bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 919: The influence of haplotype of interleukin-10 gene on the susceptibility and clinical outcome of non-Hodgkin lymphoma
Authors: Eom Hyeon-Seok , Han Mi Hwa , Park Sohee , Park Weon-Seo , Yun Tak , Kim Hyun-Ju , Sun-Young Kong
Published: February 2011

Background: Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine, and single-nucleotide polymorphisms (SNP) of this gene have been reported to affect transcription and production of IL-10. Although the association between SNP and Non-Hodgkin lymphoma (NHL) and increased serum IL-10 levels in NHL patients than controls have been known, there were a few reports in context of haplotypes of whole IL-10 gene. In this study, we investigated the association between haplotype of IL-10 gene and the risk of NHL. Moreover, we investigated the association between IL-10 haplotype, and the overall survival and prognostic factors.

Methods: A total of 209 NHL patients and 418 sex- and age- matched controls was included in this study. Through database searching 4 tagging SNPs covering 2.6 kb of IL-10 gene (rs3021094, rs1554286, rs1800872, and rs1800896) were selected considering ethnicity. Analysis was done using TaqMan probe or sequencing. Haplotype and linkage disequilibrium (LD) was analyzed by PHASE and Haploview program. We compared each genotype or haplotype frequency in controls with that in patients. Genotype was tested for its association with overall survival, clinical characteristics (e.g., cell lineage) and international prognostic indices including age, performance, LDH, stage and extra-nodal involvement.

Results: All studied SNP were in Hardy-Weinburg equation in controls. There is no strong LD between four SNPs with r2 ranged from 0.002 to 0.211. Among 15 haplotypes identified by PHASE analysis, haplotype 1 (Ht1, TATT at rs3021094, rs1554286, rs1800872, and rs1800896) composed with all of dominant polymorphisms showed a significantly increased risk for developing NHL with odds ratios (OR) of 2.08 [95% confidence interval (CI); 1.47-2.96] and 5.17 [95% CI; 2.45-10.93] in single or both allele carrier of Ht1 than other haplotypes. There was no significant association between the haplotype of IL-10 and risk factors of NHL. Furthermore, Ht1 was shown to be associated with a significantly worse overall survival in patients with diffuse large B cell lymphoma (DLBCL) with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone, n=37) chemotherapy done before introduction of rituximab therapy (p=0.04), while not significant in patients treated by R-CHOP (Rituximab plus CHOP, n=86) chemotherapy (p=0.27).

Conclusions: This study showed that the IL-10 haplotype is a susceptibility marker for the development of NHL, and it was a significant prognostic indicator for DLBCL patients treated with CHOP. However, IL-10 haplotype was not a risk factor in DLBCL patients treated with R-CHOP.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 919.
Abstract 923: Association of TGF-β1 genetic variants with HPV16-positive oropharyngeal cancer
Authors: Li Guojun , Sturgis Erich M. , Lei Dapeng , Zhang Yang , Wei Qingyi
Published: February 2011

Purpose: Transforming growth factor-β1 (TGF-β1) plays an important role in inflammation and immune responses, which control the HPV clearance and escape of immune surveillance, and may contribute to genetic susceptibility to HPV16 infection.

Experimental Design: In this case series study, we analyzed the HPV16 status in tumor specimens and genotyped three TGF-β1 polymorphisms using genomic DNA from blood of 200 squamous cell carcinoma of the oropharynx (SCCOP). We calculated odds ratio (OR) and 95% confidence intervals (CIs) in univariate and multivariable logistic regression models to examine the association between the TGF-β1 polymorphisms and HPV16 status in SCCOP.

Results: Compared with those with the common homozygous genotype, the TGF-β1 T869C variant genotypes were significantly associated with HPV16-positive tumor status among patients with SCCOP (OR, 1.97; 95% CI, 1.03 − 3.76) but no significant association was observed for the TGF-β1 C509T or G915C polymorphism. However, when all variant genotypes were combined, SCCOP patients carrying genotypes with any of these TGF-β1 variant were more than twice as likely to have an HPV16-positive tumor (OR, 2.28; 95% CI, 1.16-4.50) as patients with no variant genotypes. When stratified by demographic and clinical characteristics, those under 54 years of age, non-Hispanic white patients, never smokers, and never drinkers with any variant TGF-β1 genotypes were also more likely to have HPV16-positive tumors. Conclusions: TGF-β1 polymorphisms may serve as a susceptibility marker for tumor HPV16 status among SCCOP patients, particularly those who were never smokers and never drinkers. Large studies are needed to validate our findings.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 923.
Abstract 930: A simple and inexpensive approach to allelotyping the HLA region in a case-control study of non-Hodgkin lymphoma
Authors: Akers Nicholas K. , Curry John D. , Smith Martyn T. , Conde Lucia , Bracci Paige M. , Skibola Christine F.
Published: February 2011

Background: Non-Hodgkin lymphoma (NHL) is a heterogeneous malignancy of B- and T-cells. NHL is the fifth most common cancer in the US and NHL incidence rates are increasing, having doubled since the 1970s. As a result, finding causative factors, whether genetic or environmental, remains an important task.

The human leukocyte antigen (HLA) region has a long track record of genetic association with autoimmune disease. Our group has recently published findings that indicate a genetic link between follicular lymphoma and a locus at chr6p21.33, in the HLA Class 3 region. Extended haplotypes are typical in this region, and the overall data implicate a possible genetic association between NHL and distant, yet linked, HLA alleles.

Due to high genetic complexity, it is difficult to assess allelotype information in the HLA region without using genetic sequencing approaches. However, sequencing is expensive both in terms of dollars and DNA, making it unfeasible for pilot study work. To circumvent these research limitations and quickly and easily explore our hypothesis, we set out to create an assay that is high-throughput, inexpensive, uses minimal DNA, and gives meaningful HLA allelotype information.

Results: Using multiplexed ligation-dependent probe amplification (MLPA) we have developed an assay that is able to obtain specific allelic information for one complex HLA gene. One to two digit, bi-allelic typing requires only 100ng of genomic DNA and can be run on 96-well plates over the course of 2 days. Samples are run through an Applied Biosystems 3730xl capillary DNA analyzer to obtain raw data. Analysis is simple relative to sequencing-based typing approaches; there is no need for expensive computer programs and translating raw data to allelotypes is trivial. Compared to sequencing, this is a very affordable assay that gives broad indications of allele associations, making it an ideal methodology for pilot studies. We are currently applying MLPA technology to screen for HLA allelotypes associated with risk of NHL.

Discussion: MLPA is a useful tool that can be applied to conduct HLA allelotyping. This technology is an economically feasible approach for large-scale genotyping of closely related alleles and represents a key intermediate research tool that is more specific than genome-wide analysis and more affordable than sequencing. This assay may aid in the discovery of key HLA allelotypes associated with lymphoma, as well as help to eliminate false positive results.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 930.
Abstract 932: Molecular characterization of transcription factors binding to the cancer-related interleukin-1 B gene polymorphisms
Authors: Landvik Nina Elisabeth , Haugen Aage , Zienolddiny Shan
Published: February 2011

Pulmonary inflammation together with chemical exposure may potentiate the carcinogenic process, underlining the importance of inflammation in cancer development. Interleukin-1beta (IL-1β) encoded by the IL1B gene, has been associated with chronic inflammation and plays an important role in lung inflammatory diseases, including COPD and lung cancer. Elevated levels of IL-1β will greatly enhance the intensity of the inflammatory response. There are large inter-individual differences in IL1B gene expression, which may be explained genetically by presence of single-nucleotide polymorphisms (SNPs) scattered throughout the regulatory region (rSNPs) of the gene. These rSNPs may affect IL1B expression by changing the binding affinity of transcription factors or creating novel transcription binding sites. Our studies have shown that several polymorphisms located in the promoter and the enhancer regions of the IL1B gene may affect risk of non-small cell lung cancer. Notably, rSNPs at −3893 G, −1464 G, −511 C and −31 T position formed a specific haplotype (GGCT) with near complete linkage disequilibrium in lung cancer patients, but not in controls where the risk haplotype (GGCT) was present in 65% of cases compared with 36% of controls. The risk haplotype was correlated with significantly higher IL1B mRNA levels in the lung of lung cancer patients. Particularly, we found that the T to C SNP at the −31 position which is located close to the transcription start site of the gene resulted in binding of different transcription factors to the C and T variants. We have further characterized the specific transcription factors binding to the −31 SNP. In DNA-protein interaction studies using Electrophoretic Mobility Shift Assay (EMSA) and human lung epithelial cells we found evidence that the transcription factor Ying Yang 1 (YY1) bound preferentially to the C SNP. The binding of YY1 to the C SNP was further confirmed using Chromatin Immunoprecipitation (ChIP) assay in human lung epithelial cells.

In summary, we have characterized transcription factors that may interact differentially with base changes in the SNPs and thereby may explain the biological effects of the SNPs in modifying the risk to cancer (supported by the Norwegian Cancer Society).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 932.
Abstract 940: Mucin depleted foci as a biomarker for colon precancerous lesions in estrogen receptor β knockout mice
Authors: Saleiro Diana , Murillo Genoveva , Kopelovich Levy , Mehta Rajendra G.
Published: February 2011

The role of the estrogen receptor β (ERβ) in the colon has received considerable interest, yet in vivo models are needed to better define its protective actions. In the present study, wild-type (WT), ERα and ERβ knockout (αERKO and βERKO) mice were injected with azoxymethane (AOM). Fourteen weeks after the AOM exposure the incidence of aberrant crypt foci (ACF) was assessed by methylene blue staining. βERKO mice showed significantly higher incidence (p < 0.001) of ACF (15.0 ± 5.5) as compared to αERKO (3.4 ± 2.2) and WT (4.6 ± 2.8) mice. The colons in some βERKO mice had increased thickness and loss of normal morphology. It has been reported that ERβ has a role in maintenance of the colonic crypt architecture; this may explain the loss of crypt organization in the colonic epithelium of βERKO mice. The presence of mucin depleted foci (MDF) has been reported, both in humans and in rodents, as an early event in colon cancer. Therefore, in order to surpass the limitations with ACF scoring, we performed alcian blue-neutral red staining to assess the presence of MDF. This staining allowed the assessment of precancerous lesions on all the βERKO mice colons (38.3 ± 8.2; p < 0.001), comparing to WT and αERKO mice (6.9 ± 3.6, and 10.0 ± 4.3, respectively), and served to confirm the ACF results. Together these results support the use of MDF staining as a biomarker for precancerous lesions, and the protective role of ERβ in colon carcinogenesis. (Supported by NIH K01 CA103861, Fulbright Portugal Commission, and FCT (MCET and FSE).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 940.
Abstract 945: Sca-1 deficiency enhances the chemopreventive activity of a peroxisome proliferator-activated receptorγ (PPARγ) agonist
Authors: Yuan Hongyan , Upadhyay Geeta , Yin Yuzhi , Pollock Claire , Kopelovich Levy , Glazer Robert I.
Published: February 2011

Stem cell antigen-1 (Sca-1, Ly6A) is a glycerophosphatidylinositol (GPI)-anchored membrane protein that was first identified as a murine marker of activated lymphocytes with stem cell-like properties. Although Sca-1 is widely used to enrich for stem cells in various tissues, little is known about its function and associated signaling pathways in development and tumorigenesis. Therefore, the role of Sca-1 in mammary gland development and tumorigenesis was undertaken using Sca-1 null mice. Sca-1-deficient animals exhibited slower ductal development in an age-dependent manner, and expressed increased p21Cip1 and reduced pRB, as well as a diminished response to progestin and estrogen stimulation. Mammary epithelium from Sca-1-null mice expressed increased PTEN, and reduced PDK1, AKT and c-Src activation. Significantly, the Sca-1 null mammary gland expressed increased PPARγ and reduced PPARδ, which resulted in a 10-fold increase in the ratio of PPARγ to PPARδ. In concordance with this phenotype, Sca-1 null mice exhibited a delay in progestin/DMBA-mediated mammary carcinogenesis, and were highly sensitive to the chemopreventive effects of PPARγ agonist GW7845, where tumorigenesis was inhibited by 90%. In contrast, tumor formation in Sca-1 null mice was unaffected by PPARδ agonist GW501516. Since GPI-anchored receptors are known to be associated with members of the c-Src tyrosine kinase family, we assessed if reduction of Sca-1 by RNAi affected c-Src activity, and if reduced c-Src activity may have contributed to increased GW7845 sensitivity. Lentivirus-mediated expression of Sca-1 shRNA in mammary tumor cells markedly reduced c-Src activation. In contrast, overexpression of c-Src, but not kinase-dead c-Src, inhibited PPARγ-dependent reporter gene activity and associated with PPARγ. These data suggest for the first time that loss of Sca-1 upregulates PTEN, attenuates c-Src and enhances PPARγ agonist sensitivity. Thus, targeting Sca-1 or its human homolog may be a useful approach to amplify the chemopreventive activity of PPARγ agonists.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 945.
Abstract 95: Phylogenetic classification, structural evolution, and functional divergence of the ABC-type transporters: Inferences derived from CDTree/Cn3D software applications
Authors: Song James S. , Derbyshire Myra K. , Lu Fu , Jackson John D. , Yamashita Roxanne A. , Marchler-Bauer Aron , Bryant Stephen H.
Published: February 2011

The NCBI's Conserved Domain Database (CDD; http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml), is a collection of annotated multiple sequence alignment models representing ancient conserved protein domains, basic units of protein function and protein evolution. Domain models are annotated with functional sites and can be viewed as sequence alignments together with corresponding 3D structure using the CDTree/Cn3D software applications. CDTree/Cn3D is a domain hierarchy editor which lets the user view and examine conserved domain hierarchies interactively and in great detail. A domain hierarchy is a structured collection of domain models reflecting the domain family's molecular evolution. Here we present our current, functionally annotated evolutionary classifications of the nucleotide-binding domain, transmembrane domain, and periplasmic binding proteins of the ABC (ATP binding cassette)-type transport systems which are involved in the transport of a wide variety of substrates such as sugars, ions, peptides, and more complex organic molecules across membranes. Mutations in ABC transporters cause or contribute to multi-drug resistance, cystic fibrosis, and a range of other human diseases. Using CDTree/Cn3D functionality, subfamilies present in diverse organisms were inferred from the multiple sequence alignments, phylogenetic trees, and the domain architectures of the proteins involved. Furthermore subfamilies, some of which are only comprised of uncharacterized proteins, were annotated with molecular and cellular function and the location of conserved sites, as available in the literature and evident from protein 3D structure. We demonstrate the utility of CDTree/Cn3D in studying the molecular evolution of protein and domain families, and in accelerating the discovery of orthologous groups. CDTree/Cn3D are freely available for download via the CDD website. A version of CDTree, which supports both Mac OSX and Windows operating systems, has recently been made available.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 95.
Abstract 952: Nitric oxide donor sulindac inhibits photocarcinogenesis by modulating epithelial mesenchymal transition and mitogen activated protein kinase signaling in SKH-1 hairless mouse skin
Authors: Singh Tripti , Kapur Puneet , Chaudhary Sandeep C. , Elmets Craig A. , Kopelovich Levy , Athar Mohammad
Published: February 2011

Nitric oxide (NO)-releasing non-steroid anti-inflammatory drugs (NO-NSAIDs) have been shown to have anti-proliferative, proapoptotic and cancer inhibitory properties. Here, we have investigated the effects of NO-donor sulindac on UVB-induced skin cancer development in SKH-1 hairless mice. Mice (6-8 weeks old) were divided into three groups of ten mice each, which received either vehicle (acetone), vehicle+UVB (180mJ/cm 2) or topical application of NO-sulindac (5mg/mouse)+UVB after dissolving in acetone. Mice-treated with NO-sulindac developed significantly less number of tumors (60%) compared with non-NO-sulindac treated mice and tumor volume was also less by 90% on termination of the experiment at week 30th. Immunohistochemical and western blot analyses revealed that the expression levels of proliferation markers such as proliferating cell nuclear antigen (PCNA) and cell cycle regulatory cyclin D1 were markedly diminished in tumors of NO-sulindac treated mice. However, the treatment of NO-sulindac resulted in enhanced apoptosis in skin tumors as ascertained by the increased terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, reduced Bcl-2 and enhanced Bax expression levels in the tumors and tumor uninvolved skin. To investigate the effects of NO-sulindac on the progression of benign lesions to invasive carcinomas, we examined squamous cell carcinomas (SCC) for various epithelial-mesenchymal transition (EMT) markers. NO-sulindac decreased the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist whereas the epithelial polarity marker E-cadherin was found to be increased compared to the SCCs of non-NO-sulindac treated group. Down regulation of EMT by NO-sulindac was associated with a remarkable diminution of UVB-induced phosphorylation MAPK proteins such as, extracellular signal-regulated kinase 1/2 (Erk 1/2), c-Jun-NH2 terminal kinase 1/2 (JNK1/2) and p38 in both UVB-exposed skin and skin tumors. Together our results suggest that NO-sulindac is a potential chemopreventive agent for photocarcinogenesis and that inhibition of photocarcinogenesis by NO-sulindac is associated with the inhibition of EMT and MAPK protein expression in skin tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 952.
Abstract 960: Use of MMTV-Neu/P53 KO transgenic mice to screen for potential chemopreventive agents
Authors: Lubet Ronald A. , Juliana Margaret , Iwata Kenneth , Grubbs Clinton
Published: February 2011

The MMTV-Neu transgenic mouse develops Neu over-expressing ER− mammary cancers. Since human ER− Neu over-expressing mammary cancers often also have mutations in P53, a heterozygous KO of P53 was incorporated into the model. We have used this model to examine a wide variety of potential chemopreventive agents. The agents were routinely administered to virgin female MMTV-Neu/P53 KO mice beginning when they were 60 days of age. Initiation of treatment with the agents at this time is later than that often employed by other investigators (usually 35 days of age). Mice were routinely monitored until 360 days of age. It was found that both RXR agonists (Targretin, UAB-30) and EGFR 1 and/or 2 inhibitors (Tarceva, Lapatinib) were highly effective in preventing the development of these cancers. These results agree with previously published results by Dr. Powell Brown and colleagues. It was also observed that a wide variety of agents were ineffective; including Atorvastatin, rosiglitazone (a PPAR gamma agonist), SAHA (an HDAC inhibitor) and a soy isoflavones mixture. In separate studies, mice bearing small palpable mammary tumors were treated for five days with these various agents, and examined for alterations in potential biomarkers; including proliferation. As previously shown by our lab in an ER+ rat model of mammary cancer, effective agents (e.g., Iressa and Targretin) strongly inhibited cancer cell proliferation, whereas ineffective agents failed to significantly inhibit proliferation. Such a short-term assay might be employed to determine potential chemopreventive compounds. This model, therefore, appears useful in identifying agents that will prevent the development of breast cancer that over-express Neu. This is important since Neu over-expressing ER− cancers have a relatively poor prognosis, and Neu over-expressing ER+ tumors are relatively unresponsive to standard hormonal therapies (e.g., tamoxifen and aromatase inhibitors). Supported by NCI Contract Number HHSN261200433001C.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 960.
Abstract 969: Revising and updating NCI's best practices for biospecimen resources
Authors: Vaught Jimmie , Lockhart Nicole , Yassin Rihab , Myers Kimberly , Lim Mark David , Fore Ian , Sawyer Sherilyn , Moore Helen , Compton Carolyn
Published: February 2011

In 2007 the NCI Office of Biorepositories and Biospecimen Research (OBBR) published the NCI Best Practices for Biospecimen Resources (http://biospecimens.cancer.gov/practices/). The Best Practices were originally published following a public comment period on the Federal Register and internal review by several National Institutes of Health offices. The Best Practices do not comprise detailed laboratory procedures and are intended to be adapted, as appropriate, based on the mission and scientific needs of individual biospecimen resources. The Best Practices were developed to address the heterogeneity and the generally unknown or uneven quality of biospecimens used for research, which can lead to unreliable and irreproducible results. In addition to these technical and operational issues, many ethical, legal and policy guidelines and concerns must be addressed when conducting research involving the use of biospecimens from patients and other research participants.

The revised version of the Best Practices is intended to respond to comments received from the biospecimen resource community over the past 2 years, and provide more current and detailed recommendations related to biospecimen and data quality. Major revisions include the addition of new sections on biospecimen resource management and operations and conflicts of interest, and expansion of recommendations related to custodianship and informed consent based on the consensus findings of the 2007 NCI-hosted Workshop on Custodianship and Ownership Issues in Biospecimen Research, addition of current references throughout the document, and harmonization with current Federal guidance documents and recommendations from international biospecimen organizations.

The revised Best Practices will be launched using an interactive Web format, to provide a mechanism for more frequent updates and encourage feedback from the community. The Best Practices will continue to evolve as the field of biospecimen biology advances; novel scientific, technological, and clinical practices develop; and new ethical and legal policies and regulations emerge. Results from biospecimen research initiatives will inform future versions of the Best Practices as the community moves toward the development of evidence-based standard operating procedures that are both specimen type specific and analysis platform specific. The NCI is committed to maintaining current and scientifically accurate best practices for biospecimen resources and will continue to solicit input from stakeholders in the cancer research community.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 969.
Abstract 972: Mythbusters: Cancer research in jeopardy
Authors: Kennedy Jane , Boutte Angela , Cargen Lynne , Crowe Stephanie , Hanson Caroline , Hardin Gail , Hallock Kathy , Lancaster Diane , Lee Patricia , Markham Nick , Martin Pamela , McCollum Dan , McCullough Nancy , Moses Jeanne , Obenauf Ardeth , Piper Gary , Piper Janet , Shaw Aubie K. , Weiss Jacob
Published: February 2011

In the United States, less than 5% of eligible adult cancer patients participate in clinical trials. Lack of information and commonly held beliefs or myths are among the biggest barriers to enrollment in cancer clinical trials. Additionally, traditional methods of education can be intimidating, frightening or even boring and the most difficult time to educate patients about cancer clinical trials is at the time of diagnosis. Thus, there is a need to develop novel strategies to educate individuals and the community about clinical trials prior to a cancer diagnosis.

The Vanderbilt-Ingram Cancer Center Patient Advocacy Program and the Vanderbilt Postdoctoral Association collaborated to develop and deliver an innovative, interactive pilot program aimed at dispelling myths commonly associated with cancer clinical trials. Patient advocates, researchers, and clinicians scripted and participated in a “Jeopardy” game show format to provide factual information in a relaxed and entertaining environment.

For a community audience of 50, a response to each myth was surveyed electronically prior to the presentation. After the preliminary response of audience members was noted, an expert clarified each myth by presenting factual information. After the presentation of ten myths, a post-test was administered to assess changes in knowledge.

We found that audience knowledge was significantly increased by 20%. 96% of audience members indicated that the game show format was an effective method for learning. 87% indicated that they would discuss cancer clinical trials with family, friends or co-workers. We conclude that “Mythbusters: Cancer Research in Jeopardy” is an effective learning tool and significantly increases community knowledge about cancer clinical trials. The results of this pilot will provide a model for effective community education and may ultimately impact participation in cancer clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 972.
Abstract 98: Automated cell tracking and interaction analysis in intra-vital two-photon microscopy image data
Authors: Klauschen Frederick , Meier-Schellersheim Martin , Mandl Judith , Qi Hai , Ishii Masaru , Dietel Manfred , Germain Ronald N. , Denkert Carsten
Published: February 2011

The development of two-photon fluorescence microscopy has enabled researchers to investigate dynamic biological processes such as cell migration and interaction behavior with high spatio-temporal resolution in vivo. However, the development of computational high-throughput methods for automated and standardized quantitative analysis of the resulting 4-D image data has lagged behind the experimental advances.

Here, we introduce a novel approach for automated cell migration analysis (“cell tracking”) combined with cellular interaction analysis in 4-D intra-vital two-photon fluorescence microscopy data. Our method accounts for variations of image quality and allows for rapid, standardized, quantitative analysis and comparison of the relevant features in large data sets by integrating adaptive image segmentation and cell tracking modules. It may be used for quantitative data analysis and model validation in basic and tumor immunology studies about, for instance, lymphocyte migration and interaction dynamics in tumor or lymphoid tissues. We demonstrate the utility of our approach by applying our method to the quantification of in-vivo T-cell movement and T-/B- and dendritic cell interaction dynamics in lymph nodes and present results on the impact of a (SAP-) knock-out mutant on synapse formation and T cell function complementing the findings of a recent study.

Such measurements that may yield important information about the molecular mechanisms determining cellular migration and interaction behavior would be very difficult to perform with conventional approaches that rely on manual/semi-automated analyses. Our method should thus be highly valuable to investigators working with cell-biological microscopy who are interested in quantifying cell migration behavior not only, but especially in the context of dynamic interactions between immune and/or cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 98.
Abstract 982: Increasing HPV vaccine utilization among Hispanic girls to reduce cervical cancer disparities
Authors: Hull Pamela C. , Sanderson Maureen , Khabele Dineo , Canedo Juan
Published: February 2011

Incidence and mortality rates from cervical cancer are higher in Hispanic women compared to non-Hispanic white women. The purpose of this pilot study is to implement and assess a multilevel, culturally- and linguistically-appropriate social marketing intervention targeting the Hispanic population to increase utilization of the HPV vaccine among Hispanic girls ages 9-18 in Nashville/Davidson County, Tennessee. The specific aims are to (1) pre-test and disseminate culturally- and linguistically-appropriate media messages to promote use of the HPV vaccine in the target population; (2) provide information, referral and follow-up reminders to families to encourage initiation and completion of HPV vaccine series; and (3) assess the impact of the intervention by comparing changes in HPV vaccine utilization rates for Hispanic girls in partner clinics and in the state Immunization Registry. This pilot translational research study draws on Rogers’ Diffusion of Innovation theory. We employ the methodology of Community-Based Prevention Marketing, which combines social marketing theories and techniques with community-based participatory research (CBPR) approaches. The intervention uses a combination of Spanish-language media_radio, newspaper and printed brochures_to disseminate the messages throughout the community. A trained lay health promoter (promotora de salud) at Progreso Community Center receives phone calls to answer general questions about the vaccine and eligibility requirements for the VFC program, refers patients to appropriate locations to obtain the vaccine, and provides follow-up reminders. In this presentation we will present how formative research findings were used to develop the intervention and preliminary baseline intervention data. Targeted interventions to Hispanic communities such as this one to encourage use of a new cervical cancer vaccine could help eradicate ethnic disparities in cervical cancer. The study contributes valuable knowledge to the dearth of research on possible barriers for Hispanics to use this vaccine or about culturally- and linguistically-appropriate social marketing strategies for HPV vaccine use among Hispanics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 982.
Abstract 984: Planning for caHUB, NCI's cancer human biobank
Authors: Compton Carolyn , Dickherber Anthony , Fore Ian , Lockhart Nicole , Lim Mark David , Moore Helen , Myers Kimberly , Rogers Joyce , Sawyer Sherilyn , Tuovinen Priyanga , Vaught Jimmie
Published: February 2011

Many high-profile NCI initiatives are significantly impacted by biospecimen availability and quality. One of the newly delineated developmental pathways for transforming scientific discoveries into new clinical modalities for oncology, defined by NCI's Translational Research Working Group, is entirely biospecimen-based and is similarly impacted. Both direct experience with these initiatives as well as broader input from the scientific community, including recent results from a market research survey, have indicated a striking unmet need for high-quality human biospecimens. In response to this need, the Office of Biorepositories and Biospecimen Research (OBBR) is planning for the implementation of the cancer Human Biobank (caHUB). No centralized resource of this type exists at this time. This initiative will take advantage of resources already developed by the NCI, including the OBBR Biospecimen Research Network (BRN) and the NCI Best Practices for Biospecimen Resources (http://biospecimens.cancer.gov/practices/).

The OBBR is engaging in a detailed process with a variety of planning groups, to address the requirements for implementation of caHUB. caHUB will acquire and make available to the research community biospecimens that have been collected according to the highest technical and ethical standards; provide biospecimen reference samples that serve as benchmarks for specimen integrity and molecular type; conduct research that supports evidence-based biospecimen best practices; and create opportunities for collaboration and information exchange across the research enterprise. caHUB will ensure the quality of its inventory by acquiring biospecimens that have been collected and processed according to evidence-based standard operating procedures, annotated with comprehensive clinical, molecular, and collection data, and procured from patients who received high-quality care. caHUB proposes to contract with military, community, and academic institutions to collect biospecimens and their associated data. Through a caBIG®-compliant public network, caHUB will make specimens and data available to a broad research community, including academia, government, private foundations, and biotechnology and pharmaceutical industries, and enable new collaborations among researchers in all areas of investigation, thereby accelerating the pace of discovery and innovation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 984.
Abstract 988: A diet and exercise intervention in women being treated for breast cancer
Authors: Djuric Zora , Ellsworth Jennifer , Rapai Mary , Weldon Anne , Kim Jihye , Sen Ananda
Published: February 2011

Increases in body fat have been documented to occur in breast cancer patients during chemotherapy and radiation treatment. This is a matter of concern that can impact on health status in survivorship, especially given the difficulties in achieving weight loss once a gain has occurred. Weight gain and obesity have also been linked with recurrence. In this pilot study we investigated the feasibility of recruiting women early in their breast cancer treatment to a study that sought to prevent body fat gain. The study randomized women to receive written materials only or telephone counseling. The goals of the counseling were to decrease fat intake, increase fruit and vegetable intakes and to include at least 30 minutes of moderate to vigorous exercise daily. The counseling stressed self-monitoring of these behaviors. A total of 40 women were enrolled within 2 weeks of starting chemotherapy. This was 53% of the women who were referred to the study by their oncologists over 8 months. Baseline BMI was a mean of 27 (range 18-43 kg/m2) and 19 women were in the normal BMI range. Only 11 women had a body fat percentage in the recommended range. Retention of subjects for 12 months was 75% overall but it was better in the written arm (17 of 20 women) than in the telephone arm (13 of 20 women). Body fat increased in the written arm from 39.2 to 40.8% but it decreased from 39.0 to 37.3% in the telephone arm. Other objective measures also improved in the telephone arm such as blood pressure and leptin levels. Both total and moderate/vigorous activity increased more in the telephone arm than in the written arm. Improvements in dietary intakes at 12 months were noted in the telephone arm but not in the written arm. This preliminary data indicates that telephone support is helpful for making lifestyle changes that prevent body fat gain during treatment for breast cancer. Subject satisfaction with the study was high. The prevention of body fat gain during treatment for breast cancer is therefore feasible, and this approach could be useful for maximizing health in survivorship. Supported by the University of Michigan Metabolomics and Obesity Center, the Michigan Diabetes Research and Training Center, the Barbara Padnos Breast Cancer Research Fund and the Michigan Institute for Clinical and Health Research.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 988.
Abstract 996: Loss of alpha-dystroglycan laminin binding in epithelium-derived cancers is caused by silencing of LARGE
Authors: Beltran Daniel , Inamori Kei-ichiro , Moriguchi Takako , Weydert Christine J. , Harper Hollie A. , Willer Tobias , Muller William J. , Henry Michael D. , Campbell Kevin P.
Published: February 2011

Dystroglycan is a ubiquitously expressed cell membrane receptor that mediates interactions between cells and basement membranes in various epithelia. Dystroglycan is synthesized as a preprotein that is cleaved in two peptides: the transmembranal beta-dystroglycan, and the extracellular laminin receptor alpha-dystroglycan. In many epithelium-derived cancers, beta-dystroglycan is detected but alpha-dystroglycan has been reported to be absent. Here we report that alpha-dystroglycan is correctly expressed and trafficked to the cell membrane but lack its laminin-binding capabilities as a result of the silencing of the glycosyltransferase LARGE in a cohort of highly metastatic epithelial cell lines derived from breast, cervical, and lung cancers. As a result of this glycosylation defect, alpha-dystroglycan presents a lower MW on Western blot analysis. Exogenous expression of LARGE in these cancer cells restores the normal glycosylation and laminin-binding of alpha-dystroglycan leading to enhanced cell adhesion and reduced cell migration in vitro. The relevance of alpha-dystroglycan glycosylation in breast cancer is highlighted by the loss of the functionally active form of the receptor during mammary tumor growth in the mouse model for breast cancer MMTV-Neu(YD). Our findings demonstrate that LARGE repression underlies the defective dystroglycan-mediated cell adhesion that is observed in epithelium-derived cancer cells and uncovers dystroglycan hypo-glycosylation as factor in cancer progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 996.
Abstract 997: PKD1-β3-integrin complex increases E-cadherin shedding through MMP-2 and −9 secretion in prostate cancer
Authors: Biswas Md. Helal U. , Du Cheng , Zhang Chuanyou , Balaji K.C.
Published: February 2011

Introduction: We have previously reported that Protein Kinase D1 (PKD1), a serine threonine kinase, is down regulated in advanced prostate cancer (PC) and known complex with cell adhesion protein β3-integrin to influence cell motility. Cell motility in facilitated by degradation of extracellular matrix, which is accomplished through secretion of proteins such as Matrix Metalloproteinases (MMPs), which are neutral proteinases that catalyze degradation of various transmembrane and extracellular matrix proteins including E-cadherin at cell surface. Here, we demonstrate the presence of PKD1-β3-integrin complex in PC cells that increases MMP-2 and −9 secretion and consequently enhances E-cadherin shedding.

Methods: Protein expression, phosphorylation and secretion studies using PC cell lines were done by western blot analysis or gelatin zymography. Cell proliferation was measured by MTS assay. In silico analysis was done to validate correlation between PKD1 and MMPs expression in human PC.

Results: To find out the complex formation among PKD1 and β3-integrin in PC cell, we immunoprecipitated the PKD1 protein and immunoblotted with β3-integrin antibody and observed that the PKD1 and β3-integrin proteins were in same protein complex. Then we found that overexpression of PKD1 also colocalized in PC3 cells and that was suppressed with RGD peptide, a specific β3-integrin inhibitor, treated same cells. Additionally, we found that PKD1 overexpressed cell increased in secretion of MMP-2 and −9 as well as activation of Erk and Akt those were suppressed in RGD peptide treated cells. In contrast, we observed that downregulation of PKD1 by shRNA could suppress the phosphorylation of Erk and Akt as well as MMP-2 and MMP-9 secretion in DU145 cells. Interestingly, PKD1 enhanced the expression of E-cadherin and secretion of extracellular part of E-cadherin (sE-cadherin) in conditioned media of DU145 cells, which was suppressed by treatment by MMP-2 and −9 inhibitors. In addition, suppression of cell proliferation by PKD1 was augmented by recombinant MMP-2 and −9 proteins and rescued by MMP-2 and MMP-9 inhibitor in DU145 cells, suggesting a surprising antiproliferative role for MMP-2 and −9 in PC cells. In silico analysis of publicly available DNA microarray data set derived from human PC confirmed that expression of PKD1 and MMP-2 correlated directly in metastatic PC compared to benign prostate tissue. Conclusions: Our study has identified a novel role of PKD1-β3-integrin complex for secretion of MMP-2 and −9 in prostate cancer, which is associated with E-cadherin shedding. Our data also suggested that the proteins complex limits PC cell proliferation by modulation MMP-2 and −9 secretion.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 997.
Abstract LB-11: Clinical and genetic analysis of Peutz-Jeghers syndrome patients in Taiwan
Authors: Weng Meng Tzu , Wei Shu Chen
Published: February 2011

Background/Purpose: Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps and mucocutaneous pigmentation. Recently, germline mutations in the LKB1 gene have been reported to underlie PJS. The gene encoding this serine/threonine kinase is located at 19p 13.3. The aim of this study was to investigate the clinical and genetic characteristics of PJS patients in Taiwan.

Methods: We searched the database in the National Taiwan University Hospital, a tertiary medical center in Taiwan, between January 1990 and November 2005. Patients’ clinical information, demographic data, endoscopic pictures, and outcome details for these cases were reviewed and analyzed. After obtaining informed consent, DNA and RNA were extracted from peripheral blood mononuclear cells and the LKB1 gene was sequenced.

Results: A total of 14 non-related patients fulfilling the diagnostic criteria of PJS were included, and seven of them had genetic analysis performed. Mucocutaneous pigmentation was the most frequent presentation. Hamartomas occur most commonly in the small intestine (86%). The frequent abdominal complications include intussusceptions and gastrointestinal bleeding. Four germline mutations were found (57.1%). Three resulted in stop codons at codon 60, 162 (novel mutation), and 308. The fourth mutation was a missense mutation at codon 239 (novel mutation).

Conclusions: Compared to other reports, PJS patients in Taiwan tended to have more extensive polyps in the GI tract, causing intussusceptions as the most common abdominal symptoms. The genetic mutations in the LKB1 gene were identified in 57% of the probands in Taiwan.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-11.