection with hepatitis B virus(HBV) is a major cause of HCC. High HBV replication rate and related non-resolving inflammation are the major risk factors of HCC occurrence and postoperative recurrence. Early prophylactic options are effective in reducing HCC occurrence and improving survival. Therefore, it is important to identify HBV-infected patients who are at a higher risk of developing HCC and HBV-HCC patients who are more likely to relapse after surgery, thus providing them with more precise prophylactic strategies. Several prediction models of HCC occurrence have been constructed, with satisfactory predictive accuracy and discriminatory ability. However, there is a lack of consensus for their clinical implementation. Several staging systems have been proposed for HCC prognosis. However, the accuracy of these staging systems based on demographic characteristics and clinical measurements needs to be further improved, possibly by systematically incorporating viral and inflammatory factors. Since antiviral treatments are effective in promoting liver function reserve, reducing HCC occurrence and prolonging postoperative survival in some HBV-infected subjects, it is very important to identify subgroups of HBV-infected patients who would most benefit from antiviral treatment.

Antiviral treatment to prevent chronic hepatitis B or C-related hepatocellular carcinoma

Antiviral treatment is the only option to prevent or defer the occurrence of hepatocellular carcinoma(HCC) in patients chronically infected with hepatitis B virus(HBV) or hepatitis C virus(HCV). The approved medication for the treatment of chronic HBV infection is interferon-α(IFNα) and nucleos(t)ide analogues(NAs), including lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. IFNα is the most suitable for young patients with less advanced liver diseases and those infected with HBV genotype A. IFNα treatment significantly decreases the overall incidence of HBV-related HCC in sustained responders. However, side effects may limit its long-term clinical application. Orally administered NAs are typically implemented for patients with more advanced liver diseases. NA treatment significantly reduces disease progression of cirrhosis and therefore HCC incidence, especially in HBV e antigen-positive patients. NA-resistance due to the mutations in HBV polymerase is a major limiting factor. Of the NA resistance-associated mutants, A181 T mutant significantly increases the risk of HCC development during the subsequent course of NA therapy. It is important to initiate treatment with NAs that have a high genetic barrier to resistance, to counsel patients on medication adherence and to monitor virological breakthroughs. The recommended treatment for patients with chronic HCV infection is peg-IFN plus ribavirin that can decrease the occurrence of HCC in those who achieve a sustained virological response and have not yet progressed to cirrhosis. IFN-based treatment is reserved for patients with decompensated cirrhosis who are under evaluation of liver transplantation to reduce post-transplant recurrence of HCV. More effective therapeutic options such as direct acting antiviral agents will hopefully increase the response rate in difficult-totreat patients with HCV genotype 1. However, the risk of HCC remains in cirrhotic patients(both chronic HBV and HCV infection) if treatment is initiated after cirrhosis is established. Future research should focus on investigating new agents, especially for those patients with hepatic decompensation or post-transplantation.

Upregulation of nemo-like kinase is an independent prognostic factor in colorectal cancer

AIM: To investigate the expression and oncogenic role of nemo-like kinase(NLK) in colorectal cancer.METHODS: Expression of NLK protein was assessed by immunohistochemistry in tissue specimens from 56 cases of normal colorectal mucosa, 51 cases of colorectal adenoma, and 712 cases of colorectal cancer. In addition, NLK expression was knocked down using a lentivirus carrying NLK small hairpin RNA in colorectal cancer cells. Cell viability methylthiazoletetrazolium assays, colony formation assays, flow cytometry cell cycle assays, Transwell migration assays, and gene expression assays were performed to explore its role on proliferation and migration of colorectal cancer.RESULTS: Expression of NLK protein progressively increased in tissues from the normal mucosa through adenoma to various stages of colorectal cancer. Overexpression of NLK protein was associated with advanced tumor-lymph node-metastasis stages, poor differentiation, lymph node and distant metastases, and a higher recurrence rate of colorectal cancer(P < 0.05). Multivariate analyses showed that NLK expression was an independent prognostic factor to predict overallsurvival(hazard ratio 2.57, 95% confidence interval: 1.66-3.98; P < 0.001) and disease-free survival(hazard ratio 1.96, 95% confidence interval: 1.40-2.74: P < 0.001) of colorectal cancer patients. Furthermore, knockdown of NLK expression in colorectal cancer cell lines reduced cell viability, colony formation, and migration, and arrested tumor cells at the G0/G1 phase of the cell cycle. At the gene level, knockdown of NLK expression inhibited matrix metalloproteinase-2 expression in colorectal cancer cells. CONCLUSION: NLK overexpression is an independent prognostic factor in colorectal cancer and knockdown of NLK expression inhibits colorectal cancer progression and metastasis.

The role of hazard vulnerability assessments in disaster preparedness and prevention in China

China is prone to disasters and escalating disaster losses. Effective disaster mitigation is the foundation for efficient disaster response and rescue and for reducing the degree of hazardous impacts on the population. Vulnerability refers to the population's capacity to anticipate, cope with, and recover from the impact of a hazardous event. A hazard vulnerability assessment(HVA) systematically evaluates the damage that could be caused by a potential disaster, the severity of the impact, and the available medical resources during a disaster to reduce population vulnerability and increase the capacity to cope with disasters. In this article, we summarized HVA team membership, content(disaster identification, probability and consequences), and methods and procedures for an HVA that can be tailored to China's needs. We further discussed the role of epidemiology in an HVA. Disaster epidemiology studies the underlying causes of disasters to achieve effective disaster prevention and reduction. In addition, we made several recommendations that are already in practice in developed countries, such as the U.S., for future implementation in China and other developing countries. An effective HVA plan is crucial for successful disaster preparedness, response, and recovery.

Ebola virus disease: From epidemiology to prophylaxis

The outbreak of Ebola virus disease(EVD) continues to spread through West Africa. Since the first reported EVD in March 2014, the number of cases has increased rapidly, with the fatality rate of >50%. The most prevalent Ebola virus belongs to the species of Zaire ebolavirus, with a mortality rate as high as 90%. Although there were introduced cases in other continents, Africa is the endemic area where fruit bats and apes are suspected to be Ebola virus carriers. The virus might be transmitted from the host animals to humans if humans consume relative raw and contaminated meats; however, human-to-human transmission via close contact is the major route of current outbreaks. EVD happens at any seasons and affected people of any race in any age groups. Direct contact with body fluids of EVD patients and living in the contaminated environment greatly increase the risk of being infected. Transmission viaaerosol is less possible but the transmission via droplet is possible in humans. Thus, health care providers are facing danger of getting Ebola virus infection. So far, there are limited vaccines, drugs and/or therapies to prevent Ebola virus infection or treat EVD. Medical workers should follow the current standard prophylactic procedures. Military forces can orchestrate efficient care to mass EVD casualties. Although it is necessary to speed up the pace of developing effective vaccine and therapeutics for the prevention and treatment of EVD, public health prophylaxis is the most important issue at present to control the spread of this disease cost-effectively.

Challenges of incorporating gene expression data to predict HCC prognosis in the age of systems biology

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide.The recurrence of HCC after curative treatments is currently a major hurdle.Identification of subsets of patients with distinct prognosis provides an opportunity to tailor therapeutic approaches as well as to select the patients with specific sub-phenotypes for targeted therapy.Thus,the development of gene expression profiles to improve the prediction of HCC prognosis is important for HCC management.Although several gene signatures have been evaluated for the prediction of HCC prognosis,there is no consensus on the predictive power of these signatures.Using systematic approaches to evaluate these signatures and combine them with clinicopathologic information may provide more accurate prediction of HCC prognosis.Recently,Villanueva et al developed a composite prognostic model incorporating gene expression patterns in both tumor and adjacent tissues to predict HCC recurrence.In this commentary,we summarize the current progress in using gene signatures to predict HCC prognosis,and discuss the importance,existing issues and future research directions in this field.

Phosphatase and Tensin Homologue Genetic Polymorphisms and their Interactions with Viral Mutations on the Risk of Hepatocellular Carcinoma

Background： Chronic hepatitis B virus （HBV） infection is the major cause of hepatocellular carcinoma （HCC）. Some HBV mutants and dysregulation of phosphatase and tensin homolog （PTEN） may promote the development of HCC synergistically. We aimed to test the effects of PTEN genetic polymorphisms and their interactions with important HBV mutations on the development of HCC in HBV-infected subjects. Methods： Quantitative po[ymerase chain reaction was applied to genotype PTEN polymorphisms （rs1234220, rs2299939, rsl234213） in 1012 healthy controls, 302 natural clearance subjects, and 2011 chronic H BV-infected subjects including 1021 HCC patients. HBV mutations were determined by sequencing. The associations of PTEN polymorphisms and their interactions with HBV mutations with HCC risk were assessed using multivariate logistic regression analysis. Results： Rs1234220 C allele was significantly associated with HCC risk compared to healthy controls （adjusted odds ratio [AOR] = 1.35, 95% confidence interval [CI] = 1,07-1.69） and HCC-free HBV-infected subjects （AOR = 1.27, 95% CI = 1.01-1 .57）. rsl234220 C allele was significantly associated with increased frequencies of HCC-risk A 1652G, C 1673T, and C 1730G mutations in genotype B H BV-in fected subjects. Rs2299939 GT genotype was inversely associated with HCC risk in HBV-infected patients （AOR 0.75, 95% CI 0.62-0.92）. The interaction of rs2299939 variant genotypes （GT＋TT） with A3054T mutation significantly increased HCC risk （AOR = 2.41, 95% CI = 1.08-5.35）; whereas its interaction with C3116T mutation significantly reduced HCC risk （AOR = 0.34, 95% CI 0.18-0.66）. These significant effects were only evident in males alter stratification. Conclusions： PTEN polymorphisms and their interactions with HBV mutations may contribute to hepatocarcinogenesis in males. The host-virus interactions are important in identifying HBV-infected subjects who are more likely to develop HCC.

Increased circulating level of interleukin-6 and CD8+T cell exhaustion are associated with progression of COVID-19

Background: Coronavirus disease 2019(COVID-19)is pandemic.It is critical to identify COVID-19 patients who are most likely to develop a severe disease.This study was designed to determine the clinical and epidemiological features of COVID-19 patients associated with the development of pneumonia and factors associated with disease progression.Methods:: Seventy consecutive patients with etiologically confirmed COVID-19 admitted to PLA General Hospital in Beijing,China from December 27,2019 to March 12,2020 were enrolled in this study and followed-up to March 16,2020.Differences in clinical and laboratory findings between COVID-19 patients with pneumonia and those without were determined by theχ2 test or the Fisher exact test(categorical variables)and independent group t test or Mann–Whitney U test(continuous variables).The Cox proportional hazard model and Generalized Estimating Equations were applied to evaluate factors that predicted the progression of COVID-19.Results: The mean incubation was 8.67(95%confidence interval,6.78–10.56)days.Mean duration from the first test severe acute respiratory syndrome coronavirus 2-positive to conversion was 11.38(9.86–12.90)days.Compared to pneumonia-free patients,pneumonia patients were 16.5 years older and had higher frequencies of having hypertension,fever,and cough and higher circulating levels of neutrophil proportion,interleukin-6,low count(<190/µl)of CD8+T cells,and neutrophil/lymphocyte ratio.Thirteen patients deteriorated during hospitalization.Cox regression analysis indicated that older age and higher serum levels of interleukin-6,C-reactive protein,procalcitonin,and lactate at admission significantly predicted the progression of COVID-19.During hospitalization,circulating counts of T lymphocytes,CD4+T cells,and CD8+T cells were lower,whereas neutrophil proportion,neutrophil/lymphocyte ratio,and the circulating levels of interleukin-6,C-reactive protein,and procalcitonin were higher,in pneumonia patients than in pneumonia-free patients.CD8+lymphocyte count in pneumonia patients did not recover when discharged.Conclusions: Older age and higher levels of C-reactive protein,procalcitionin,interleukin-6,and lactate might predict COVID-19 progression.T lymphocyte,especially CD8+cell-mediated immunity is critical in recovery of COVID-19.This study may help in predicting disease progression and designing immunotherapy for COVID-19.

Cancer Evo-Dev,a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis

Non-resolving inflammation, which may be maintained by infection, pollution, and metabolic stimulants and their interactions with immunogenetic predisposition, provides a fertile field for cancer development. This is strongly evident in hepatocellular carcinoma. Here, the framework of a hypothesis called Cancer Evo-Dev is presented,based on the advances in hepatitis B virus-induced hepatocarcinogenesis. Several aspects central to this theory are as follows: (1) immune imbalance caused by the interaction of immunogenetic predispositions and hepatitis B virus infection maintains non-resolving inflammation;(2) active inflammation executants promote mutations in viral and host genomes via disbalancing mutagenic forces including cytidine deaminases and mutation-repairing forces including uracil-DNA glycosylases, thus promoting cancer-related somatic mutations and viral mutations;(3) a small percentage of the cells whose somatic mutations alter the survival signalling adapt to the inflammatory microenvironment, de-differentiate via demethylating role of cytidine deaminases, and reversely develop into tumor-initiating cells (TICs);(4) under the cultivation of some factors like POSTN from tumor-infiltrating fibroblasts and M2 macrophages, TICs acquire the stemness, cancer-stem cells obtain distinct metastatic and drug-resistant potentials under the selection pressure from distinct microenvironments;(5) glycolysis persistence in the presence of oxygen provides essential energy for cell survival and the raw material for DNA synthesis. Thus, cancer development is characterized by an evolutionary process of 'mutation-selection-adaptation'. The framework of Cancer Evo-Dev can be verified in other cancers.Cancer Evo-Dev lays theoretical foundation for understanding the mechanisms by which inflammation promotes cancer development, and it also plays a role in specific prophylaxis, prediction, and targeted treatment of cancers.

Association of novel mutations and heplotypes in the preSregion of hepatitis B virus with hepatocellular carcinoma

The association of viral mutations and haplo-typic carriages with mutations in the preS region of hepatitis B virus(HBV)genotypes B and C with hepatocellular carcinoma(HCC)is of great significance for the prediction of this malignancy,but it remains obscure.We analyzed the preS sequences of HBV genotypes B and C from 1172 HBV-infected subjects including 231 patients with HCC.As compared with the HBV-infected subjects without HCC,C2875T,G2946C,A3054C,C3060A,T3066C,C3116T,A3120C,G3191A,A1C,C7A,C10A,A31C,C76T,G105C,and G147C in both genotypes were significantly associated with increased risks of HCC.C2875A,G2950A,G2951A,A3054T,C3060T,T3066A,T3069G,A3120T,and G3191C were significantly associated with increased risks of HCC in genotype C,whereas these mutations were inversely associated with HCC in genotype B.Multivariate regression analyses showed that C76A/T was a novel factor independently associated with an increased risk of HCC,as compared with those without HCC.The frequencies of haplotypes 2964A-3116T-preS2 start codon wild-type-7C,2964C-3116T-7A-76C,and 2964A-3116T-7C-76A/T were significantly higher in the patients with HCC(P<0.001),whereas a haplotypic carriage with a single mutation and another three wild-types were inversely associated with HCC.Conclusively,the association of HBV mutations in the preS region with HCC depends on HBV genotype and haplotypic carriage with two or more mutations that are each associated with an increased risk of HCC independently.

Novel predictive and prognostic strategies of hepatitis B virus related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a common malignancy and an important cause of cancer death worldwide.Chronic hepatitis B virus(HBV)infection is the major cause of HCC.Recent studies of HBV-induced carcinogenesis not only discovered many new biomarkers but also developed a novel theory:Cancer Evolution-Development(Cancer Evo-Dev).Cancer Evo-Dev provides an evolutionary insight of developing more reasonable predictive and prognostic strategies.Characterizing chronic inflammatory microenvironment of cancer evolution,genetic polymorphisms of inflammatory factors,and HCC-related HBV mutations that negatively selected by host immunity may help greatly in identifying HBV-infected individuals who are more likely to develop HCC or benefit from HCC prophylactic options.Gene expression signatures and somatic mutation profiles reflect the different patterns of signaling pathway networks underlying tumor heterogeneity and can be applied to improve the molecular classification and prognostic stratification of HCC patients.Mutant cells that survive the selection can retro-differentiate into tumor initial cells and aggressive sub-clones.Detection of mutants or their hallmarks in cell-free DNA in peripheral blood potentially improve the early diagnosis,prognosis prediction,and personalized treatment of HBV-caused HCC.