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1.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
2.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer 
Wang, Yufei | McKay, James D. | Rafnar, Thorunn | Wang, Zhaoming | Timofeeva, Maria | Broderick, Peter | Zong, Xuchen | Laplana, Marina | Wei, Yongyue | Han, Younghun | Lloyd, Amy | Delahaye-Sourdeix, Manon | Chubb, Daniel | Gaborieau, Valerie | Wheeler, William | Chatterjee, Nilanjan | Thorleifsson, Gudmar | Sulem, Patrick | Liu, Geoffrey | Kaaks, Rudolf | Henrion, Marc | Kinnersley, Ben | Vallée, Maxime | LeCalvez-Kelm, Florence | Stevens, Victoria L. | Gapstur, Susan M. | Chen, Wei V. | Zaridze, David | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Mates, Dana | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Krokan, Hans E. | Gabrielsen, Maiken Elvestad | Skorpen, Frank | Vatten, Lars | Njølstad, Inger | Chen, Chu | Goodman, Gary | Benhamou, Simone | Vooder, Tonu | Valk, Kristjan | Nelis, Mari | Metspalu, Andres | Lener, Marcin | Lubiński, Jan | Johansson, Mattias | Vineis, Paolo | Agudo, Antonio | Clavel-Chapelon, Francoise | Bueno-de-Mesquita, H.Bas | Trichopoulos, Dimitrios | Khaw, Kay-Tee | Johansson, Mikael | Weiderpass, Elisabete | Tjønneland, Anne | Riboli, Elio | Lathrop, Mark | Scelo, Ghislaine | Albanes, Demetrius | Caporaso, Neil E. | Ye, Yuanqing | Gu, Jian | Wu, Xifeng | Spitz, Margaret R. | Dienemann, Hendrik | Rosenberger, Albert | Su, Li | Matakidou, Athena | Eisen, Timothy | Stefansson, Kari | Risch, Angela | Chanock, Stephen J. | Christiani, David C. | Hung, Rayjean J. | Brennan, Paul | Landi, Maria Teresa | Houlston, Richard S. | Amos, Christopher I.
Nature genetics  2014;46(7):736-741.
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (rs17879961; OR=0.38 P=1.27×10−13). We also showed an association between common variation at 3q28 (TP63; rs13314271; OR=1.13, P=7.22×10−10) and lung adenocarcinoma previously only reported in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants having substantive effects on cancer risk from pre-existing GWAS data.
doi:10.1038/ng.3002
PMCID: PMC4074058  PMID: 24880342
3.  Potential Relationship between Inadequate Response to DNA Damage and Development of Myelodysplastic Syndrome 
Hematopoietic stem cells (HSCs) are responsible for the continuous regeneration of all types of blood cells, including themselves. To ensure the functional and genomic integrity of blood tissue, a network of regulatory pathways tightly controls the proliferative status of HSCs. Nevertheless, normal HSC aging is associated with a noticeable decline in regenerative potential and possible changes in other functions. Myelodysplastic syndrome (MDS) is an age-associated hematopoietic malignancy, characterized by abnormal blood cell maturation and a high propensity for leukemic transformation. It is furthermore thought to originate in a HSC and to be associated with the accrual of multiple genetic and epigenetic aberrations. This raises the question whether MDS is, in part, related to an inability to adequately cope with DNA damage. Here we discuss the various components of the cellular response to DNA damage. For each component, we evaluate related studies that may shed light on a potential relationship between MDS development and aberrant DNA damage response/repair.
doi:10.3390/ijms16010966
PMCID: PMC4307285  PMID: 25569081
myelodysplastic syndrome; hematopoietic stem cells; DNA damage response/repair; aging
4.  Clinical trial with traditional Chinese medicine intervention ''tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment'' for chronic hepatitis B-associated liver failure 
World Journal of Gastroenterology : WJG  2014;20(48):18458-18465.
AIM: To study the clinical efficacy of traditional Chinese medicine (TCM) intervention “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) for treating liver failure due to chronic hepatitis B.
METHODS: We designed the study as a randomized controlled clinical trial. Registration number of Chinese Clinical Trial Registry is ChiCTR-TRC-12002961. A total of 144 patients with liver failure due to infection with chronic hepatitis B virus were enrolled in this randomized controlled clinical study. Participants were randomly assigned to the following three groups: (1) a modern medicine control group (MMC group, 36 patients); (2) a “tonifying qi and detoxification” (“TQD”) group (72 patients); and (3) a “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) group (36 patients). Patients in the MMC group received general internal medicine treatment; patients in the “TQD” group were given a TCM formula “tonifying qi and detoxification” and general internal medicine treatment; patients in the “TTK” group were given a TCM formula of “TTK” and general internal medicine treatment. All participants were treated for 8 wk and then followed at 48 wk following their final treatment. The primary efficacy end point was the patient fatality rate in each group. Measurements of various virological and biochemical indicators served as secondary endpoints. The one-way analysis of variance and the t-test were used to compare patient outcomes in the different treatment groups.
RESULTS: At the 48-wk post-treatment time point, the patient fatality rates in the MMC, “TQD”, and “TTK” groups were 51.61%, 35.38%, and 16.67%, respectively, and the differences between groups were statistically significant (P < 0.05). However, there were no significant differences in the levels of hepatitis B virus DNA or prothrombin activity among the three groups (P > 0.05). Patients in the “TTK” group had significantly higher levels of serum total bilirubin compared to MMC subjects (339.40 μmol/L ± 270.09 μmol/L vs 176.13 μmol/L ± 185.70 μmol/L, P = 0.014). Serum albumin levels were significantly increased in both the “TQD” group and “TTK” group as compared with the MMC group (31.30 g/L ± 4.77 g/L, 30.72 g/L ± 2.89 g/L vs 28.57 g/L ± 4.56 g/L, P < 0.05). There were no significant differences in levels of alanine transaminase among the three groups (P > 0.05). Safety data showed that there was one case of stomachache in the “TQD” group and one case of gastrointestinal side effect in the “TTK” group.
CONCLUSION: Treatment with “TTK” improved the survival rates of patients with liver failure due to chronic hepatitis B. Additionally, liver tissue was regenerated and liver function was restored.
doi:10.3748/wjg.v20.i48.18458
PMCID: PMC4277987  PMID: 25561817
Clinical study; “Tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”); Liver regeneration; Treatment with integrated traditional and Western medicine; Chronic hepatitis B-associated liver failure
5.  Short telomere lengths in peripheral blood leukocytes are associated with an increased risk of oral premalignant lesion and oral squamous cell carcinoma 
Cancer  2013;119(24):10.1002/cncr.28367.
Background
Oral premalignant lesions (OPLs) are precursors of oral squamous cell carcinoma (OSCC). Short telomeres in peripheral blood leukocytes are associated with increased risks of several cancers. However, whether short leukocyte telomere length (LTL) predisposes to OPL and OSCC is unclear.
Methods
LTLs were measured in PBLs of 266 patients with OPL (N=174) or OSCC (N=92) at diagnosis and 394 age- and gender-matched control subjects. The association between LTL and OPL or OSCC risk, as well as the interaction of telomere length, cigarette smoking and alcohol drinking on OPL or OSCC risk were analyzed.
Results
The age-adjusted relative LTL was the shortest in OSCC (1.64±0.29), intermediate in OPL (1.75±0.43), and longest in controls (1.82±0.36) (P for trend < 0.001). When dichotomized at the median value in controls, adjusting for age, gender, smoking and alcohol drinking status, the odds ratio (OR) for OPL and OSCC risks associated with short LTL was 2.03 (95% CI = 1.29–3.21) and 3.47 (95% CI = 1.84–6.53), respectively, with significant dose-response effects for both associations. Among 174 OPL patients, 23 progressed to OSCC and the mean LTL was shorter than in progressors than non-progressors (1.66±0.35 vs. 1.77±0.44), although the difference did not reach statistical significance (P=0.258) likely due to the small number of progressors. Interaction analysis shows that short LTL, smoking, and alcohol drinking are independent risk factors for OPL and OSCC.
Conclusion
Short LTL is associated with increased risks of developing OPL and OSCC and likely predisposes to the malignant progression of OPL patients.
doi:10.1002/cncr.28367
PMCID: PMC3855186  PMID: 24105340
Telomere length; peripheral blood leukocyte; oral premalignant lesion; oral squamous cell carcinoma; smoking; alcohol drinking
6.  Genome-wide methylation analysis shows similar patterns in Barrett’s esophagus and esophageal adenocarcinoma 
Carcinogenesis  2013;34(12):2750-2756.
Barrett’s esophagus (BE) is a precursor of esophageal adenocarcinoma (EAC). To identify novel tumor suppressors involved in esophageal carcinogenesis and potential biomarkers for the malignant progression of BE, we performed a genome-wide methylation profiling of BE and EAC tissues. Using Illumina’s Infinium HumanMethylation27 BeadChip microarray, we examined the methylation status of 27 578 CpG sites in 94 normal esophageal (NE), 77 BE and 117 EAC tissue samples. The overall methylation of CpG sites within the CpG islands was higher, but outside of the CpG islands was lower in BE and EAC tissues than in NE tissues. Hierarchical clustering analysis showed an excellent separation of NE tissues from BE and EAC tissues; however, the clustering of BE and EAC tissues was less clear, suggesting that methylation occurs early during the progression of EAC. We confirmed many previously reported hypermethylated genes and identified a large number of novel hypermethylated genes in BE and EAC tissues, particularly genes encoding ADAM (A Disintegrin And Metalloproteinase) peptidase proteins, cadherins and protocadherins, and potassium voltage-gated channels. Pathway analysis showed that a number of channel and transporter activities were enriched for hypermethylated genes. We used pyrosequencing to validate selected candidate genes and found high correlations between the array and pyrosequencing data (rho > 0.8 for each validated gene). The differentially methylated genes and pathways may provide biological insights into the development and progression of BE and become potential biomarkers for the prediction and early detection of EAC.
doi:10.1093/carcin/bgt286
PMCID: PMC3845893  PMID: 23996928
7.  TGF-β-induced CD4+Foxp3+ T cells attenuate acute graft-versus-host disease via suppressing expansion and killing of effector CD8+ cells 
TGF-β-induced CD4+Foxp3+ T cells (iTregs) have been identified as important prevention and treatment strategies for cell therapy in autoimmune diseases and other disorders. However, the potential use of iTregs as a treatment modality for acute graft-verse-host disease (GVHD) has not been realized because iTregs may be unstable and less suppressive in this disease. Here we restudied the ability of iTregs to prevent and treat acute GVHD in two different mouse models. Our results showed that so long as an appropriate iTreg-generation protocol is used, these iTregs consistently displayed a potent ability to control acute GVHD development and reduce mortality in the acute GVHD animal models. iTreg infusion markedly suppressed the engraftment of donor CD8+ cells and CD4+ cells, the expression of Granzyme A and B, the cytotoxic effect of donor CD8+ cells and the production of T cell cytokines in acute GVHD. We therefore conclude that so long as the right methods for generating iTreg cells have been employed, iTregs can indeed prevent and even treat acute GVHD.
doi:10.4049/jimmunol.1400207
PMCID: PMC4247987  PMID: 25156367
8.  Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma 
Carcinogenesis  2013;34(11):2521-2524.
Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes and the risk of esophageal adenocarcinoma (EAC) has not been reported. In this study, we determined relative mtDNA copy number in peripheral blood leukocytes of 218 EAC cases and 218 frequency-matched controls. We calculated odds ratios and 95% confidence intervals using unconditional logistic regression, adjusting for age, sex and smoking status. MtDNA copy number was significantly lower in cases than in controls (mean ± SD, 1.16 ± 0.30 versus 1.27 ± 0.43, P = 0.002). Dichotomized at the median value of mtDNA copy number in the controls, low mtDNA copy number was significantly associated with an increased risk of EAC (odds ratio: 1.55, 95% confidence interval: 1.05–2.29). A significant dose–response relationship was observed between mtDNA copy number and risk of EAC in quartile analysis. Our results suggest that low mtDNA copy number in peripheral blood leukocytes is associated with increased susceptibility to EAC.
doi:10.1093/carcin/bgt230
PMCID: PMC3810839  PMID: 23803692
9.  Risk assessment of esophageal adenocarcinoma using γ-H2AX assay 
Background
Mutagen-induced DNA damage as measured in peripheral blood lymphocytes (PBLs) has been associated with increased risks of cancers. The formation of γ-H2AX is an early cellular response to DNA double-strand breaks (DSBs). We hypothesize that higher level of radiation-induced γ-H2AX in PBLs may be associated with an increased risk of esophageal adenocarcinoma (EAC).
Methods
Laser scanning cytometer–based immunocytochemical method was used to measure baseline and irradiation-induced γ-H2AX levels in PBLs from 211 EAC patients and 211 healthy controls. The ratio of induced γ-H2AX level to baseline level was used to evaluate individual susceptibility to DSBs. Relative risks for EAC associated with γ-H2AX were assessed by multivariable logistic regression analysis.
Results
Radiation-induced γ-H2AX level and the γ-H2AX ratio were significantly higher in cases than in controls. Dichotomized at the median in controls, a significantly increased risk for EAC was observed in association with high γ-H2AX ratio (odds ratio=2.94, 95% confidence interval=1.83–4.72). Quartile analyses showed significant dose-response associations between higher γ-H2AX ratio and increased risk of EAC (P for trend, 1.64E-06). In addition, joint effect between γ-H2AX ratio and smoking was observed: smokers who had high γ-H2AX ratio exhibited the highest risk of EAC (OR =5.53, 95% CI: 2.71–11.25) compared to never-smokers with low γ-H2AX ratio.
Conclusion
Radiation-induced DNA damage assessed by γ-H2AX ratio is associated with an increased risk of EAC.
Impact
γ-H2AX assay is a new and robust method to measure DSB damage in PBLs, which can be used to assess mutagen sensitivity and EAC risk.
doi:10.1158/1055-9965.EPI-13-0485
PMCID: PMC3824382  PMID: 23904462
Double strand break; γ-H2AX; mutagen sensitivity assay; esophageal cancer risk
10.  An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin 
Cancer research  2013;73(19):6024-6035.
HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of PI3K signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-drive tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells and it displayed single agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations and was similarly active in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope within domains 2 and 4 that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that in combination with HER2 or EGFR-targeted agents may leverage their clinical efficacy in ErbB-driven cancers.
doi:10.1158/0008-5472.CAN-13-1198
PMCID: PMC3924863  PMID: 23928993
Antibody; HER; EGFR; HER2; HER3; ERBB3; NRG; neuregulin; ligand-dependent; ligand-independent; cancer; feedback; SCCHN; PIK3CA; PI-3 kinase; resistance
11.  Elevated autocrine EDIL3 protects hepatocellular carcinoma from anoikis through RGD-mediated integrin activation 
Molecular Cancer  2014;13(1):226.
Background
A remolded microenvironment in hepatocellular carcinoma (HCC) caused by abnormally expressed matricellular proteins could promote HCC progression. The cell-matrix interactions mediated by integrins play an important role in tumor microenvironment. Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein with angiogenic and anti-inflammatory effects, is abnormally highly expressed in HCC. Here we aim to analyze its expression in liver and HCC tissues, investigate the underlined mechanisms accounted for HCC progression.
Methods
EDIL3 expression level is examined in normal liver, cirrhotic liver and HCC at both mRNA and protein level. The association between EDIL3 and clinical outcomes is analyzed. The pattern of EDIL3 expression and location is examined using Immunofluorescence and ELISA. Overexpression or knock-down of EDIL3 in a panel of cell lines are subjected to assays related to proliferation, invasion, and anoikis to investigate the mechanisms of this matrix protein in HCC progression. Recombinant EDIL3 treatment is applied to confirm the results.
Results
Compared with normal liver and cirrhotic liver, EDIL3 is elevated in HCC. High level of EDIL3 protein is much more commonly in patients with larger tumor or portal vein tumor thrombus (PVTT) formation, associated with poor prognosis. EDIL3 is abundantly expressed in HCC cells and secreted by cancer cells. In vitro and in vivo studies indicate that EDIL3, probably in an autocrine manner, inhibits anoikis and promotes anchorage-independent growth of HCC cells. Further mechanistic studies suggest integrin ligation by EDIL3 and thus that the sustained activation of the FAK-Src-AKT signal is responsible for the anoikis resistance and anchorage independence. Both the administration of cilengitide, a RGD-containing integrin antagonist, and silencing of integrin αV, an important RGD-binding integrin, results in the blockade of anoikis-resistance induced by EDIL3.
Conclusion
Our study suggests that high levels of autocrine EDIL3 may contribute to a receptive microenvironment for the survival of detached HCC cells and may involve in cancer cell spreading. We also highlight the importance of interaction between EDIL3 and integrin αV and suggest disrupting the ligation of EDIL3 to integrins via RGD-blocking in selected patients may bear potential therapeutic value.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-226) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-4598-13-226
PMCID: PMC4200221  PMID: 25273699
Epidermal growth factor-like repeats and discoidin I-like domains 3; Hepatocellular carcinoma; Anoikis resistance; Integrin activation
12.  Genetic polymorphisms in microRNA-related genes as predictors of clinical outcomes in colorectal adenocarcinoma patients 
Purpose
To evaluate the effects of single-nucleotide polymorphisms (SNPs) in microRNA-related genes on clinical outcomes in colorectal cancer (CRC) patients receiving first-line fluoropyrimidine-based chemotherapy.
Experimental Design
Forty-one SNPs in 26 microRNA-related genes were genotyped in 1,097 CRC patients recruited at the University of Texas MD Anderson Cancer Center. Patients were enrolled between 1990 and 2008 and last follow-up was in 2010. The associations between genotypes and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) stratified by clinical stage were analyzed in 741 newly diagnosed patients (diagnosed within 1 year) and replicated the findings in additional 356 patients.
Results
In patients with stage III disease, mir608:rs4919510 was associated with increased risk for both recurrence (HR=2.72; 95%CI, 1.38 to 5.33) and death (HR=3.53; 95%CI, 1.42 to 8.73). The associations were confirmed in the replication set and the combined HR for training and replication sets was 1.94 (95% CI, 1.31 to 2.86) for recurrence and 2.35 (95%CI, 1.40 to 3.93) for death, respectively. The mir219-1:rs213210 showed consistent association with death in the training set (HR=3.86; 95%CI, 1.33 to11.22), the replication set (HR = 3.33; 95% CI, 1.39 to 7.98) and combined dataset (HR = 3.53; 95% CI, 1.80 to 6.95). In combined analysis of these two SNPs, patients carrying the variant genotypes at both sites exhibited a 5.6 fold increased risk of death.
Conclusion
Genetic polymorphisms in the microRNA pathway may predict prognosis in stage III CRC patients treated with fluoropyrimidine-based chemotherapy.
doi:10.1158/1078-0432.CCR-11-2951
PMCID: PMC4141857  PMID: 22661538
colorectal cancer; polymorphism; microRNA; chemotherapy; recurrence; survival
13.  Operative versus non-operative treatment for clavicle fracture: a meta-analysis 
International Orthopaedics  2013;37(8):1495-1500.
Purpose
The purpose of this study was to assess the effects of operative and non-operative treatment on clavicle fractures.
Method
Relevant clinical trials on the operative and non-operative treatment for clavicle fractures were retrieved through searching the databases MEDLINE, Embase, OVID and the Cochrane Central Register of Controlled Trials up to December 2011. The quality of the included studies was assessed by two authors. A meta-analysis was carried out on homogeneous studies. Five studies involving 633 clavicle fractures were included.
Results
The differences in nonunion [risk ratio (RR) 0.12, 95 % confidence interval (CI) 0.05–0.29], malunion (RR 0.11, 95 % CI 0.04–0.29) and neurological complications (RR 0.45, 95 % CI 0.25–0.81) were statistically significant between operative and non-operative treatment. There was no statistically significant difference in delayed union (RR 0.78, 95 % CI 0.31–1.95).
Conclusion
Operative treatment is better than non-operative treatment, but decisions should be made in accordance with specific conditions for clinical application.
doi:10.1007/s00264-013-1871-z
PMCID: PMC3728389  PMID: 23645080
14.  Pathway-based serum microRNA profiling and survival in patients with advanced-stage non-small cell lung cancer 
Cancer research  2013;73(15):4801-4809.
This study was designed to identify TGF-β signaling pathway-related serum microRNAs (miRNAs) as predictors of survival in advanced non-small cell lung cancer (NSCLC). Serum samples from 391 patients with advanced NSCLC were collected prior to treatment. Global miRNA microarray expression profiling based on sera from four patients with good survival (>24 months) and four patients with poor survival (<6 months) was used to identify 140 highly expressed serum miRNAs, among which 35 miRNAs had binding sites within the 3’-untranslated regions of a panel of 11 genes in the TGF-β signaling pathway and were assayed by quantitative RT-PCR for their associations with survival in a training (n=192) and testing set (n=191). Out of the 35 miRNAs, survival analysis using Cox regression model identified 17 miRNAs significantly associated with 2-year patient survival. MiR-16 exhibited the most statistically significant association: high expression of miR-16 was associated with a significantly better survival (adjusted hazard ratio = 0.4, 95% confidence interval: 0.3–0.5). A combined 17-miRNA risk score was created that was able to identify patients at the highest risk of death. Those with a high risk score had a 2.5-fold increased risk of death compared to those with a low risk score (95% CI=1.8–3.4, P=1.1×10−7). This increase in risk of death was corresponding to an 7.8 month decrease in median survival time (P=9.5×10−14). Our results suggest that serum miRNAs could serve as predictors of survival for advanced NSCLC.
doi:10.1158/0008-5472.CAN-12-3273
PMCID: PMC3760306  PMID: 23774211
serum miRNA; TGF-β; survival; NSCLC
15.  Aerobic Exercise for Parkinson's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(7):e100503.
Background
Although some trials assessed the effectiveness of aerobic exercise for Parkinson's disease (PD), the role of aerobic exercise in the management of PD remained controversial.
Objective
The purpose of this systematic review is to evaluate the evidence about whether aerobic exercise is effective for PD.
Methods
Seven electronic databases, up to December 2013, were searched to identify relevant studies. Two reviewers independently extracted data and assessed methodological quality based on PEDro scale. Standardised mean difference (SMD) and 95% confidence intervals (CI) of random-effects model were calculated. And heterogeneity was assessed based on the I2 statistic.
Results
18 randomized controlled trials (RCTs) with 901 patients were eligible. The aggregated results suggested that aerobic exercise should show superior effects in improving motor actions (SMD, −0.57; 95% CI −0.94 to −0.19; p = 0.003), balance (SMD, 2.02; 95% CI 0.45 to 3.59; p = 0.01), and gait (SMD, 0.33; 95% CI 0.17 to 0.49; p<0.0001) in patients with PD, but not in quality of life (SMD, 0.11; 95% CI −0.23 to 0.46; p = 0.52). And there was no valid evidence on follow-up effects of aerobic exercise for PD.
Conclusion
Aerobic exercise showed immediate beneficial effects in improving motor action, balance, and gait in patients with PD. However, given no evidence on follow-up effects, large-scale RCTs with long follow-up are warrant to confirm the current findings.
doi:10.1371/journal.pone.0100503
PMCID: PMC4077570  PMID: 24983753
16.  Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells 
Vascular Cell  2014;6:12.
The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 106 MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm3, sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44+/CD24- or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an innovative therapeutic strategy in TNBC therapy by using sunitinib plus γ-secretase inhibitor to simultaneously target angiogenesis and CSC.
doi:10.1186/2045-824X-6-12
PMCID: PMC4049452  PMID: 24914410
Sunitinib; Basal-like triple-negative breast cancer; Xenografts; Angiogenesis; Proliferation; Migration; Apoptosis; Breast cancer stem cell; Notch-1
17.  Combined Hysterolaparoscopy for the Diagnosis of Female Infertility: a Retrospective Study of 132 Patients in China 
Materia Socio-Medica  2014;26(3):156-157.
Objectives:
To evaluate the effects and safeness of combined hysterolaparoscopy on evaluation the causes of infertility.
Methods:
This retrospective study was conducted at the Department of Gynecology (The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China) from January 2011 to April 2014. Patients aged 21–43 years with infertility were included in this study. The prevalence of different lesions was collected to analyze.
Results:
132 infertile patients were included, 71 (53.8%) women had primary infertility and the rest 61 (46.2%) had secondary infertility. Laparoscopic abnormalites were more common than hysteroscopy abnormalites both in primary infertility group and secondary infertility group. Pelvic inflammatory disease (59.09 %) and endometriosis (29.55%) were the most common abnormalities in two groups. The most common intrauterine pathology was uterine polyps and the most common uterine malformation was uterine septum in two groups. Out of 12 patients having malformation uterus, only one was double uterus and double cervical with double vagina. There was no major surgical or anesthetic complication in any of our patients, other than mild abdominal pain.
Conclusion:
Hysterolaparoscopy is an effective and safe tool in comprehensive evaluation of infertility to diagnosis and treat the lesions of pelvic and uterus in the same time. Hysterolaparoscopy may be recommended as the first and final procedure for evaluation of female infertility.
doi:10.5455/msm.2014.26.156-157
PMCID: PMC4130695  PMID: 25126006
hysterolaparoscopy; hysteroscopy; laparoscopy; infertility
18.  Long telomeres in peripheral blood leukocytes are associated with an increased risk of soft tissue sarcoma 
Cancer  2013;119(10):10.1002/cncr.27984.
Background
Human telomeres consisting of long, tandem repeats of the nucleotide sequence TTAGGG at the chromosome ends are essential for maintaining chromosomal stability. Previous epidemiologic studies have indicated that shorter telomere length in peripheral blood leukocytes (PBLs) is associated with the development of many cancers. However, the relationship between PBL telomere length and the risk of soft tissue sarcoma (STS) has not been investigated.
Methods
We determined the relative telomere length (RTL) in PBLs using real-time polymerase chain reaction (PCR) in this case-control study. The study participants included 137 patients with histologically confirmed STS (cases) with no prior chemotherapy or radiotherapy and 137 healthy controls frequency-matched to cases on age, gender, and ethnicity.
Results
The cases had significantly longer RTL than controls did (1.46 ± 0.42 for cases vs.1.15 ± 0.39 for controls, P < 0.001). Using median RTL in the controls as a cutoff, individuals with long telomere length were associated with a significantly increased risk of STS compared with those with short telomere length (adjusted odds ratio =4.71; 95% confidence interval, 2.63–8.44). When participants were categorized further into three or four groups according to the tertile or quartile RTL values of healthy controls, we observed a significant dose-response relationship between longer RTL and increased risks of STS.
Conclusions
The present study provides the first epidemiologic evidence that longer telomere length in PBLs is significantly associated with an increased risk of STS, potentially suggesting an important role for telomere maintenance in STS development.
doi:10.1002/cncr.27984
PMCID: PMC3807211  PMID: 23408253
telomere length; peripheral blood leukocyte (PBL); soft tissue sarcoma (STS); cancer risk
19.  Rapamycin Regulates iTreg Function through CD39 and Runx1 Pathways 
Journal of Immunology Research  2014;2014:989434.
It has been shown that rapamycin is able to significantly increase the expression of FoxP3 and suppress activity in induced Treg (iTreg) cells in vivo and in vitro. CD39 is a newly determined Treg marker that relates to cell suppression. Runx1, a regulator of FoxP3, controls the expression of adenosine deaminase (ADA) gene, which is found recently in the downstream of CD39 pathway in trophoblast cells. Whether rapamycin would influence CD39 pathway and regulate the expression of Runx1 remains to be determined. The addition of rapamycin to human CD4+ naïve cells in the presence of IL-2, TGF-β promotes the expression of FoxP3. In this paper, we found that CD39 positively correlated with the FoxP3 expression in iTreg cells. Rapamycin induced iTreg cells showed a stronger CD39/Runx1 expression with the enhanced suppressive function. These data suggested that CD39 expression was involved in iTreg generation and the enhanced suppressive ability of rapamycin induced Treg was partly due to Runx1 pathway. We conclude that rapamycin favors CD39/Runx1 expression in human iTreg and provides a novel insight into the mechanisms of iTreg generation enhanced by rapamycin.
doi:10.1155/2014/989434
PMCID: PMC3988749  PMID: 24741640
20.  Global assessment of genetic variation influencing response to retinoid chemoprevention in head and neck cancer patients 
Head and neck squamous cell carcinoma (HNSCC) patients are at an increased risk of developing a second primary tumor (SPT) or recurrence following curative treatment. 13-cis-retinoic acid (13-cRA) has been tested in chemoprevention clinical trials but the results have been inconclusive. We genotyped 9,465 SNPs in 450 patients from the Retinoid Head and Neck Second Primary Trial. SNPs were analyzed for associations with SPT/recurrence in patients receiving placebo to identify prognosis markers and further analyzed for effects of 13-cRA in patients with these prognostic loci. Thirteen loci identified a majority subgroup of patients at a high risk of SPT/recurrence and in whom 13-cRA was protective. Patients carrying the common genotype of rs3118570 in the retinoid X receptor (RXRA) were at a 3.33-fold increased risk (95% confidence interval [CI], 1.67–6.67) and represented over 70% of the study population. This locus also identified individuals who received benefit from chemoprevention with a 38% reduced risk (95% CI, 0.43–0.90). Analyses of cumulative effect and potential gene-gene interactions also implicated CDC25C:rs6596428 and JAK2:rs1887427 as two other genetic loci with major roles in prognosis and 13-cRA response. Patients with all three common genotypes had a 76% reduction in SPT/recurrence (95% CI, 0.093–0.64) following 13-cRA chemoprevention. Carriers of these common genotypes constituted a substantial percentage of the study population, indicating that a pharmacogenetics approach could help select patients for 13-cRA chemoprevention. The lack of any alternatives for reducing risk in these patients highlights the need for future clinical trials to prospectively validate our findings.
doi:10.1158/1940-6207.CAPR-10-0125
PMCID: PMC3955084  PMID: 21292633
HNSCC; SPT; single nucleotide polymorphisms; retinoids
21.  Ionizing radiation-induced γ-H2AX activity in whole blood culture and the risk of lung cancer 
Background
Phenotypic biomarkers of DNA damage repair may enhance cancer risk prediction. The γ-H2AX formed at the sites of double strands break (DSB) after ionizing radiation (IR) is a specific marker of DNA damage.
Methods
In an ongoing case-control study, the baseline and IR-induced γ-H2AX levels in peripheral blood lymphocytes (PBLs) from frequency-matched 306 untreated lung cancer patients and 306 controls were measured by a laser scanning cytometer-based immunocytochemical method. The ratio of IR-induced γ-H2AX level to the baseline was used to evaluate inter-individual variation of DSB damage response and to assess the risk of lung cancer by using unconditional multivariable logistic regression with adjustment of age, sex, ethnicity, smoking status, family history of lung cancer, dust exposure and emphysema.
Results
The mean γ-H2AX ratio was significantly higher in cases than controls (1.46±0.14 vs. 1.41±0.12, P < 0.001). Dichotomized at the median in controls, high γ-H2AX ratio was significantly associated with increased risk of lung cancer (OR = 2.43, 95% CI: 1.66–3.56). There was also a significant dose-response relationship between γ-H2AX ratio and lung cancer risk in quartile analysis. Analysis of joint effects with other epidemiological risk factors revealed elevated risk with increasing number of risk factors.
Conclusion
γ-H2AX activity as shown by measuring DSB damage in IR-irradiated PBLs may be a novel phenotypic marker of lung cancer risk.
Impact
γ-H2AX assay is a robust and quantifiable image-based cytometer method that measures mutagen-induced DSB response in PBLs as a potential biomarker in lung cancer risk assessment.
doi:10.1158/1055-9965.EPI-12-0794
PMCID: PMC3601549  PMID: 23300022
Double strands break; γ-H2AX; mutagen sensitivity; lung cancer risk
22.  MicroRNA expression signatures during malignant progression from Barrett’s esophagus to esophageal adenocarcinoma 
Barrett’s esophagus (BE) is the precursor lesion of esophageal adenocarcinoma (EA), whose progression follows sequential stages. However, the low progression rate and the inadequacy and subjective interpretation of histological grading in predicting BE progression call for more objective biomarkers that can improve risk prediction. We performed a genome-wide profiling of 754 human microRNAs (miRNAs) in 35 normal epithelium (NE), 34 BE, and 36 EA tissues using Taqman real-time PCR-based profiling. Unsupervised hierarchical clustering using 294 modestly to highly expressed miRNAs showed clear clustering of two groups: NE versus BE/EA tissues. Moreover, there was an excellent clustering of Barrett’s metaplasia (BM, without dysplasia) tissues from NE tissues. However, BE tissues of different stages and EA tissues were interspersed. There were differentially expressed miRNAs at different stages. The majority of miRNA aberrations involved upregulation of expression in BE and EA tissues, with the most dramatic alterations occurring at the BM stage. Known oncomirs, such as miR-21, miR-25 and miR-223, and tumor suppressor miRNAs, including miR-205, miR-203, let-7c, and miR-133a, showed progressively altered expression from BE to EA. We also identified a number of novel miRNAs that showed progressively altered expression, including miR-301b, miR-618, and miR-23b. The significant miRNA alterations that were exclusive to EA but not BE included miR-375 downregulation and upregulation of five members of the miR-17-92 and its homologue clusters, which may become promising biomarkers for EA development.
doi:10.1158/1940-6207.CAPR-12-0276
PMCID: PMC3608471  PMID: 23466817
microRNA expression; Barrett’s esophagus; esophageal cancer
23.  Regulation of matrix metalloproteinase-9 protein expression by 1α,25-(OH)2D3 during osteoclast differentiation 
Journal of Veterinary Science  2014;15(1):133-140.
To investigate 1α,25-(OH)2D3 regulation of matrix metalloproteinase-9 (MMP-9) protein expression during osteoclast formation and differentiation, receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) were administered to induce the differentiation of RAW264.7 cells into osteoclasts. The cells were incubated with different concentrations of 1α,25-(OH)2D3 during culturing, and cell proliferation was measured using the methylthiazol tetrazolium method. Osteoclast formation was confirmed using tartrate-resistant acid phosphatase (TRAP) staining and assessing bone lacunar resorption. MMP-9 protein expression levels were measured with Western blotting. We showed that 1α,25-(OH)2D3 inhibited RAW264.7 cell proliferation induced by RANKL and M-CSF, increased the numbers of TRAP-positive osteoclasts and their nuclei, enhanced osteoclast bone resorption, and promoted MMP-9 protein expression in a concentration-dependent manner. These findings indicate that 1α,25-(OH)2D3 administered at a physiological relevant concentration promoted osteoclast formation and could regulate osteoclast bone metabolism by increasing MMP-9 protein expression during osteoclast differentiation.
doi:10.4142/jvs.2014.15.1.133
PMCID: PMC3973756  PMID: 24136216
1α,25-(OH)2D3; bone lacunar resorption; MMP-9; osteoclast; TRAP
24.  Genome-Wide Catalogue of Chromosomal Aberrations in Barrett’s Esophagus and Esophageal Adenocarcinoma: a High-Density SNP Array Analysis 
To better understand the molecular mechanisms behind esophageal adenocarcinoma (EAC) tumorigenesis, we used high-density single nucleotide polymorphism (SNP) arrays to profile chromosomal aberrations at each of the four sequential progression stages – Barrett’s metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC, in 101 patients. We observed a significant trend toward increasing loss of chromosomes with higher progression stage. For BM, LGD, HGD, and EAC, respectively, the average numbers of chromosome arms with loss per sample were 0.30, 3.21, 7.70, and 11.90 (P for trend= 4.82 × 10−7), and the mean percentages of SNPs with allele loss were 0.1%, 1.8%, 6.6%, and 17.2% (P for trend = 2.64 × 10−6). In LGD, loss of 3p14.2 (68.4%) and 16q23.1 (47.4%) was limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, whereas loss of 9p21 (68.4%) occurred in larger regions. A significant increase in the loss of other chromosomal regions was seen in HGD and EAC; loss of 17p (47.6%) was one of the most frequent events in EAC. Many recurrent small regions of chromosomal loss disrupted single genes, including FHIT, WWOX, RUNX1, KIF26B, MGC48628, PDE4D, C20orf133, GMDS, DMD, and PARK2, most of which are common fragile site (CFS) regions in the human genome. But RUNX1 at 21q22 appeared to be a potential tumor suppressor gene in EAC. Amplifications were less frequent than losses and mostly occurred in EAC. The 8q24 (containing Myc) and 8p23.1 (containing CTSB) were the two most frequently amplified regions. In addition, a significant trend toward increasing amplification was associated with higher progression stage.
doi:10.1158/1940-6207.CAPR-09-0265
PMCID: PMC3932797  PMID: 20651033
25.  Maize Yield Response to Water Supply and Fertilizer Input in a Semi-Arid Environment of Northeast China 
PLoS ONE  2014;9(1):e86099.
Maize grain yield varies highly with water availability as well as with fertilization and relevant agricultural management practices. With a 311-A optimized saturation design, field experiments were conducted between 2006 and 2009 to examine the yield response of spring maize (Zhengdan 958, Zea mays L) to irrigation (I), nitrogen fertilization (total nitrogen, urea-46% nitrogen,) and phosphorus fertilization (P2O5, calcium superphosphate-13% P2O5) in a semi-arid area environment of Northeast China. According to our estimated yield function, the results showed that N is the dominant factor in determining maize grain yield followed by I, while P plays a relatively minor role. The strength of interaction effects among I, N and P on maize grain yield follows the sequence N+I >P+I>N+P. Individually, the interaction effects of N+I and N+P on maize grain yield are positive, whereas that of P+I is negative. To achieve maximum grain yield (10506.0 kg·ha−1) for spring maize in the study area, the optimum application rates of I, N and P are 930.4 m3·ha−1, 304.9 kg·ha−1 and 133.2 kg·ha−1 respectively that leads to a possible economic profit (EP) of 10548.4 CNY·ha−1 (CNY, Chinese Yuan). Alternately, to obtain the best EP (10827.3 CNY·ha−1), the optimum application rates of I, N and P are 682.4 m3·ha−1, 241.0 kg·ha−1 and 111.7 kg·ha−1 respectively that produces a potential grain yield of 10289.5 kg·ha−1.
doi:10.1371/journal.pone.0086099
PMCID: PMC3896526  PMID: 24465896

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