bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A73: Metabolite profiling reveals the glutathione biosynthetic pathway as a therapeutic target in triple negative breast cancers
Authors: Beatty Alexander , Fink Lauren , Strigun Alexander , Rennefahrt Ulrike , Peter Erik , Reszka Regina , Schiewe Hajo , Peterson Jeffrey R. 
Published: May 2016

Abstract
Identifying metabolic pathway alterations that are critical to support cancer growth is a key hurdle for developing therapeutic strategies that exploit these pathways. We have applied metabolomic and pharmacological approaches to identify targetable pathways in triple negative breast cancer (TNBC). TNBC is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies.
To identify dysregulated metabolic pathways in TNBC, we conducted mass spectrometry-based metabolomics of TNBC and control cells. The relative steady-state levels of 155 intracellular metabolites distinguished TNBC from non-transformed breast epithelia, and revealed two metabolic subtypes within TNBC that, unexpectedly, correlate with markers of basal-like versus non-basal-like status. Distinguishing metabolites included amino acids, lipids and the cellular redox buffer glutathione. Levels of glutathione were generally lower in TNBC cell lines compared to controls, and markedly lower in the metabolic subtype containing non-basal-like TNBC. Further, these cell lines showed enhanced sensitivity to inhibition of glutathione biosynthesis, demonstrating a dependence on glutathione production for survival.
These findings demonstrate the potential of targeting the glutathione biosynthetic pathway as a therapeutic strategy in TNBC, and suggest that existing clinical biomarkers may provide a means for stratifying TNBC tumors to identify likely responders to anti-glutathione therapy.
Note: This abstract was not presented at the conference.
Citation Format: Alexander Beatty, Lauren Fink, Alexander Strigun, Ulrike Rennefahrt, Erik Peter, Regina Reszka, Hajo Schiewe, Jeffrey R. Peterson. Metabolite profiling reveals the glutathione biosynthetic pathway as a therapeutic target in triple negative breast cancers. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A73.
Abstract B14: Targeting heat shock protein 90 with ganetespib for the treatment of lymphoma
Authors: Liu Hanqing , Liang Zhiquan , Zhang peishan , Zhao Jingjing , Ruan Lingling , Lu Yongjin , Shang Dongsheng , Sun Ying , Tu Zhigang 
Published: May 2016

Abstract
Effective treatments for lymphoma remain a serious unmet medical need: the incidence of lymphoma continues to rise, and lyphoma tumors can relapse in patients who initially respond to treatment. Heat shock protein 90 (HSP90) has become an attractive therapeutic target in treating many cancers including blood cancers. In our study, we show that ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor, dramatically reduced growth of a couple of different kinds of lymphoma, such as mantle cell lymphoma and Burkitt's lymphoma in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all studied cell lines, such as Ramos, Jeko-1, Granta-519, Raji, etc. Ganetespib significantly inhibited growth of xenograft tumors in vivo as a single agent or in combination with doxorubicin. Results of H&E staining, TUNEL assays, and immunohistochemistry staining of Ki-67 revealed significant differences in ganetespib-treated tumors. A panel of signaling network proteins with a hub of HSP90 were screened for the effects of ganetespib and these pathways were studied mechanistically. In summary, our data suggest that ganetespib can be potentially used for the molecularly targeted therapy of lyphoma patients.
Acknowledgments: This work was supported by the Jiangsu Specially-Appointed Professor Program (to H. Liu); Jiangsu Recruitment Program of Leading Creative and Entrepreneurial Talents (to H. Liu and Z. Tu); National Natural Science Foundation 81402145 (to H. Liu) and 31471294 (to Z. Tu); Natural Science Foundation of Jiangsu Province BK20140572 (to H. Liu); Start-up Scientific Research Fund for the Returned Oversea Scholars from Chinese Ministry of Education (to Z. Tu); Senior Talent Start-up Funds of Jiangsu University 14JDG050 (to H. Liu) and 14JDG011 (to Z. Tu); Priority Academic Program Development of Jiangsu Higher Education Institutions (to School of Pharmacy and Institute of Life Sciences of Jiangsu University).
Note: This abstract was not presented at the conference.
Citation Format: Hanqing Liu, Zhiquan Liang, peishan Zhang, Jingjing Zhao, Lingling Ruan, Yongjin Lu, Dongsheng Shang, Ying Sun, Zhigang Tu. Targeting heat shock protein 90 with ganetespib for the treatment of lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B14.
Abstract B37: Concomitant blockade of glucose uptake and paracrine HGF signaling uncovers the metabolic vulnerability of KRAS-mutant colorectal tumors
Authors: Mira Alessia , Michieli Paolo 
Published: May 2016

Abstract
Mutations in KRAS and over-expression of MET, the hepatocyte growth factor (HGF) receptor, are both negative prognostic factors for colorectal cancer (CRC). We studied the KRAS-MET interplay using human isogenic CRC cells with defined KRAS status and human HGF knock-in SCID mice, thereby reproducing species-specific HGF-MET paracrine signaling. We show that KRAS-mutant CRC cells display an extraordinary high glycolytic rate that makes them ‘addicted’ to glycolysis. When glucose availability is scarce or upon drug-mediated impairment of glucose metabolism, KRAS-mutant cells rapidly undergo apoptosis, unless ‘salvaged’ by micro-environment-borne HGF, which permits their survival by enhancing glucose influx, sustaining glycolysis and activating autophagy, thus improving energetic efficiency and preventing a mitotic catastrophe. In an orthotopic model of metastatic CRC using human HGF knock-in SCID mice and human KRAS-mutant CRC cells, combined pharmacological blockade of glucose metabolism and of HGF/MET signaling resulted in synthetic lethality and achieved superior tumor inhibition and metastasis suppression compared to metabolism-active drugs or HGF/MET inhibitors alone. In the same system, paracrine HGF signaling also protected KRAS-mutant tumors against anti-angiogenic therapy, which caused more dramatic and less specific metabolic stress by depriving tumors of both nutrients and oxygen. However, in contrast to selective glucose metabolism impairment, anti-angiogenic therapy exacerbated tumor hypoxia, promoted HGF-dependent metastatic dissemination and gave rise to acquired resistance. These results indicate that selective impairment of glucose metabolism is a much safer and more effective approach to target KRAS-mutant CRC metabolic vulnerability compared to angiogenesis inhibition. They also show that microenvironment-borne HGF is a major source of resistance to anti-tumor therapies that cause metabolic stress to cancer cells. Considering that angiogenesis inhibition is the only biological therapy currently available for KRAS-mutant tumors, the data generated by this study open new perspectives for the treatment of this highly aggressive cancer type.
Citation Format: Alessia Mira, Paolo Michieli. Concomitant blockade of glucose uptake and paracrine HGF signaling uncovers the metabolic vulnerability of KRAS-mutant colorectal tumors. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B37.
Abstract B70: Decitabine, the DNA demethylating agent, works in solid tumor patients by promoting the proliferation and lysis activity of T lymphocytes
Authors: Jing Nie 
Published: May 2016

Abstract
Epigenetic alterations, such as DNA methylation, play crucial roles in cancer development and metastasis. Epigenetic therapy has been approved in hematological malignancies treatment, while its application in solid tumors is ongoing and the clinical function mechanism is not clear. Clinical trials using the demethylating agent decitabine on solid tumor patients have been undertaken in our department of biological therapy. Notably, low dose decitabine treatment significantly enhanced the activation and proliferation of the peripheral T cells both in vitro and in vivo. Moreover, the cytotoxic ability of peripheral T cells was increased with a marked enhancement in Th1 response post the epigenetic therapy. The sequencing analysis confirmed the enrichment for pathways in cell cycle, mitosis, immune response and methylation after decitabine treatment. Our findings provided the molecular evidences that the DNA demethylating agent treatment could promote the anti-tumor capacity of T cells in solid tumor patients.
Citation Format: Nie Jing. Decitabine, the DNA demethylating agent, works in solid tumor patients by promoting the proliferation and lysis activity of T lymphocytes. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B70.
Abstract B80: Beneficial regulation of metabolic profiles by black raspberries in human colorectal cancer patients
Authors: Pan Pan , Skaer Chad W. , Stirdivant Steven M. , Young Matthew R. , Stoner Gary D. , Lechner John F. , Huang Yi-Wen , Wang Li-Shu 
Published: May 2016

Abstract
Objectives: Dietary intervention of freeze-dried black raspberries (BRBs) in a group of human colorectal cancer patients has demonstrated beneficial effects, including pro-apoptosis, anti-proliferation and anti-angiogenesis. The aim of this study was to investigate BRB-mediated metabolite changes from this same cohort of patients.
Methods: 28 colorectal cancer patients were given 60 g BRB powder daily for 1-9 weeks. Urine and plasma specimens were collected before and after BRB intervention. A comprehensive mass spectrometry-based nontargeted metabolomic analysis was conducted on each specimen.
Results: A total of more than 400 metabolites were annotated in each specimen. Of these 69 and 58 metabolites were significantly changed by BRBs in urine and plasma, respectively. An increased level of 4-methylcatechol sulfate was correlated with a higher apoptotic marker (TUNEL) in post-BRB tumors, while a decreased level of N-acetylglycine was correlated with a lower cell proliferation marker (Ki67) in post-BRB tumors. Cis-aconitate and isocitrate, two tricarboxylic acid (TCA) cycle metabolites, were increased in post-BRB urine. Fatty acid β-oxidation and synthesis were decreased in post-BRB plasma. In addition, BRB-derived polyphenols were absorbed and metabolized to various benzoate species, which were significantly increased in post-BRB specimens. Increased benzoate levels were positively correlated with enhanced amino acid and carbohydrate metabolism but were negatively correlated with decreased fatty acid metabolism.
Conclusion: These results suggest that BRBs may induce systemic changes that affect energy generating pathways. This study supports the hypothesis that BRBs might be beneficial to colorectal cancer patients through altering multiple intrinsic metabolic pathways.
Citation Format: Pan Pan, Chad W. Skaer, Steven M. Stirdivant, Matthew R. Young, Gary D. Stoner, John F. Lechner, Yi-Wen Huang, Li-Shu Wang. Beneficial regulation of metabolic profiles by black raspberries in human colorectal cancer patients. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B80.
Abstract IA06: De novo purine biosynthesis dictates glutamine dependency of glioblastoma cells
Authors: Gottlieb Eyal 
Published: May 2016

Abstract
L-Glutamine has the unique physiological function of balancing carbon and nitrogen requirements of tissues. It has been proposed that cancer cells undergoing aerobic glycolysis require glutamine carbons to replenish the tricarboxylic acid (TCA) cycle and sustain accelerated anabolism (anaplerosis). Yet we showed that, in glioblastoma (GBM) cells, about half of the glutamine-derived glutamate is secreted out of the cells and does not enter the TCA cycle. In the absence of glutamine, replenishment of the TCA cycle is insufficient to restore cell proliferation. In contrast, cataplerotic reactions culminating with the conversion of glutamate to glutamine by Glutamine Synthetase (GS) are sufficient to sustain growth in the absence of glutamine. GS is expressed in ~80% of human GBM tumours, and 13C-glucose tracing showed that GS utilizes TCA cycle-derived carbons to produce glutamine in patients. GS-derived glutamine provides the amide nitrogen for de novo biosynthesis of nucleotides and thereby dictates GBM dependency on glutamine.
Citation Format: Eyal Gottlieb. De novo purine biosynthesis dictates glutamine dependency of glioblastoma cells. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA06.
Abstract IA13: The LKB1-AMPK pathway reprograms cancer cell metabolism
Authors: Shaw Reuben J. 
Published: May 2016

Abstract
The serine/threonine kinase LKB1 is a tumor suppressor gene mutated in the familial cancer condition Peutz-Jeghers syndrome, as well as in 30% of non-small cell lung cancer (NSCLC). One of the critical substrates of LKB1 is AMPK, a highly conserved sensor of cellular energy status that restores metabolic homeostasis following stress. Thus LKB1 is a unique energy-state sensitive regulator of growth and metabolic reprogramming via its effects on AMPK. Our laboratory has performed a three-pronged screen to identify novel substrates of AMPK and related kinases that may mediate LKB1 effects on tumor suppression, metabolism, and metastasis. These findings have also spurred examination of whether compounds that activate AMPK may exhibit anti-cancer activities. Notably, the most widely used type 2 diabetes therapeutic in the US and worldwide, metformin, is a mitochondrial OXPHOS inhibitor that activates AMPK. We have therefore examined the potential anti-cancer effects of metformin and compounds against other metabolic targets.
Citation Format: Reuben J. Shaw. The LKB1-AMPK pathway reprograms cancer cell metabolism. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA13.
Abstract B04: Early detection of ovarian cancer recurrence using p53-mutated circulating tumor DNA as non-invasive biomarkers.
Authors: Lee Ha-Young , Lee Shin-Wha , Na Geum-Hee , Lee Sang-Eun , Kang Dong-Woo , Kim Yong-Man 
Published: May 2016

Abstract
Objectives: Epithelial ovarian cancer is the most lethal gynecologic cancer and it has a very high recurrence rate. Early detection of recurrence is very important as well as good treatment; however, the accuracy of CA-125 is approximately 50%. Circulating cell-free DNA (cfDNA) carrying tumor-specific somatic alterations, as called circulating tumor DNA (ctDNA), can be isolated from human body fluids. Recently, ctDNA is emerging as a new generation of non-invasive cancer biomarker Moreover ctDNA could be a more sensitive and specific biomarker than CA-125 in epithelial ovarian cancer. According to The Cancer Genome Atlas (TCGA) data, 95% of high-grade serous ovarian cancer (HGS-OC) has mutations in the p53 gene. This study is to investigate that p53-mutated ctDNA could be a biomarker for the early detection of recurrence comparing to CA-125 in HGS-OC.
Procedures: We enrolled 85 patients with suspected ovarian cancer from July 2013 to June 2015 and 51 patients were epithelial ovarian cancer. We monitored the level of p53-mutated ctDNA compared with CA-125 in 25 of 38 patients (66%) with HGS-OC who were receiving surgery and continuing chemotherapy treatment. We used targeted-p53 whole exon sequencing to detect somatic genomic alterations from cancer tissue and used droplet digital polymerase chain reaction (ddPCR) to verify ctDNA in serially collected plasma samples.
Results: We evaluated ctDNA levels as a monitoring method of the response to chemotherapy and tumor progression. We detected p53 mutations in 38 of 51 women (76%) by whole exon sequencing in cancer tissue and somatic genomic alteration of p53 showed in various sites. Ten of twenty-five (40%) patients who were monitored by ctDNA showed increasing levels of p53-mutated ctDNA during or after scheduled chemotherapy. Even though the ctDNA levels of these 10 patients were increased, the levels of CA-125 were still remained in normal range (under 35 Unit/mL). Especially, 3 patients, the disease progression was observed by imaging method after a few months after the increasing ctDNA.
Conclusions: In conclusion, these data suggest that sequential monitoring of p53-mutated ctDNA may have potential as a sensitive and specific biomarker for early detection of recurrence in HGS-OC
Citation Format: Ha-Young Lee, Shin-Wha Lee, Geum-Hee Na, Sang-Eun Lee, Dong-Woo Kang, Yong-Man Kim. Early detection of ovarian cancer recurrence using p53-mutated circulating tumor DNA as non-invasive biomarkers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B04.
Molecular Characterization of the Lipid Genome-Wide Association Study Signal on Chromosome 18q11.2 Implicates HNF4A-Mediated Regulation of the
TMEM241
Gene
Authors: Rodríguez Alejandra , Gonzalez Luis , Ko Arthur , Alvarez Marcus , Miao Zong , Bhagat Yash , Nikkola Elina , Cruz-Bautista Ivette , Arellano-Campos Olimpia , Muñoz-Hernández Linda L. , Ordóñez-Sánchez Maria-Luisa , Rodriguez-Guillen Rosario , Mohlke Karen L. , Laakso Markku , Tusie-Luna Teresa , Aguilar-Salinas Carlos A. , Pajukanta Päivi 
Published: May 2016

Objective—
We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region.

Approach and Results—

We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (
r
2
>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (
P
<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α–binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (
TMEM241
) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (
P
=6.11×10
−07
–5.80×10
−04
). These results were replicated in expression profiles of
TMEM241
from the Multiple Tissue Human Expression Resource (MuTHER; n=856).

Conclusions—

The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional
TMEM241
gene. Our data suggest that decreased transcript levels of
TMEM241
contribute to increased triglyceride levels in Mexicans.
JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells
Authors: Boeckel Jes-Niels , Derlet Anja , Glaser Simone F. , Luczak Annika , Lucas Tina , Heumüller Andreas W. , Krüger Marcus , Zehendner Christoph M. , Kaluza David , Doddaballapur Anuradha , Ohtani Kisho , Treguer Karine , Dimmeler Stefanie 
Published: May 2016

Objective—
Jumonji C (JmjC) domain–containing proteins modify histone and nonhistone proteins thereby controlling cellular functions. However, the role of JmjC proteins in angiogenesis is largely unknown. Here, we characterize the expression of JmjC domain–containing proteins after inducing endothelial differentiation of murine embryonic stem cells and study the function of JmjC domain–only proteins in endothelial cell (EC) functions.

Approach and Results—
We identified a large number of JmjC domain–containing proteins regulated by endothelial differentiation of murine embryonic stem cells. Among the family of JmjC domain–only proteins, Jmjd8 was significantly upregulated on endothelial differentiation. Knockdown of Jmjd8 in ECs significantly decreased in vitro network formation and sprouting in the spheroid assay. JMJD8 is exclusively detectable in the cytoplasm, excluding a function as a histone-modifying enzyme. Mass spectrometry analysis revealed JMJD8-interacting proteins with known functions in cellular metabolism like pyruvate kinase M2. Accordingly, knockdown of pyruvate kinase M2 in human umbilical vein ECs decreased endothelial sprouting in the spheroid assay. Knockdown of JMJD8 caused a reduction of EC metabolism as measured by Seahorse Bioscience extracellular flux analysis. Conversely, overexpression of JMJD8 enhanced cellular oxygen consumption rate of ECs, reflecting an increased mitochondrial respiration.

Conclusions—
Jmjd8 is upregulated during endothelial differentiation and regulates endothelial sprouting and metabolism by interacting with pyruvate kinase M2.
Regional Influences of Natural External Forcings on the Transition from the Medieval Climate Anomaly to the Little Ice Age
Authors: Andres Heather J. , Peltier W. R. 
Published: May 2016

Abstract
Reconstructions of historical climate changes indicate that surface air temperatures decreased over the preindustrial last millennium. Conflicting explanations have been proposed for the cause of the transition from the Medieval Climate Anomaly (MCA) in the early part of the last millennium to the Little Ice Age (LIA) near its end. The possible causes include volcanic emissions, total solar irradiance (TSI) variations, greenhouse gas concentration fluctuations, and orbital forcing variations. In the present paper, it is demonstrated that all of these climate forcings contribute significantly to simulated surface air temperature (SAT) and sea ice concentration changes over this period. On the other hand, simulated ocean heat content appears to respond significantly only to volcanic and TSI variations.
In model simulations at T85 spectral resolution, TSI reductions and volcanic emissions together generate significant increases in sea ice extent in the Barents Sea, which is found to be responsible for most of the temperature reductions over northwestern Europe. TSI appears less important to Arctic sea ice and SAT changes in simulations at T42 spectral resolution, which are weaker than at T85 resolution. Such resolution dependence is attributed to differences in background conditions in the responses to these external climate forcings. Nonlinearities in the forcing responses and sensitivities to background conditions challenge the assumption that sensitivity tests for given forcings can be run independently. Additionally, it is demonstrated that an ensemble of model simulations is required to isolate forcing responses even over a period as long as the last millennium.