Fujun Han

Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics

It has been generally accepted that both natural and man‐made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low‐dose radiation (LDR) are different from those of high‐dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti‐cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application.

Repetitive exposure to low-dose X-irradiation attenuates testicular apoptosis in type 2 diabetic rats, likely via Akt-mediated Nrf2 activation.

To determine whether repetitive exposure to low-dose radiation (LDR) attenuates type 2 diabetes (T2DM)-induced testicular apoptotic cell death in a T2DM rat model, we examined the effects of LDR exposure on diabetic and age-matched control rats. We found that testicular apoptosis and oxidative stress levels were significantly higher in T2DM rats than in control rats. In addition, glucose metabolism-related Akt and GSK-3β function was downregulated and Akt negative regulators PTP1B and TRB3 were upregulated in the T2DM group. Superoxide dismutase (SOD) activity and catalase content were also found to be decreased in T2DM rats. These effects were partially prevented or reversed by repetitive LDR exposure. Nrf2 and its downstream genes NQO1, SOD, and catalase were significantly upregulated by repetitive exposure to LDR, suggesting that the reduction of T2DM-induced testicular apoptosis due to repetitive LDR exposure likely involves enhancement of testicular Akt-mediated glucose metabolism and anti-oxidative defense mechanisms.

Novel Insights Into Etiologies of Leukemia: A HuGE Review and Meta-Analysis of CYP1A1 Polymorphisms and Leukemia Risk

We conducted a meta-analysis to investigate the association of 2 single nucleotide polymorphisms in the cytochrome P450, family 1, subfamily 1A1 gene (CYP1A1), CYP1A1*2A and CYP1A1*2C, with the risk of developing different subtypes of leukemia in adults and children. A total of 26 studies published between 1999 and 2011 were identified by searching the PubMed, EMBASE, Medline, and Web of Science databases. The odds ratios for the CYP1A1 polymorphisms and leukemia risk were calculated. The cumulative evidence in genetic associations was graded by using the Venice criteria of the Human Genome Epidemiology Network (Atlanta, Georgia). The results showed that the cumulative evidence was moderate for the association of the CYP1A1*2A variant with leukemia in Caucasians and with childhood acute lymphoid leukemia in Caucasians. In addition, there was moderate evidence that children who carry both the CYP1A1*2A variant and the glutathione S-transferase M1 null genotype have an increased risk of acute lymphoid leukemia. For the CYP1A1*2C polymorphism, the cumulative evidence of an association with leukemia risk was moderate for adults and weak for children. Logistic regression analysis demonstrated an interaction between the CYP1A1*2C polymorphism and age. This meta-analysis showed that the CYP1A1*2A and CYP1A1*2C polymorphisms were associated with an increased risk of leukemia, and that the associations might vary by ethnicity, gene-gene interactions, age, and leukemia subtype.

Screening for lung cancer using low-dose computed tomography: concerns about the application in low-risk individuals.

Low-dose computed tomography (LDCT) has been increasingly accepted as an efficient screening method for high-risk individuals to reduce lung cancer mortality. However, there remains a gap of knowledge in the practical implementation of screening on a larger scale, especially for low-risk individuals. The aim of this study is to initiate discussion through an evidence-based analysis and provide valuable suggestions on LDCT screening for lung cancer in clinical practice. Among previously published randomized controlled trials (RCTs), the National Lung Screening Trial (NLST) is the only one demonstrating positive results in a high-risk population of old age and heavy smokers. It is also shown that the potential harms include false-positive findings, radiation exposure etc., but its magnitude is uncertain. In the meantime, the current risk stratification system is inadequate, and is difficult to define selection criteria. Thus, the efficacy of LDCT in lung cancer screening needs to be confirmed in future trials, and the procedure should not be proposed to individuals without comparable risk to those in the NLST. Furthermore, there is a lack of evidence to support the expansion of LDCT screening to low-risk individuals. Therefore, recommendation of LDCT screening for these patients could be premature in clinical practice although some of them might be missed based on current definition of risk factors. Further studies and advances in risk assessment tools are urgently needed to address the concerns about lung cancer screening in order to improve the outcomes of lung cancer.

Prognostic value of MICA/B in cancers: a systematic review and meta-analysis

Purpose MHC class I chain related-proteins A (MICA) and B (MICB) are natural killer group 2D ligands that mediate tumor surveillance. Several studies have suggested that MICA/B levels predict clinical outcomes in patients with cancer; however, this remains contentious. Here, we present a systematic review and meta-analysis of available studies of the prognostic value of MICA/B in cancer. Materials and Methods We searched PubMed, Embase, Clinicaltrials.gov, and Cochrane Library to identify studies published from inception to July 2017 that assessed MICA/B in patients with cancer. The hazard ratio (HR) and 95% confidence interval (CI) of MICA/B were extracted for overall survival (OS) analysis. Results A total of 19 studies comprising 2,588 patients with 10 different types of cancer were included in the study. Low sMICA/B levels were found associated with significantly longer OS (HR = 1.65, 95% CI [1.42–1.92], P < 0.00001). Patients with cancers of digestive system that exhibited high MICA/B expression had significantly longer OS in (HR = 0.56, 95% CI [0.39–0.80], P = 0.002) compared with those with lower MICA/B expression (I2 = 35%, P = 0.18). Conclusions Serum soluble MICA/B represents a potential prognostic marker in various human cancers. High cell-surface MICA/B expression in cancers of the digestive system was found associated with increased survival.

Significant benefits of adding neoadjuvant chemotherapy before concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: a meta-analysis of randomized controlled trials

Purpose We did a meta-analysis to compare the efficacy and safety of neoadjuvant chemotherapy (NACT) followed by concurrent chemoradiotherapy (CCRT) versus CCRT with or without adjuvant chemotherapy (AC) for patients with locoregionally advanced nasopharyngeal carcinoma based on randomized controlled trials. Methods We searched PubMed, Embase, Web of Science, ClinicalTrials.gov, Chinese National Knowledge Infrastructure, and meeting proceedings of major relevant conferences to identify published and unpublished randomized controlled trials. Progression-free survival (PFS) was the primary endpoint. Results This meta-analysis included 9 randomized clinical trials with 2215 patients. NACT followed by CCRT significantly improved PFS (HR=0.68, 95% CI 0.56 – 0.81, P < 0.001) compared versus CCRT with or without AC, and no heterogeneity was observed (I2 = 0.0%, P = 0.975). NACT was associated with a significant improvement in overall survival (HR = 0.64, 95% CI 0.49 – 0.84, P = 0.001; I2 = 0.0%, P = 0.467) and distant failure-free survival (HR = 0.72, 95% CI 0.53 – 0.97, P = 0.031; I2 = 0.0%, P = 0.744). No significant benefit was shown by NACT for locoregional control. NACT with CCRT increased risks of grade 3 – 4 anemia, thrombocytopenia, leukopenia, and fatigue, compared versus CCRT with or without AC. Conclusions Our meta-analysis confirmed that the addition of NACT to CCRT significantly improved PFS and OS versus CCRT with or without AC for locoregionally advanced nasopharyngeal carcinoma. These results may alter the standard of care - CCRT with or without AC, for locoregionally advanced nasopharyngeal carcinoma.

Distinct biological effects of low-dose radiation on normal and cancerous human lung cells are mediated by ATM signaling

Low-dose radiation (LDR) induces hormesis and adaptive response in normal cells but not in cancer cells, suggesting its potential protection of normal tissue against damage induced by conventional radiotherapy. However, the underlying mechanisms are not well established. We addressed this in the present study by examining the role of the ataxia telangiectasia mutated (ATM) signaling pathway in response to LDR using A549 human lung adenocarcinoma cells and HBE135-E6E7 (HBE) normal lung epithelial cells. We found that LDR-activated ATM was the initiating event in hormesis and adaptive response to LDR in HBE cells. ATM activation increased the expression of CDK4/CDK6/cyclin D1 by activating the AKT/glycogen synthase kinase (GSK)-3β signaling pathway, which stimulated HBE cell proliferation. Activation of ATM/AKT/GSK-3β signaling also increased nuclear accumulation of nuclear factor erythroid 2-related factor 2, leading to increased expression of antioxidants, which mitigated cellular damage from excessive reactive oxygen species production induced by high-dose radiation. However, these effects were not observed in A549 cells. Thus, the failure to activate these pathways in A549 cells likely explains the difference between normal and cancer cells in terms of hormesis and adaptive response to LDR.

Single Nucleotide Polymorphism rs1801516 in Ataxia Telangiectasia-Mutated Gene Predicts Late Fibrosis in Cancer Patients After Radiotherapy: A PRISMA-Compliant Systematic Review and Meta-Analysis.

AbstractStudies on associations between ataxia telangiectasia-mutated (ATM) polymorphisms and late radiotherapy-induced adverse events vary in clinical settings, and the results are inconsistent.We conducted the first meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to investigate the role of the ATM polymorphism rs1801516 in the development of radiotherapy-induced late fibrosis.We searched PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure databases to identify studies that investigated the effect of the ATM polymorphism rs1801516 on radiotherapy-induced late fibrosis before September 8, 2015. Summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to assess the association between late fibrosis and the rs1801516 polymorphism. Subgroup analyses were conducted to evaluate the influence of clinical features on the genetic association. Tests of interaction were used to compare differences in the effect estimates between subgroups.The overall meta-analysis of 2000 patients from 9 studies showed that the minor allele of the rs1801516 polymorphism was associated with a significantly increased risk of developing late fibrosis (OR = 1.78, 95% CI: 1.07, 2.94), with high between-study heterogeneity (I2 = 66.6%, P = 0.002). In subgroup analyses, we identified that the incidence of late fibrosis was a major source of heterogeneity across studies. The OR for patients with a high incidence of late fibrosis was 3.19 (95% CI: 1.86, 5.47), in contrast to 1.09 (95% CI: 1.01, 1.17) for those with a low incidence. There was a significant difference in the effect estimates between the 2 subgroups (ratio of OR = 2.94, 95% CI 1.70, 5.08, P = 0.031).This meta-analysis supported previously reported effect of the ATM polymorphism rs1801516 on radiotherapy-induced late fibrosis. This finding encouraged further researches to identify more genetic polymorphisms that were predictive for radiotherapy-induced adverse events. In addition, we showed that the inconsistency of the associations seen in these studies might be related to variations in the incidence of late fibrosis in the patients. This suggested that future studies should consider the incidence of radiotherapy-induced adverse events when investigating radiosensitivity signature genes.

Knockdown of COPS3 Inhibits Lung Cancer Tumor Growth in Nude Mice by Blocking Cell Cycle Progression

COPS3 encodes the third subunit of the COP9 signalosome and its aberrant expression is associated with many RITE (“Region of Increased Tumor Expression”) genes in lung cancer tissues. To elucidate the specific role of COPS3 in lung cancer, we examined its expression in lung cancer tissues by immunohistochemical staining. We found that COPS3 was overexpressed in most of the lung cancer samples examined, particularly in small cell carcinoma and squamous cell carcinoma. The expression of COPS3 protein was positively correlated with the level of Ki-67 cell proliferation index (p=0.001) and negatively related to the degree of tumor differentiation (p=0.012). In a xenograft tumor model in nude mice, shRNA-knockdown of COPS3 significantly reduced tumor growth. In lung adenocarcinoma A549 cells, shRNA-knockdown of COPS3 induced cell cycle arrest at G0/G1 phase by upregulating the cell cycle regulator protein P21 and downregulating cyclin B1 and CDK4. These data suggest that COPS3 may promote tumor growth by regulating cell-cycle associated proteins.

Dual Effects of Cellular Immunotherapy in Inhibition of Virus Replication and Prolongation of Survival in HCV-Positive Hepatocellular Carcinoma Patients

Immune cells play an important role in the development and progression of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). We conducted a retrospective study to evaluate the influence of adoptive cellular immunotherapy (CIT) on viral load and progression-free survival (PFS) for HCC patients infected with HCV. Patients (n = 104) were divided into a control group (conventional therapy, n = 73) and study group (combination of CIT and conventional therapy, n = 31). Autologous mononuclear cells were induced into natural killer, γδT, and cytokine-induced killer cells and infused intravenously to study group patients. More patients had shown viral load decrease or were stable in study group (100% versus 75%) (p = 0.014). The median PFS of the study group and control group was 16 and 10 months, respectively (p = 0.0041), and only CIT was an independent prognostic factor for PFS (hazard ratio, 0.422; p = 0.005). Three patients developed transient moderate fever after infusion, and there were no significant differences in alanine aminotransferase and aspartate aminotransferase levels before and after treatment in both groups. Our results show that CIT contributes to improvement of prognosis and inhibition of viral replication in HCV-related HCC patients, without impairment of liver function.