bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 994: Colorectal cancer, adenoma and normal whole genome methylation sequencing in Africa Americans
Authors: Ashktorab Hassan , Rahi Hamed , Tbaishat Rana , Daremipouran Mohammad , Smoot Duane T. , Lee Edward L. , Varma Sudhir , Sun Xueguang , Jia Xi-Yu , Chung Hunter , Bacon Eliza , Leavitt Ron , Siegel Peter , Brim Hassan 
Published: August 2012

Abstract
Background: Colorectal adenoma (CRA) to cancer (CRC) progression involves epigenetic changes including DNA methylation. Here we performed whole genome Bisulfite Next-Generation Sequencing (WGBNGS) on a normal, a tubular adenoma and a tumor patients’ tissue DNA to elucidate epigenetic drivers in normal to cancer progression. Patients and Methods: Genomic DNA was isolated from fresh frozen tissues from a patient with normal colon, from a tubular adenoma lesion (20X depth was performed on these DNA samples., Alignment, mapping and CpG methylation analyses were done. Pyrosequencing and immunohistochemistry (IHC) were used to confirm selected methylation target genes. Results: We identified 94 unique CpG sites hypermethylated in 4 novel genes in adenoma compared to normal and 180 unique CpG sites in 7 genes in cancer. Ingenuity pathway analysis (IPA) showed that the methylated genes including a novel gene ATXN7L1 were involved in WNT pathway, ubiquitination process and cross-talk with B-catenin, in the adenoma. Three of the hypermethylated genes in cancer were, Loc100506436: a novel gene with 17 unique CpG sites (EGFR pathway, cRNA CpG site hypermethylated is part of MEK1/2), GPNMB with 7 unique CpG sites (membrane protein likely in complexes with integrins) and TNFAIP2 with 8 unique CpG sites (its role was noted in Head and neck cancer). IHC confirmed the lack of GPNMB expression in cancer tissues. Conclusion: This work provides insight into differential CpG island methylation profiles in CRA, CRC vs. normal colon tissue and provides a window into the more complex factors, including alteration of known and novel genes as multiple CpG methylation drivers in colorectal carcinogenesis. Investigations into the possible roles of the novel genes targets in the context of early and prognostic methylation biomarker are underway.
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 994. doi:1538-7445.AM2012-994
Abstract 998: Oncogenic potential of mitochondria regulate the cellular tumor characteristics
Authors: Ma Yewei , Gupta Vineet , Trieu Robert , Lap Lee Tin , Kaipparettu Benny A. , Wong Lee-Jun 
Published: August 2012

Abstract
Mitochondrial-nucleus cross-talks and mitochondrial retrograde regulation of nuclear genes can play significant role in cellular properties. Several studies reported that somatic mitochondrial DNA alterations are often detected in cancer cells. Most of such alterations are polymorphisms without functional significance. Here we use a transmitochondrial cybrid (cybrids) approach to understand the significance of mitochondrial property in regulating the oncogenic properties of a cell irrespective of its mutational and nuclear status. Cybrid models in two differently defined nuclear backgrounds were studied. In the first model, mitochondria depleted rho zero (≥0) from an aggressive osteosarcoma cell lines 143B TK− was used as a common nuclear background. 143B β0 cells were fused with mitochondria from non-cancerous breast epithelial cell line MCF10A, low metastatic breast cancer cell line MDA-MB-468 and highly metastatic 143B TK− cell lines. In the second model, we used the common nuclear background of A1N4, a non-tumorigenic immortalized breast epithelial cell. A1N4 β0 cells were fused with MCF-10A and metastatic breast cancer cells MDA-MB-231. Studies in parental mitochondrial donor cells suggested that cancer cell lines have reduced ATP synthesis, oxygen consumption and respiratory chain activities compared to non-cancerous cells. Interestingly, in spite of the common nuclear backgrounds, cybrids also showed properties similar to their parental cells under both cancerous and non-cancerous nuclear backgrounds. Functional studies in cybrids under non-cancerous nuclear background observed that fusion with cancerous mitochondria resulted in loss of growth contact inhibition, induction of colony formation potential in soft agar and increased survival potential under serum starvation. Similarly, functional studies in cybrids with cancerous nuclear background suggested that non-cancerous mitochondria could reverse different oncogenic characteristics of cancer cell including cell proliferation, viability under hypoxic condition, anti-apoptotic properties, resistance to anti-cancer drug, invasion, colony formation in soft agar, and in vivo tumor growth in nude mice. Microarray analysis of cybrids under cancerous nuclear background suggested that several oncogenic pathways are inhibited due to non-cancerous mitochondria. Interestingly, under non-cancerous nuclear background, induction of important oncogenes was observed in cybrids containing cancerous mitochondria. These results suggest that mitochondrial-nuclear cross talk have significant contribution to cancer cell properties. Also it highlights mitochondria as a promising target in cancer therapy.
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 998. doi:1538-7445.AM2012-998
Abstract LB-119: Therapeutic sensitivity and predictive markers for CDK4/6 inhibition defined by ex vivo analyses of human tumors
Authors: Witkiewicz Agnieszka , Dean Jeffry , McClendon Amy , Knudsen Erik S. 
Published: August 2012

Abstract
To model the heterogeneity of breast cancer as observed in the clinic, we employed an ex vivo model of breast tumor tissue. This methodology maintained the histological integrity of the tumor tissue in unselected breast cancers, and importantly, the explants retained key molecular markers that are currently used to guide breast cancer treatment (e.g. ER and Her2 status). The primary tumors displayed the expected wide range of positivity for the proliferation marker Ki67, and a strong positive correlation between the Ki67 indices of the primary and corresponding explanted tumor tissues was observed. Collectively, these findings indicate that multiple facets of tumor pathophysiology are recapitulated in this ex vivo model. To interrogate the potential of this preclinical model to inform determinants of therapeutic response, we investigated the cytostatic response to the CDK4/6 inhibitor, PD-0332991. This inhibitor was highly effective at suppressing proliferation in approximately 85% of cases, irrespective of ER or HER2 status. However, 15% of cases were completely resistant to PD-0332991. Marker analyses in both the primary tumor tissue and the corresponding explant revealed that cases resistant to CDK4/6 inhibition lacked the RB-tumor suppressor. These studies provide important insights into the spectrum of breast tumors that could be treated with CDK4/6 inhibitors, and defines functional determinants of response analogous to those identified through neoadjuvant studies.
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 LB-119. doi:1538-7445.AM2012-LB-119
Abstract LB-12: Building a novel multifaceted nano-carrier: In vivo and in vitro applications of multifunctional nanolipoprotein particles
Authors: He Wei , Yi Sun , Luo Juntao , Lam Kit , Murphy William , Coleman Matthew 
Published: August 2012

Abstract
We have developed a novel process of production and assembly of nanolipoprotein particles (NLPs) as a multifaceted reagent for cancer imaging, drug delivery, immunomodulation and stabilizing membrane protein complexes for in vitro studies. Nanolipoproteins are components of the human HDL lipoprotein complexes that could be isolated and reconstituted to form NLPs. NLPs are discoidal nanoparticles of 10∼20 nm that self-assemble around a phospholipid bilayer. This bilayer mimics closely the cell membrane can support molecules such as dyes and proteins. NLPs present distinct advantages in terms of particle size, monodispersity and consistency: the circular protein belt constrains the dimensions of the bilayer and ensures NLP particle size distributions can be monodispersed and consistent between preparations. We have demonstrated when targeting agents and imaging agents are attached to the NLPs, they were able to accumulate at the tumor region and can be used for tumor imaging; We also managed to conjugate recombinant IL2 to NLPs. Our data showed that IL2-NLP conjugates were able to stimulate immunomodulation in mice both in vivo and in vitro. NLPs also have shown great promise for solubilizing and characterizing membrane proteins and may make many more membrane protein related complexes accessible for biophysical and biochemical study. Our approach represents a unique solution to the challenge of generating soluble and functional polytopic membrane proteins, facilitating the structural and functional characterization, providing a platform for high-throughput drug screening, and potentially a new type of carrier for tumor imaging and drug delivery.
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 LB-12. doi:1538-7445.AM2012-LB-12
Abstract LB-120: Site of origin of basal cell carcinoma stromal cells
Authors: Wang Grace Y. , Wang Joy , Wang Lynn , Epstein Ervin 
Published: August 2012

Abstract
We have adapted a transgenic tetracycline-regulatable mouse model to identify slow dividing cells in murine basal cell carcinomas (BCCs). This system consists of 2 transgenes: histone H2B-green fluorescence protein (GFP) controlled by a tetracycline-responsive element (TRE) upstream of a CMV promoter; and a tissue specific promoter-driven tetracycline-regulatable activator protein (rTA). In the absence of rTA, the H2B-GFP expression should be silent. However, we and other labs have found that mice carrying the H2B-GFP transgene with or without the K5-rTA transgene showed significant numbers of GFP-expressing bone marrow cells, which are not regulated by doxycycline. To study BCCs, we crossed these leaky mice with our Ptch1+/− mouse and treated the offspring with ionizing radiation. Although the mice with the H2B-GFP transgene developed microscopically detectable BCCs in a manner similar to Ptch+/− parental mice, the presence of the H2B-GFP transgene significantly delayed the microscopic-to-macroscopic transition of tumors (i.e. mice develop their first macroscopic tumor at age 9-13 month for Ptch+/− vs. 13-18 months for Ptch1+/− K5rTA H2B-GFP). Moreover, approximately one third of the Ptch1+/− K5rTA H2B-GFP mice died with unknown causes before 9-month of age, the time point when we collected skin biopsies for evaluating microscopic tumors, in comparison to 10-15% mouse death in Ptch1+/− mice by this age. Studying the limited number of visible BCCs arising in Ptch1+/− H2B-GFP (no K5-rTA transgene), we found that all the tumor cells were GFP-negative; however, the stromal cells nearly uniformly expressed GFP. By contrast, microscopic BCCs had no GFP+ stromal cells. As expected, both tumor cells and stromal cells were GFP-positive in unchased Ptch1+/− K5rTA H2B-GFP mice. By immunostaining, the GFP-expressing stromal cells, unlike the tumor cells, did not express keratins 5 and 14 but were vimentin-positive, Ki67-negative and frequently located in proximity to blood vessels. Using flow cytometry analysis with a panel of cell surface markers, we further characterized the GFP-expressing tumor stromal cells and the bone marrow cells. However further assessment is needed to confirm that the BCC stromal cells are derived from the GFP-expressing bone marrow cells and to determine their potential role in the microscopic to visible tumor transition. Our findings suggest that bone marrow cells may be the cells of origin of tumor stromal cells in BCCs perhaps in other cancers in general.
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 LB-120. doi:1538-7445.AM2012-LB-120
Abstract LB-126: Cancer-retina antigens as potential therapeutic targets for immunotherapy
Authors: Jesiak Maria , Osen Wolfram , Gardyan Adriane , Soltek Sabine , Heinzelmann Anita , Bazhin Alexandr , Eichmueller Stefan 
Published: August 2012

Abstract
Melanoma is a fast progressing tumor, which originates from melanocytes and it is known to be highly resistant to many therapies. Although it has been proven to be very immunogenic and a number of various melanoma associated antigens are well known, nevertheless, the immune response of the patients is often not able to fight back and eliminate all tumor cells. It has been recently shown that a new class of tumor antigens, called cancer-retina antigens (CRA), apart from being expressed in a healthy retina, can be expressed at the mRNA and protein level in melanoma. The aberrant expression of transducin, cGMP-phosphodiesterase 6 (PDE6), guanylyl cyclase, recoverin and arrestin have been detected in tumor cells of melanoma patients and in tumor-bearing mice. These antigens can elicit humoral and cellular immune responses. We aim to investigate if CRA could serve as potential target antigens for immunotherapy approaches against melanoma. Among these antigens, human PDE6 was selected and analyzed for its immunogenicity in normal C57BL/6 mice and in HLA-DRB1*0301tg mice. Human (xenogenic) PDE6 alpha has been cloned and used for DNA immunization of BL/6 and HLA transgenic mice. By IFN-γ ELISPOT assay employing synthetic peptide libraries, immunogenic peptides have been identified and CRA specific T cell epitopes were determined. Further on, PDE6-specific T cells lines will be generated and their therapeutic efficiency will be checked in transplantable tumor mouse models or in transgenic mice with spontaneous melanoma formation. In addition, peripheral blood mononuclear cells (PBMCs) from tumor patients will be analyzed for the presence of specific T cells against the epitopes identified in HLA-transgenic mice. These T cells will be expanded and tested for their reactivity against HLA-matched human melanoma cell lines in vitro. Finally, both established CRA-specific T-cell lines and synthetic polypeptides will be tested as vaccines in therapeutical and preventive settings in melanoma animal tumor models. Immunized animals will be monitored for any signs of autoimmune retinopathy.
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 LB-126. doi:1538-7445.AM2012-LB-126
Abstract LB-127: Identifying an IDO-expressing “fibrocyte” subset of myeloid suppressor cells in pediatric cancer patients
Authors: Zhang Hua , Mackall Crystal L. 
Published: August 2012

Abstract
Human myeloid derived suppressor cells (MDSC) have been described as CD14-CD11b+CD33+HLADR- cells that exert T cell suppression via ROS, ARG1 and iNOS2. Here, we report a novel myeloid subset found within mononuclear fraction elutriated from apheresis samples of pediatric cancer patients vs. healthy controls. Of 60 pediatric cancer patients studied, we frequently observed expanded numbers of CD14-CD123-CD11chi cells, which were rare and found only at low levels in healthy donors. Like previously described MDSC, these cells were CD11b+, but CD33lo/-HLADR+. In addition, these abnormal myeloid cells were CD34+CD15+CD16+CD66b+CD68+PDL1+ and IL4Rα+. Interestingly they also expressed α smooth muscle actin and collagen I/V on their surface, which are hallmarks of fibrocytes. The fibrocytes expressed high levels of indoleamine oxidase (IDO), but did not express ARG1, ARG2, iNOS2. They suppressed T cell proliferation in response to OKT3, which was partially reversed by the addition of 1MT, an inhibitor of IDO. Given the IL4Rα expression, we sought to induce these cells in vitro from normal monocytes using IL-4. Indeed, IL4 alone was sufficient to drive monocytes to differentiate into fibrocytes, which demonstrate a spindle-like shape, adhere to plastic, acquire the CD11chiCD14-CD34+CD16+collagenI+ phenotype, and express IDO. Fibrocytes have previously been implicated in chronic inflammation, angiogenesis and wound healing. We conclude that they also constitute a novel subset of myeloid derived suppressor cells in cancer patients, and could contribute to tumor progression.
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 LB-127. doi:1538-7445.AM2012-LB-127
Abstract LB-131: Peptide vaccine therapy for childhood gliomas: interim results of a pilot study
Authors: Pollack Ian F. , Jakacki Regina I. , Butterfield Lisa H. , Okada Hideho 
Published: August 2012

Abstract
Introduction: Malignant astrocytomas of the brainstem and cerebral hemispheres and multiply recurrent low-grade gliomas carry a poor prognosis despite current treatments, and new therapeutic approaches are needed. Having gained significant experience with immunotherapy for adult gliomas, we extended these insights to childhood gliomas, based on our observations regarding their profiles of glioma-associated antigen (GAA) expression. Methodology: We initiated a pilot trial of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 given every 3 weeks for 8 courses along with intramuscular injections of poly-ICLC in HLA-A2+ children with newly diagnosed brainstem gliomas (BSG), cerebral high-grade gliomas (HGG), or recurrent gliomas. GAAs were EphA2, IL13Rα2, and survivin. Primary endpoints were safety and T cell responses against vaccine-targeted GAAs, assessed by ELISPOT and tetramer analysis. Treatment response was evaluated clinically and by MR imaging. Results: To date, 24 children have been enrolled, 13 with newly diagnosed BSG, 5 with newly diagnosed HGG, and 6 with recurrent gliomas. No dose-limiting non-CNS toxicity has been encountered. One child with a BSG had transient tumor enlargement in association with acute neurological deterioration 4 months after beginning vaccination that later regressed and culminated in a sustained partial response (PR), consistent with pseudoprogression. Two other children with BSG had symptomatic pseudoprogression, with transient neurological deterioration and tumor enlargement followed by stabilization on decreasing steroid doses. Among 22 patients evaluable for response, 4 had rapidly progressive disease, 14 had stable disease for &gt; 3 months, 2 had PRs, 1 had an MR, and 1 had prolonged disease-free status after surgery. ELISPOT analysis, completed in seven children, showed response to IL13Rα2 in 5, EphA2 in 3, and survivin in 3. Conclusion: Peptide vaccination in children with gliomas is generally well tolerated, and has preliminary evidence of both immunological and clinical activity. Pseudoprogression can initially be difficult to distinguish from true tumor progression and aggressive management may be warranted.
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 LB-131. doi:1538-7445.AM2012-LB-131
Abstract LB-134: Personalized peptide vaccination as the second line therapy for patients with chemotherapy-resistant advanced pancreatic cancer.
Authors: Sasada Tetsuro , Yutani Shigeru , Yoshitomi Munehiro , Matsueda Satoko , Komatsu Nobukazu , Itoh Kyogo 
Published: August 2012

Abstract
Background: Since the prognosis of advanced pancreatic cancer remains poor, development of novel therapeutic approaches, including cancer vaccine, would be highly desirable. We conducted a phase II study of personalized peptide vaccine (PPV) in chemotherapy-resistant advanced pancreatic cancer patients. Methods: Forty-one advanced pancreatic cancer patients (7 Stage IVa, 24 Stage IVb, 10 recurrence) who failed to respond to the first line chemotherapy were enrolled. Median duration of chemotherapy prior to the enrollment was 8 months. A maximum of four HLA-matched vaccine peptides showing higher antigen-specific immune responses were selected based on the titers of IgG against each of 31 different peptide candidates, and employed for subcutaneous vaccination. In order to identify potentially prognostic biomarkers for overall survival (OS), pre-vaccination clinical findings and laboratory data were retrospectively assessed and evaluated by multivariate Cox proportional hazards model in 36 patients who completed at least one cycle of 6 vaccinations. Results: Median OS from the first vaccination was 7.9 M with a one-year survival rate of 24%. Notably, median OS from the first line chemotherapy was 19.2 M. The main toxicity of PPV was skin reactions at the injection sites, but no vaccine-related serious adverse events were observed. Among the pre-vaccination factors examined, high level of serum amyloid A (SAA) and high titer of the IgG against 31 vaccine peptide candidates were significantly unfavorable for OS [hazard ratio (HR) = 1.019, P = 0.006; HR = 0.999, P = 0.0001; respectively] by the Cox multivariate analysis. The clinical stage was also associated with OS, as expected (HR = 0.496, P = 0.014). Conclusions: Even in chemotherapy-resistant advanced pancreatic cancer patients, PPV might improve the prognosis. Further randomized clinical trials of PPV would be recommended in advanced pancreatic cancer patients.
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 LB-134. doi:1538-7445.AM2012-LB-134