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Articles from this Volume

Frederic Reynier, Alex F de Vos, Jacobien J Hoogerwerf, Paul Bresser, Jaring S van der Zee, Malick Paye, Alexandre Pachot, Bruno Mougin, and Tom van der Poll more...
Posted by Leah Caracappa on Mar 30, 2016 8:17 AM CDT
Xiao Su, Xiaomei Feng, Niccolo Terrando, Yan Yan, Ajay Chawla, Lauren G Koch, Steven L Britton,
Michael A Matthay, and Mervyn Maze
Posted by Leah Caracappa on Mar 12, 2013 10:52 AM CDT
Xinqi He, Yujuan Dong, Chung Wah Wu, Zengren Zhao, Simon S M Ng, Francis K L Chan,
Joseph J Y Sung, and Jun Yu

Deregulated miRNAs participate in colorectal carcinogenesis. In this study, miR-218 was found to be downregulated in human colorectal cancer (CRC) by miRNA profile assay. miR-218 was silenced or downregulated in all five colon cancer cells (Caco2, HT29, SW620, HCT116 and LoVo) relative to normal colon tissues. miR-218 expression was significantly lower in 46 CRC tumor tissues compared with their adjacent normal tissues (P < 0.001). Potential target genes of miR-218 were predicted and BMI1 polycomb ring finger oncogene (BMI-1), a polycomb ring finger oncogene, was identified as one of the potential targets. Upregulation of BMI-1 was detected in CRC tumors compared with adjacent normal tissues (P < 0.001) and in all five colon cancer cell lines. Transfection of miR-218 in colon cancer cell lines (HCT116, HT29) significantly reduced luciferase activity of the wild-type construct of BMI-1 3′ untranslated region (3′UTR) (P < 0.001), whereas this effect was not seen in the construct with mutant BMI-1 3′UTR, indicating a direct and specific interaction of miR-218 with BMI-1. Ectopic expression of miR-218 in HCT116 and HT29 cells suppressed BMI-1 mRNA and protein expression. In addition, miR-218 suppressed protein expression of BMI-1 downstream targets of cyclin-dependent kinase 4, a cell cycle regulator, while upregulating protein expression of p53. We further revealed that miR-218 induced apoptosis (P < 0.01), inhibited cell proliferation (P < 0.05) and promoted cell cycle arrest in the G2 phase (P < 0.01). In conclusion, miR-218 plays a pivotal role in CRC development through inhibiting cell proliferation and cycle progression and promoting apoptosis by downregulating BMI-1.

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Posted by Leah Caracappa on Mar 12, 2013 10:46 AM CDT
Heike Pohla, Alexander Buchner, Birgit Stadlbauer, Bernhard Frankenberger, Stefan Stevanovic, Steffen Walter, Ronald Frank, Tim Schwachula, Sven Olek, Joachim Kopp, Gerald Willimsky, Christian G Stief, Alfons Hofstetter, Antonio Pezzutto, Thomas Blankenstein, Ralph Oberneder, and Dolores J Schendel

Our previously reported phase I clinical trial with the allogeneic gene–modified tumor cell line RCC-26/CD80/IL-2 showed that vaccination was well tolerated and feasible in metastatic renal cell carcinoma (RCC) patients. Substantial disease stabilization was observed in most patients despite a high tumor burden at study entry. To investigate alterations in immune responses that might contribute to this effect, we performed an extended immune monitoring that included analysis of reactivity against multiple antigens, cytokine/chemokine changes in serum and determination of the frequencies of immune suppressor cell populations, including natural regulatory T cells (nTregs) and myeloid-derived suppressor cell subsets (MDSCs). An overall immune response capacity to virus-derived control peptides was present in 100% of patients before vaccination. Vaccine-induced immune responses to tumor-associated antigens occurred in 75% of patients, demonstrating the potent immune stimulatory capacity of this generic vaccine. Furthermore, some patients reacted to peptide epitopes of antigens not expressed by the vaccine, showing that epitope-spreading occurred in vivo. Frequencies of nTregs and MDSCs were comparable to healthy donors at the beginning of study. A significant decrease of nTregs was detected after vaccination (p = 0.012). High immune response rates, decreased frequencies of nTregs and a mixed T helper 1/T helper 2 (TH1/TH2)-like cytokine pattern support the applicability of this RCC generic vaccine for use in combination therapies.

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Posted by Leah Caracappa on Mar 12, 2013 10:39 AM CDT
Eileen M Bauer, Richard Shapiro, Han Zheng, Ferhaan Ahmad, David Ishizawar, Suzy A Comhair,
Serpil C Erzurum, Timothy R Billiar, and Philip M Bauer
Posted by Leah Caracappa on Mar 12, 2013 10:33 AM CDT
Mariella Dono, Carlotta Massucco, Silvana Chiara, Claudia Sonaglio, Marco Mora, Anna Truini, Giannamaria Cerruti, Gabriele Zoppoli, Alberto Ballestrero, Mauro Truini, Manlio Ferrarini, and Simona Zupo

Metastatic colorectal cancer (mCRC) is frequently characterized by the presence of mutations of the KRAS oncogene, which are generally associated with a poor response to treatment with anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies. With the methods currently used, a case is classified as KRAS-mutated when approximately 20% of the cells bear an activating KRAS mutation. These considerations raise the question of whether cells with a mutated KRAS can be found in mCRC cases classified as KRAS wild-type when more sensitive methods are used. In addition, the issue arises of whether these mCRC cases with low proportion of KRAS-mutated cells could account at least in part for the therapeutic failure of anti-EGFR therapies that occur in 40–60% of cases classified as KRAS wild type. In this study, we compared the classical assays with a very sensitive test, a locked nucleic acid (LNA) polymerase chain reaction (PCR), capable of detecting KRAS-mutated alleles at extremely low frequency (detection sensitivity limit 0.25% mutated DNA/wild-type DNA). By analyzing a cohort of 213 mCRC patients for KRAS mutations, we found a 20.6% discordance between the sequencing/TheraScreen methods and the LNA-PCR. Indeed, 44 mCRC patients initially considered KRAS wild type were reclassified as KRAS mutated by using the LNA-PCR test. These patients were more numerous among individuals displaying a clinical failure to anti-EGFR therapies. Failure to respond to these biological treatments occurred even in the absence of mutations in other EGFR pathway components such as BRAF.

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Posted by Leah Caracappa on Mar 12, 2013 10:26 AM CDT

Rakshita A Charan, Gabriela Niizawa, Hiroyuki Nakai,3and Paula R Clemens1,

Duchenne muscular dystrophy (DMD) is a genetic muscle disease caused by the absence of a functional dystrophin protein. Lack of dystrophin protein disrupts the dystrophin-glycoprotein complex causing muscle membrane instability and degeneration. One of the secondary manifestations resulting from lack of functional dystrophin in muscle tissue is an increased level of cytokines that recruit inflammatory cells, leading to chronic upregulation of the nuclear factor (NF)-κB. Negative regulators of the classical NF-κB pathway improve muscle health in the mdx mouse model for DMD. We have previously shown in vitro that a negative regulator of the NF-κB pathway, A20, plays a role in muscle regeneration. Here, we show that overexpression of A20 by using a musclespecific promoter delivered with an adeno-associated virus serotype 8 (AAV8) vector to the mdx mouse decreases activation of the NF-κB pathway in skeletal muscle. Recombinant A20 expression resulted in a reduction in number of fibers with centrally placed nuclei and a reduction in the number of T cells infiltrating muscle transduced with the AAV8–A20 vector. Taken together, we conclude that overexpression of A20 in mdx skeletal muscle provides improved muscle health by reduction of chronic inflammation and muscle degeneration. Theseresults suggest A20 is a potential therapeutic target to ameliorate symptoms of DMD.

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Posted by Leah Caracappa on Mar 12, 2013 10:20 AM CDT
Posted by Leah Caracappa on Mar 12, 2013 10:17 AM CDT
Posted by Leah Caracappa on Mar 12, 2013 10:14 AM CDT
Posted by Leah Caracappa on Mar 12, 2013 10:07 AM CDT
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