bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4393: Optimizing DC vaccination by combination with oncolytic adenovirus coexpressing IL-12 and GM-CSF
Authors: Zhang Song-Nan , Choi Il-Kyu , Huang Jing-Hua , Yoo Ji-Young , Choi Kyung-Ju , Yun Chae-Ok 
Published: August 2012

Abstract
Dendritic cell (DC)-based vaccination is a promising strategy for cancer immunotherapy. However, clinical trials have indicated that immunosuppressive microenvironments induced by tumors profoundly suppress antitumor immunity and inhibit vaccine efficacy, resulting in insufficient reduction of tumor burdens. To overcome these obstacles and enhance the efficiency of DC vaccination, we generated IL-12- and GM-CSF-coexpressing oncolytic adenovirus (Ad-αB7/IL12/GMCSF) as suitable therapeutic adjuvant to eliminate immune suppression and promote DC function. By treating tumors with Ad-αB7/IL12/GMCSF prior to DC vaccination, DCs elicited greater antitumor effects than in response to either treatment alone. DC migration to draining lymph nodes (DLNs) dramatically increased in mice treated with the combination therapy. This result was associated with upregulation of CCL21+ lymphatics in tumors treated with Ad-αB7/IL12/GMCSF. Moreover, the proportion of CD4+CD25+ T cells and VEGF expression was decreased in mice treated with the combination therapy. Furthermore, combination therapy using immature DCs also showed effective antitumor effects when combined with Ad-αB7/IL12/GMCSF. The combination therapy had a remarkable therapeutic efficacy on large tumors. Taken together, oncolytic adenovirus coexpressing IL-12 and GM-CSF in combination with DC vaccination has synergistic antitumor effects and can act as a potent adjuvant for promoting and optimizing DC vaccination.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4393. doi:1538-7445.AM2012-4393
Abstract 4394: Combination therapy of dendritic cells and cytokine-induced killer cells prolong survival after the removal of tumor in gastrointestinal cancer
Authors: Gao Diaqing , Yang Yizeng 
Published: August 2012

Abstract
Heterogeneity of cancer cells with expression of MHC-I is a major concern for insufficiency of immunotherapy. Targeting either cancer cells with MHC-I, such as cytotoxic T cells (CTL) initiated by dendritic cells (DCs) stimulated with tumor antigens, or cells without MHC-I, such as cytokine-induced killer cells (CIK), have been believed to kill all type of cancer cells. In present study, we recruited 26 cases of gastrointestinal tract cancers registered in our center during 2005-2010 including 12 gastric cancer, 13 colorectal cancers and 1 esophagus cancer. Subjects were administrated with 1X105 unites of IL-2 for 5 days before mononuclear cells and CIKs were isolated from peripheral blood. After original tumor were removed by surgery, 1-3 dose of DCs and CIKs were perfused via peripheral veins. Our results show that 84% patient's symptoms were improved, 8 cases got relapse in 5 year after surgery, 3 were died. Total survival rates in 1, 3 years are 98%, 93.5%, while control group are only 35%, 33%. Location of tumor in gastrointestinal tract did not show significant difference in 1,3,5 years survival rate, gastric cancer (96%, 95%, 95%) and colorectal cancers (100%, 100%, 100%), but tumor free survival rate in gastric cancer (92%, 88%,88%) was lower than colorectal cancer (100%, 91%, 91%). Our results suggested that the combination of multiple approaches, particularly DC-CIK, significantly improve the efficacy of immunotherapy in gastrointestinal tract cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4394. doi:1538-7445.AM2012-4394
Abstract 4395: Cure of castration-resistant prostate cancer in TRAMP mice by reactivating tumor immunity with a phosphatidylserine-targeting antibody
Authors: Yin Yi , Huang Xianming , Barbero Gustavo , Ye Dan , Thorpe Philip E. 
Published: August 2012

Abstract
Androgen deprivation therapy (ADT) is initially effective against prostate cancer, but many patients eventually relapse and die from the outgrowth of castration-resistant disease. Here, we tested the hypothesis that tumor immunity against castration-resistant prostate cancer can be elicited by combining ADT with treatment with a monoclonal antibody that binds exposed phosphatidylserine (PS). The rationale was that PS is an immunosuppressive lipid that becomes exposed on tumor blood vessels and malignant cells in prostate tumors responding to ADT, and inhibits immune responses to prostate tumor antigens. To validate this hypothesis, we castrated TRAMP mice after they had developed prostatic adenocarcinomas and treated them with the PS-targeting antibody, mch1N11. We first demonstrated that PS exposure was induced on tumor vascular endothelium and tumor cells by castration. PS exposure on vessels coincided with regions of hypoxia generated in the tumor microenvironment. Next, we demonstrated that castration combined with treatment with mch1N11 inhibited tumor growth and progression. About half of the treated TRAMP mice did not develop castration-resistant tumors, and eventually died of old age. Immunohistochemical studies revealed that the mch1N11 treatment combined with castration generated T-cell immune responses against TRAMP tumor antigens that kept the tumor in check. Extensive disruption of tumor vasculature and abundant infiltration of immune cells, including CD8 positive T lymphocytes, Natural killer (NK) cells and dendritic cells were observed. Splenocytes from mice treated with mch1N11 plus castration were able to kill TRAMP-C2 specifically in vitro, whereas splenocytes from mice in the other groups could not. These results demonstrate that PS, which becomes exposed on prostate cancer cells and tumor vasculature after ADT, inhibits immunity to TRAMP tumor antigens. Treatment with the PS-targeting antibody mch1N11 reactivates tumor immunity, which can permanently hold new tumor development in check.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4395. doi:1538-7445.AM2012-4395
Abstract 4398: Liver is a major primary target for the Toll-like receptor-5 agonist CBLB502 providing radioprotective, antimicrobial and antitumor responses
Authors: Burdelya Lyudmila , Leonova Katerina , Gitlin Ilya , Kojouharov Bojidar , Aygun-Sunar Semra , Veith Jean , Johnson Christopher , Gleiberman Anatoli , Haderski Gary , Allamaneni Shyam , Skitzki Joseph , Stanhope-Baker Patricia , Scheblyakov Dmitry , Logunov Denis , Narodisky Boris , Gudkov Andrei 
Published: August 2012

Abstract
We have previously shown that activation of Toll-like receptor 5 (TLR5) by bacterial flagellin and by pharmacologically optimized flagellin derivative CBLB502 protects mice and monkeys from lethal radiation injury to the hematopoietic and gastrointestinal systems. Here, we report that the liver is a major primary CBLB502 target organ in mice, with hepatocytes specifically showing rapid and strong NF-kB and STAT3 activation. Livers from CBLB502-treated mice showed up-regulation of numerous downstream genes encoding intracellular and secreted proteins with anti-apoptotic, anti-microbial and immunomodulatory activities. Unlike the TLR4 agonist LPS, the liver response to TLR5 agonists appears to be direct and does not involve high levels of proinflammatory cytokines. Thus, while LPS is toxic, TLR5 agonists have strong clinical potential. The importance of liver for CBLB502 radioprotective activity was confirmed by temporary occlusion of liver blood circulation which completely abrogated the protective effect of CBLB502 on hematopoietic precursor cells in irradiated mice. CBLB502 also protected liver tissue itself, increasing mouse resistance to lethal Salmonella tiphymurium liver infection and to hepatotoxic Fas agonistic antibodies. By testing CBLB502 in combination with radiation treatment of experimental mouse tumors in vivo, we demonstrated that its tissue protection properties are limited to normal tissues with no tumor protection detected in any of numerous mouse tumor models. Moreover, direct antitumor effects of CBLB502 treatment was observed in several tumor models. Comparison of the effect of CBLB502 on in vivo growth of isogenic pairs of tumor cell lines differing in their TLR5 status showed that the antitumor effect of the TLR5 agonist is TLR5 dependent and is associated with tumor infiltration by immunocytes, presumably attracted following activation of TLR5 signaling in the tumor cells. Remarkably, CBLB502 caused an immunotherapeutic effect in TLR5-negative tumors (CT26 colon adenocarcinoma and A20 lymphoma) growing as experimental liver metastases. Based on these results, we project clinical applications of CBLB502 as an anticancer immunotherapeutic drug against liver metastases independently on TLR5 status and TLR5-expressing tumors in other locations as well as supporting care drug to reduce adverse hepatotoxicity from radiation and chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4398. doi:1538-7445.AM2012-4398
Abstract 440: Wnt signaling regulates neuropilin-2 (NRP2) expression and contributes to cancer cell invasiveness in castration-resistant prostate cancer (CRPC)
Authors: Liu Shuman , Jia Zhengyu , Sun Zheng , Li Xuesen , Guo Yi , Lilly Micheal , Mercola Dan , Hoang Bang H. , Zi Xiaolin 
Published: August 2012

Abstract
Progression to CRPC represents a major challenge for treatment of advanced PCa. However, underlying mechanisms of this process remain largely unknown. We found that androgen deprivation in mice bearing PCa patient-derived tumors and in PCa LNCaP cells resulted in increased expression of wnt transcriptional factors: TCF4 and LEF1, as well as c-myc and NRP2. Using GenBank and MatInspector software, we identified five potential binding sites for TCF4 in the 5′ flanking promoter region spanning from –3891 to +108 base pairs of the NRP2 gene. Treatment of LNCaP cells with Wnt3a and Wnt 5a conditioned medium increased NRP2 mRNA expression; and inhibition of Wnt signaling by overexpression of secreted Wnt antagonists (WIF1 and Frzb/sFRP3) in two CRPC cell lines: C4-2B and PC3 down-regulated the expression of NRP2 in both in vitro cell cultures and in in vivo xenograft tumors. Chromatin immunoprecipitation/real-time PCR a! nalysis revealed that both WIF1 and Frzb/sFRP3 expression decreased the in vivo binding of TCF4 and beta-catenin to the NRP2 promoter at five predicted sites. Knock-down of NRP2 by short-hairpin RNA in CRPC cell lines markedly reduced cellular invasiveness and migration capacity. Furthermore, we analyzed gene microarray data sets from the UCI SPECS project. The total of 204 samples from 82 patients include 66 tumors, 65 tumor-adjacent stromas, 28 far stromas and 45 normal prostate samples. The mRNA expression levels of the genes of interest were normalized to the average expression levels of these genes from the normal prostate samples. We showed that the percentage of samples with WIF1 down-regulation progressively increased from far stroma to adjacent stroma and tumors. Strikingly, the levels of NRP2 mRNA are up-regulated in all tested adjacent stroma and most of tumor samples. Furthermore, the expression levels of NRP2 in far and adjacent stroma and tumors are inversely related to WIF1 mRNA levels (correlation coefficients are –0.6918, –0. 2349 and –0.5931; Ps&lt;0.01). For a large series of clinical samples, NRP2 expression appears to be associated with WIF1 down-regulation. These results suggest that NRP2 may be a novel Wnt target gene and contribute to progression of CRPC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 440. doi:1538-7445.AM2012-440
Abstract 4414: Distinct taxonomic, metagenomic and metabolomic profiles from a comprehensive gut flora analysis in healthy and colon adenoma African Americans
Authors: Brim Hassan , Sumner Susan , Lee Edward , Namin Hassan Hassanzadeh , Smoot Duane T. , Nelson Karen , Yooseph Shibu , Sears Cynthia , Pathmasiri Wimal , Ashktorab Hassan 
Published: August 2012

Abstract
Background: Gut flora has long been suspected to play a role in colorectal cancer (CRC) pathogenesis. Elegant experiments have substantiated such claims with the use of single pathogenic bacteria in germ free colon cancer mouse models. Here we run a comprehensive taxonomic, metagenomic and metabolomics analysis of stool samples from healthy and colon adenoma African American (AA) patients to define further this role. Patients & Methods: DNA extracts from stool samples of 6 healthy and 6 colon adenoma patients were used for the taxonomic and metagenomic analysis. The sequencing was done using a 454 pyrosequencer and the generated data was processed using informatics pipeline for phylogenetic bacterial affiliation and for bacterial functions assignment. For the metabolomics analysis, 10 fecal water extracts from healthy individuals and 10 from colon adenoma patients were analysed for their metabolites’ contents using NMR spectrometry. Results: The analysis of 16S-rDNA sequences revealed the existence of 22 groups of bacteria. A phylogenetic clustering revealed colon adenoma cases clustering together. Most predominant groups in both sets of samples were Clostridia and Bacteroides. No Lactobacilli or Bifidobacteria (good bacteria) were detected. The synergistetes_Dynergistia group -involved in gastrointestinal infections and Firmicutes phylum: Firmicutes group - involved in energy resorption and obesity were 20 and 10 folds more prevalent in adenoma patients, respectively. Bacteria TM7 group that contain active agents in IBD was 5 folds more represented in the control compared to the adenoma group. The metagenomic experiment have led to the generation of about 100,000 reads per sample, 80% of which were successfully annotated. Among the annotated functions, many were differentially present in the colon adenoma compared to healthy individuals. The metabolomics analysis led to a strong clustering of the adenoma samples metabolomes further consolidating the role of bacteria and their metabolites in colon cancer pathology. Conclusion: Our taxonomic, metagenomic and metabolomics analysis have led the presence of clear differential profiles in colon adenoma patients vs. healthy persons. Lack of detection of “good bacteria” (Lactobacilli and Bifidobacteria) in this study defines already a first level of intervention in this high risk CRC population. A comprehensive analysis of all the results is underway to bridge the Taxo, Meta and metabolomics data.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4414. doi:1538-7445.AM2012-4414
Abstract 4418: The histopathological characteristics of mucin-depleted foci in patients with sporadic colorectal cancer
Authors: Sakai Eiji , Takahashi Hirokazu , Yamada Eiji , Higurashi Takuma , Ohkubo Hidenori , Hosono Kunihiro , Endo Hiroki , Kato Shingo , Nakajima Atsushi , Cui Changxu , Takamatsu Reika , Yoshimi Naoki 
Published: August 2012

Abstract
Introduction: In experimental models, Mucin-depleted foci (MDF), formed by dysplastic crypts devoid of mucin production have been recognized to be correlated with colorectal carcinogenesis and to serve as preneoplastic lesions of colorectal cancer (CRC). In humans, there is only one report of identification of MDF mainly in patients with familial adenomatous polyposis, however the histological characteristics of human MDF was not discussed sufficiently in this report. Therefore, we conducted this study to identify MDF in sporadic CRC patients and to evaluate the histological characteristics of human MDF. Materials and Methods: Colonic samples from 53 patients of sporadic CRC were stained with Alcian blue and examined for the presence of MDF. Subsequently, the samples were also examined for the presence of aberrant crypt foci (ACF) by methylene blue staining. We classified MDF into two categories, namely, flat-MDF and protruded-MDF (having the characteristics of both ACF and MDF), and analyzed their histological characteristics. Results: We found a total of 354, 41 and 19 colonic mucosal lesions with a mean multiplicity of 44, 38.9 and 66.9 crypts (ACF, flat-MDF and protruded-MDF, respectively). The density of MDF was 0.0082 lesions/cm2. ACF identified in sporadic CRC patients corresponded to hyperplastic or non-dysplasic lesions. On the other hand, MDF (both of flat-MDF and protruded-MDF) identified in these patients corresponded to low-grade dysplasia. In addition, we found that Paneth cell metaplasia and inflammatory cell infiltration were specific histological features of MDF. These histopathological characteristics have been reported to be associated with the development of CRC. Conclusions: This is the first report of a study conducted to investigate the density and histopathological characteristics of MDF in a large sample of sporadic CRC patients. Our results indicate that MDF might represent preneoplastic lesions in human colorectal carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4418. doi:1538-7445.AM2012-4418
Abstract 4420: Serum regulates reovirus-mediated cytopathy in K-Ras activated colorectal cancer and intestinal epithelial cell lines
Authors: Maitra Radhashree , Augustine Titto , Seetharam Raviraja N. , Coffey Matthew C. , Klampfer Lidija , John.Mariadason John , Goel Sanjay 
Published: August 2012

Abstract
Background: The oncolytic potency of replication competent REOvirus has been demonstrated in various cancers. The activity is most pronounced in Kras mutant cancer cells, which account for 30-40 % of all cancers. Herein we simultaneously utilized isogenic human derived colorectal cancer cell lines that differ only by the presence of mutant Kras and normal rat intestinal epithelial cells with inducible Kras to evaluate whether the presence of oncogenic Kras alters the sensitivity of colon cancer cells to reovirus. Methods: Reovirus was obtained from Oncolytics Biotech Inc. Rat IEC's harboring IPTG inducible mutant Ras oncogene (IEC-iKras) were treated with reovirus ± IPTG. The infectivity was maintained at a multiplicity of infection (MOI) of 2. MTT assay was performed at 72 hours to determine cell vability (CV). Similar experiments were also performed with HCT116 (Kras mut) and its isogenic derivative Hke3 [(Kras wild type (WT)]. Cells were cultured and treated in both serum rich (SR) and serum free (SF) media to determine the effect of growth factors on sensitivity to reovirus. Alterations in gene expression were determined by real time PCR and protein expression by western blot. Results: The activity of reovirus was observed in all cell lines studied. Reduction in CV was greater in Kras mutant HCT116 compared to WT Hke3 cells. Consistently, induction of Kras in IEC cells increased the potency of reovirus. Furthermore, this effect was more prominent in cells cultured in SF suggesting that growth factors in the serum may attenuate the effect of mutant Kras on reovirus sensitivity. Expression of the cell cycle regulator, p21 was preferentially increased upon reovirus infection in Kras mutant compared to WT cells, and in cells cultured in SF compared to SR conditions. Conclusion: Oncogenic Kras mutations increase the sensitivity of colon cancer cells to Reovirus. Clinical trials are underway testing reovirus in patients with Kras mutant metastatic colorectal cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4420. doi:1538-7445.AM2012-4420
Abstract 4479: Polymorphisms in the nucleotide excision repair genes, ERCC1 and ERCC2/XPD and carcinogen DNA adducts in human lung
Authors: Lee Mi-Sun , Liu Chen-yu , Su Li , Wain John C. , Mark Eugene J. , Christiani David C. 
Published: August 2012

Abstract
Objectives Excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide excision repair (NER) pathways that removes DNA damage caused by tobacco smoking carcinogen such as polycyclic aromatic hydrocarbons (PAHs). However, no studies have examined their role in DNA adducts in target human lung tissue, a dosimeter for lung cancer risk. Therefore, we investigated whether the polymorphisms in SNPs in NER pathways associated with the DNA adduct formation in human lung tissue. We further analyzed these relationship divided by adenocarcinoma and squamous cell carcinoma, main type of non-small cell lung cancer (NSCLC). Methods The study population consisted of 135 lung cancer patients from the Massachusetts General Hospital (MGH). Genotyping was completed for SNPs in ERCC1 [C8092A (rs3212986) and C118T (rs11615)] and ERCC2/XPD [Asp312Asn (rs1799793) and Lys751Gln (rs1052559)] using PCR-RFLP method and the PCR with fluorescent allele-specific oligonucleotide probes (TaqMan method). DNA adduct levels were measured as relative adduct levels per 1010 nucleotides by 32P-postlabeling in the lung. Multiple regression models were used to estimate adjusted percent change in DNA adduct levels associated with genotypes of the NER genes ERCC1 and ERCC2/XPD. Results After adjusting for potential confounders, DNA adduct levels in lung increased by 73.5% [95% confidence interval (CI), –22.6 to 288.9] for the ERCC2/XPD rs1799793AA genotype and by 43.7% (95% CI, –30.0 to 194.6) for ERCC2/XPD rs1052559GG genotype compared with their corresponding wild type homozygous genotypes in overall lung cancer patients, but it did not reach statistical significance. We found that DNA adducts levels in lung increased by 166.6% (95% CI, –5.0 to 648.3, P = 0.07) for ERCC2/XPD rs1799793AA genotype in patients with squamous cell carcinoma and the trend was borderline significant (P for trend = 0.06). Conclusions Polymorphisms of DNA repair genes, ERCC2/XPD Asp312Asn, may affect increased level of DNA adducts in the lung. Further large scale studies are needed to confirm our findings. Supported by NIH grants CA074386, CA092824, and CA90578.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4479. doi:1538-7445.AM2012-4479