bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B40: Effect of Sasa quelpaertensis leaf extracts on the gut microbiota in dextran sodium sulfate-induced colitis in mice
Authors: Yeom Yiseul , Kim Yuri
Published: May 2016

Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are chronic inflammatory disorders of gastrointestinal tract. Although the etiology of IBD is not clear, it may be associated with genetics and lifestyle factors, diet and gut microbiome. In particular, the imbalance among the immune system and gut microbiota and diet may play a key role in developing IBD. Sasa quelpaertensis leaves have shown anti-inflammatory and anticarcinogenic effects, although the effect of these leaves on gut microbiota in colitis remains unclear. The present study hypothesized that Sasa quelpaertensis leaves extract (SQE) exerts a protective effect against a dextran sulfate sodium (DSS)-induced colitis in mice through modulating gut microbiota. SQE (100 mg/kg or 300 mg/kg b.w.) were pre-treated to mice by gavage two weeks before inflammation which was induced by 2.5% DSS in drinking water for two cycles of each 7 days and tap water for 7 days was provided between DSS treatment. Disease activity index (DAI), colon length were measured and microbiota were analyzed using pyrosequencing in fecal samples. SQE attenuated the severity of DSS-induced colitis. In addition, SQE group had more Firmicutes in phylum level compared to DSS group, Bacteroidetes/Firmicutes ratio of DSS group was significantly higher than control and SQE groups. Furthermore, major microbiota compositions were different in class, family, genus, and species level among control, DSS control, and SQE group. Estimator of community richness, the OTUs, in DSS group tended to lower compared with SQE groups and estimator of evenness and diversity, Chao-1, ACE, Shannon, NP Simpson, were significantly lower in DSS group compared with SQE groups (p<0.05). Our results suggest that SQE affects microbiome composition and number change on DSS-induced colitis mouse model, these change in the microbiome may be beneficial and can be an effective strategy for prevention of IBD (This work was conducted with the support of the Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ009777) Rural Development Administration, Republic of Korea, and the Brain Korea 21 Plus (Project No. 22A20130012143).

Citation Format: Yiseul Yeom, Yuri Kim. Effect of Sasa quelpaertensis leaf extracts on the gut microbiota in dextran sodium sulfate-induced colitis in mice. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B40.
Abstract IA05: Polycomb repressive complex-2 is a barrier to Kras-driven inflammation and epithelial-mesenchymal transition in non-small cell lung cancer
Authors: Serresi Michela , Gargiulo Gaetano , Proost Nathalie , Siteur Bjorn , Cesaroni Matteo , Koppens Martijn , Xie Huafeng , Sutherland Kate , Hulsman Danielle , Citterio Elisabetta , Orkin Stuart , Berns Anton , Lohuizen Maarten van
Published: May 2016

Polycomb repressive complexes (PRC) are frequently implicated in human cancer acting either as oncogenes or tumor suppressors. Here we show that PRC2 is a critical regulator of Kras-driven non-small-cell lung cancer (NSCLC) progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances Kras-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell autonomous epithelial-to- mesenchymal transition (EMT) program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt-signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application.

Citation Format: Michela Serresi, Gaetano Gargiulo, Nathalie Proost, Bjorn Siteur, Matteo Cesaroni, Martijn Koppens, Huafeng Xie, Kate Sutherland, Danielle Hulsman, Elisabetta Citterio, Stuart Orkin, Anton Berns, Maarten van Lohuizen. Polycomb repressive complex-2 is a barrier to Kras-driven inflammation and epithelial-mesenchymal transition in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA05.
Abstract IA06: Stem cells in mammalian epidermis
Authors: Watt Fiona M.
Published: May 2016

Multiple epidermal stem cell subpopulations in adult mouse skin have been identified over the last decade. Although they are all competent to give rise to all the different epidermal lineages following transplantation, wounding or genetic modification, under steady state conditions they maintain the epidermis in a compartmentalized manner. Stem cells in the lower hair follicle express LGR5, while stem cells in the upper follicle express LGR6 and cells in the junctional zone express LRIG1. In addition, a subset of stem cells in the interfollicular epidermis expresses LGR6. In my presentation I will discuss the consequences of selectively expressing activated beta-catenin in the different epidermal stem cell populations.

Citation Format: Fiona M. Watt. Stem cells in mammalian epidermis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA06.
Abstract IA10: Notch signaling and cancer
Authors: Junker Fabian , Lehal Rajwinder , Frimantas Viktoras , Bornhauser Beat C. , Bourquin Jean-Pierre , Koch Ute , Radtke Freddy
Published: May 2016

Cancer can be seen as disease of perturbed self-renewal. In the last decades it became clear that many of the signaling pathways known to be important during embryonic development also play important roles in regulating self-renewing tissues. Deregulation of the self-renewal process results in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis all of which are hallmarks of cancer. The major question is how do these deregulated signaling cascades mechanistically contribute to cancer and are they suitable for targeting therapy?

The Notch pathway is one such cascade required for normal stem cell maintenance and development of different organs. Over activation of this pathway due to mutations in the Notch receptor are found in more than 50% of human T-cell leukemia and deregulated Notch signaling has been shown to promote tumor progression of various organs. The oncogenic mediators of aberrant Notch function in T-ALL and other Notch-driven cancers appear to be manifold and complex. The modulatory function of individual miRNAs in Notch driven T-ALLs has recently been established. However, whether Dicer1-processed miRNAs are essential for Notch-driven T-ALL is currently unknown. We used conditional and inducible genetic loss of function approaches to show that development and maintenance of Notch-driven T-ALL is dependent on Dicer1 function. Lineage tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. Herein, we demonstrate that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4.

Moreover, we will report on the identification of a novel small molecule inhibitor (CB103) that blocks Notch signaling by interfering with the transcriptional activation complex. The compound CB103 has shown remarkable ability to block Notch signaling in human cancer cell lines as well as primary human T-ALL cells, thus abrogating their proliferative properties. In addition, compound CB103 exhibit in vivo activity as demonstrated by its ability to impinge upon Notch dependent developmental processes and by impeding tumor growth in xenograft models of human leukemia and breast cancer.

Citation Format: Fabian Junker, Rajwinder Lehal, Viktoras Frimantas, Beat C. Bornhauser, Jean-Pierre Bourquin, Ute Koch, Freddy Radtke. Notch signaling and cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA10.
Abstract IA16: SWI/SNF (BAF) complex mutations in cancer
Authors: Roberts Charles W. M.
Published: May 2016

Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription.

My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented.

Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) complex mutations in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA16.
Abstract A14: Role of mitochondrial folate metabolism in cancer cell growth and proliferation
Authors: Ducker Gregory S. , Esposito Mark B. , Kang Yibin , Rabinowitz Joshua D.
Published: May 2016

Introduction: Increased expression of mitochondrial folate enzymes, especially mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2), is one of the most consistent gene expression changes in human tumors. Folate metabolism is a major consumer of serine, the primary donor of one-carbon units. One-carbon units generated from serine in the mitochondrion can be transferred into the cytosol as formate for use in cytosolic biosynthesis. Using genetics and quantitative metabolic methods, we examined the role of mitochondrial folate metabolism in cell growth in culture and in xenografted tumors.

Methods: Using CRISPR-Cas9 technology, we created deletion mutant cell lines for enzymes in folate metabolism. Cells deleted for MTHFD2 were grown as xenografts in mice. Metabolites from cultured cells and xenografts were analyzed by liquid chromatography mass spectrometry (LC-MS).

Results: Mitochondrial folate metabolism is not required for growth in standard tissue culture media conditions. The reversal of the direction of cytosolic one-carbon flux enables rapid cell growth of MTHFD2 mutants albeit with metabolic hallmarks of 10-formyltetrahydrofolate deficiency. However, MTHFD2 deletion cells are, as previously shown, glycine auxotrophs and under those conditions show metabolic hallmarks of oxidative stress. Exogenous formate rescues the 10-formyltetrahydrofolate deficiency but not the glycine auxotrophy. Additionally, we find these cells are also growth impaired under low serine conditions. Importantly, compared to paired wild type tumors, growth of MTHFD2 mutant subcutaneous xenografts was markedly reduced.

Conclusions: Mitochondrial folate metabolism is conditionally required for rapid cell growth. High expression of mitochondrial folate genes in cancer may function to meet requirements for one-carbon units, glycine, or redox homeostasis under nutrient stress.

Citation Format: Gregory S. Ducker, Mark B. Esposito, Yibin Kang, Joshua D. Rabinowitz. Role of mitochondrial folate metabolism in cancer cell growth and proliferation. [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 A14.
Abstract A17: Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth
Authors: Jin Lingtao , Li Dan , Alesi Gina , Fan Jun , Kang Hee-Bum , Zhou Lu , Boggon Titus , Jin Peng , Egnatchik Robert , DeBerardinis Ralph , Magliocca Kelly , He Chuan , Arellano Martha , Khoury Hanna , Shin Dong , Khuri Fadlo , Kang Sumin
Published: May 2016

How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1), commonly upregulated in human cancers, is predominantly important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate (a-KG) and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a ROS scavenging enzyme glutathione peroxidase 1 (GPx1) to regulate redox homeostasis, which provides a proliferative advantage to cancer cells and tumor growth. Our findings not only provide novel insights into understanding of the role of glutaminolysis in redox homeostasis but also suggest a novel signaling function of fumarate that regulates GPx1, allowing additional crosstalk between glutaminolysis, TCA cycle and redox status. Targeting GDH1 by shRNA or a newly identified small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth. Thus, our findings provide proof-of-principle suggesting GDH1 as a promising therapeutic target in the treatment of human cancers associated with elevated glutamine metabolism.

Citation Format: Lingtao Jin, Dan Li, Gina Alesi, Jun Fan, Hee-Bum Kang, Lu Zhou, Titus Boggon, Peng Jin, Robert Egnatchik, Ralph DeBerardinis, Kelly Magliocca, Chuan He, Martha Arellano, Hanna Khoury, Dong Shin, Fadlo Khuri, Sumin Kang. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. [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 A17.
Abstract A48: Metabolic adaptations to serine starvation
Authors: Labuschagne Christiaan F. , Maddocks Oliver D.K. , Vousden Karen H.
Published: May 2016

Folate dependent one carbon metabolism is essential for cell growth and proliferation and provides building blocks for nucleotide synthesis, NADPH production and methylation of DNA, protein and lipids. The non-essential amino acid serine is an important one-carbon donor and although cells can make serine, many cancer cell lines that have not up-regulated the de novo serine synthesis pathway are dependent on exogenous serine for optimal growth. Indeed, many rapidly proliferating cancer cells take up high quantities of serine from the external environment to support one-carbon metabolism. Using a genetically engineered mouse tumor model, we have now also shown that intestinal tumors in vivo take up more serine than surrounding normal tissue.

Through metabolic analysis and by measuring enzyme expression, we investigated how cancer cells adapt to serine starvation. We have found that cells prioritize different metabolic processes during serine starvation, favouring NADPH production over anabolic pathways such as nucleotide synthesis.

Citation Format: Christiaan F. Labuschagne, Oliver D.K. Maddocks, Karen H. Vousden. Metabolic adaptations to serine starvation. [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 A48.
Abstract A53: Antiproliferative, antiangiogenic and proapoptotic actions qualify Nigella sativa as taxane therapy adjuvant in ovarian cancer
Authors: Mathur Rajani , Tiwari Mukesh
Published: May 2016

Taxane {Docetaxel (DTX), Paclitaxel (PTX)} based standard chemotherapeutic management of ovarian cancer faces the limitations of resistant phenotype and systemic toxicity. To explore potential agents for adjuvant drug therapy, ethanolic extract of seeds of medicinal plant-Nigella sativa (NS) and Thymoquinone (THM), an isolated volatile oil from its seeds are investigated here against Human Epithelial Ovarian Cancer cell line (SKOV3).

Using SKOV3 cells, grown and maintained under standardised protocols of cell culture, the anti-proliferative effect of DTX, PTX, NS and THM was evaluated individually at 4µM, 4µM, 100µg and 100µM respectively. Combination of DTX(2µM)/PTX(2µM)+NS(50µg)/THM(50µM) were evaluated at sub IC50 for anti-proliferative activity and putative mechanistic basis (IL-8, TNFα, VEGF, Bcl2, Bax).

Here, IC50 value of DTX, PTX, NS and THM is reported as 4.7µM, 5.3µM, 71.8µg and 0.11pM, respectively. Cytotoxicity of DTX+NS/THM and PTX+NS/THM was 54.22,59.85, 55.5 and 60.36%, respectively that was greater than either DTX , PTX, NS or THM at 48.24, 47.18, 59.4 and 48.35% respectively.

Following 24 hr treatment, DTX, PTX, NS, THM and DTX/PTX+NS/THM significantly induced levels of IL-8 and pro-apoptotic protein Bax, but, reduced secretion of TNF-α, VEGF and anti-apoptotic protein Bcl-2 vs control.

Agents that interact synergistically or additively with chemotherapeutic drugs can be used as adjuvants in cancer chemotherapy to act by multi-targeted therapeutic approach so as to reduce dose, side effects and resistance. Cytokines such as IL-8, TNF-α, VEGF are important components of tumor microenvironment and play major role in cancer invasion, angiogenesis and metastasis. Bax and Bcl-2 are proteins of apoptotic pathway that check for cell survival and senescence. Anti-proliferative, anti-angiogenic and pro-apoptotic activities of NS and THM, unequivocally demonstrates their potential as adjuvants for taxane therapy in ovarian cancer.

Combination of NS and THM with DTX and PTX stalls SKOV3 growth through IL-8, TNF-α, VEGF and Bax/Bcl-2 mediated pathways.

Citation Format: Rajani Mathur, Mukesh Tiwari. Antiproliferative, antiangiogenic and proapoptotic actions qualify Nigella sativa as taxane therapy adjuvant in ovarian cancer. [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 A53.
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

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

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

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

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

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

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

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

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.
No Evidence of Human Polyomavirus 9, WU and KI DNA in Kidney and Urinary Bladder Tumour Tissue Samples
Authors: Csoma Eszter , Bidiga László , Méhes Gábor , Gergely Lajos
Published: May 2016

Background/Aims: The oncogenic potential of human polyomaviruses (HPyVs) has been proposed, but so far only Merkel cell carcinoma polyomavirus seems to be associated with a human tumour. The role of BK polyomavirus (BKPyV) in human tumourigenesis remains controversial. BKPyV establishes persistent infection in the urinary tract, and renal and bladder neoplasms have been studied extensively, but conflicting prevalence data are reported. KI, WU and HPyV9 were detected in urine samples suggesting that these viruses may also infect the urinary tract, but their presence in urinary tract tumours has not been studied. The aim of this work was to examine the prevalence of KIPyV, WUPyV, HPyV9 and BKPyV by PCR in renal and bladder neoplasms. Methods: A total of 190 formalin-fixed paraffin-embedded renal neoplasms, bladder cancer and kidney biopsy samples were analysed for the presence of BKPyV, KIPyV, WUPyV and HPyV9 DNA by real-time and nested PCR. Results: Amplifiable DNA was extracted from all the samples, but none of the studied viruses were detected in benign renal neoplasia (0/23), malignant renal tumours (0/89) or bladder cancer (0/76). Conclusion: Our study did not find any evidence that BKPyV, KIPyV, WUPyV or HPyV9 are associated with bladder and renal tumours.
Genetic Variants in Toll-Like Receptor 4 Gene and Their Association Analysis with Estimated Glomerular Filtration Rate in Mexican American Families
Authors: Thameem Farook , Puppala Sobha , Farook Vidya S. , Kasinath Balakuntalam S. , Blangero John , Duggirala Ravindranath , Abboud Hanna E.
Published: May 2016

Background/Aim: Toll-like receptor 4 (TLR4) is one of the regulators of the innate immune response. Genetic variations in TLR4 have been associated with inflammatory diseases, including type 2 diabetes. However, to our knowledge, there are no reports on the role of variations in TLR4 in chronic kidney disease susceptibility. The objective of this study is to determine whether the genetic variants in TLR4 are associated with the estimated glomerular filtration rate (eGFR), a measure of renal function. Methods: To evaluate the association between TLR4 variants and eGFR, we used data obtained from 434 Mexican American participants from the San Antonio Family Diabetes/Gallbladder Study. GFR was estimated using the Modification of Diet in Renal Disease formula. The Asp(299)Gly (rs4986790) and Thr(399)Ile (rs4986791) variants of TLR4 were genotyped using the TaqMan assay. Association analyses between genotypes and eGFR were performed using the measured genotype approach. Results: Of the two genetic markers examined for association, only the Asp(299)Gly variant of TLR4 exhibited a nominally significant association with eGFR (p = 0.025) after accounting for the covariate effects of age and sex terms, diabetes, duration of diabetes, systolic blood pressure, body mass index, and antihypertensive treatment. Carriers of Gly299 had significantly decreased eGFR values. Although, the Thr(399)Ile variant failed to exhibit a statistically significant association with eGFR, the carriers of Ile399, however, showed a trend towards decrease in eGFR. Conclusion: We show for the first time that Asp(299)Gly variants of TLR4 are associated with decrease in renal function in Mexican Americans.
Os estudos de bioequivalência: Relevância para a medicina veterinária
Authors: Palermo-Neto João , Righi Dario Abbud
Published: May 2016

Os estudos de Bioequivalência (BE) são utilizados para a comparação de diferentes produtos farmacêuticos que contêm o mesmo princípio ativo, de diferentes lotes de um mesmo produto ou, ainda e de uma maneira ampla, de diferentes vias de administração de um mesmo medicamento. No Brasil dos dias de hoje, encontramos legislações sobre medicamentos genéricos e bioequivalência apenas na área de Medicina Humana. No campo da Medicina Veterinária, os testes de BE têm sido considerados, em muitos países, como requerimentos necessários para o registro de produtos destinados aos animais visto que eles asseguram, ao mesmo tempo, a eficácia do produto, a saúde dos animais tratados e a qualidade dos alimentos provenientes desses animais. O presente trabalho faz uma revisão crítica sobre BE. Para tanto, o assunto foi dividido em três grandes partes: 1- Entendendo a bioequivalência: importância de estudos de BE para a saúde animal e humana; 2- tipos de estudos de BE; 3- considerações gerais sobre delineamentos experimentais que envolvam estudos de bioequivalência
Análise da associação da escolaridade com renda e com cuidados de saúde e ectoparasitismo em cães na cidade de Araguaína, Tocantins
Authors: Baptista Francisco , Souto Monalisa De Sousa Moura , Morais Arielle Nunes , Barros Raimunda De Sousa Canêdo , Schneider Adayanna Karolline Moreira
Published: May 2016

Um inquérito epidemiológico realizado em 2005, na cidade de Araguaína, Estado do Tocantins, revelou existir associação entre escolaridade e renda de proprietários de cães (p;0,05). No grupo de proprietários com menor escolaridade, o aumento da instrução formal, para nove ou mais anos, pode reduzir o número de cães sem confinamento, vacinação (exceto contra a raiva) ou vermifugação em 23,3% (IC95%=10,9-35,2), 30,5% (IC95%=18,7-41,1) e 22,3% (IC95%=10,7-33,2), respectivamente; no conjunto de proprietários de cães esta redução pode ser, na mesma ordem, de 10,7% (IC95%=0,8-19,3), 14,3% (IC95%=3,9-24,3) e 10,7% (IC95%=1,0-19,5). A promoção sócio-econômica regional, com mais ações de educação sanitária e aumento da escolaridade, é condição essencial para a melhoria da saúde dos cães e, conseqüentemente, da saúde pública.
Eletroforese de proteínas séricas de tartarugas cabeçudas (Caretta caretta) de vida livre e mantidas em cativeiro no litoral norte da Bahia
Authors: Pires Thaís Torres , Rostan Gonzalo , Bittencourt Thereza Cristina Calmon de , Almeida Maria Ângela Ornelas de , Guimarães José Eugênio
Published: May 2016

Este trabalho objetivou a determinação e comparação do perfil eletroforético das proteínas séricas de tartarugas cabeçudas (Caretta caretta), fêmeas, de vida livre (n=20) que desovam no Litoral Norte da Bahia e daquelas mantidas em cativeiro (n=5) no Centro de Visitantes do Projeto Tamar-Ibama da Praia do Forte, Bahia, Brasil. Os valores obtidos para os animais de vida livre para as variáveis foram: proteína total de 3,84±0,56g/dL, albumina 1,39±0,30g/dL, alfa-1 e alfa-2 globulina 0,34±0,09g/dL e 0,42±0,22g/dL, beta globulina 0,57±0,26g/dL e gama globulina 1,16±0,30g/dL, e relação A:G de 0,58±0,16. Para os animais cativos estes valores foram de: proteína total 4,98±1,31g/dL, albumina 1,64±0,55g/dL, enquanto que para as frações alfa-1, alfa-2, beta e gama globulinas de 0,39±0,24g/dL, 0,68±0,44g/dL, 0,68±0,13g/dL e 1,59±0,31g/dL, respectivamente; e para a relação A:G de 0,49±0,08. Avaliando os resultados observaram-se diferenças estatísticas significativas (p<0,05) para os valores de proteína total onde os animais de cativeiro apresentaram níveis mais elevados, o que pode ser atribuído a alimentação rica em proteína oferecida, e para a gama globulina onde o grupo de vida livre obteve valores inferiores, possivelmente devido a uma imunodepressão relacionada ao estresse reprodutivo. Apesar destas diferenças o padrão eletroforético foi semelhante entre os grupos estudados.
Perfil eletroforético das proteínas de fase aguda em caprinos experimentalmente infectados com Trypanosoma evansi
Authors: Patelli Thais Helena Constantino , Marques Luiz Carlos , Fagliari José Jurandir , Silva Paulo César
Published: May 2016

Considerado como um dos principais agentes das tripanossomíases, Trypanosoma evansi causa uma doença genericamente conhecida como "surra" e de ampla distribuição geográfica. Esse trabalho teve como objetivo principal estudar o perfil eletroforético das proteínas de fase aguda de caprinos experimentalmente infectados com este hematozoário. Para tal, foram utilizadas dez fêmeas caprinas, com vários graus de mestiçagem, com idade aproximada de 4 meses, clinicamente sadias e sorologicamente negativas para a presença de anticorpos anti-T. evansi (Reação de Imunofluorescência Indireta - RIFI). Os animais foram divididos em dois grupos: grupo 1 (G1): seis animais inoculados via intravenosa com 2,38 x 10(6) tripomastigotas de T. evansi e grupo 2 (G2): quatro animais utilizados como testemunhos. O sangue para a obtenção do soro foi obtido diariamente até o 14º dia após a inoculação (DAI), semanalmente até o 98º DAI e quinzenalmente até o 364º DAI. O fracionamento das proteínas foi obtido por em gel de poliacrilamida contendo duodecil sulfato de sódio (SDS- PAGE). Vinte e uma proteínas foram encontradas nos soros caprinos. Destas, oito foram nominalmente identificadas; fosforilase, transferrina, albumina, antitripsina, glicoproteína ácida, haptoglobina, hemoglobina e imunoglobulina de cadeia leve.