bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4585: Breaking metastatic dormancy during surgical resection of a primary tumor and implications for treatment strategies.
Authors: Granitto Selena R. , Giles Amber , Lavotshkin Simon , Rutigliano Daniel , Lyden David , Kaplan Rosandra N. 
Published: August 2014

Abstract
At the time of a cancer diagnosis, most patients have localized tumors. Despite elaborate staging schemas for each cancer type in an attempt to stratify patients, the vast majority of patients that die will do so from metastatic disease. We hypothesized that surgery augments the already ongoing activation and mobilization of bone marrow-derived progenitor cells that are critical to colonizing tumor cells at distant sites. These bone marrow-derived cells, by inducing a local inflamed tumor microenvironment, provide survival signals to these seeding tumor cells. Our data show increased metastatic burden in the lung after surgical resection of the primary tumor using two murine cancer models, B16 melanoma and E0771 breast carcinoma. In these models, we also show a surge in hematopoietic and endothelial progenitor cells in the hours and days immediately following resection of the primary tumor, which is not similarly observed in control mice, where surgery was performed in the absence of the primary tumor. We also confirmed that a factor specific to the plasma of the tumor-bearing mice is responsible for this mobilization by using in vitro migration assays, whereby plasma from tumor-bearing mice and surgically resected mice induced an increased migration of lineage negative bone marrow cells compared to the plasma of wild type mice. We confirmed increased levels of MCP-1 and MCSF, both known to mobilize progenitor cells, in the plasma of mice with surgical resection. Additionally, targeting these bone marrow derived hematopoietic and endothelial progenitor cells with Pazopanib prevents the surge in bone marrow-derived cells into the circulation, abolishes the enhanced metastatic spread in mice undergoing surgical resection of the primary tumor, and provides a significant prolongation of survival. Finally, we correlated these data to a cohort of breast cancer patients where circulating levels of progenitor cells were analyzed at time points before and after surgery, which confirmed the mobilization of progenitor cells with surgery. Together, these results provide evidence for the increased risk of metastatic spread after surgical resection of the primary tumor and suggest that blocking progenitor cell mobilization by adjuvant treatment during or immediately following surgery, the incidence of metastatic recurrence may be reduced.
Citation Format: Selena R. Granitto, Amber Giles, Simon Lavotshkin, Daniel Rutigliano, David Lyden, Rosandra N. Kaplan. Breaking metastatic dormancy during surgical resection of a primary tumor and implications for treatment strategies. [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 4585. doi:10.1158/1538-7445.AM2013-4585
Abstract 4598: Identification of driver genes in hepatocellular carcinoma by exome sequencing.
Authors: Cleary Sean P. , Jeck William R. , Zhao Xiaobei , Selitsky Sara R. , Savich Gleb L. , Tan Ting-Xu , Wu Michael C. , Getz Gad , Lawrence Michael S. , Parker Joel S. , Li Jinyu , Powers Scott , Kim Hyeja , Fischer Sandra E. , Guindi Maha , Ghanekar Anand , Chiang Derek Y. 
Published: August 2014

Abstract
Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to an average coverage of 59x. The overall mutation rate was roughly 2.5 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (20%), CTNNB1 (15%), IGSF3 (9%) and KEAP1 (8%). Significantly affected gene families include the nucleotide-binding domain and leucine rich repeat containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family of methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Clinical data demonstrated significantly decreased disease-free survival in tumors with p53 mutations (p=0.006) and a trend was observed towards higher rates of recurrence and shorter disease free survival among MLL mutation carriers. The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma. The elucidation of genetic changes in HCC will enhance our understanding of hepatocarcinogenesis and influence disease prognosis and therapy.
Citation Format: Sean P. Cleary, William R. Jeck, Xiaobei Zhao, Sara R. Selitsky, Gleb L. Savich, Ting-Xu Tan, Michael C. Wu, Gad Getz, Michael S. Lawrence, Joel S. Parker, Jinyu Li, Scott Powers, Hyeja Kim, Sandra E. Fischer, Maha Guindi, Anand Ghanekar, Derek Y. Chiang. Identification of driver genes in hepatocellular carcinoma by exome sequencing. [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 4598. doi:10.1158/1538-7445.AM2013-4598
Abstract 4605: CDIP-BAP31 complex bridges endoplasmic reticulum and mitochondria during ER-stress mediated apoptosis.
Authors: Namba Takushi , Tian Fang , Chu Kiki , Hwang So-Young , Lee Sam W. 
Published: August 2014

Abstract
Resolved ER stress response is fundamentally essential for intracellular homeostatic balance, but unsettled ER stress can lead to apoptosis. In addition, imbalances in homeostasis would result in improper cell functioning that may become an important pathogenic factor in a number of prevalent diseases, including neurodegenerative diseases, metabolic disorders, and cancers. However, the molecular mechanisms relating ER stress to apoptosis still remain largely unfamiliar. Here, we show that a proapoptotic p53 target, CDIP, acts as a key signal transducer of ER stress response. Applying a biochemical/proteomics approach, we characterize BAP31, B-cell receptor-associated protein 31 that is an integral protein of ER and known to crosstalk with mitochondrial proteins during the apoptosis process, as an interacting partner of CDIP. Upon ER stress, CDIP is induced and enhances an association with BAP31 at the ER membrane. We found that the CDIP-BAP31 complex formation is essential for ER stress-mediated apoptotic process. CDIP-/- or CDIP knock-down cells are strongly resistant to ER-stress-induced apoptosis. Moreover, we show that CDIP up-regulation and binding to BAP31 is required for BAP31 cleavage via caspase-8 activation in response to ER stress and also responsible for BAP31-Bcl-2 association, then resulting in Bcl-2 sequestration from BAX. The recruitment of Bcl-2 with BAP31-CDIP complex triggers BAX oligomerization/activation that causes its translocation to the mitochondria, followed by cyctochrome c release. Genetic knockout of CDIP in mice also leads to impaired response to ER-stress-mediated apoptosis, likely through reduced BAX activation. Together, our data demonstrate that the CDIP-BAP31→Bcl-2/BAX regulatory circuit represents a novel mechanism for establishing an ER-mitochondrial cross-talk for ER stress-mediated apoptosis signaling.
Citation Format: Takushi Namba, Fang Tian, Kiki Chu, So-Young Hwang, Sam W. Lee. CDIP-BAP31 complex bridges endoplasmic reticulum and mitochondria during ER-stress mediated apoptosis. [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 4605. doi:10.1158/1538-7445.AM2013-4605
Abstract 4608: Autophagy is required for prostate cancer progression.
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2014

Abstract
Autophagy (also referred to as macroautophagy) is a self-catabolic process that maintains intracellular homeostasis and prolongs cell survival by the autophagosomic-lysosomal degradation of cytoplasmic contents during metabolic stress or nutrient starvation. Inactivation of PTEN tumor suppressor function is a common characteristic of human prostate cancer that leads to the upregulation of the PI3K/Akt/mTOR signaling pathway, and has emerged as promising candidate for targeted therapies. mTOR is one of the upstream regulators of autophagy, therefore, inhibiting the PI3K/Akt/mTOR axis putatively stimulates autophagy. However, the role of autophagy in cancer is complex, acting both as a tumor suppressor and promoter, and its role in prostate tumorigenesis remains to be defined. Here we demonstrate that prostate cancer is dependent on autophagy for its growth and progression through the use genetically modified mouse models of prostate cancer.
We had previously reported a conditional knockout mouse model in which homozygous deletion of PTEN lead to the stage-specific development of invasive adenocarcinoma. Characterization of tumors from the mice showed that although autophagy was suppressed early in tumor development, tumors eventually restored autophagic function despite increased PI3K/Akt/mTOR signaling. To determine the effect of defective autophagy on prostate cancer progression, we generated prostate-specific conditional double knockout mice harboring both inactivated PTEN and ATG7, a key regulator for the formation of autophagosomes. Prostate-specific inactivation of ATG7 function alone did not result in changes to the development or function of the prostate gland. Prostate-specific inactivation of both PTEN and ATG7 led to the early development of prostate adenocarcinoma similar to homozygous PTEN-mutant mice. However, prostate tumors failed to progress and showed regression. Our data suggests that impaired autophagy can be induced independent of mTOR and defective autophagy contributes to suppress tumor progression. Thus, our findings support the role of autophagy as a therapeutic target for advance prostate cancer.
Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Autophagy is required for prostate cancer 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 4608. doi:10.1158/1538-7445.AM2013-4608
Abstract 4612: Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth.
Authors: Hitosugi Taro , Zhou Lu , Arellano Martha , Khoury Hanna , Boggon Titus , Kang Sumin , He Chuan , Chen Jing 
Published: August 2014

Abstract
The current understanding of the Warburg effect consists of an increase in aerobic glycolysis in cancer cells. The connection between glycolysis and PPP/biosynthesis is based upon a model in which glycolytic intermediates can be diverted into PPP and biosynthesis pathways as precursors. However, it remains unclear how cancer cells coordinate glycolysis and biosynthesis to fulfill the request of rapidly growing tumors. We found that glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), commonly upregulated in human cancers due to loss of TP53, regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate (3-PG) and product 2-phosphoglycerate (2-PG). Our co-crystal structure based analysis revealed that 3-PG binds to and inhibits 6-phosphogluconate dehydrogenase in the oxidative pentose phosphate pathway (PPP) as a competitive inhibitor, while 2-PG activates 3-phosphoglycerate dehydrogenase (PHGDH) to provide feedback control of 3-PG levels. Inhibition of PGAM1 by shRNA results in increased 3-PG and decreased 2-PG levels in cancer cells, leading to significantly decreased glycolysis, PPP flux and biosynthesis, as well as attenuated cell proliferation and tumor growth. These findings uncover that PGAM1 controls the intracellular 3-PG and 2-PG levels to serve as a novel link between glycolysis, biosynthesis, cancer cell proliferation and tumor development.
Moreover, we screened and developed novel small molecule PGAM1 inhibitor (PGMI)-004A, which effectively inhibits PGAM1 enzyme activity, resulting in aberrant cancer cell metabolism with reduced glycolysis and PPP/anabolic biosynthesis, as well as attenuated cell proliferation in diverse human cancer cell lines, but not control normal human proliferating cells including human dermal fibroblasts and human foreskin fibroblasts. PGMI-004A treatment attenuates tumor growth in xenograft nude mice with minimal toxicity in vivo. Furthermore, PGMI-004A inhibits cell proliferation of primary leukemia cells from human AML, CML and B-ALL patients, but not control CD34+ cells isolated from bone marrow samples or mononucleocytes isolated from peripheral blood samples from healthy donors, suggesting minimal toxicity of PGMI-004A in human cells.These results together provide “proof of principle” for the development of PGAM1 inhibitors as anti-cancer agents.
Citation Format: Taro Hitosugi, Lu Zhou, Martha Arellano, Hanna Khoury, Titus Boggon, Sumin Kang, Chuan He, Jing Chen. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. [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 4612. doi:10.1158/1538-7445.AM2013-4612
Abstract 463: Differential cellular localization of programmed death ligand 1 (PD-L1) and enhanced expression of programmed death-1 (PD-1) in melanoma progression.
Authors: Chakravarti Nitin , Bassett Roland , Hwu Wen-Jen , Ivan Doina , Curry Jonathan L. , Prieto Victor G. 
Published: August 2014

Abstract
Melanoma is an aggressive malignancy with a relatively high metastatic rate, responsible for almost 60% of lethal skin tumors. Although many human cancers such as melanoma express tumor antigens recognized by T cells, host immune responses often fail to control tumor growth for mostly unexplained reasons. Escaping immune destruction is one of the tenets of tumorigenesis; there have been several studies suggesting an important role of PD-1/PD-L1 (B7-H1) interactions in inhibiting the effector functions of cytotoxic T-lymphocyte in tumor. Ghebeh et al., reported that doxorubicin treatment caused decrease in cytosolic B7-H1 and increased nuclear translocalization in breast carcinoma (Breast Cancer Res. 2010;12(4):R48). It is unknown whether differential cellular expression of PD-L1 contributes to the pathogenesis of melanoma. To address the role of PD-L1 and its receptor PD-1 in different stages of malignant melanoma, we have performed semiquantitative immunohistochemical analysis of PD-L1 and PD-1 in benign nevi (n=59), primary melanomas without metastasis (n=22) or with metastasis (n=17), and melanoma metastases (n=32 cases). Benign nevi had significantly higher levels of nuclear PD-L1 immunopositivity (p=0.004) and low levels of PD-1 protein expression (p=0.002). With progression from benign nevi to primary melanoma there was an increase in cytoplasmic positivity for PD-L1 (p=0.03). Also, a significant positive correlation was observed between the percentage of positive cells (p=0.0007) and intensity (p=0.0009) for PD-1 in primary melanomas. Although there was no significant difference in PD-1 levels in between primaries with or without metastasis, a trend was observed for PD-L1 expression: primaries with metastasis having a larger number of tumor cells with cytosolic localization than primaries without metastasis (p=0.07). Interestingly, primary melanomas without metastasis showed significantly larger number of tumor infiltrating lymphocytes (TILs) cells having intense immunoreactivity for PD-L1 protein than did metastatic melanomas (p=0.03). In conclusion, differential cellular localization of PD-L1 protein and high levels of PD-1 protein correlates with disease progression and high-risk histologic features in melanoma and might partially explain the resistance of melanoma cells against the immune system.
Citation Format: Nitin Chakravarti, Roland Bassett, Wen-Jen Hwu, Doina Ivan, Jonathan L. Curry, Victor G. Prieto. Differential cellular localization of programmed death ligand 1 (PD-L1) and enhanced expression of programmed death-1 (PD-1) in melanoma 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 463. doi:10.1158/1538-7445.AM2013-463
Abstract 4635: The avidity hypothesis: comparing bispecific and monospecific antibodies in preclinical oncology models.
Authors: Sachsenmeier Kris F. , Dimasi Nazzareno , Huang Qihui , Sult Erin , Bezabeh Binyam , Fleming Ryan , Hay Carl , Zhong Helen , Breen Shannon , Gao Changshou , Agoram Balaji , Jermutus Lutz , Hollingsworth Robert 
Published: August 2014

Abstract
Bi-specific antibodies are suggested to possess unique advantages when compared with mono-specific antibodies as anti-cancer therapeutics. These advantages include greater efficacy, superior combination with standard of care agents, and evasion of resistance mechanisms. Data are presented supporting the hypothesis that the increased avidity of a tetravalent (non BiTE-like) bi-specific antibody mediates such advantages when compared with conventional bi-valent mono-specific antibodies. Experiments include functional comparisons of antibodies binding the Epidermal Growth Factor (EGFR) and the Insulin-like Growth Factor 1 Receptor (IGF1R) at the biochemical, cellular and tumor xenograft levels. These data support the ongoing use of multi-specific antibodies in oncology research and describe a mechanism that may contribute to superior activity compared to mono-specific antibodies and drug combinations. It is noted that advantages of bi-specific antibody formats remain to be seen clinically in terms of both efficacy and safety.
Citation Format: Kris F. Sachsenmeier, Nazzareno Dimasi, Qihui Huang, Erin Sult, Binyam Bezabeh, Ryan Fleming, Carl Hay, Helen Zhong, Shannon Breen, Changshou Gao, Balaji Agoram, Lutz Jermutus, Robert Hollingsworth. The avidity hypothesis: comparing bispecific and monospecific antibodies in preclinical oncology models. [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 4635. doi:10.1158/1538-7445.AM2013-4635
Abstract 4638: Anti-tumor activity of pimasertib in combination with SAR245409 or SAR245408 in human primary colorectal cancer xenograft models bearing PI3K/KRas and KRas mutations.
Authors: Sidhu Sukhvinder S. , Egile Coumaran , Malfilatre Marc , Lefranc Celine , Ruffin Yvette , Ma Jianguo , Hsu Karl , Lager Joanne , Marzabal Stephane , Ogden Janet A. , Vincent Loic 
Published: August 2014

Abstract
The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK are interlinked growth and survival signaling pathways that are often constitutively activated in human tumors as a result of amplifications and/or mutations in PIK3CA, RAS and BRAF genes. In the present work, we have investigated the anti-tumor activity and documented the steady state pharmacodynamic impact of combinations between 2 selective pan PI3K Class I inhibitors, SAR245408 (XL147) and SAR245409 (XL765) with the selective allosteric inhibitor of MEK1/2, pimasertib (AS703026; MSC1936369B) against several different patient derived colorectal cancer (CRC) xenograft models harboring either KRAS mutations, dual KRAS and BRAF mutations or dual KRAS and PIK3CA mutations.
In the BRAF driven CRC model, effects of the combinations were not significantly different from that of single agent treatment of pimasertib alone. In the G12V KRAS or G12D KRAS mutant CRC models, both combinations led to significantly greater anti-tumor activity than that of single agent treatment. In the dual PIK3CA/KRAS mutant tumors, combination therapies lead to a potent inhibition of both TORC1 and TORC2 pathways, in addition to inhibition of the MAPK pathway in contrast to single agent treatments. Overall, pimasertib combined with either SAR245409 or SAR245408 showed a significantly greater anti-tumor activity as compared to single agent treatment alone in primary models bearing KRAS mutations or dual PIK3CA/KRAS mutations. The combination of pimasertib and SAR245409 is currently being investigated in patients with PIK3CA/KRAS mutant colorectal cancer as part of an ongoing Phase Ib dose escalation trial of oral combination therapy with pimasertib (MSC1936369B) and SAR245409 in subjects with locally advanced or metastatic solid tumors.
Citation Format: Sukhvinder S. Sidhu, Coumaran Egile, Marc Malfilatre, Celine Lefranc, Yvette Ruffin, Jianguo Ma, Karl Hsu, Joanne Lager, Stephane Marzabal, Janet A. Ogden, Loic Vincent. Anti-tumor activity of pimasertib in combination with SAR245409 or SAR245408 in human primary colorectal cancer xenograft models bearing PI3K/KRas and KRas mutations. [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 4638. doi:10.1158/1538-7445.AM2013-4638