bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4880: MAGE gene family expression in pediatric medulloblastoma: frequency and possible therapeutic target
Authors: Collins Rebecca R. , Tacer Klementina Fon , Rakheja Dinesh , Potts Patrick Ryan 
Published: July 2017

Abstract
Background: The melanoma antigen gene family (MAGE) is a group of related genes that were first discovered in malignant melanoma. Among the approximately 40 MAGE genes in the human genome, two thirds are classified as Type I (MAGE-A, MAGE-B, and MAGE-C), referred to also as cancer testis antigens (CTAs), proteins that are restricted to testis but often aberrantly expressed in many adult cancers. Despite their common expression in adult cancers and their oncogenic potential, little is known about their expression and role in pediatric cancers. To determine the frequency of MAGE expression in pediatric medulloblastoma, we measured expression levels of Type I MAGEs in patient tumors. In addition, we examined how MAGE expression in medulloblastoma cells affects their growth and oncogenic potential.
Methods: We searched the Children’s Health pathology database for pediatric medulloblastoma between 2008 - 2015 and were able to recover an adequate amount of RNA from formalin-fixed paraffin-embedded tissue samples of 34 patients. The RNA was converted to cDNA using reverse transcriptase, and the relative expression of 23 Type I MAGE genes was measured by qRT-PCR.
To determine if MAGE expression is critical for medulloblastoma cell survival we knocked down several MAGEs using siRNAs in two MAGE-expressing medulloblastoma cell lines (D283 and DAOY) and evaluated the effect by cell viability (Alamar Blue and Cell titer Glo), apoptosis assays (Annexin V), and colony formation in soft agar.
Results: In 34 medulloblastoma patient samples we found that 10 (29.4%) expressed at least one MAGE gene, and one case had high levels of expression of 10 of the 23 Type I MAGEs. MAGE expression was associated with the non-WNT/SHH (G3/G4) molecular subgroup of tumors in our study. There was no correlation between MAGE expression and histologic subtype. Furthermore, using MAGE-A/-B2 positive medulloblastoma cell lines, we showed that siRNA knock down of multiple MAGE-As and -B2 decreased cell viability by 15 - 80%, increased apoptosis (-B2), and decreased growth of cells in soft agar.
Conclusion: Type I MAGE genes are expressed in 30% of pediatric medulloblastoma in our study. In MAGE positive medulloblastoma cells, MAGE genes are important for cell survival and clonogenic growth. The decreased cell survival after MAGE knockdown appears to be related, at least in part, to increased apoptosis. Our results indicate that targeting of MAGEs in medulloblastoma may be a potential therapeutic option.
Citation Format: Rebecca R. Collins, Klementina Fon Tacer, Dinesh Rakheja, Patrick Ryan Potts. MAGE gene family expression in pediatric medulloblastoma: frequency and possible therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4880. doi:10.1158/1538-7445.AM2017-4880
Abstract 4926: Gut microbiota regulates cisplatin mediated cachexia and systemic toxicity
Authors: Roy Soumen , Neves Rodrigo Das , Dzutsev Amiran , Smith Carolyne , Edwards Bathai , Dawson Miranda , Difilippantonio Simone , Smith Loretta , Huang April , Kim Young , Trinchieri Giorgio 
Published: July 2017

Abstract
Chemotherapy induced toxicity severely affect the cancer survivors and lowers the quality of life. By 2020, there will be more than 18 million of cancer survivors all over the world. Majority of them might develop long term nephrotoxicity, ototoxicity and gut toxicity. In addition, chemotherapy may also facilitate the initiation and progression of cachexia. Recent studies have shown that gut microbiota modulates the efficacy of anti-cancer chemotherapy, however very limited knowledge is available regarding the role of gut microbiota in regulating systemic toxicity and cachexia. We hypothesized that gut microbiota modulates cisplatin induced systemic toxicity as well as cachexia. Four groups (n=10 in each group) of 6-8 weeks old C57B/6 mice were treated with cisplatin, cisplatin+antibiotics cocktails (ABX), ABX only and control. ABX cocktail contained primaxin, vancomycin and neomycin. This experiment was validated using C57B/6 germ free mice. We performed anti-p-γ-H2AX based toxicity assay for DNA damage. In addition, we performed immunohistochemistry for studying cachexia. H&E staining and DNA damage were assessed by light and super resolution confocal microscopy (Zeiss 880) and quantified by 3-D reconstruction using IMARIS. We also performed high content imaging to evaluate DNA damage in bone marrow and spleen. Body weight and kidney blood content were also analyzed to determine the degree of toxicity. Depletion of gut microbiota significantly reduced nephrotoxicity and gut toxicity. In addition, we found that depletion of gut microbiota prevents muscle and adipose tissue loss by down-regulating UCP-1and PGC-1α in adipose tissue and MURF-1 and Atrogin-1 in muscle. Experiments are confirmed by using Germ free mice. Our data suggest that modulation of gut microbiota may be utilized to reduce chemotherapy associated cachexia and systemic toxicity.
Citation Format: Soumen Roy, Rodrigo Das Neves, Amiran Dzutsev, Carolyne Smith, Bathai Edwards, Miranda Dawson, Simone Difilippantonio, Loretta Smith, April Huang, Young Kim, Giorgio Trinchieri. Gut microbiota regulates cisplatin mediated cachexia and systemic toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4926. doi:10.1158/1538-7445.AM2017-4926
Abstract 493: Pathologic findings at RRSO in germline BRCA mutation carriers with breast cancer: significance of bilateral RRSO at the optimal age in germline BRCA mutation carriers
Authors: Lee YoungJae , Kim YongMan , Lee ShinWha 
Published: July 2017

Abstract
Objective: Most BRCA1/2 carriers do not undergo risk-reducing salpingo-oophorectomy (RRSO) by the recommended age. This study aimed to find the incidence of precursor lesions and cancer after RRSO.
Methods: We retrospectively reviewed breast cancer patients identified as BRCA mutation carriers who underwent RRSO at Asan Medical Center, Seoul, Korea, from 2010 to 2014. From 2013, all cases were examined according to the SEE/FIM protocol and underwent immunohistochemically (IHC) staining. RRSO was performed in 63 patients, 27 in 2010-2012 and 36 in 2013-2014.
Results: The median age at RRSO was 46.5 years (32-73 years). Occult invasive cancer was detected in 8 patients, of ovarian origin in 5 and of tubal origin in 3. All occult invasive cancer cases with metastasis were detected in patients older than 40 years. Of the 36 patients from the 2013-2014 cohort, 7 showed p53 overexpression, 1 showed Ki-67 overexpression, 2 showed serous tubal intraepithelial carcinoma (STIC), and 3 showed occult cancer. The detection rate of precursor lesions or cancer was 36.1% (13/36). In the analysis according to age, precursor lesions were more common in BRCA1 mutation carriers younger than 40 years old (66.7% vs 20.0%). In BRCA2 mutation carriers, precursor lesions were only detected in those older than 40 years of age, indicating the possible faster occurrence of precursor lesions in BRCA1 mutation carriers.
Conclusions: Many patients still tend to delay RRSO until after they are 40 years old. Our findings support the significance of RRSO before the age of 40 in germline BRCA mutation carriers.
Citation Format: YoungJae Lee, YongMan Kim, ShinWha Lee. Pathologic findings at RRSO in germline BRCA mutation carriers with breast cancer: significance of bilateral RRSO at the optimal age in germline BRCA mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 493. doi:10.1158/1538-7445.AM2017-493
Abstract 4941: Lysophosphatidic acid receptor signaling and pancreatic adenocarcinoma tumor microenvironment
Authors: Skill Nicholas J. , Maluccio Mary A. 
Published: July 2017

Abstract
Introduction: Changes in lipid biosynthesis has attracted significant attention in the study of cancer. Its value in our understanding of pancreatic cancer has not yet been realized. This study examined lysophosphatidic acid (LPA) variant biosynthesis in patients with stage II-III pancreatic ductal adenocarcinoma (PDAC), evaluating serum, bile, and tissue levels of LPA, its receptors, and downstream metabolites. LPA, a product of phospholipase D activity of the enzyme autotaxin (ATX) is a potent mitogenic agent. Data suggests that changes in lipid biosynthesis contribute to the tumor microenvironment in PDAC.
Methods: PDAC, matched adjacent non-malignant tissues, gall bladder bile and serum samples were collected from patients with Stage II-III pancreatic cancer at the time of surgery. Control bile and serum were collected from patients undergoing cholecystectomy for benign disease and living renal donors respectively.
Results: Serum and biliary LPA levels were increased in patients with PDAC when compared to controls. ATX activity, and LPA receptors, LPAR1, LPAR2, and LPAR5 were greater in PDAC adjacent pancreatic tissue when compared to PDAC tissue. In contrast, TNFα receptors TNFα1 and TNFα2 and LPA receptor LPAR3 receptor expression was greater in PDAC lesions when compared to adjacent tissue.
Conclusion: PDAC patients display a modified LPA biosynthesis profile, when compared to non-PDAC patients, potentially providing a paracrine-signaling cascade to promote pancreatic tumorigenesis through increased expression of mitogenic cytokines and growth factors.
Citation Format: Nicholas J. Skill, Mary A. Maluccio. Lysophosphatidic acid receptor signaling and pancreatic adenocarcinoma tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4941. doi:10.1158/1538-7445.AM2017-4941
Abstract 496: Ubiquitin specific peptidases 37 promotes constitutive replication fork movement by stabilizing Chk1 via its deubiquitination
Authors: Singh Mayank , Burrows Amy C. , Dickson Andrew , Komal Komal , Pal Debjani , Summers Matthew K. 
Published: July 2017

Abstract
Protein deubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. Ubiquitin specific peptidases (USPs) remove ubiqiuitin tags from target proteins to control both protein fate and function. USP37 (Ubiquitin specific peptidase 37) has been implicated in cancer and we have previously shown that antagonizes the tumor suppressor APCCDH1and promotes S phase entry. However, the role of USP37 during S-phase was unknown. Here, we report that in cells experiencing replication stress USP37 overexpression confers survival advantage while its depletion enhances sensitivity. USP37 overexpressing cells were able to resolve different DNA damage markers much more effectively then the control cells or cells in which USP37 was depleted. Mechanistically, our data indicate that USP37 binds and stabilizes the active form of CHK1 and deubiquitinates Chk1 to increase its stability and promote the checkpoint response. USP37 overexpression results in constitutive replication fork movement and long tract DNA synthesis while USP37 depleted cells were unable to carry out long tract DNA synthesis. Notably, expression of low level of Chk1 in USP37 depleted cells rescues cell survival and DNA damage response. Overall our data suggest that inhibition of USP37 may represent a novel mechanism to modulate Chk1 activity.
Note: This abstract was not presented at the meeting.
Citation Format: Mayank Singh, Amy C. Burrows, Andrew Dickson, Komal Komal, Debjani Pal, Matthew K. Summers. Ubiquitin specific peptidases 37 promotes constitutive replication fork movement by stabilizing Chk1 via its deubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 496. doi:10.1158/1538-7445.AM2017-496
Abstract 4967: RAF kinase inhibition synergizes with MEK inhibitors in KRAS mutant tumors
Authors: Yen Ivana , Klijn Christiaan , Shanahan Frances , Merchant Mark , Orr Christine , Hunsaker Thomas , Durk Matthew , La Hank , Zhang Xiaolin , Martin Scott , Lin Eva , Chan John , Yu Yihong , Gustafson Amy , Rudolph Joachim , Malek Shiva 
Published: July 2017

Abstract
While activating mutations in the KRAS oncogene frequently drive tumorigenesis in human cancers (40% CRC, 20% NSCLC) through constitutive activation of the MAPK pathway, there are currently no targeted treatments available for KRAS mutant cancers. Inhibitors of the individual nodes of the MAPK pathway have been developed, but these molecules have been largely ineffective against KRAS mutant tumors in the clinic. Multiple studies have shown rational combinations of MAPK inhibitors may have anti-tumor activity in KRAS mutant models. In order to understand the versatility of combining RAF inhibitors in this context, we conducted a library screen consisting of 430 small molecule tool compounds in combination with RAF inhibitor AZ-628. Here we show: RAF inhibitors combine especially well with other MAPK pathway inhibitors in KRAS mutant tumor cells. In particular, Type II RAF inhibitors are synergistic with the MEK inhibitor Cobimetinib in vitro and exhibit tumor regressing efficacy in xenograft mouse model studies in vivo. Mechanistically, we have found the MEK inhibitor disables ERK induced negative feedback on the MAPK pathway resulting in activation of CRAF in a KRAS dependent manner. The combination of RAF with MEK inhibition blunts KRAS-dependent activation of CRAF kinase activity and robustly inhibits MAPK signaling, thereby driving efficacy in KRAS mutant tumors. Broad cell line profiling with the combination of RAF and MEK inhibitors demonstrates that a majority of KRAS mutant lung and colorectal tumor lines exhibit synergy with the combination. Therefore, combining a Type II pan-RAF inhibitor with a MEK inhibitor has the potential to improve the therapeutic outcome in KRAS mutant cancers.
Citation Format: Ivana Yen, Christiaan Klijn, Frances Shanahan, Mark Merchant, Christine Orr, Thomas Hunsaker, Matthew Durk, Hank La, Xiaolin Zhang, Scott Martin, Eva Lin, John Chan, Yihong Yu, Amy Gustafson, Joachim Rudolph, Shiva Malek. RAF kinase inhibition synergizes with MEK inhibitors in KRAS mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4967. doi:10.1158/1538-7445.AM2017-4967
Abstract 4970: Oxidative phosphorylation as a target in triple negative breast cancer therapy
Authors: Meric-Bernstam Funda , Evans Kurt , Zheng Xiaofeng , Su Xiaoping , Yuca Erkan , Scott Stephen , Akcakanat Argun , Ueno Naoto , Lim Bora , Litton Jennifer , Valero Vicente , Symmans Fraser , Hortobagyi Gabriel , Perou Charles , Tripathy Debu , Draetta Guilio , Marszalek Joe , Gonzalez-Angulo Ana Maria , Moulder Stacy 
Published: July 2017

Abstract
Altered cellular metabolism is a hallmark of cancer. It is increasingly recognized that selected tumors are dependent on oxidative phosphorylation (OXPHOS). However, the role of OXPHOS in TNBC is not well understood. We performed RNA sequencing in pre-treatment biopsies from 43 patients with operable triple negative breast cancer (TNBC) who received sequential taxane- and anthracycline-based neoadjuvant chemotherapy. At a median follow-up of 63 months, 14 patients recurred and 12 patients died. At a false discovery rate of 0.05, 33 genes were differentially expressed between the patients who did and did not have a subsequent recurrence. Ingenuity pathway analysis demonstrated that one of the top canonical pathways that differed was higher expression of oxidative phosphorylation signature (p=5.89E-0.7). The patients who recurred had significantly higher levels of mitochondrial genes: MT-ND1 (adjusted p or FDR-BH; q=0.007); MT-ND5 (q=0.03) and MT-ND4 (q=0.04). Further, 21 genes were differentially expressed between patients based on survival, including MT-ND5 (q=0.001); MT-ND4 (q=0.005), MT-ND4L (q=0.015), MT-ND6 (q=0.018), and MT-ATP6 (P=0.03). Top canonical pathway that was differentially expressed based on survival was oxidative phosphorylation (p=9.98E-10). We therefore sought to determine the efficacy of IACS-10759, a novel inhibitor of OXPHOS, in 10 different TNBC patient-derived xenografts representing different gene expression based Lehmann TNBC subtypes. Growth inhibition was observed in multiple subtypes, with regression in one basal-like 1(BL1) 1 model, and stabilization of growth in multiple BL1 and immunomodulatory expression subtypes. Taken together, our data suggests that high OXPHOS is associated with higher recurrence and lower survival. OXPHOS is a promising target in several TNBC subtypes. A Phase I trial of IACS-10759, a potent inhibitor of complex I of oxidative phosphorylation, in leukemia is ongoing and planned in TNBC and other solid tumors.
Citation Format: Funda Meric-Bernstam, Kurt Evans, Xiaofeng Zheng, Xiaoping Su, Erkan Yuca, Stephen Scott, Argun Akcakanat, Naoto Ueno, Bora Lim, Jennifer Litton, Vicente Valero, Fraser Symmans, Gabriel Hortobagyi, Charles Perou, Debu Tripathy, Guilio Draetta, Joe Marszalek, Ana Maria Gonzalez-Angulo, Stacy Moulder. Oxidative phosphorylation as a target in triple negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4970. doi:10.1158/1538-7445.AM2017-4970
Abstract 4981: Extracellular spacer and co-stimulatory domains define target sensitivity and persistence of CAR T cells for the treatment of PSCA+ bone metastatic prostate cancer
Authors: Kennewick Kelly , Tilakawardane Dileshni , Gerdts Ethan , Murad John , Park Anthony , Jeang Brook , Yamaguchi Yukiko , Forman Stephen J. , Priceman Saul 
Published: July 2017

Abstract
Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer should be amenable to CAR-based immunotherapy given that several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. The selectivity of CARs for solid cancers is crucial, however, due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that optimized co-stimulatory signaling and extracellular spacer domains are essential in defining a CAR’s selectivity towards tumor cells that over-express the target antigen. The 4-1BB co-stimulatory domain in PSCA-CARs confers enhanced tumor selectivity with dampened yet dose-responsive cytokine production, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory domain. CARs containing a short extracellular spacer demonstrate the most selective killing of high PSCA-expressing tumors but are unable to produce the inflammatory cytokines important for a complete anti-tumor response. We show that longer extracellular spacers in PSCA-CARs are necessary for both tumor killing and cytokine production. PSCA-CARs exhibit robust in vivo anti-tumor activity in subcutaneous and orthotopic bone-metastatic patient-derived prostate cancer xenograft models, and 4-1BB-containing CARs show superior persistence in controlling metastatic disease compared with CD28-containing CARs. Our study demonstrates the critical impact of CAR components in defining an optimized tumor-selective CAR T cell, and also highlights the importance of clinically relevant animal models in developing effective solid cancer CAR T cell therapies.
Citation Format: Kelly Kennewick, Dileshni Tilakawardane, Ethan Gerdts, John Murad, Anthony Park, Brook Jeang, Yukiko Yamaguchi, Stephen J. Forman, Saul Priceman. Extracellular spacer and co-stimulatory domains define target sensitivity and persistence of CAR T cells for the treatment of PSCA+ bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4981. doi:10.1158/1538-7445.AM2017-4981
Abstract 5001: Functional biomarker discovery from cancer patient serum with PEP technology
Authors: Wang David L. , Fu Guofeng , Davies Micheal , Wang Xing 
Published: July 2017

Abstract
Proteins play essential roles in numerous biological processes and being able to pinpoint functional differences between cell or tissue samples can greatly aid in understanding disease processes and metabolic changes. The PEP technology allows systematic analysis of protein functions within a proteome. Hundreds of functional proteins can be separated and functionally assayed to generate a comprehensive three-dimensional landscape of protein families such as protein kinases, phosphatases, proteinases and oxido-reductases. This information can then be integrated into other genomic and proteomic knowledge bases to provide further insight of important biological processes such as cancer development and aging.
In the PEP technology, complex protein mixtures are first separated by a modified two-dimensional gel electrophoresis process, giving enhanced resolution while still maintaining protein function. This is followed by an efficient protein transfer to a specially designed 1536-well Protein Elution Plate. After further transfer of the samples from the PEP plate to multiple 384-well microplates, functional assays can be performed on each well to generate an enzyme activity profile displayed in 3-D. Protein components of each well can be further characterized by mass spectrometry if desired.
Using the PEP technology, functional biomarker candidates have been identified from lung and breast cancer patient serum. Both qualitative and quantitative differences of metabolic enzymes and proteases were observed when comparing the cancer patient serum and normal serum. Some of the active enzymes were identified by mass spectrometry and validated in selected bioassays. It is believed that this functional proteomics technology provides a unique approach in the discovery of potential cancer biomarkers for diagnostic and prognostic applications.
Citation Format: David L. Wang, Guofeng Fu, Micheal Davies, Xing Wang. Functional biomarker discovery from cancer patient serum with PEP technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5001. doi:10.1158/1538-7445.AM2017-5001