bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 165: Predicting risk of colorectal cancer depending on tumor pathology features for first-degree relatives of persons with colorectal cancer.
Authors: Win Aung K. , Buchanan Daniel D. , Rosty Christophe , Giles Graham G. , Hopper John L. , Jenkins Mark A. 
Published: August 2014

Abstract
Background: We hypothesised that colorectal cancer (CRC) risk for relatives of persons diagnosed with CRC could be predicted by tumor molecular pathology features.
Methods: We studied a cohort of 5200 first-degree relatives (2550 women) of 792 probands with an incident invasive CRC who were recruited to the Australasian Colorectal Cancer Family Registry via population cancer registries. We excluded 32 families that were known to be Lynch syndrome. For the probands, a standardised tumor morphology review had been conducted; BRAF V600E mutation testing had been performed; and the DNA mismatch repair (MMR) status was determined by microsatellite instability and/or immunohistochemistry for MMR proteins. We calculated standardized incidence ratios (SIR) by comparing the number of CRCs observed in relatives with the number expected based on Australian incidence rates specific for age and sex. We also compared CRC risks for relatives of probands depending on the presence or absence of specific tumor pathology features.
Results: We observed 191 CRCs in relatives at mean age at diagnosis of 62.7 (SD 14.3) years and SIR was 2.14 (95% confidence interval, CI 1.85-2.48). Compared with the general population, an increased risk of CRC was observed for relatives of probands with MMR-proficient CRC (SIR 1.98, 95% CI 1.71-2.32), MMR-deficient CRC (SIR 3.60, 95% CI 2.20-6.23), rectal cancer (SIR 1.71, 95% CI 1.36-2.18), distal colon cancer (SIR 2.12, 95% CI 1.63-2.82) and proximal colon cancer (SIR 2.90, 95%CI 2.27-3.75). An increased risk of CRC was observed for relatives of probands with proximal colon cancer compared with rectal cancer (hazard ratio, HR 1.70, 95% CI 1.21-2.39, p=0.002) and for relatives of probands with MMR-deficient CRC compared with MMR-proficient CRC (HR 1.84, 95% CI 1.09-3.12, p=0.02). There was no evidence of increased risk of CRC for relatives of probands with other pathology features of CRC (tumor grade, margin, peritumoral lymphocytes, tumor infiltrating lymphocytes, Crohn-like reactions, venous invasion, BRAF mutation and contiguous adenoma) compared with those without these features.
Conclusions: First-degree relatives of persons with MMR-deficient CRC (not caused by Lynch syndrome) have a higher risk of CRC compared with first-degree relatives of persons with MMR-proficient CRC.
Citation Format: Aung K. Win, Daniel D. Buchanan, Christophe Rosty, Graham G. Giles, John L. Hopper, Mark A. Jenkins. Predicting risk of colorectal cancer depending on tumor pathology features for first-degree relatives of persons with colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 165. doi:10.1158/1538-7445.AM2013-165
Abstract 1659: Exhaustion of autophagy-mediated cell survival underlies the pre-clinical and clinical activity of chemotherapy combined with the AKT inhibitor MK-2206 in BRAF wild-type melanoma.
Authors: Rebecca Vito W. , Massaro Renato R. , Maria-Engler Silvya S. , Messina Jane L. , Gibney Geoffrey T. , Sondak Vernon K. , Kudchadkar Ragini , Smalley Keiran S. 
Published: August 2014

Abstract
Although targeted therapy strategies are currently lacking for patients whose melanomas are BRAF wild-type, some therapeutic efficacy was noted in a phase I clinical trial of the AKT inhibitor MK-2206 in combination with Carboplatin (C) and Paclitaxel (P). In the present study we addressed the mechanism underlying the responses to MK-2206 + CP in BRAF wild-type melanoma. As single agents, MK-2206, carboplatin and paclitaxel had only limited cytotoxic activity in both 2D and 3D cell culture and induced very little apoptosis. Prolonged treatment (&gt;9 days) with the AKT inhibitor in combination with C+P led to significant levels of cell death in 4 3D spheroid culture models of BRAF-wild type melanoma. In contrast, treatment with single agent MK-2206 or C+P alone induced little cell death. To investigate the mechanism of interaction between these three compounds we focused upon autophagy induction. It was noted that significant levels of autophagy, as demonstrated by increased LC3-II staining, p62 expression and increased acridine orange staining, were induced following up to 6 days of treatment with the combination. In this context autophagy was protective, with levels of cell death induced by the combination significantly enhanced following treatment with the autophagy inhibitor chloroquine. The protective autophagy induced by MK-2206 + CP was only transient, with diminished levels of autophagy being observed by 9 days. The observed reduction in autophagic flux was associated with marked increases in cell death. In summary it appears that chronic insult with MK-2206 and CP pushes autophagy to its limit, relinquishing its protective role and enhancing sensitivity of the cells to therapy-induced apoptosis. These studies form the basis for a phase II trial evaluating MK-2206 in combination with chemotherapy, as well as autophagy inhibitors, in patients whose melanomas are BRAF-wild type.
Citation Format: Vito W. Rebecca, Renato R. Massaro, Silvya S. Maria-Engler, Jane L. Messina, Geoffrey T. Gibney, Vernon K. Sondak, Ragini Kudchadkar, Keiran S. Smalley. Exhaustion of autophagy-mediated cell survival underlies the pre-clinical and clinical activity of chemotherapy combined with the AKT inhibitor MK-2206 in BRAF wild-type melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1659. doi:10.1158/1538-7445.AM2013-1659
Abstract 1671: A genome-wide RNA interference screen identifies autophagy mediators with therapeutic implications in chronic myeloid leukemia.
Authors: Sheng Zhi , Guo Sujuan , Murphy Susan , Varmark Hanne , Virbasius Amy , Green Michael 
Published: August 2014

Abstract
Autophagy plays a critical role in cancer formation and therapeutic resistance. However, little is known about how autophagy is regulated in cancer and how it mediates therapeutic resistance. Here we elect to use chronic myeloid leukemia (CML) as a cancer model to study autophagy in that it is driven by a single onco-protein BCR-ABL, whose activity can be selectively blocked by imatinib a front-line treatment for CML. Moreover, imatinib resistance frequently occurs in CML patients. Thus, unraveling autophagy regulation in CML and its role in overcoming imatinib resistance has substantial therapeutic benefits not only for CML but also for other cancers that can be treated by imatinib. In this report, we performed a genome-wide RNA interference screen in K562 human CML cells using monodansylcadaverine (MDC) that marks autolysosomes followed by fluorescence-activated cell sorting to label and isolate autophagic cells. We have identified 336 candidate genes, knockdown of which significantly increased MDC fluorescence. Our further validation utilized Cyto-IDTM Green dye that selectively stains autophagy vacuoles and quantitative RT-PCR that measures knockdown efficiency of shRNAs. We have uncovered a set of genes acting as autophagy mediators in K562 cells. To study their role in imatinib resistance, we measured the effect of imatinib in combination with the knocking down of autophagy mediators. Our results showed that the shRNA of VAMP7, a pivotal factor in vesicle transportation, substantially sensitized K562 cells to imatinib. Intriguingly, our further work revealed that depletion of VAMP7 blocked the activity of key autophagy suppressors AKT and mTOR, suggesting that VAMP7 and perhaps other autophagy mediators regulate imatinib sensitivity through signaling pathways that inhibit autophagy. In conclusion, a set of genes revealed by a genome-wide RNA interference screen mediates autophagy in CML cells and, more importantly, some of these genes render CML cells resistant to imatinib thereby becoming appealing drug targets.
Citation Format: Zhi Sheng, Sujuan Guo, Susan Murphy, Hanne Varmark, Amy Virbasius, Michael Green. A genome-wide RNA interference screen identifies autophagy mediators with therapeutic implications in chronic myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1671. doi:10.1158/1538-7445.AM2013-1671
Abstract 1689: The cytoprotective role of the UPR during c-Myc dependent transformation and tumor progression.
Authors: Tameire Feven , Hart Lori S. , Qiu Bo , Koumenis Constantinos 
Published: August 2014

Abstract
The Unfolded Protein Response (UPR) is a conserved cellular adaptation program that is elicited due to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). The PERK-pEIF2A-ATF4 arm of UPR is triggered by ER stress and primarily serves in the global attenuation of protein translation, and promotes cell survival via selective upregulation of stress induced genes. We recently showed that oncogenic Myc activation initiates UPR due to the accumulation of unfolded proteins in the ER. Using multiple genetic models, we demonstrated that ablation of UPR signaling leads to decreased cell survival in vitro and reduced tumor growth in vivo. The proto-oncogene c-Myc has been shown to activate both pro-tumorigenic and anti-tumorigenic pathways. In c-Myc driven cancers, the pro-apoptotic state is bypassed via a yet undefined pro-survival mechanism. We are interested in elucidating the role of UPR in promoting activation of pro-survival pathways during c-Myc induced tumorigenesis. We previously demonstrated that autophagy, one such pro-survival pathway, is induced and sustained during c-Myc activation in a PERK dependent manner. Moreover, genetic and pharmacological inhibition of autophagy in c-Myc induced cells decreases cell survival. Using a Qiagen Autophagy PCR Array system we screened for autophagy genes that were differentially expressed in a c-Myc dependent manner. Preliminary results indicate that several genes that regulate different steps of autophagy such as ATG9b, ATG5 and ATG16L1 are upregulated upon c-Myc induction, which was validated by qPCR. In PERK-/- MEFs, ATG5 and ATG16L1 were not upregulated and LC3B processing, a marker of autophagy induction, was significantly attenuated upon c-Myc activation. This indicates that PERK is required for the induction of autophagy genes upon c-Myc activation. To further investigate the role of the PERK-pEIF2A-ATF4 arm of UPR in cell survival during c-Myc induction, we looked at the transcription factor ATF4 which is a major downstream mediator of PERK. Using ATF4-/- MEFs, we observed significant cell death and decreased clonogenic survival upon c-Myc activation compared to ATF4+/+ MEFs. We are currently investigating how ATF4 is mediating cell survival during c-Myc induction. Our findings establish that UPR plays as an activator of pro-survival pathways such as autophagy and therefore UPR can be targeted as a therapy modality in c-Myc driven cancers.
This research is supported by NIH grant 5R01CA139362-04
Citation Format: Feven Tameire, Lori S. Hart, Bo Qiu, Constantinos Koumenis. The cytoprotective role of the UPR during c-Myc dependent transformation and tumor progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1689. doi:10.1158/1538-7445.AM2013-1689
Abstract 169: Temporal trends, predictors, and outcome of chemotherapy in elderly women with advanced stage endometrial cancer.
Authors: Garg Gunjal , Siddiq Zainab , Zhou Gongfu , Powell Matthew A. , Herzog Thomas , Mutch David G. , Wright Jason D. 
Published: August 2014

Abstract
Objective. Randomized clinical trials have suggested that adjuvant chemotherapy improves survival for women with advanced stage (III-IV) endometrial cancer. Despite the fact the endometrial cancer is common in the elderly, a minority of women &gt;65 years of age were represented in these trials. We performed a population-based analysis to determine the use and impact on survival of adjuvant chemotherapy in elderly women with advanced stage endometrial cancer. Methods. The Surveillance Epidemiology, and End Results (SEER)-Medicare database was utilized to identify women diagnosed with stage III-IV endometrial cancer diagnosed from 1998-2007. Only those patients who had undergone a hysterectomy were included. The use of chemotherapy within 6 months of diagnosis and its impact on survival was examined using multivariable logistic regression and Cox proportional hazards models. Results. A total of 1819 women including 1193 with stage III and 626 with stage IV tumors were identified. Adjuvant chemotherapy was given to 46% of women. Use of chemotherapy increased with time from 42% in 1998 to 63% in 2007 (P&lt;0.0001). By 2007, 54% of women with endometrioid tumors, 82% with serous tumors and 80% with carcinosarcomas received adjuvant chemotherapy. Use of whole pelvic radiotherapy decreased slightly from 40% in 1998 to 37% in 2007 while use of brachytherapy was stable at 22%. In a multivariable regression model, later year of diagnosis, non-endometrioid histology, residence in the eastern U.S., and stage IV disease were associated with receipt of chemotherapy while older women were less likely to receive chemotherapy (P&lt;0.05). In a multivariable model including clinical and demographic characteristics women who received chemotherapy, mortality was reduced by 17% (HR=0.83; 95% CI, 0.72-0.96) compared to those who did not receive chemotherapy. Conclusion. Although the use of chemotherapy for elderly women with advanced stage endometrial cancer is increasing, fewer than half of patients &gt;65 years of age receive chemotherapy. In addition to year of diagnosis, stage and histology are the strongest predictors of receipt of chemotherapy. Among elderly women with endometrial cancer, chemotherapy is associated with a reduction in mortality.
Citation Format: Gunjal Garg, Zainab Siddiq, Gongfu Zhou, Matthew A. Powell, Thomas Herzog, David G. Mutch, Jason D. Wright. Temporal trends, predictors, and outcome of chemotherapy in elderly women with advanced stage endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 169. doi:10.1158/1538-7445.AM2013-169
Abstract 1706: Estrogen induces stearoyl-CoA desaturase expression in human MCF-7 breast carcinoma cells.
Authors: Belkaid Anissa , Ouellette Rodney J. , Surette Marc E. 
Published: August 2014

Abstract
Approximately 95% of breast cancers are estrogen-dependant. Estrogen plays a crucial role in many cellular processes in estrogen-sensitive breast cancer such as carcinogenesis, production of growth factors, angiogenesis and growth stimulation. To sustain cell growth, many cancer cells exhibit an altered metabolism that is characterized by increased glycolysis and lipogenesis.
We observed for the first time an up regulation of stearoyl-CoA desaturase-1 (SCD1) in response to estrogen in the hormone-dependent MCF7 human breast carcinoma cell line. SCD1 is a key enzyme in the production of monounsaturated fatty acids that are essential for membrane biogenesis. Using estrogen-starved MCF7 cells, treatment with 2 nM of estrogen induced cell proliferation, increased SCD-1 gene expression measured by qPCR (2.6±0.1 fold increase, p&lt;0.05) and SCD-1 protein expression (7.2 fold increase) determined by immunoblot analysis, compared to control cells. Estrogen-induced SCD1 expression was accompanied by important changes in cellular fatty acid compositions with significant increases in the monounsaturated fatty acid content in membrane phospholipids and in SCD-1 product/substrate ratios with a 4.3±0.03 fold increase in the 16:1n-7/16:0 ratio and a 1.9±0.01 fold increase in the 18:1n-9/18:0 ratio compared to untreated cells (both p&lt;0.05). Treatment of estrogen-stimulated cells with a selective SCD1 inhibitor inhibited estrogen-induced cell proliferation and prevented the estrogen-induced changes in membrane lipid composition.
Overall, these results show for the first time that estrogen induces SCD-1 expression in breast carcinoma cells and suggests a crucial role for SCD1 in estrogen dependent cancer cell proliferation. SCD1 may therefore represent a potential therapeutic target for estrogen-dependent cancer.
(This work was supported by the Canadian Institutes of Health Research and the Canada Research Chairs Program).
Citation Format: Anissa Belkaid, Rodney J. Ouellette, Marc E. Surette. Estrogen induces stearoyl-CoA desaturase expression in human MCF-7 breast carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1706. doi:10.1158/1538-7445.AM2013-1706
Abstract 1711: Bax delta2: A gain-of-function Bax mutant for selective chemotherapy.
Authors: Zhang Honghong , Haferkamp Bonnie , Xiang Jialing 
Published: August 2014

Abstract
The pro-death Bcl-2 family protein and tumor suppressor Bax is frequently mutated in tumors with microsatellite instability (MSI). Recently, we identified a novel Bax homolog, BaxΔ2, which is generated by a unique combination of mutation and alternative splicing in MSI tumors. BaxΔ2 is a potent cell death inducer. Unlike the parental Baxα, BaxΔ2 does not directly target to mitochondria, rather activates the caspase 8-mediated mitochondrial pathway. BaxΔ2-positive cancer cells are less invasive and more sensitive to a sub-set of chemotherapeutic agents. Thus, our data provide evidence that gain-of-function BaxΔ2 mutant resulted from mutation and aberrant splicing may be detrimental to tumor and thereby could be beneficial for treatment of cancer.
Citation Format: Honghong Zhang, Bonnie Haferkamp, Jialing Xiang. Bax delta2: A gain-of-function Bax mutant for selective chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1711. doi:10.1158/1538-7445.AM2013-1711
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1712: Transmembrane domain required for MCL1 function.
Authors: Wei Guo , Wu Xiaohua , Golub Todd R. 
Published: August 2014

Abstract
MCL1 is an anti-apoptotic family member of the BCL2 family of proteins that exerts its anti-apoptotic function at least in large measure by sequestering BH3 domain containing pro-apoptotic proteins within the outer mitochondrial membrane. Several lines of evidence point to MCL1 as an important oncology target. MCL1 is among the top 10 most frequently amplified genes in human cancer. Consistent with its frequent amplification, MCL1 is highly expressed in many tumor types, and high expression levels of MCL1 contribute to tumor development and resistance to chemotherapy. MCL1 is required for survival of a sub-group of tumor cells that are characterized by low levels of expression of another anti-apoptotic BCL2 family protein, BCL-xL. Despite the important role of MCL1 in cancer, no inhibitors of MCL1 have reached the clinic. We employed mutagenesis to further explore the anti-apoptotic mechanism of MCL1. Deletion of the N-terminus portion of MCL1, including the PEST domain, did not significantly affect its anti-apoptotic function. However, deletion of the transmembrane (TM) domain of MCL1 abolished the anti-apoptotic function of MCL1. Furthermore, an MCL1 point mutation within the TM domain impaired its anti-apoptotic function, however, it could still bind to the pro-apoptotic proteins BIM and BAK. Therefore, the TM domain may represent an alternative site for pharmaceutical targeting of MCL1.
Citation Format: Guo Wei, Xiaohua Wu, Todd R. Golub. Transmembrane domain required for MCL1 function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1712. doi:10.1158/1538-7445.AM2013-1712
Abstract 1727: Evidence that E2F1-mediated upregulation of Bim, a proapoptotic BH3-only protein, functions as a prosurvival molecule in cancer.
Authors: Yadav Neelu , Gogada Raghu , Liu Junwei , Tang Shaohua , Zhang Dianmu , Aldaz C Marcelo , Tang Dean , Chandra Dhyan 
Published: August 2014

Abstract
Proapoptotic BH3-only protein Bim plays an important role in Bax/Bak-mediated cytochrome c release and apoptosis. Here we provide evidence for a novel prosurvival function of Bim in cancer cells. Bim was constitutively overexpressed in multiple prostate and breast cancer cells as well as in primary tumor cells. Quantitative real time PCR analysis showed that Bim was transcriptionally upregulated. We have identified eight endogenous E2F1-binding sites on the Bim promoter using in silico analysis. Luciferase assay demonstrated that Bim expression was E2F1-dependent as mutation of E2F1-binding sites on the Bim promoter inhibited luciferase activities. In support, E2F1 silencing led to the loss of Bim expression in cancer cells. Bim primarily localized to mitochondrial and cytoskeleton-associated fractions. Bim-silencing or microinjection of anti-Bim antibodies into the cell cytoplasm resulted in cell rounding, detachment, and subsequent apoptosis. We observed upregulation of prosurvival proteins Bcl-xL and Mcl-1, which sequester Bim in cancer cells. In addition, phosphorylated form of Bim was also elevated in cancer cells. These findings suggest that the constitutively overexpressed Bim may function as a prosurvival molecule in epithelial cancer cells, and phosphorylation and association with Bcl-xL/Mcl-1 block its proapoptotic functions.
The prosurvival functions associated with multiple proapoptotic proteins raise the possibility that anticancer agents that only harness proapoptotic function of Bim or other BH3-only proteins may not be an efficient approach for the permeabilization of mitochondria. Our findings demonstrate that in order to induce efficient apoptosis, inhibition of prosurvival function of Bim may provide a new approach for efficient cancer therapy.
Citation Format: Neelu Yadav, Raghu Gogada, Junwei Liu, Shaohua Tang, Dianmu Zhang, C Marcelo Aldaz, Dean Tang, Dhyan Chandra. Evidence that E2F1-mediated upregulation of Bim, a proapoptotic BH3-only protein, functions as a prosurvival molecule in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1727. doi:10.1158/1538-7445.AM2013-1727