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Koshiol J.,U.S. National Cancer Institute | Castro F.,U.S. National Cancer Institute | Castro F.,REAL WORLD | Kemp T.J.,Frederick National Laboratory for Cancer Research | And 15 more authors.
Cytokine | Year: 2016

Most gallbladder cancer (GBC) cases arise in the context of gallstones, which cause inflammation, but few gallstone patients develop GBC. We explored inflammation/immune-related markers measured in bile and serum in GBC cases compared to gallstone patients to better understand how inflammatory patterns in these two conditions differ. We measured 65 immune-related markers in serum and bile from 41 GBC cases and 127 gallstone patients from Shanghai, China, and calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GBC versus gallstones. We then focused on the markers that were significantly elevated in bile and serum to replicate the findings in serum from 35 GBC cases and 31 gallstone controls from Chile. Comparing the highest versus lowest quantile, 15 markers (23%) were elevated in both serum and bile from GBC versus gallstone patients in the Shanghai study (p < 0.05). The strongest OR was for CXCL8 (interleukin-8) in serum (96.8, 95% CI: 11.9-790.2). Of these 15 markers, 6 were also significantly elevated in serum from Chile (CCL20, C-reactive protein, CXCL8, CXCL10, resistin, serum amyloid A). Pooled ORs from Shanghai and Chile for these 6 markers ranged from 7.2 (95% CI: 2.8-18.4) for CXCL10 to 58.2 (95% CI: 12.4-273.0) for CXCL8. GBC is associated with inflammation above and beyond that generated by gallstones alone. This local inflammatory process is reflected systemically. Future longitudinal studies are needed to identify the key players in cancer development, which may guide translational efforts to identify individuals at high risk of developing GBC. © 2016.

Kohli A.,U.S. National Institutes of Health | Kohli A.,Frederick National Laboratory for Cancer Research | Osinusi A.,Frederick National Laboratory for Cancer Research | Osinusi A.,Dalhousie University | And 37 more authors.
The Lancet | Year: 2015

Background Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration. Methods In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with, number NCT01805882. Findings Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs. Interpretation In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis. Funding National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences. © 2015 Elsevier Ltd.

Wang J.-B.,National Cancer InstituteMD | Wang J.-B.,Peking Union Medical College | Wang J.-B.,Zhejiang University | Dawsey S.M.,National Cancer InstituteMD | And 12 more authors.
Cancer Epidemiology | Year: 2015

Background: Few studies have examined the association of common genetic variants related to vitamin D metabolism and signaling to esophageal squamous cell carcinoma (ESCC). Methods: We evaluated the association between 12 single nucleotide polymorphisms (SNPs) in four genes related to vitamin D levels and ESCC risk using data from a genome-wide association study. Participants were recruited from the Shanxi Upper Gastrointestinal Cancer Genetics Project and the Linxian Nutrition Intervention Trials, and included 1942 ESCC cases and 2111 controls. We used logistic models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the SNP associations, after controlling for age and gender. Results: None of the 12 evaluated SNPs in the four vitamin D-related genes were significantly associated with risk of ESCC. The strongest associations were for rs3794060 (. P=. 0.07) and rs12800438 (. P=. 0.08) in the DHCR7/. NADSYN1 gene. No association between vitamin D-related SNPs and risk of ESCC was observed in a genotype score analysis that included all 12 SNPs. ORs for quartiles 2, 3 and 4 of the genotype scores were 0.83 (95% CI: 0.68, 1.01), 1.02 (0.85, 1.21), and 1.08 (0.89, 1.30), respectively, with no evidence for a significant monotonic trend (. P=. 0.120). Conclusions: Our results suggested that common genetic variants related to vitamin D levels are not associated with risk of ESCC in this Chinese population. © 2015.

Song H.,CFD Research Corporation | Rosano J.M.,CFD Research Corporation | Wang Y.,CFD Research Corporation | Garson C.J.,CFD Research Corporation | And 8 more authors.
MicroTAS 2015 - 19th International Conference on Miniaturized Systems for Chemistry and Life Sciences | Year: 2015

This paper presents a continuous-flow, label-free microfluidic device for separating stem cells and their differentiation progeny. The principle is based on the accumulation of DEP force to deflect cells laterally in conjunction with alternating on/off electric field for cell manipulation. The microfluidic device, which features PDMS fluidic channels containing a large array of oblique interdigitated gold-on-glass electrodes, was fabricated using a combination of standard and soft lithography techniques. Experimental tests with human mesenchymal stem cells and their differentiation progeny were carried out at different sample flow rates, and clear separation of the two populations was achieved. © 15CBMS-0001.

Goedert J.J.,National Cancer InstituteMD | Martin M.P.,Laboratory of Experimental ImmunologyMD | Martin M.P.,Massachusetts Institute of Technology | Vitale F.,University of Palermo | And 8 more authors.
Journal of Infectious Diseases | Year: 2016

Background. Kaposi sarcoma (KS) is a complication of KS-associated herpesvirus (KSHV) infection. Other oncogenic viral infections and malignancies are associated with certain HLA alleles and their natural killer (NK) cell immunoglobulin-like receptor (KIR) ligands. We tested whether HLA-KIR influences the risk of KSHV infection or KS. Methods. In population-based case-control studies, we compared HLA class I and KIR gene frequencies in 250 classic (non-AIDS) KS cases, 280 KSHV-seropositive controls, and 576 KSHV-seronegative controls composing discovery and validation cohorts. Logistic regression was used to calculate sex- and age-adjusted odds ratios (ORs) and 95% confidence intervals. Results. In both the discovery and validation cohorts, KS was associated with HLA-A∗11:01 (adjusted OR for the combined cohorts, 0.4; P =. 002) and HLA-C∗07:01 (adjusted OR, 1.6; P =. 002). Consistent associations across cohorts were also observed with activating KIR3DS1 plus HLA-B Bw4-80I and homozygosity for HLA-C group 1. With KIR3DS1 plus HLA-B Bw4-80I, the KSHV seroprevalence was 40% lower (adjusted OR for the combined cohorts, 0.6; P =. 01), but the KS risk was 2-fold higher (adjusted OR, 2.1; P =. 002). Similarly, the KSHV seroprevalence was 40% lower (adjusted OR, 0.6; P =. 01) but the KS risk 80% higher with HLA-C group 1 homozygosity (adjusted OR, 1.8; P =. 005). Conclusions. KIR-mediated NK cell activation may decrease then risk of KSHV infection but enhance KSHV dissemination and progression to KS if infection occurs. © Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Opina A.C.,U.S. National Institutes of Health | Wong K.J.,National Cancer InstituteMD | Griffiths G.L.,Frederick National Laboratory for Cancer Research | Turkbey B.I.,National Cancer InstituteMD | And 5 more authors.
Nanomedicine | Year: 2015

Aims: To demonstrate the use of gadolinium (Gd)-labeled dendrimers as lymphatic imaging agents and establish the long-term biodistribution (90-day) of this type of agent in mice. Materials & methods: A G5-Gd-BnDOTA dendrimer was prepared and injected into mice and monkeys for MR lymphangiography, and long-term biodistribution of the conjugate was studied. Results: Administration of G5-Gd-BnDOTA in mice demonstrated a rapid uptake in the deep lymphatic system while injection in monkeys showed enhanced internal iliac nodes, indicating its general utility for lymphatic tracking. Biodistribution studies to 90 days showed that gadolinium conjugate is slowly being eliminated from the liver and other organs. Conclusion: The use of G5-Gd-BnDOTA holds great promise for lymphatic imaging, but its slow clearance from the body might hamper its eventual clinical translation. © 2015 Future Medicine Ltd.

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