bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3248: Over-expression of 1-ACBP, B-ACBP and PBR genes in mast cells infiltrating oesophageal squamous cell tumors
Authors: Dlamini Zodwa 
Published: July 2016

Abstract
Oesophageal cancer ranks as the sixth most common malignancy in the world, and recent evidence has shown that its incidence is increasing. ACBPs (Acyl-coA binding proteins) act as intracellular carrier-proteins for medium to long chain acyl-coA, mediating fatty acid transport to the mitochondrion for ß-oxidation. ACBPs are also believed to be putative ligands of PBR (peripheral benzodiazepine receptor), and bound to this receptor facilitate mitochondrial membrane permeabilization giving the notion that favours apoptosis. The main aim of the study was to establish the expression patterns of 1-ACBP, B-ACBP, and PBR in oesophageal cancer, and to link their roles with the disease. Probes specific to the genes encoding 1-ACBP, B-ACBP, and PBR were PCR amplified and cloned into pGEM-T easy vectors using gene specific primers. The cloned products were sequenced and screened against the GENBANK database (NCBI) to verify the identity and orientation of cloned products within the vector. Antisense and sense probes were then generated using T7 or SP6 RNA polymerase after digestion with either Pst1 or Apa1, respectively. In situ hybridization and quantitative real-time PCR methods were performed to determine localization and the expression levels of the three genes in oesophageal cancer. All three genes illustrated substantial up-regulation within the malignant tissue sections as compared to normal oesophageal sections, all three transcripts localized specifically to plasma cells and lymphocytes in diseased and normal tissue section. In the diseased tissue B-ACBP and 1-ACBP mRNA localized to endothelial cells of blood vessels in the submucosa. B-ACBP also localized to the nucleus of squamous epithelial cells. PBR localization was indicated in tumour islands of invasive tissue sections. Quantitative RT-PCR also indicated that the expression levels of PBR were higher as compared to the ACBP genes expression in tumours. These results show that 1-ACBP, B-ACBP and PBR play a role in the pathogenesis of oesophageal tumours and also suggest the interaction between these genes with the immune system and that was also confirmed using bioinformatics analysis.
Citation Format: Zodwa Dlamini. Over-expression of 1-ACBP, B-ACBP and PBR genes in mast cells infiltrating oesophageal squamous cell tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3248.
Abstract 3316: The effects of dopamine receptor 2 on breast cancer tumor initiating cells
Authors: Tegowski Matthew , Santos Charlene , Baldwin Albert 
Published: July 2016

Abstract
Despite advances in early detection and treatment of breast cancers, metastatic disease remains a significant problem and a large cause of mortality in the US. Although tumors are characterized as a mass of uncontrolled cell division, it is thought that only small populations of cells, known as tumor initiating cells (TICs), are primarily responsible for metastasis. TICs are less differentiated than most tumor cells and many TICs show an epithelial-to-mesenchymal transition (EMT). Recently, the FDA-approved drug thioridazine, a dopamine receptor 2 (DRD2) antagonist, has been shown to inhibit pluripotency gene expression only in transformed stem cells. To test whether DRD2 can regulate TICs in breast cancer cells, two main assays were performed. The tumorsphere assay is used to measure TIC activity within a population of cells in vitro. In this assay, single cells are cultured in suspension, in the absence of serum. Cells must escape anoikis and grow without cell-cell contacts or the assortment of factors contained in serum. However, the gold standard in vivo assay to measure tumor initiation is the transplantation assay at limiting dilutions. Cells are injected into immunocompromised mice in decreasing numbers and the number of tumors each population of cells is capable of forming is measured. In this study the tumorsphere assay and transplantation assay both show that DRD2 supports TICs in breast cancers. Interestingly, our data suggest that DRD2 regulates TICs and cellular differentiation through the activity of the STAT3 transcription factor. Activation of STAT3 has been shown to induce gene expression changes that support TICs and upregulate the pluripotency factor OCT4. STAT3 activity can also induce EMT and resistance to some therapeutics. By inducing the expression of its own activator, IL-6, STAT3 can initiate a feed forward loop to maintain continual expression to promote TICs, EMT, and drug resistance. Halting the continual activation of STAT3 in these cells should be an important objective. Our data supports the concept that DRD2 may represent a new, and druggable target for therapies to decrease metastasis and/or recurrence by interfering with STAT3 and inhibiting TIC-like activities.
Citation Format: Matthew Tegowski, Charlene Santos, Albert Baldwin. The effects of dopamine receptor 2 on breast cancer tumor initiating cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3316.
Abstract 3322: Estrogen and nuclear respiratory factor 1 act as joint mediators of redox modulation and stem cell aging that contribute in the pathogenesis of breast cancer
Authors: Vazquez Juan , Roy Deodutta , Das Jayant 
Published: July 2016

Abstract
Deterioration of adult stem cell function with increasing age is a risk factor of breast cancer. Metastasis of breast cancer seems to be also influenced by aging or senescent cells overexpressing mitophagy/autophagy genes. Recently, estrogen, ROS, mitochondria and NRF1 activity have been implicated with stem cell aging, health and longevity. The exact underlying mechanisms of how aging of stem cells may increase the susceptibility to estrogen-induced carcinogenicity remain unknown. The main objective of this study was to examine whether estrogen, through activation of NRF1-mediated redox modulation and autophagic genes involved in senescence of stem cells, contributes in the development of breast cancer. To test this hypothesis, first we investigated the role of NRF1 to induce stemness by re-programming of breast epithelial cells (MCF-10A) and breast cancer cells (MCF-7 and MDA-MB231). We found that NRF1 promoted pluripotency markers: Oct4, Sox 2, and Nanog compare to MCF10A, MCF-7 or MDAMB 231 control cells. Loss of E-cadherin expression and gain of N-cadherin and vimentin expression in NRF1 overexpressing cells suggested that NRF1 promotes epithelial- mesenchymal transition. NRF1 promoted the ability to differentiate in vitro into a variety of cells (e.g chondrocytes, neurons, and smooth muscle cells). This suggested that NRF1 promotes multilineage differentiation potentials. Our data also showed that higher expression of NRF1 increased sizes of spheroids and ROS levels compared to controls. Mitophagy/Autophagy that regulates clearance of damaged mitochondria/apoptotic cells has important functions in regulating stem cell aging and tumorigenesis. Therefore, we examined the effect of estrogen on aging-associated diseases-related genes in NRF1 overexpressing as well as NRF1 silenced cells. Autophagy/Mitophagy/Apoptosis-related genes - BNIP3, PINK1, DJ-1 and LKB1 were altered in response to exposure of a carcinogenic concentration of estrogen. This effect of estrogen on these genes was further amplified by NRF1 overexpression and was inhibited by loss of NRF1. In summary, estrogen and NRF1 act as joint mediators of stem cell fate and reprogramming through a panel of critical stem cell proteins involved in modulating senescence and cell death. NRF1 seems to function as a rheostat to coordinate various cellular processes, such as resistance to apoptosis, autophagy and mitophagy of stem cells required for the stem cell aging as well as for the pathogenesis of breast cancer.
Citation Format: Juan Vazquez, Deodutta Roy, Jayant Das. Estrogen and nuclear respiratory factor 1 act as joint mediators of redox modulation and stem cell aging that contribute in the pathogenesis of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3322.
Abstract 3552: Regulation of immune homeostasis by direct activator BH3-only proteins
Authors: Ludwig Lindsey M. , Roach Lauren E. , Fisher Jill K. , Walensky Loren D. , LaBelle James L. 
Published: July 2016

Abstract
The BH3-only proteins BIM, BID, and PUMA have emerged as both inhibitors of anti-apoptotic BCL-2 family proteins and direct activators of the pro-apoptotic executioner proteins BAX and BAK, and have been implicated in regulating immune cell homeostasis. For example, BIM is a master regulator of B and T cells and its deletion in mice causes splenomegaly and lymphocytosis. Although deletion of Bid or Puma do not grossly impact murine hematopoietic organs, loss of each can protect lymphocytes from certain forms of cell death. Combined deletion of Puma and Bim causes increased lymphocytosis and spontaneous development of B-cell lymphoma, while loss of BID and BIM leads to delayed T cell contraction following antigen-mediated proliferation. To investigate the role of direct activator BH3-only proteins in regulating the adaptive immune response over time, we performed peripheral lymphocyte analyses on single and combinatorial knock-outs of Bim, Puma, and Bid. Select genotypes, such as Bim−/−, Bim−/−Puma−/−, and Bim−/−Puma−/−Bid−/− mice, show lymphocytosis early in life but, unexpectedly, counts were observed to gradually normalize by 40 weeks of age. Given the dominant role of BIM in immune cell homeostasis, we investigated whether this phenotype was dictated by global deletion of Bim or intrinsic to T or B cell-specific Bim deletion. In generating and analyzing Lck-cre and CD19-cre Bim floxed animals, we found that T cell-specific Bim deletion recapitulated early lymphocyte expansion followed by contraction, whereas the lymphocytosis of mice with B cell-specific Bim deletion showed no age-related changes. Further characterization of aged Lck-cre Bim floxed mice revealed spleen weights similar to wild type mice, and thymocytes with increased sensitivity to a range of apoptotic stimuli; these mice also have an increased percentage of regulatory T cells compared to similarly aged wild-type mice, as has been reported for globally-deleted Bim−/− animals. To determine the mechanism underlying the observed lymphocyte contraction, we performed qRT-PCR analysis for a panel of BCL-2 family proteins. We find that aged Lck-cre Bim floxed mice manifest upregulation of a series of BH3-only transcripts, including Puma and Bid, reflective of an intriguing compensatory mechanism to remedy, over time, the lymphocytosis that derives from Bim deletion in T cells. These studies provide new insight into the complexity and dynamism underlying BH3-only regulation of immune cell homeostasis during health, disease, and aging.
Citation Format: Lindsey M. Ludwig, Lauren E. Roach, Jill K. Fisher, Loren D. Walensky, James L. LaBelle. Regulation of immune homeostasis by direct activator BH3-only proteins. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3552.
Abstract 3565: Dinaciclib, a CDK inhibitor promotes proteasomal degradation of Mcl-1 and enhances ABT-737 mediated cell death in malignant human glioma cell lines
Authors: Jane Esther P. , Premkumar Daniel , Cavaleri Jonathon , Rajasekar Thatchana , Sutera Philip , Pollack Ian 
Published: July 2016

Abstract
The prognosis of malignant glioma, the most common brain tumor, is still poor, thus underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell cycle control, there is a strong rationale to examine the potential efficacy of strategies to counteract this process. In this study, we examined the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact or deleted or mutated p53 or PTEN or p14ARF, or EGFR amplification status. Dinaciclib was found to inhibit cell proliferation and induce cell cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a standard 72 h MTS assay, at clinically relevant concentrations, dose-dependent antiproliferative effects were observed but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitor ABT-263 or ABT-737 with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential, the release of cytochrome c, smac/DIABLO and apoptosis-inducing factor (AIF), phosphatidylserine exposure on the plasma membrane surface and activation of caspases and PARP. Mechanistic studies revealed that dinaciclib promoted proteasomal degradation of Mcl-1.
Citation Format: Esther P. Jane, Daniel Premkumar, Jonathon Cavaleri, Thatchana Rajasekar, Philip Sutera, Ian Pollack. Dinaciclib, a CDK inhibitor promotes proteasomal degradation of Mcl-1 and enhances ABT-737 mediated cell death in malignant human glioma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3565.
Abstract 363: Establishment of multicellular tumor spheroids-based assay for screening of novel therapeutics
Authors: Song Yeonhwa , Seo Haengran 
Published: July 2016

Abstract
3D cell culture system is highlighted as new method to screen for new cancer therapies. The multicellular tumor spheroid cultures are closely similar to pathophysiological gradients of in vivo tumors and subsequently an ideal screening model for new drugs. Hepatocellular carcinomas (HCC) is resistant to conventional chemotherapeutic agents and remains an unmet medical need. Hence, we focused in developing tumor spheroids-based screening assay to identify new drugs to treat HCC.
Tumor spheroid cultures were formed in hydrogel coated multi-well plates within 3 days followed by 3 days treatment with reference compounds (Doxorubicin, Etoposide, Methotrexate, Taxol, etc.). Bright images of tumor spheroids were visualized by Operetta imaging system in the presence and absence of reference compounds. Cell viability of spheroids were measured by resazurin assay.
In the results, assay was developed and validated using multicellular tumor spheroids (MCTS) cultures composed of Huh7 (HCC cells), WI38 (fibroblasts), LX2 (hepatic stellate cells) and HUVEC (endothelial cells) to recapitulate HCC tumor microenvironments. We also addressed the effect of sorafenib on the growth of spheroids composed of Huh7 alone or MCTS. Results from this study indicate that sorafenib was less efficacious (IC50 = 8.0μM) in the MCTS compared to its effect on Huh7 spheroid (IC50 = 3.8 μM).
In summary, we have established and validated a highly reproducible MCTS-based assay. Based on this results, MCTS based-HTS system can offer a new model for drug screening and significantly improve the efficiency of identifying new drugs for liver cancer therapy.
Citation Format: Yeonhwa Song, Haengran Seo. Establishment of multicellular tumor spheroids-based assay for screening of novel therapeutics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 363.
Abstract 3641: ReCapSeg: Validation of somatic copy number alterations for CLIA whole exome sequencing
Authors: Lichtenstein Lee , Woolf Betty , MacBeth Alyssa , Birsoy Ozge , Lennon Niall 
Published: July 2016

Abstract
The presence of specific somatic copy number alterations (SCNAs) in tumor genomes can be used to predict sensitivity to specific treatments and to predict outcomes. CapSeg Revised (ReCapSeg) detects SCNAs from tumor sequencing data. The Broad Institute is integrating ReCapSeg into the Clinical Research Sequencing Platform (CRSP), a CLIA-certified platform, to enable physicians to use detected SCNAs in treatment decisions. By using sequencing data CRSP can produce SCNA reports using the same data being generated for other reports (e.g. somatic single nucleotide variants). ReCapSeg produces copy ratio estimates for regions of the genome and includes a caller that labels regions as amplified, deleted, or neutral. ReCapSeg leverages a panel of normals (PoN), which obviates the need for the matched normal for a given tumor sample.
Validation for ReCapSeg, in CRSP, is repeatable and standardized with a process for creating a PoN and gathering performance metrics from case samples. Additional QC metrics and criteria on input sequencing data were identified and included, so that reports can indicate when reduced performance can be expected.
Citation Format: Lee Lichtenstein, Betty Woolf, Alyssa MacBeth, Ozge Birsoy, Niall Lennon. ReCapSeg: Validation of somatic copy number alterations for CLIA whole exome sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3641.
Abstract 3654: In vivo CRISPR screen identidied Nf1 as a new tumor suppressor recurrently inactivated in liver cancer
Authors: Song Chunqing 
Published: July 2016

Abstract
Our CRISPR screen identified NF1, encoding a RasGAP, as a new tumor-suppressor gene. CRISPR mediated loss-of-function mutations in NF1 led to increase RAS activation and increased tumor formation in liver cells. NF1 expression was reduced in 60% (225/373) of human HCC and was associated with reduced patient survival. Point mutations of NF1 was found in 3% of HCC. These findings identify NF1 inactivation as a new tumor suppressor in the liver and highlight the importance of RasGAPs in liver cancer.
Citation Format: Chunqing Song. In vivo CRISPR screen identidied Nf1 as a new tumor suppressor recurrently inactivated in liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3654.
Abstract 3676: Prognostic significance of PTEN alteration in Middle Eastern colorectal carcinoma
Authors: Siraj Abdul K. , Beg Shaham , Bu Rong , Al-Rasheed Maha , Al-Sanea Nasser , Al-Dayel Fouad , Al-Kuraya Khawla 
Published: July 2016

Abstract
Phosphatase and tensin homolog (PTEN) detected on chromosome 10 is a tumour suppressor commonly reported to be inactivated in colorectal cancers, but the prognostic significance of PTEN remains controversial. Here, we investigated the clinical associations and the significant prognostic value of combined PTEN mutation, genomic deletion and loss of expression in a large cohort of Middle Eastern colorectal cancers. We examined PTEN protein expression using immunohistochemistry in 400 sporadic colorectal cancers with full clinical investigations and follow up data. PTEN mutations were studied using capture sequencing and Sanger sequencing validation. PTEN copy number alteration was carried out using Fluorescence In-Situ Hybridization (FISH). Of the all CRC tumours analysed 83/347 (24%) cases showed absence of PTEN staining, 189/347 (54.5%%) cases showed weak staining and remaining 75/347 (21.5%) cases showed staining similar to normal & internal positive control. 17 mutations in coding region of PTEN were identified in 13 (3.2%) CRC cases. Further, PTEN deletion was identified in 24/338 (7.1%) of CRC cases. No amplification of PTEN gene was detected. Interestingly when combining all PTEN alterations (protein expression loss, PTEN mutation and PTEN genomic deletion), it accounted for 97 (29.7%) CRC cases. Significant association of combined PTEN alterations was seen disease free survival (p = 0.0367). On multivariate analysis, this stands true (p = 0.0227) when adjusted for Age, Sex, Site, Grade and Stage. Thus, PTEN alteration is an independent marker of poor prognosis in CRC. In conclusion, PTEN gene alteration plays an important role in Middle Eastern colorectal cancer pathogenesis and it can help in identifying a subgroup of CRC with particular poor outcome.
Citation Format: Abdul K. Siraj, Shaham Beg, Rong Bu, Maha Al-Rasheed, Nasser Al-Sanea, Fouad Al-Dayel, Khawla Al-Kuraya. Prognostic significance of PTEN alteration in Middle Eastern colorectal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3676.
Abstract 3690: Metabolic regulation of mutant p53 stability by the mevalonate pathway
Authors: Iwakuma Tomoo , Ranjan Atul , Iyer Swathi V. , Padhye Subhash , Weir Scott , Roy Anuradha 
Published: July 2016

Abstract
Introduction: Mutations in the p53 gene are mostly missense mutations and result in accumulation of dysfunctional p53 protein in tumors with oncogenic gain-of-function activities. Increasing evidence indicates that stabilization of mutant p53 (mutp53) in tumors is crucial for its oncogenic activities including tumor progression and drug resistance, while downregulation of mutp53 reduces oncogenicity of cancer cells. These observations suggest that malignant properties of cancer cells are dependent on the presence of mutp53, thus providing a rationale to identify compounds that deplete mutant p53 with little impact on wild-type p53.
Experimental procedures: Toward this goal, we performed high throughput screens of chemical libraries (∼9,000 compounds) with Saos2 (p53 null) cells expressing a fusion protein of p53R175H and luciferase, using luciferase as a reporter.
Summary of data: This screening led us to identify “statins”, a class of cholesterol-lowering medications, as compounds that induced degradation of p53R175H. We found that other inhibitors of the mevalonate pathway, such as 6-fluoromevalonate and zoledronic acid, failed to induce p53R175H degradation, while statin-mediated inhibition of HMG-CoA reductase and subsequent reduction in mevalonte-5-phosphate triggered p53R175H degradation. These results suggest that statin's effect on p53R175H is specific and independent of protein prenylation/lipidation or cholesterol synthesis. Moreover, nuclear export of p53R175H was required for the statin-mediated degradation, which was mediated through an E3 ubiquitin ligase CHIP, but not MDM2. Interestingly, statins induced degradation of mainly conformational p53 mutants with minimal effects on the levels of wild-type p53 and DNA contact mutants.
Conclusions: This is the first study demonstrating that mutp53 stability is regulated through a specific process of the mevalonate pathway, thereby providing a novel regulatory mechanism of mutp53 degradation. Our findings suggest that p53 mutation status in tumors may have an impact on efficacy of statins in cancer therapy.
Citation Format: Tomoo Iwakuma, Atul Ranjan, Swathi V. Iyer, Subhash Padhye, Scott Weir, Anuradha Roy. Metabolic regulation of mutant p53 stability by the mevalonate pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3690.