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1.  Lipid profiles and ischemic stroke risk: variations by sex within racial/ethnic groups 
Evidence implicates lipid abnormalities as important but modifiable risk factors for stroke. This study assesses whether hypercholesterolemia can be used to predict the risk for etiologic subtypes of ischemic stroke between sexes within racial/ethnic groups. Data elements related to stroke risk, diagnosis, and outcomes were abstracted from the medical records of 3,290 acute stroke admissions between 2006 and 2010 at a regional stroke center. Sex comparison within racial/ethnic groups revealed that South Asian and Hispanic men had a higher proportion of ischemic stroke than women, while the inverse was true for Whites and African Americans (P=0.0014). All women, except South Asian women, had higher mean plasma total cholesterol and higher blood circulating low-density lipoprotein levels (≥100 mg/dL) than men at the time of their admissions. The incidence of large-artery atherosclerosis (LAA) was more common among women than men, except among Hispanics, where men tended to have higher incidences. A regression analysis that considered patients diagnosed with either LAA or small-artery occlusion etiologic subtype as the outcomes and high-density lipoproteins and triglycerides as predictors showed inconsistent associations between lipid profiles and the incidence of these subtypes between the sexes within racial/ethnic groups. In conclusion, our investigation suggests that women stroke patients may be at increased risk for stroke etiologic subtype LAA than men. Although the higher prevalence of stroke risk factors examined in this study predicts the increase in the incidence of the disease, lack of knowledge/awareness and lack of affordable treatments for stroke risk factors among women and immigrants/non-US-born subpopulations may explain the observed associations.
PMCID: PMC4051728  PMID: 24940081
ischemic stroke; risk factors; sex; race/ethnicity; cerebrovascular disease; comorbidities
2.  Genome-wide approaches for identifying genetic risk factors for osteoporosis 
Genome Medicine  2013;5(5):44.
Osteoporosis, the most common type of bone disease worldwide, is clinically characterized by low bone mineral density (BMD) and increased susceptibility to fracture. Multiple genetic and environmental factors and gene-environment interactions have been implicated in its pathogenesis. Osteoporosis has strong genetic determination, with the heritability of BMD estimated to be as high as 60%. More than 80 genes or genetic variants have been implicated in risk of osteoporosis by hypothesis-free genome-wide studies. However, these genes or genetic variants can only explain a small portion of BMD variation, suggesting that many other genes or genetic variants underlying osteoporosis risk await discovery. Here, we review recent progress in genome-wide studies of osteoporosis and discuss their implications for medicine and the major challenges in the field.
PMCID: PMC3706967  PMID: 23731620
3.  Importin 13 Regulates Neurotransmitter Release at the Drosophila Neuromuscular Junction 
In an unbiased genetic screen designed to isolate mutations that affect synaptic transmission, we have isolated homozygous lethal mutations in Drosophila importin 13 (imp13). Imp13 is expressed in and around nuclei of both neurons and muscles. At the larval neuromuscular junction (NMJ), imp13 affects muscle growth and formation of the subsynaptic reticulum without influencing any presynaptic structural features. In the absence of imp13, the probability of release of neurotransmitter and quantal content is increased, yet the abundance of the postsynaptic receptors and the amplitude of miniature excitatory junctional potentials are not affected. Interestingly, imp13 is required in the muscles to control presynaptic release. Thus, imp13 is a novel factor that affects neurotransmitter release at the fly NMJ. Its role in the context of synaptic homeostasis is discussed.
PMCID: PMC4011492  PMID: 19403829
4.  Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau 
Carcinogenesis  2013;34(5):1044-1050.
Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2×10−5) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.
PMCID: PMC3643420  PMID: 23354305
5.  Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications 
BJU international  2013;111(5):745-752.
• To quantify the impact of androgen deprivation therapy (ADT) in men with a high baseline risk of skeletal complications and evaluate the risk of mortality after a fracture.
Patients and methods
• We studied 75 994 men, aged ≥ 66 years, with localized prostate cancer from the Surveillance, Epidemiology and End Results–Medicare linked data.
• Cox proportional hazard models were employed to evaluate the risk.
• Men with a high baseline risk of skeletal complications have a higher probability of receiving ADT than those with a low risk (52.1% vs 38.2%, P < 0.001).
• During the 12-year follow-up, more than 58% of men with a high risk and 38% of men with a low risk developed at least one fracture after ADT.
• The dose effect of ADT is stronger among men who received ADT only compared to those who received ADT with other treatments.
• In the high-risk group, the fracture rate increased by 19.9 per 1000 person-years (from 52.9 to 73.0 person-years) for men who did not receive ADT compared to those who received 18 or more doses of gonadotropin-releasing hormone agonist among men who received ADT only, and by 14.2 per 1000 person-years (from 45.2 to 59.4 person-years) among men who received ADT and other treatments.
• Men experiencing a fracture had a 1.38-fold higher overall mortality risk than those who did not (95% CI, 1.34–1.43).
• Men with a high baseline risk of skeletal complications developed more fractures after ADT.
• The mortality risk is 40% higher after experiencing a fracture.
• Consideration of patient risk before prescribing ADT for long-term use may reduce both fracture risk and fracture-associated mortality.
PMCID: PMC3625488  PMID: 23331464
ADT; baseline risk; fracture; prostate cancer
6.  High expression and frequently humoral immune response of melanoma-associated antigen D4 in glioma 
MAGE-D4 is a novel member of MAGE super-family. It has preliminarily been demonstrated that MAGE-D4 mRNA is not expressed in majority of normal tissues except for brain and ovary in which only trace amount of MAGE-D4 mRNA can be detected, but predominantly expressed in glioma. MAGE-D4 protein expression and its immunogenicity in glioma have not been elucidated well. This study was designed to analyze MAGE-D4 expression both at mRNA and protein level, characteristic of humoral immune response, and their relationships with glioma patients’ clinicopathological parameters. Recombinant MAGE-D4 protein and antiserum were generated. Quantitative RT-PCR analysis revealed that MAGE-D4 mRNA expression was overall up-regulated in 41 glioma specimens compared with that in 14 normal brain tissues. Immunohistochemistry analysis showed that 78% (21/27) glioma tissues expressed MAGE-D4 protein, which was predominantly located in the cytoplasm of tumor cells, but absent in any neuroglia cell of normal brain tissues. ELISA analysis demonstrated that humoral response against MAGE-D4 was detected in 17% (7/41) of glioma patients’ sera but not in 77 healthy donors. No apparent correlation was observed between the expression and immunogenicity of MAGE-D4 with clinicopathological parameters of glioma. In summary, these results indicate that MAGE-D4 is highly expressed in glioma and can develop specifically humoral response in glioma patients, which supports that it may be a promising biomarker for glioma diagnosis and immunotherapy.
PMCID: PMC4069931  PMID: 24966945
Glioma; tumor antigen; melanoma-associated antigen D4; gene expression; immunogenicity
7.  A triple combination of atorvastatin, celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors 
International Journal of Oncology  2014;44(6):2139-2145.
Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.
PMCID: PMC4063540  PMID: 24647860
statin; cyclooxygenase-2; farnesyl transferase; Ras; pancreatic cancer
8.  Genome-Wide Association Study Identified Copy Number Variants Important for Appendicular Lean Mass 
PLoS ONE  2014;9(3):e89776.
Skeletal muscle is a major component of the human body. Age-related loss of muscle mass and function contributes to some public health problems such as sarcopenia and osteoporosis. Skeletal muscle, mainly composed of appendicular lean mass (ALM), is a heritable trait. Copy number variation (CNV) is a common type of human genome variant which may play an important role in the etiology of many human diseases. In this study, we performed genome-wide association analyses of CNV for ALM in 2,286 Caucasian subjects. We then replicated the major findings in 1,627 Chinese subjects. Two CNVs, CNV1191 and CNV2580, were detected to be associated with ALM (p = 2.26×10−2 and 3.34×10−3, respectively). In the Chinese replication sample, the two CNVs achieved p-values of 3.26×10−2 and 0.107, respectively. CNV1191 covers a gene, GTPase of the immunity-associated protein family (GIMAP1), which is important for skeletal muscle cell survival/death in humans. CNV2580 is located in the Serine hydrolase-like protein (SERHL) gene, which plays an important role in normal peroxisome function and skeletal muscle growth in response to mechanical stimuli. In summary, our study suggested two novel CNVs and the related genes that may contribute to variation in ALM.
PMCID: PMC3953533  PMID: 24626161
9.  Retaining MKP1 expression and attenuating JNK-mediated apoptosis by RIP1 for cisplatin resistance through miR-940 inhibition 
Oncotarget  2014;5(5):1304-1314.
The elucidation of chemoresistance mechanisms is important to improve cancer patient survival. In this report, we investigated the role and mechanism through which receptor-interacting protein 1 (RIP1), a mediator in cell survival and death signaling, participates in cancer's response to chemotherapy. In lung cancer cells, knockdown of RIP1 substantially increased cisplatin-induced apoptotic cytotoxicity, which was associated with robust JNK activation. The expression of the JNK inactivating phosphatase, MKP1, was substantially reduced in RIP1 knockdown cells. Although MKP1 protein stability was not altered by RIP1 suppression, the synthesis rate of MKP1 was dramatically reduced in RIP1-suppressed cells. Furthermore, we found that the expression of miR-940 was substantially increased in RIP1 knockdown cells. Knockdown of miR-940 restored MKP1 expression and attenuated cisplatin-induced JNK activation and cytotoxicity. Importantly, ectopic expression of MKP1 effectively attenuated cisplatin-induced JNK activation and cytotoxicity. In addition, activation of the JNK upstream signaling kinase, MKK4, was also potentiated in RIP1 knockdown cells. Altogether, our results suggest that RIP1 contributes to cisplatin resistance by suppressing JNK activation that involves releasing miR-940-mediated inhibition of MKP1 and suppressing activation of MKK4. Intervention targeting the RIP1/miR-940/MKP1/JNK pathway may be used to sensitize platinum-based chemotherapy.
PMCID: PMC4012727  PMID: 24675421
RIP1; MKP1; JNK; cisplatin; lung cancer; apoptosis; chemoresistance
10.  Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum 
PLoS ONE  2014;9(2):e87208.
Previous genetic studies demonstrated association between the transcription factor ENGRAILED2 (EN2) and Autism Spectrum Disorder (ASD). Subsequent molecular analysis determined that the EN2 ASD-associated haplotype (rs1861972-rs1861973 A-C) functions as a transcriptional activator to increase gene expression. EN2 is flanked by 5 genes, SEROTONIN RECEPTOR5A (HTR5A), INSULIN INDUCED GENE1 (INSIG1), CANOPY1 HOMOLOG (CNPY1), RNA BINDING MOTIF PROTEIN33 (RBM33), and SONIC HEDGEHOG (SHH). These flanking genes are co-expressed with EN2 during development and coordinate similar developmental processes. To investigate if mRNA levels for these genes are altered in individuals with autism, post-mortem analysis was performed.
qRT-PCR quantified mRNA levels for EN2 and the 5 flanking genes in 78 post-mortem cerebellar samples. mRNA levels were correlated with both affection status and rs1861972-rs1861973 genotype. Molecular analysis investigated whether EN2 regulates flanking gene expression.
EN2 levels are increased in affected A-C/G-T individuals (p = .0077). Affected individuals also display a significant increase in SHH and a decrease in INSIG1 levels. Rs1861972-rs1861973 genotype is correlated with significant increases for SHH (A-C/G-T) and CNPY1 (G-T/G-T) levels. Human cell line over-expression and knock-down as well as mouse knock-out analysis are consistent with EN2 and SHH being co-regulated, which provides a possible mechanism for increased SHH post-mortem levels.
EN2 levels are increased in affected individuals with an A-C/G-T genotype, supporting EN2 as an ASD susceptibility gene. SHH, CNPY1, and INSIG1 levels are also significantly altered depending upon affection status or rs1861972-rs1861973 genotype. Increased EN2 levels likely contribute to elevated SHH expression observed in the post-mortem samples
PMCID: PMC3919719  PMID: 24520327
11.  Immunosuppressive Drugs Modulate the Replication of Hepatitis B Virus (HBV) in a Hydrodynamic Injection Mouse Model 
PLoS ONE  2014;9(1):e85832.
Hepatitis B virus (HBV) reactivation and recurrence are common in patients under immunosuppression and can be controlled by hepatitis B immunoglobulin, antivirals, and hepatitis B vaccine. However, the detailed analysis of HBV infection under immunosuppression is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV replication and T cell responses were analyzed in a HBV-transfected mouse model under immunosuppressive therapy. During the treatment, HBV replication was at a high level in mice treated with dexamethasone, cyclosporine, and cyclophosphamide, whereas was terminated in mice treated with mycophenolate mofetil. After the withdrawal, HBV replication was at low or high levels in the dexamethasone-treated mice or in both cyclosporine- and cyclophosphamide-treated mice. The early withdrawal of cyclosporine allowed the recovery of suppressed T cell responses and led to subsequent HBV clearance, while the adoptive immune transfer to the mice with HBV persistence led to HBV suppression. Taken together, long-term HBV persistence under immunosuppression depends on the immunosuppressive drugs used and on the treatment duration and is mediated by the suppressed intrahepatic CD8 T cell response. These data may be helpful for individualized immunosuppressive therapy in patients with high risk of HBV reactivation and recurrence, and the mouse system is suitable for studying HBV reactivation and recurrence under immunosuppression.
PMCID: PMC3897536  PMID: 24465734
12.  Expression of Voltage-Gated Sodium Channel Nav1.3 Is Associated with Severity of Traumatic Brain Injury in Adult Rats 
Journal of Neurotrauma  2013;30(1):39-46.
During the secondary injury period after traumatic brain injury (TBI), depolarization of neurons mediated by voltage-gated sodium channels (VGSCs) leads to cellular abnormalities and neurological dysfunction. Alterations in expression of different α subunits of VGSCs can affect early brain pathology following TBI. This study detected the expression of Nav1.3 mRNA and protein in the rat cortex post-TBI. Adult male Sprague–Dawley rats were randomly assigned to sham-TBI, mild-TBI (mTBI), or severe-TBI (sTBI) groups. TBI was induced using a fluid percussion device at magnitudes of 1.5–1.6 atm (mTBI) and 2.9–3.0 atm (sTBI). Nav1.3 mRNA and protein levels in the ipsilateral-injured cortex were examined at 2 h, 12 h, 24 h, and 72 h post-TBI by real-time reverse transcriptase quantitative polymerase chain reaction and Western blot. Brains were collected at 24 h, 72 h, and 7 days post-TBI for TUNEL staining and cell count analysis. Immunofluorescence was performed to localize expression of Nav1.3 protein in the ipsilateral-injured cortex. Expression of Nav1.3 mRNA and protein were significantly upregulated in mTBI and sTBI groups when compared with the sham-TBI group at 2 h and 12 h post-TBI. Nav1.3 mRNA and protein levels in the sTBI group were much higher than in the mTBI group at 12 h post-TBI. TUNEL-positive cell numbers were significantly higher in the sTBI group than in the mTBI at 24 h, 72 h, and 7 days post-TBI. Expression of Nav1.3 was observed predominantly in neurons of the cortex. These findings indicated significant upregulation in the expression of Nav1.3 mRNA and protein in the rat ipsilateral-injured cortex at the very early stage post-TBI, and were also correlated with TBI severity.
PMCID: PMC3530945  PMID: 22928478
Nav1.3; rat; sodium channel; TBI
13.  Baseline Prognostic Factors and Statistic Model to Predict Early Virological Response in Telbivudine-Treated Patients With Chronic Hepatitis B 
Hepatitis Monthly  2013;13(12):e15573.
Hepatitis B virus (HBV) infection is still a worldwide disease, which may cause liver cirrhosis or even hepatocellular carcinoma. Telbivudine is a potent nucleoside analogue used in the treatment of chronic hepatitis B (CHB); however, drug resistance has remained a challenge. As early virological response can predict long-term efficacy of nucleotide analogue treatment, numerous studies have been conducted in this area.
The aim of this study was to establish baseline prognostic factors and a statistical model to predict early virological response in telbivudine-treated CHB patients.
Patients and Methods:
One hundred and eight CHB patients without any experience of nucleotide analogue therapy were assigned to receive telbivudine (600 mg, once daily) for at least 24 weeks, and then were followed up every two weeks. Cox proportional hazard regression model analyses were employed to evaluate baseline variables, and further developing a statistical model to predict early virological response.
Negative family history of HBV infection (P = 0.000235), baseline higher serum TBIL (P = 0.038714) and AST (P = 0.020684) concentrations, and lower level of HBV-DNA (P = 0.0034784) were identified to be associated with higher possibility of early virological response. A model was established based on these variables to calculate the risk scores (R) for CHB patients. R > -0.38 suggested early virological response to telbivudine. The model was validated among an independent set of 20 patients.
Family history as well as baseline bilirubin, AST and HBV DNA levels can predict early virological response. The model provides a better tool for response prediction based on the four prognostic factors.
PMCID: PMC3877653  PMID: 24403918
Hepatitis B, Chronic; Telbivudine; Proportional Hazards Models; Virology
14.  Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2- and RIPK1/RIP1-mediated MAPK8/JNK activation 
Autophagy  2012;8(12):1811-1821.
Although it is known that tumor necrosis factor-related apoptosis-inducing ligand (TNFSF10/TRAIL) induces autophagy, the mechanism by which autophagy is activated by TNFSF10 is still elusive. In this report, we show evidence that TRAF2- and RIPK1-mediated MAPK8/JNK activation is required for TNFSF10-induced cytoprotective autophagy. TNFSF10 activated autophagy rapidly in cancer cell lines derived from lung, bladder and prostate tumors. Blocking autophagy with either pharmacological inhibitors or siRNAs targeting the key autophagy factors BECN1/Beclin 1 or ATG7 effectively increased TNFSF10-induced apoptotic cytotoxicity, substantiating a cytoprotective role for TNFSF10-induced autophagy. Blocking MAPK8 but not NFκB effectively blocked autophagy, suggesting that MAPK8 is the main pathway for TNFSF10-induced autophagy. In addition, blocking MAPK8 effectively inhibited degradation of BCL2L1/Bcl-xL and reduction of the autophagy-suppressing BCL2L1–BECN1complex. Knockdown of TRAF2 or RIPK1 effectively suppressed TNFSF10-induced MAPK8 activation and autophagy. Furthermore, suppressing autophagy inhibited expression of antiapoptosis factors BIRC2/cIAP1, BIRC3/cIAP2, XIAP and CFLAR/c-FLIP and increased the formation of TNFSF10-induced death-inducing signaling complex (DISC). These results reveal a critical role for the MAPK8 activation pathway through TRAF2 and RIPK1 for TNFSF10-induced autophagy that blunts apoptosis in cancer cells. Thus, suppression of MAPK8-mediated autophagy could be utilized for sensitizing cancer cells to therapy with TNFSF10.
PMCID: PMC3541290  PMID: 23051914
autophagy; MAPK8/JNK; RIPK1/RIP1; TRAF2; TNFSF10/TRAIL; apoptosis
15.  Does Primary Androgen-Deprivation Therapy Delay the Receipt of Secondary Cancer Therapy for Localized Prostate Cancer? 
European urology  2012;62(6):966-972.
Despite evidence that shows no survival advantage, many older patients receive primary androgen-deprivation therapy (PADT) shortly after the diagnosis of localized prostate cancer (PCa).
This study evaluates whether the early use of PADT affects the subsequent receipt of additional palliative cancer treatments such as chemotherapy, palliative radiation therapy, or intervention for spinal cord compression or bladder outlet obstruction.
Design, setting, and participants
This longitudinal population-based cohort study consists of Medicare patients aged ≥66 yr diagnosed with localized PCa from 1992 to 2006 in areas covered by the Surveillance Epidemiology and End Results (SEER) program. SEER-Medicare linked data through 2009 were used to identify the use of PADT and palliative cancer therapy.
Outcome measurements and statistical analysis
Instrumental variable analysis methods were used to minimize confounding effects. Confidence intervals were derived from the bootstrap estimates.
Results and limitations
This study includes 29 775 men who did not receive local therapy for T1–T2 PCa within the first year of cancer diagnosis. Among low-risk patients (Gleason score 2–7 in 1992–2002 and Gleason score 2–6 in 2003–2006) with a median age of 78 yr and a median follow-up of 10.3 yr, PADT was associated with a 25% higher use of chemotherapy (hazard ratio [HR]: 1.25; 95% confidence interval [CI], 1.08–1.44) and a borderline higher use of any palliative cancer surgery (HR: 1.07; 95% CI, 0.97– 1.19) within 10 yr of diagnosis in regions with high PADT use compared with regions with low PADT use. Because this study was limited to men >65 yr, the results may not be applicable to younger patients.
Early treatment of low-risk, localized PCa with PADT does not delay the receipt of subsequent palliative therapies and is associated with an increased use of chemotherapy.
PMCID: PMC3472155  PMID: 22608160
Prostatic neoplasm; Medicare; SEER program; Antineoplastic agents–hormonal
16.  Cancer testis antigen OY-TES-1 expression and serum immunogenicity in colorectal cancer: its relationship to clinicopathological parameters 
Cancer testis (CT) antigens are attractive targets for cancer immunotherapy because their expression is restricted in normal germ line tissues but frequently detected in variety of tumors. OY-TES-1 is identified as a member of CT antigens. Current knowledge about OY-TES-1 expression in colorectal cancer (CRC) is solely based on mRNA analysis. None of previous researches has studied OY-TES-1 at protein level. In this study, OY-TES-1 polyclonal antibody was generated. The expression of OY-TES-1 mRNA and protein was detected by RT-PCR and immunohistochemistry in 60 CRC and paired adjacent non-tumor tissues, 24 colorectal adenoma and 3 normal colon tissues, respectively. Sera from 73 CRC patients were also tested for OY-TES-1 antibody by ELISA. Our results showed that the frequency of OY-TES-1 mRNA expression was statistically higher in CRC (73.3%, 44/60) than that in adjacent non-tumor tissue (55.0%, 33/60) and colorectal adenoma (45.8%, 11/24). For the first time, OY-TES-1 protein expression was found in (43.3%, 26/60) of CRC tissues, but absent in any of adjacent non-tumor and colorectal adenoma tissues. No OY-TES-1 expression was found in normal colon by either RT-PCR or immunohistochemistry. Furthermore, OY-TES-1 protein expression was correlated with tumor invasion stage (P=0.004) and histological grade (P=0.040). Anti-OY-TES-1 antibody was detected in (9.6%, 7/73) of CRC patients’ sera but not in 76 healthy donors. This finding demonstrates that OY-TES-1 is frequently expressed in CRC and is able to induce humoral immune response spontaneously in CRC patients, suggesting that it might be a promising immunotherapy target for CRC.
PMCID: PMC3843263  PMID: 24294369
Cancer testis antigen; OY-TES-1; colorectal cancer
17.  Obesity and prostate cancer detection: insights from three national surveys 
The American journal of medicine  2010;123(9):10.1016/j.amjmed.2010.05.011.
Previous studies suggest that obesity is associated with higher prostate cancer progression and mortality despite an association with lower prostate cancer incidence. This study aims to better understand these apparently inconsistent relationships among obese men, by combining evidence from three nationally representative cross-sectional surveys.
We evaluated relationships between obesity and (1) testosterone concentrations in the Third National Health and Nutrition Examination Survey (NHANES III; n=845), (2) prostate-specific antigen (PSA) in NHANES 2001–2004 (n=2,458) and (3) prostate biopsy rates in the National Health Interview Survey (NHIS 2000; n=4,789) population. Mean testosterone, PSA concentrations and biopsy rates were computed for body mass index (BMI) categories.
Testosterone concentrations were inversely associated with obesity (p-trend<0.0001) in NHANES III. In NHANES 2001–2004 obese (BMI >35) versus lean (BMI <25) men were less likely to have PSA concentrations that reached the biopsy threshold of >4 ng/ml (3% versus 8%; p<0.0001). Among NHIS participants all BMI groups had similar rates of PSA testing (p=0.24). However, among men who had PSA tests, 11% of men with BMI >30 versus 16% with BMI <25, achieved a PSA threshold of 4 ng/ml; p=0.01. Furthermore, biopsy rates were lower among men with BMI >30 versus BMI <25 in NHIS participants (4.6% vs. 5.8%; p=0.05).
Obesity was associated with lower PSA-driven biopsy rates. These data support further studies to test the hypothesis that obesity affects prostate cancer detection independent of prostate cancer risk by decreasing the PSA-driven biopsy rates.
PMCID: PMC3826172  PMID: 20800152
obesity; prostate cancer; prostate-specific antigen; biopsy
18.  Severe Genitourinary Toxicity Following Radiation Therapy for Prostate Cancer: How Long Does it Last? 
The Journal of urology  2012;189(1):10.1016/j.juro.2012.08.091.
Radiation therapy (RT) is a common treatment for localized prostate cancer, but long-term data regarding treatment- related toxicities compared to observation is sparse. In this study, we evaluate the time course of grade 2–4 genitourinary (GU) toxicities in men treated with either primary radiation or observation for T1-T2 prostate cancer.
Methods and Materials
We performed a population-based cohort study, using Medicare claims data linked to the Surveillance, Epidemiology, and End Results (SEER) data. Cumulative incidence functions for time to first GU event were computed based on the competing risks model, with death before any GU event as a competing event. The generalized estimating equation (GEE) method was used to evaluate the risk ratios of recurrent events.
Among patients in this study, 60,134 received RT and 25,904 underwent observation. The adjusted risk ratio for GU toxicity is 2.49 (95% CI 2.00–3.11) for 10 years and beyond. Patients who had required prior procedures for obstruction/stricture (including TURP) before RT experienced a significantly increased risk of GU toxicities: risk ratio 2.78 (95% CI 2.56–2.94)
This study demonstrates that the increased risk of grade 2–4 GU toxicity attributable to RT persists 10 years and beyond after treatment. Patients who had required prior procedures for obstruction/stricture experienced a higher risk of GU toxicity than those without these pre-existing conditions.
PMCID: PMC3819428  PMID: 23164376
prostate cancer; radiation therapy; Toxicity; Urinary; SEER Program
19.  Longitudinal associations of blood markers of insulin and glucose concentrations and cancer mortality in the Third National Health and Nutrition Examination Survey 
Cancer causes & control : CCC  2010;21(4):10.1007/s10552-009-9492-y.
Insulin and glucose may influence cancer mortality via their proliferative and anti-apoptotic properties. Using longitudinal data from the nationally representative Third National Health and Nutrition Examination Survey (NHANES III;1988–1994), with an average follow-up of 8.5y to mortality, we evaluated markers of glucose and insulin concentrations, with cancer mortality, ascertained using death certificates using the National Death Index. Plasma glucose, insulin, C-peptide, and lipid concentrations were measured. Anthropometrics, lifestyle, medical and demographic information was obtained during in-person interviews. After adjusting for age, race, sex, smoking status, physical activity and body mass index, for every increase in 50 mg/dl of plasma glucose, there was a 22% increased risk of overall cancer mortality. Insulin resistance was associated with a 41% (95% confidence interval (CI)(1.07–1.87;p=0.01) increased risk of overall cancer mortality. These associations were stronger after excluding lung cancer deaths for insulin resistant individuals (HR:1.67; 95% CI:1.15–2.42;p=0.01), specifically among those with lower levels of physical activity (HR:2.06; 95% CI:1.4–3.0;p=0.0001). Similar associations were observed for other blood markers of glucose and insulin, albeit not statistically significant. In conclusions, hyperglycemia and insulin resistance may be ‘high-risk’ conditions for cancer mortality. Managing these conditions may be effective cancer control tools.
PMCID: PMC3817266  PMID: 20094767
cancer mortality; insulin; glucose control; epidemiology; longitudinal study
20.  Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen-receptor positive, but not HER-2 breast cancer 
Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ- or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). While administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (p<0.01) and 7.1 ± 0.7 g (p<0.01), respectively. Tumor multiplicity was also reduced in δ- and γ-tocopherol treatment groups by 42% (p<0.001) and 32% (p<0.01), respectively. In contrast, α-tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of pro-apoptotic markers (BAX, cleaved-caspase 9, cleaved-caspase 3, cleaved-PARP) were increased, while anti-apoptotic markers (Bcl2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKC α), survival (PPARγ, PTEN, phospho-Akt) and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, appear to be promising agents for the prevention of hormone-dependent breast cancer.
PMCID: PMC3491089  PMID: 22964476
Breast Cancer; Tocopherols; Apoptosis; Cell Cycle; PPARγ
21.  Endoscopic ultrasound elastography for differentiating between pancreatic adenocarcinoma and inflammatory masses: A meta-analysis 
AIM: To evaluate the accuracy of endoscopic ultrasound (EUS) elastography for differentiating between pancreatic ductal adenocarcinoma (PDAC) and pancreatic inflammatory masses (PIM).
METHODS: Electronic databases (updated to December 2012) and manual bibliographical searches were carried out. A meta-analysis of all diagnostic clinical trials evaluating the accuracy of EUS elastography in differentiating PDAC from PIM was conducted. Heterogeneity was assessed among the studies. The meta-analysis was performed to evaluate the accuracy of EUS elastography in differentiating PDAC from PIM in homogeneous studies.
RESULTS: Ten studies involving 781 patients were included in the analysis. Significant heterogeneity in sensitivity was observed among the studies (Cochran Q test = 24.16, df = 9, P = 0.0041, I2 = 62.8%), while heterogeneity in specificity was not observed (Cochran Q test = 5.93, df = 9, P = 0.7473, I2 = 0.0%). The area under the curve under the Sports Rights Owners Coalition was 0.8227. Evaluation of heterogeneity suggested that the different diagnostic standards used in the included studies were the source of heterogeneity. In studies using the color pattern as the diagnostic standard, the pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR and diagnostic OR were 0.99 (0.97-1.00), 0.76 (0.67-0.83), 3.36 (2.39-4.72), 0.03 (0.01-0.07) and 129.96 (47.02-359.16), respectively. In studies using the hue histogram as the diagnostic standard, the pooled sensitivity, specificity, positive LR, negative LR and diagnostic OR were 0.92 (0.89-0.95), 0.68 (0.57-0.78), 2.84 (2.05-3.93), 0.12 (0.08-0.19) and 24.69 (12.81-47.59), respectively.
CONCLUSION: EUS elastography is a valuable method for the differential diagnosis between PDAC and PIM. And a preferable diagnostic standard should be explored and improvements in specificity are required.
PMCID: PMC3787361  PMID: 24115828
Endoscopic ultrasound; Elastography; Pancreatic adenocarcinoma; Meta-analysis
22.  Ambient Air Pollution and the Risk of Stillbirth 
American Journal of Epidemiology  2012;176(4):308-316.
The purpose of the present study was to examine the risk of stillbirth associated with ambient air pollution during pregnancy. Using live birth and fetal death data from New Jersey from 1998 to 2004, the authors assigned daily concentrations of air pollution to each birth or fetal death. Generalized estimating equation models were used to estimate the relative odds of stillbirth associated with interquartile range increases in mean air pollutant concentrations in the first, second, and third trimesters and throughout the entire pregnancy. The relative odds of stillbirth were significantly increased with each 10-ppb increase in mean nitrogen dioxide concentration in the first trimester (odds ratio (OR) = 1.16, 95% confidence interval (CI): 1.03, 1.31), each 3-ppb increase in mean sulfur dioxide concentration in the first (OR = 1.13, 95% CI: 1.01, 1.28) and third (OR = 1.26, 95% CI: 1.03, 1.37) trimesters, and each 0.4-ppm increase in mean carbon monoxide concentration in the second (OR = 1.14, 95% CI: 1.01, 1.28) and third (OR = 1.14, 95% CI: 1.06, 1.24) trimesters. Although ambient air pollution during pregnancy appeared to increase the relative odds of stillbirth, further studies are needed to confirm these findings and examine mechanistic explanations.
PMCID: PMC3491970  PMID: 22811493
air pollution; fetal death; pregnancy outcomes; stillbirth
23.  Polymorphism of ORM1 Is Associated with the Pharmacokinetics of Telmisartan 
PLoS ONE  2013;8(8):e70341.
The pharmacokinetics (PKs) and pharmacodynamics (PDs) of telmisartan varies among the individuals, and the main causes remain unknown. The aim of this study was to evaluate the impact of ORM1, as well as ABCC2, ABCB1, ABCG2 and SLCO1B3 polymorphisms, on the disposition of the drug and BP change after taking 40 mg telmisartan in 48 healthy Chinese males.
A total of 48 healthy males were included in this trial. Every volunteer ingested a single dose of 40 mg telmisartan, and the plasma drug concentration and blood pressure (BP) were measured up to 48 h.
In this study, the area under the plasma concentration-time curve (AUC) in the heterozygotes of ORM1 113AG was higher than that in the wild-type homozygotes, AUC(0–48) (113AA vs. 113AG, 1,549.18±859.84 ng·h/ml vs. 2,313.54±1,257.71 ng·h/ml, P = 0.033), AUC(0–∞) (113AA vs. 113AG, 1,753.13±1,060.60 ng·h/ml vs. 2,686.90±1,401.87 ng·h/ml, P = 0.016), and the change(%) of the diastolic blood pressure (DBP) from the baseline BP value also showed a significant difference between the ORM1 113AG and 113AA genotypes at 5 h after taking telmisartan (P = 0.026). This study also showed that the allele of ABCC2 C3972T would affected the disposition of telmsiartan and the DBP change significantly after taking the drug. However, the common SNPs of ABCG2 C421, ABCB1 C3435T, and SLCO1B3 T334G showed no impacts on the PKs of telmisartan or BP change(%) in our trial.
The ORM1 A113G polymorphism was associated with the PKs variability after taking telmsiartan, as well as ABCC2 C3972T. The heterozygotes of ORM1 113AG showed a larger AUC and a notable BP change(%) from the baseline compared with the wild-type.
Trial Registration
Chinese Clinical Trial Registry ChiCTR-TNC-10000898
PMCID: PMC3734062  PMID: 23940561
24.  Metabotropic Glutamate Receptor 1 Expression and Its Polymorphic Variants Associate with Breast Cancer Phenotypes 
PLoS ONE  2013;8(7):e69851.
Several epidemiological studies have suggested a link between melanoma and breast cancer. Metabotropic glutamate receptor 1 (GRM1), which is involved in many cellular processes including proliferation and differentiation, has been implicated in melanomagenesis, with ectopic expression of GRM1 causing malignant transformation of melanocytes. This study was undertaken to evaluate GRM1 expression and polymorphic variants in GRM1 for associations with breast cancer phenotypes. Three single nucleotide polymorphisms (SNPs) in GRM1 were evaluated for associations with breast cancer clinicopathologic variables. GRM1 expression was evaluated in human normal and cancerous breast tissue and for in vitro response to hormonal manipulation. Genotyping was performed on genomic DNA from over 1,000 breast cancer patients. Rs6923492 and rs362962 genotypes associated with age at diagnosis that was highly dependent upon the breast cancer molecular phenotype. The rs362962 TT genotype also associated with risk of estrogen receptor or progesterone receptor positive breast cancer. In vitro analysis showed increased GRM1 expression in breast cancer cells treated with estrogen or the combination of estrogen and progesterone, but reduced GRM1 expression with tamoxifen treatment. Evaluation of GRM1 expression in human breast tumor specimens demonstrated significant correlations between GRM1 staining with tissue type and molecular features. Furthermore, analysis of gene expression data from primary breast tumors showed that high GRM1 expression correlated with a shorter distant metastasis-free survival as compared to low GRM1 expression in tamoxifen-treated patients. Additionally, induced knockdown of GRM1 in an estrogen receptor positive breast cancer cell line correlated with reduced cell proliferation. Taken together, these findings suggest a functional role for GRM1 in breast cancer.
PMCID: PMC3724883  PMID: 23922822
25.  Vaccination Enhances Early Immune Responses in White Shrimp Litopenaeus vannamei after Secondary Exposure to Vibrio alginolyticus 
PLoS ONE  2013;8(7):e69722.
Recent work suggested that the presence of specific memory or some form of adaptive immunity occurs in insects and shrimp. Hypervariable pattern recognition molecules, known as Down syndrome cell adhesion molecules, are able to mount specific recognition, and immune priming in invertebrates. In the present study, we attempted to understand the immune response pattern of white shrimp Litopenaeus vannamei which received primary (PE) and secondary exposure (SE) to Vibrio alginolyticus.
Immune parameters and proliferation of haematopoietic tissues (HPTs) of shrimp which had received PE and SE to V. alginolyticus were measured. In the PE trial, the immune parameters and proliferation of HPTs of shrimp that received heat-killed V. alginolyticus (HVa) and formalin-inactivated V. alginolyticus (FVa) were measured. Mortality, immune parameters and proliferation of HPTs of 7-day-HVa-PE shrimp (shrimp that received primary exposure to HVa after 7 days) and 7-day-FVa-PE shrimp (shrimp that received primary exposure to FVa after 7 days) following SE to live V. alginolyticus (LVa) were measured. Phagocytic activity and clearance efficiency were examined for the 7∼35-day-HVa-PE and FVa-PE shrimp.
HVa-receiving shrimp showed an earlier increase in the immune response on day 1, whereas FVa-receiving shrimp showed a late increase in the immune response on day 5. The 7-day-FVa-PE shrimp showed enhancement of immunity when encountering SE to LVa, whereas 7-day-HVa-PE shrimp showed a minor enhancement in immunity. 7-day-FVa-PE shrimp showed higher proliferation and an HPT mitotic index. Both phagocytic activity and clearance maintained higher for both HVa-PE and FVa-PE shrimp after 28 days.
HVa- and FVa-receiving shrimp showed the bacteria agglutinated prior to being phagocytised. FVa functions as a vaccine, whereas HVa functions as an inducer and can be used as an immune adjuvant. A combined mixture of FVa and HVa can serve as a “vaccine component” to modulate the immunity of shrimp.
PMCID: PMC3718771  PMID: 23894531

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