bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4095: The potential of PD-1/PD-L1 signaling inhibition outlined from clinical analysis of colorectal cancer
Authors: Grimmig Tanja , Mönch Romana , Rosenwald Andreas , Germer Christoph T. , Gasser Martin , Waaga-Gasser Ana Maria 
Published: May 2015

Abstract
Background: Recent data demonstrate the programmed death-1/programmed death ligand (PD-1/PD-L) pathway in T cell activation to play an important role in tumor evasion from host immunity. The aim of this study was to analyze the clinical significance of PD-1/PD-L1/L2 signaling in colorectal cancer (CRC).
Methods: Gene and protein expression levels of PD-1, PD-L1, PD-L2, CD4, CD8 and Foxp3 were analyzed in tumors from patients with CRC (n=116 with completed 5-year follow up) by immunohistochemistry and RT-qPCR. Obtained data were analyzed for their prognostic significance with respect to outcome analysis.
Results: 90.5% of the investigated tumors showed T cell infiltration, with 58% of the patients demonstrating PD-1-positive T cells in their tumors. Increased PD-L1-expression levels were found in patients who developed PD-1-positive T cell infiltration compared to PD-1-T cell negative individuals. Statistical analysis showed ligand expression (PD-L1/PD-L2) in the cancer tissues combined with dense PD-1-positive T cell infiltration to be associated with poor prognosis in affected patients (p&lt;0.001). Multivariate analysis demonstrated PD-L expression in the tumors to be an independent prognostic factor in CRC.
Conclusion: The presented results from clinical cancers suggest for the first time for CRC that negative signaling of infiltrating PD-1-positive T cells through PD-L1 expression within the tumor is promoting tumor progression through downregulation of anti-tumor immunity. In conclusion, this study demonstrates the importance of strategies inhibiting negative PD-1/PD-L1 signaling in CRC.
Citation Format: Tanja Grimmig, Romana Mönch, Andreas Rosenwald, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser. The potential of PD-1/PD-L1 signaling inhibition outlined from clinical analysis of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4095. doi:10.1158/1538-7445.AM2014-4095
Abstract 410: Epigallocatechin gallate inhibits colon cancer cell proliferation by modulating epigenetic enzymes (DNMTs, HDACs, and HATs)
Authors: Cabang April B. , Fang Yuan , Morris Jay , Wargovich Michael J. 
Published: May 2015

Abstract
Epigallocatechin gallate (EGCG), a major constituent of green tea, has been shown to exhibit antioxidant and antitumorigenic properties using in vitro and in vivo models of colon cancer and in small cohort studies of colorectal cancer patients. The development of colon cancer is influenced by both genetic and epigenetic factors, with increased risk associated with age, lifestyle, and environmental exposures. Thus, parsing the interactions of genetic components and epigenetic modulators of gene expression in colon cancer development and progression is essential. The mechanism by which EGCG exerts antitumorigenic activity against colon cancer has not been completely elucidated. This study investigates potential mechanism(s) by which EGCG inhibits proliferation of HCT-116 and HT-29 colon cancer cell lines, via epigenetic pathways.
Briefly, HCT-116 and HT-29 cells were treated with EGCG (5-150 µM) and control drugs: 5-FU (50-200 µg/mL), 5-AZA (5 µM), SAHA (1-10 µM), and anacardic acid (10 µM) for 48-72 h. Cell proliferation (MTT), cell cycle and apoptosis (PI-FC and TUNEL), enzyme activity, gene and protein expression were measured. EGCG inhibited proliferation of HCT-116 and HT-29 by promoting S-phase cell cycle arrest and apoptosis. Expression and global enzyme activity of DNMTs (1, 3a, 3b), HDACs (1-4), and HATs (P300, PCAF, P400) were differentially expressed in both cell lines. A consistent upregulation of DNMT3b and downregulation of HDAC3 in both cell lines were observed. Global and gene-specific regulation of DNA methylation and histone acetylation by EGCG is under current study in our lab.
The antiproliferative effects of EGCG can potentially be attributed to restoring normal global and gene-specific methylation/acetylation pattern in colon cancer cells by regulating DNMTs, HDACs, and HATs. This study provides evidence for the utilization of EGCG as a potential chemopreventive agent against colon cancer. Furthermore, identifying mechanisms by which EGCG overrides tumor-driven genetic deregulation to inhibit carcinogenesis expands our knowledge on pathways contributing to colon cancer and plausible targets for epigenetic therapy/prevention.
This project is supported by NIH: RO1CA96694 and P30CA054174.
Citation Format: April B. Cabang, Yuan Fang, Jay Morris, Michael J. Wargovich. Epigallocatechin gallate inhibits colon cancer cell proliferation by modulating epigenetic enzymes (DNMTs, HDACs, and HATs). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2014-410
Abstract 4104: Obesity and colon cancer: Does time of exposure matter
Authors: Xu Jinyu , Thomas-Ahner Jennifer , DeMarsh Samantha , Clinton Steven K. , Olivo-Marston Susan E. 
Published: May 2015

Abstract
Purposes: Obesity is associated with an increased risk of colon cancer in many epidemiology studies, while calorie restriction (CR) has shown protective effects on colon tumorigenesis in animal studies. This preclinical study was designed to investigate the long-term impacts of early exposure to high fat diet or CR diet on colon tumorigenesis.
Methods: 50 three-week-old female C57/B6J mice were assigned into five groups: 1) control; 2) HF-control; 3) control-HF; 4) HF and 5) CR-control. Mice were initially placed on a control diet (10% kcal from fat), HF diet (45% kcal from fat), or 30% CR diet and fed ad libitum for nine weeks from the time of weaning and followed by a seven-week control diet. Azoxymethane was injected once a week for five weeks at a dose of 10 mg/kg beginning at 13 weeks of age. At 18 week-old, mice were placed on either a control diet or a HF diet. Mice were euthanized at 46 week-old and colons were collected to assess tumorigenesis.
Results: After nine weeks of diet intervention, the percentage of body fat was higher in the mice on the HF diet (31.9%) and lower in those on the CR diet (18.4%), compared to mice on the control diet (20.0%, p=0.08). Mice on a CR diet in early life had lower body weights at the endpoint, compared to those on the control diet (p=0.03). Analysis of colon histopathology is ongoing as well as evaluation of apoptosis and proliferation.
Conclusions: Early life exposure to calorie restriction has long-term impacts on body weight. Early life exposure to high fat diet may increase the risk of colon tumorigenesis. This model is currently being used to investigate the effects of early alterations in energy balance on colon cancer development and underlying molecular mechanisms.
Citation Format: Jinyu Xu, Jennifer Thomas-Ahner, Samantha DeMarsh, Steven K. Clinton, Susan E. Olivo-Marston. Obesity and colon cancer: Does time of exposure matter. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4104. doi:10.1158/1538-7445.AM2014-4104
Abstract 4110: Gartanin from the mangosteen fruit modulates androgen receptor and ER stress proteins in prostate cancer cells leading to apoptosis
Authors: Li Gongbo , Petiwala Sakina , Johnson Jeremy 
Published: May 2015

Abstract
Background: The Purple mangosteen (Garcinia mangostana) has a long history of usage as a medicinal plant in Southeast Asia. Many studies have shown that the chemical constituents of Garcinia mangostana, mainly xanthone derivatives, have a variety of health-promoting properties including antioxidant, anti-inflammatory, antitumoral, antiallergic, antibacterial and antiviral activities. In this study, we evaluated the anticancer effects of gartanin, one of the major xanthones from the mangosteen fruit, in human prostate cancer cells. Next, we investigated the possible mechanisms involved in its anticancer effects.
Methods: Two human prostate cancer cell lines, 22Rv1 and LNCaP, were treated with gartanin. Cell apoptosis, viability, proliferation, androgen receptor, prostate specific antigen (PSA), endoplasmic reticulum (ER) stress were evaluated by TdT-mediated dUTP Nick-End Labeling (TUNEL), 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), BrdU, Western blot, RT-PCR, androgen receptor competitor assay, siRNA transfection, ELISA and fluorescent microscopy.
Results: Gartanin decreased viability and inhibited proliferation of prostate cancer cells in a dose-dependent manner. Gartanin induced apoptosis as evidenced by TUNEL staining, increased caspase-3 and Bax/Bcl-2 ratio. As a valuable target of prostate cancer, androgen receptor (AR) expression was significantly inhibited by gartanin. Further, gartanin was shown to be an effective AR antagonist, similar to flutamide. Gartanin decreased PSA, a prostate cancer risk factor regulated by the AR signaling pathway. Gartanin increased ER stress proteins and chaperones, such as phosphorylated PERK, CHOP, IRE1 and Bip. Gartanin also induced spliced XBP-1 mRNA, which is an ER stress marker. CHOP knockdown partly inhibited gartanin-induced apoptosis in LNCaP cells, as evidenced by cleaved caspase-3 decrease. Interestingly, CHOP knockdown showed evidence of restoring AR expression in gartanin treated cells.
Conclusions: Our study demonstrated that gartanin inhibited proliferation and induced apoptosis on prostate cancer cells in vitro. It achieves its anticancer effects partly through inhibiting AR and promoting ER stress. The ability of gartanin to inhibit prostate cancer cells suggests further research is needed to evaluate gartanin as a novel agent for the management of prostate cancer.
Citation Format: Gongbo Li, Sakina Petiwala, Jeremy Johnson. Gartanin from the mangosteen fruit modulates androgen receptor and ER stress proteins in prostate cancer cells leading to apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4110. doi:10.1158/1538-7445.AM2014-4110
Abstract 4112: Inositol hexaphosphate (IP6) and inositol against large granular lymphocytic leukemia (LGLL)
Authors: Vucenik Ivana , Beumer Jan H. , Eiseman Julie L. 
Published: May 2015

Abstract
Introduction: The anticancer activity of dietary IP6 and its parent compound inositol, either alone or in combination, has been shown in many different experimental models. Using rat leukemia RNK-16 cells, we investigated the in vitro efficacy of IP6 and inositol in large granular lymphocytic leukemia (LGLL) that develops spontaneously in male Fisher 344 rats and is very similar to human disease. RAS and ERK are constitutively active in LGLL in both humans and rats, and the PI3K/Akt pathway plays a major role in proliferation and survival of these leukemic cells. Therefore, we also investigated the effect of IP6 and inositol on these pathways.
Methods: We have previously shown that after in vitro or in vivo administration, exogenous IP6 rapidly dephosphorylates to inositol. In this study, we first implemented the assay for the measurement of unlabeled intracellular myo-inositol by LC-MS/MS after in vitro exposure to IP6 and inositol. Cytotoxicity of IP6 and inositol against Fisher 344 RNK-16 cells alone and in combination with 4-OH-cyclophosphamide was measured by MTT cytotoxicity assay. Western blot analysis was used for protein expression.
Results: Uptake of inositol increased more than 5-fold following exposure to 2 mM inositol, and no differences were observed between unsynchronized and synchronized cells. Inositol was relatively non-toxic (30% cytotoxicity at 100 mM), while IP6 had an IC50 of approximately 2 mM. 4-OH-cyclophosphamide had an IC50 of 180 µg/mL, and co-administration of either IP6 or inositol decreased its IC50 by 3-fold. While the expression and phosphorylation status of ERK1/2 were unaffected, p-Akt was completely inhibited between 5 and 60 min after 2 mM IP6 and between 15 and 60 min after inositol, by 2-fold. Furthermore, IP6 treatment caused a significant increase in the expression of the Cdk inhibitor p27Kip1 in RNK-16 cells (1.9-fold) 5 and 15 min.
Conclusion: Our data data suggest the use of inositol and IP6 as chemopreventive agents in control of LGLL in humans or as adjuvant therapies. Further studies are justified and warranted.
Support: P30-CA-47904
Citation Format: Ivana Vucenik, Jan H. Beumer, Julie L. Eiseman. Inositol hexaphosphate (IP6) and inositol against large granular lymphocytic leukemia (LGLL). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4112. doi:10.1158/1538-7445.AM2014-4112
Abstract 4113: Restricted ketogenic diet reduces growth and distant organ metastasis in the murine VM-M3 metastatic tumor model
Authors: Akgoc Zeynep , Shelton Laura M. , Ryan David , Zhu Xijun , Seyfried Thomas N. 
Published: May 2015

Abstract
Metastasis involves the spread of tumor cells throughout the body and is one of the leading causes of cancer death. Most current drug therapies for metastatic cancer are toxic and only marginally effective in providing long-term management. Respiratory insufficiency with compensatory aerobic fermentation (Warburg effect) is the hallmark biochemical phenotype of nearly all neoplastic cells within tumors. Most tumor cells are incapable of utilizing ketone bodies for energy due to their respiratory insufficiency. Calorie restriction, which lowers blood glucose and elevates ketone bodies, is known to reduce tumor growth. We previously showed that ketogenic diets with high fat/protein + carbohydrate ratios of 3-4:1 are better able to lower blood glucose and elevate ketone levels than is calorie restriction alone. We evaluated the influence of a new ketogenic diet formula from Solace Nutrition (KetoGen) on the growth and metastatic spread of the VM-M3 tumor. VM-M3 is a highly metastatic macrophage-like tumor that arose spontaneously in the brain of the syngeneic inbred VM/Dk mouse strain. The VM-M3 cells spread rapidly (within days) to lungs, liver, spleen, kidney, and brain with 100% fidelity following subcutaneous implantation. Tumor bearing VM mice were fed either a standard lab chow diet in unrestricted amounts (SD-UR), a standard lab chow restricted to obtain an 18% reduction in body weight (SD-R), or the KetoGen diet restricted (KG-R) to match the body weights of the SD-R control group. Tumor size was significantly smaller and organ metastasis was significantly less in the KG-R group than in the SD-UR or SD-R groups. Although blood glucose was reduced similarly in both the SD-R and KG-R groups, blood ketones were 3-fold higher in the KG-R group than in the SD-R group. These results show that VM-M3 tumor growth and systemic metastasis was managed better with the restricted KetoGen KD than with calorie restriction of a high carbohydrate standard diet. As all human and mouse tumors cells suffer from respiratory insufficiency, our findings suggest that the KetoGen diet should be an effective non-toxic therapy against systemic metastatic cancer.
Citation Format: Zeynep Akgoc, Laura M. Shelton, David Ryan, Xijun Zhu, Thomas N. Seyfried. Restricted ketogenic diet reduces growth and distant organ metastasis in the murine VM-M3 metastatic tumor model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4113. doi:10.1158/1538-7445.AM2014-4113
Abstract 4134: Prevalence of cervical cancer and associated mortality in Grenada: A ten-year analysis (2000 - 2010)
Authors: Bahadoor - Yetman Avi' A T , Riley Laura , Gibbons Ashley , Fields Paul J. , Mapp-Alexander Veronica , Hage Robert , Baldwin Amy 
Published: May 2015

Abstract
According to recent WHO estimates, cervical cancer is ranked as the second most frequently diagnosed cancer among women ages 15 - 44 years in the Caribbean and disproportionately affects developing countries. Globally, 80 to 85% of deaths occur in low- and middle-income countries. However, little is known about cervical cancer burden in much of the Eastern Caribbean and particularly for Grenada, West Indies. Grenada is a Tri-Island state comprised of Grenada, Carriacou and Petite Martinique, with a population of 35,000 women ages 15 years and older who are at risk of developing cervical cancer.
To investigate cervical cancer prevalence and its associated mortality, a study was conducted on de-identified records obtained from the Grenada General Hospital Histopathology Laboratory of women who visited hospital and clinic facilities during 2000 - 2010. Ten years of hand-written records (12,016 entries) were compiled into an electronic master sheet, and cervical cancer prevalence was assessed. Of the 12,016 entries, 9,003 were female (7,160 individuals) between ages 8 - 94 years. Sampling without replacement resulted in inclusion of 2,524 entries for analysis. Identified cancer cases were matched to corresponding patient data from death registries collected at the Ministry of Health and used to identify and calculate associated mortality rates.
The highest rates of cervical cancer occurred in the 35 - 44 year age group followed by the 45 - 64 age group. Prevalence rate of cervical cancer was determined as 52.4 per 100,000 women (ages 15 and above). A total of 65 deaths attributable to cervical cancer occurred during 2000 - 2010, with women over 65 years old experiencing a majority of these deaths. The mortality rate was determined to be 16.7 per 100,000, almost twice the rates estimated by WHO for the region or reported for the previous decade (9.7 per 100,000).
This study reports data that demonstrate the need for a comprehensive cervical cancer-screening program in Grenada. It should be used in the generation of public health policy and should aid future studies in determining how to appropriately execute public health policy for screening, prevention, and control of cervical cancer in Grenada.
Citation Format: Avi' A T Bahadoor - Yetman, Laura Riley, Ashley Gibbons, Paul J. Fields, Veronica Mapp-Alexander, Robert Hage, Amy Baldwin. Prevalence of cervical cancer and associated mortality in Grenada: A ten-year analysis (2000 - 2010). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4134. doi:10.1158/1538-7445.AM2014-4134
Abstract 4167: Harvesting knowledge from unexploited genomic data: Estimating relative telomere length from targeted-resequencing
Authors: Abaan Ogan D. , Waterfall Joshua , Davis Sean , Edelman Daniel , Gomez Allison , Savage Sharon , Pommier Yves , Meltzer Paul 
Published: May 2015

Abstract
Telomeres play an essential role in maintaining the fidelity of chromosome ends during replication, but without an active telomere maintenance mechanism, their length decreases with each successive cell division. Aberrant telomere biology is a critical component of tumorigenesis. Replicative immortality is a hallmark of cancer and tumor cells circumvent cellular crisis associated with telomere shortening via two main mechanisms, activation of telomerase or the alternative lengthening of telomeres process (ALT). Targeted-resequencing, such as whole exome sequencing (WES), is becoming a tool for molecular diagnostics and gene discovery. While WES contains mostly data from the targeted region, a significant amount of off-target reads are not utilized for analysis. These off-target sequences likely contain additional information from the patients' genome that may be analyzed as well. Telomeric repeats, in general, are not targeted in WES, however due to their high abundance, they are present in the off-target fraction. We developed an algorithm that can estimate relative telomere length (RTL) using off-target reads from targeted-resequencing data. For proof-of-principle, we used the WES data for 14 osteosarcoma cell lines. RTL values calculated demonstrate correlations between lower RTL values in samples with hTERT expression and higher values in ALT positive cell lines, consistent with the known association of ALT and longer telomeres. In order to validate the algorithm's robustness, we evaluated published WES data for the NCI-60 panel of cell lines. The results suggest that most cells display the classic telomere shortening, while a few cell lines, such as LOX-IMVI, have long telomeres. These results will be compared to alternative techniques for measuring telomere length. In summary, we believe that this approach will enable utilization of otherwise overlooked off-target data generated by targeted-resequencing based molecular diagnostic tests.
Citation Format: Ogan D. Abaan, Joshua Waterfall, Sean Davis, Daniel Edelman, Allison Gomez, Sharon Savage, Yves Pommier, Paul Meltzer. Harvesting knowledge from unexploited genomic data: Estimating relative telomere length from targeted-resequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4167. doi:10.1158/1538-7445.AM2014-4167
Abstract 4171: Integrating pan-molecular data sets by bimodality to nominate synthetic lethal gene pairs and biomarkers of drug response
Authors: Dry Jonathan R. , Wappett Mark , Yang Ron 
Published: May 2015

Abstract
Large cancer genome profiling efforts are releasing pan-molecular information for large numbers of patients into the public domain. A large proportion of novel oncogenic events discovered through these efforts are deleterious to gene/protein function. Recent clinical data from PARP inhibitors has highlighted the promise of tumor cell selective killing where loss of function of a tumor suppressor gene, in this case BRCA, results in a targetable dependency. We sought to take advantage of the pan-molecular information in these data sets to identify molecular patterns indicative of the mutually exclusive loss of function expected between synthetic lethal gene pairs. We have developed a toolkit comprising BiSEp (BImodality Subsetting ExPression) and SLinG (Synthetic Lethality in Genomics) with which we are able to identify instances of genetic and/or gene expression loss that are mutually exclusive between functionally redundant genes. We demonstrate the power of this toolkit to identify known synthetic lethal gene pairings from cancer literature and yeast based screens. We have also revealed a number of novel candidate synthetic lethal gene pairings, and highlight the value of paired biomarkers provided through this approach to select disease models for hypothesis testing. Through a further adaptation, BEEP (Bimodal Expression Exclusive with Pharmacology), we have gone on to identify biomarkers of response to a number of clinical drug candidates. Here we present these algorithms and supporting data for a number of candidate target and biomarker hypotheses discovered, and discuss rationale for their application in cancer drug research.
Citation Format: Jonathan R. Dry, Mark Wappett, Ron Yang. Integrating pan-molecular data sets by bimodality to nominate synthetic lethal gene pairs and biomarkers of drug response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4171. doi:10.1158/1538-7445.AM2014-4171