bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-220: Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma
Authors: Napolitano A. , Pellegrini L. , Dey A. , Larson D. , Tanji M. , Flores E. G. , Kendrick B. , Lapid D. , Powers A. , Kanodia S. , Pastorino S. , Pass H. I. , Dixit V , Yang H. , Carbone M.
Published: August 2015

Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma (MM). MM pathogenesis is generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after even minimal exposure.

In a set of short-term experiments, we intraperitoneally injected BAP1+/- and wild-type littermates with low doses of asbestos fibers and analyzed the inflammatory response both at a cellular and humoral level. In a long-term experiment following a similar protocol, we assessed the incidence of MM in mice with and without germline BAP1 mutations and their survival.

We found that, compared to their wild type littermates, BAP1+/- mice exposed to low doses of asbestos fibers showed significant alterations of the peritoneal inflammatory response. In particular, we observed significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1+/- mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, and shorter survival.

Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.

Citation Format: A. Napolitano, L. Pellegrini, A. Dey, D. Larson, M. Tanji, E. G. Flores, B. Kendrick, D. Lapid, A. Powers, S. Kanodia, S. Pastorino, H. I. Pass, V Dixit, H. Yang, M. Carbone. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-220. doi:10.1158/1538-7445.AM2015-LB-220
Abstract LB-235: Therapeutic human papillomavirus vaccine design based on epitopes identified on the tumor cell surface by mass spectrometry
Authors: Hoppe Stephanie , Blatnik Renata , Schessner Julia P. , Dressler Lisa , Steinbach Alina , Winter Jan , Wuehl Martin , Klevenz Alexandra , Khallouf Hadeel , Riemer Angelika B.
Published: August 2015

Detailed knowledge about T cell epitopes, which are bona fide presented on the surface of human papillomavirus (HPV)-transformed cells, is essential for rational design of therapeutic HPV vaccines. HPV affects the cellular antigen processing machinery, thus not every epitope derived from viral proteins is presented on human leukocyte antigen (HLA) molecules. Even the presented epitopes are displayed in low abundance.

In this study, we developed a highly sensitive nano-UPLC-ESI-MS3 multiple-reaction monitoring mass spectrometry (MS) approach for direct detection of low-abundant epitopes on the cell surface. Several web-based prediction algorithms were used to predict prospective epitopes from the HPV16 E6 and E7 proteins. These candidate epitopes were tested for actual HLA binding in cellular binding assays. The presence of binding peptides on HPV16-transformed cells was analyzed by our MS technology. Immunogenicity of candidate peptides was assessed in vitro with short-term and long-term T cell line experiments, generated from peripheral blood mononuclear cells of healthy donors, and in vivo for a selected HLA-A2-restricted epitope in HLA-A2/DR-1 transgenic mice.

To ensure >95% population coverage, prospective HPV epitopes were predicted for the HLA supertypes HLA-A1, A2, A3, A11, A24, B7, and B15. Close to 500 peptides were tested in competition-based binding assays and multiple novel binders were identified. MS epitope detection was first established for HLA-A2 epitopes, and is now extended to the other supertypes. In the immunogenicity assays, several peptides induced robust IFN-γ responses.

In conclusion, several new HPV16 E6 and E7 epitopes were identified and validated in this study. They represent promising candidates for inclusion into a therapeutic HPV vaccine. Validated epitopes are the basis of rational therapeutic vaccine design and are also important for immunomonitoring purposes.

Citation Format: Stephanie Hoppe, Renata Blatnik, Julia P. Schessner, Lisa Dressler, Alina Steinbach, Jan Winter, Martin Wuehl, Alexandra Klevenz, Hadeel Khallouf, Angelika B. Riemer. Therapeutic human papillomavirus vaccine design based on epitopes identified on the tumor cell surface by mass spectrometry. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-235. doi:10.1158/1538-7445.AM2015-LB-235
Abstract LB-239: The Hippo effector YAP promotes resistance to RAF and MEK targeted therapies
Authors: Lin Luping , Sabnis Amit , Chan Elton , Olivas Victor , Cade Lindsay , Pazarentzos Evangelos , Asthana Saurabh , Neel Dana , Yan Jenny Jiacheng , Lu Xinyuan , Pham Luu , Wang Mingxue , Karachaliou Niki , Cao Maria G. , Manzano Jose L. , Ramirez Jose L. , Torres Jose M. , Buttitta Fiamma , Rudin Charles M. , Collisson Eric A. , Algazi Alain , Robinson Eric , Osman Iman , Munoz-Couselo Eva , Cortes Javier , Frederick Dennie T. , Cooper Zachary A. , McMahon Martin , Marchetti Antonio , Rosell Rafael , Flaherty Keith T. , Wargo Jennifer A. , Bivona Trever G.
Published: August 2015

Resistance to RAF-MEK targeted therapy is a major clinical challenge. RAF-MEK inhibitors are initially but only transiently effective in some but not all BRAF mutant patients, and largely ineffective in RAS mutant patients because of resistance. Through a genetic screen in BRAF mutant tumor cells, we show that the Hippo pathway effector YAP acts as a parallel survival input to promote resistance to RAF-MEK inhibitor therapy. Combined YAP and RAF-MEK inhibition was synthetically lethal not only in several BRAF mutant tumor types but also in RAS mutant tumors. Increased YAP in BRAFV600E patient tumors was a biomarker of worse initial response to RAF inhibition in patients, establishing the clinical relevance of our findings. Our data uncover YAP as a novel mechanism of resistance to RAF-MEK targeted therapy. The findings unveil the synthetic lethality of YAP and RAF-MEK co-suppression as a promising strategy to enhance response and patient survival.

Citation Format: Luping Lin, Amit Sabnis, Elton Chan, Victor Olivas, Lindsay Cade, Evangelos Pazarentzos, Saurabh Asthana, Dana Neel, Jenny Jiacheng Yan, Xinyuan Lu, Luu Pham, Mingxue Wang, Niki Karachaliou, Maria G. Cao, Jose L. Manzano, Jose L. Ramirez, Jose M. Torres, Fiamma Buttitta, Charles M. Rudin, Eric A. Collisson, Alain Algazi, Eric Robinson, Iman Osman, Eva Munoz-Couselo, Javier Cortes, Dennie T. Frederick, Zachary A. Cooper, Martin McMahon, Antonio Marchetti, Rafael Rosell, Keith T. Flaherty, Jennifer A. Wargo, Trever G. Bivona. The Hippo effector YAP promotes resistance to RAF and MEK targeted therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-239. doi:10.1158/1538-7445.AM2015-LB-239
Abstract LB-241: HGF promotes resistance to MET inhibitor AMG337 in MET-amplified gastric cancer cells
Authors: Gordon Marcia , Croft Alexandra , Li Chi-Ming , Taylor Sean , Caenepeel Sean R. , Quon Kim
Published: August 2015

The MET oncoprotein is a tyrosine kinase that is the only known receptor for its ligand, HGF (Hepatocyte Growth Factor). In approximately 5% of gastric cancers, MET is activated by focal amplification, rendering it constitutively active and ligand independent. MET-amplified cancer cell lines and xenografts are typically dependent on MET signaling for proliferation or survival. To test this dependency in patients, a number of small molecule MET inhibitors, including AMG337, are currently undergoing clinical evaluation for the treatment of MET-amplified tumors.Here we characterize resistance mechanisms to MET inhibitor AMG337 in vitro. We show that under standard culture conditions, resistance does not readily arise in MET-amplified gastric cell lines SNU620 and MKN45 treated with a therapeutic dose (>IC90) of AMG337. Surprisingly however, exogenous recombinant human HGF enables resistance to readily appear, with emergent cultures possessing resistance mutations in the MET activation loop at positions D1228 and Y1230. Phosphoprotein analysis shows that HGF increases autophosphorylation and activation of mutant MET sufficiently to drive cell proliferation even in the presence of AMG337.Notably, deep sequencing and clonal analysis of individually barcoded cells show that pre-existing mutant clones are likely present in cultures prior to drug treatment. However, such clones are unable to robustly proliferate in drug-containing media unless HGF is present. Based on copy number analysis, we propose that a single or small number of pre-existing mutant MET alleles in an individual cell is sufficient to drive resistance in the presence of exogenous HGF. In contrast, in HGF-negative media, a single mutant MET allele is insufficient and thus resistance does not readily arise unless gradual drug dose escalation protocols that select for increased mutant MET copy number are employed.Our results identify a key mechanism by which HGF can promote resistance to MET inhibitors in MET-amplified cancer cell lines. Because HGF is present in tumor microenvironments, combining anti-HGF antibodies with maximally-tolerated doses of small molecule MET inhibitors such as AMG337 may be beneficial in preventing resistance and in promoting durable responses.

Citation Format: Marcia Gordon, Alexandra Croft, Chi-Ming Li, Sean Taylor, Sean R. Caenepeel, Kim Quon. HGF promotes resistance to MET inhibitor AMG337 in MET-amplified gastric cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-241. doi:10.1158/1538-7445.AM2015-LB-241
Abstract LB-248: Protein arginine methyltransferase 5 (PRMT5) inhibition as a therapeutic strategy in B-cell lymphoma
Authors: Barbash Olena , Gerhart Sarah , Soong David , Thompson Christine , Montes de Oca Rocio , Zhang Ping , McHugh Charles , Kuplast Kristy , Majer Christina , Chesworth Richard , Smith Jesse , Copeland Robert , Penebre Elayne , Duncan Kenneth , Johnson Neil , Carpenter Chris , Kruger Ryan
Published: August 2015

PRMT5 is responsible for symmetric dimethylation of arginine residues in glycine and arginine rich (GAR) motifs on a variety of cytosolic and nuclear proteins including histones, spliceosome components, regulators of translation, transcription factors, kinases and others. PRMT5 driven methylation of some of these proteins has been implicated in tumorigenesis. For example, PRMT5 deposits repressive marks on histones and silences a subset of tumor suppressor genes, such as RB and ST7. PRMT5 methylation of non-histone substrates (such as E2F1 and p53) also contributes to cancer cell growth and death. PRMT5 driven methylation of spliceosome subunits and components of translational machinery has been well described but its connection to PRMT5's role in cancer has not been established. We have identified first-in-class small molecules that are highly potent, selective, reversible inhibitors of PRMT5. Cellular mechanistic studies revealed that PRMT5 inhibition decreases symmetric arginine dimethylation on a variety of cellular proteins including spliceosome components, histones and transcription factors. PRMT5 inhibition leads to gene expression and splicing changes ultimately resulting in the induction of p53 in lymphoma cell lines. In addition to impacting the p53 pathway, PRMT5 inhibition leads to attenuation of the expression of cell cycle related genes, genes involved in ribosome and spliceosome homeostasis, as well as genes important for cellular metabolism. PRMT5 inhibitor attenuates proliferation and induces cell death in a subset of mantle cell and diffuse large B-cell lymphoma cell lines and inhibits tumor growth in xenograft models of mantle cell lymphoma. These data underline the potential of PRMT5 inhibitors as a therapeutic strategy in mantle cell and diffuse large B-cell lymphoma.

Citation Format: Olena Barbash, Sarah Gerhart, David Soong, Christine Thompson, Rocio Montes de Oca, Ping Zhang, Charles McHugh, Kristy Kuplast, Christina Majer, Richard Chesworth, Jesse Smith, Robert Copeland, Elayne Penebre, Kenneth Duncan, Neil Johnson, Chris Carpenter, Ryan Kruger. Protein arginine methyltransferase 5 (PRMT5) inhibition as a therapeutic strategy in B-cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-248. doi:10.1158/1538-7445.AM2015-LB-248
Abstract LB-254: High-throughput drug matrix screen with SMAC (second mitochondria-derived activator of caspases)-mimetic birinapant in high-grade serous ovarian cancer cell lines identifies synergism
Authors: Bunch Kristen , Goldlust Ian , Thomas Craig , Hernandez Lidia , Guha Rajarshi , Annunziata Christina
Published: August 2015

Background: Inhibitors of apoptosis (IAPs) are attractive anti-cancer therapeutic targets as a mechanism to sensitize cancer cells to apoptosis. IAPs are overexpressed in ovarian cancer and portend a poor prognosis. SMAC- mimetics are IAP antagonists that have shown in vitro and in vivo antitumor activity in ovarian cancer, but preclinical and clinical studies suggest SMAC mimetics may be more effective in combination therapies.

Methods: Birinapant (B) was initially screened in combination with each of 1,912 compounds using an automated acoustic drug dispensation system in 6×6 matrices. Seventy compounds were chosen from the initial screen, based on synergistic characteristics, and verified in 10×10 matrices. The most clinically rational drug combinations with B were further evaluated in 8 high-grade serous ovarian cancer cell lines (CAOV3, CAOV4, OV-90, OVCAR4, OVCAR5, OVCAR8, PEO1, PEO4), focusing on 3 synergistic (docetaxel, panobinostat, volasertib) and 2 antagonistic combinations (cisplatin, olaparib) for exploration of mechanism. Combination index was determined using Compusyn software.

Results: Specific classes of drugs were identified to have synergism with B, including taxanes, HDAC inhibitors, and PLK1 inhibitors, while platinum agents and PARP inhibitors were found to be antagonistic. Four of the 8 cell lines were sensitive to B. Caspase-Glo 3/7 assay was performed in B-sensitive cell lines and confirmed increased caspase-3 activity in the combination treatments. Ongoing studies include genomic analysis, mechanistic interrogation, and in vivo xenograft studies.

Conclusions: B is a promising novel therapy for use in combination treatment for ovarian, fallopian tube, or primary peritoneal cancers. Our findings provide insight on optimal therapies to combine with B, and constitute a foundation for further evaluation of predictive and pharmacodynamic biomarkers to select the patient population most likely

to respond to this targeted therapeutic approach.

Citation Format: Kristen Bunch, Ian Goldlust, Craig Thomas, Lidia Hernandez, Rajarshi Guha, Christina Annunziata. High-throughput drug matrix screen with SMAC (second mitochondria-derived activator of caspases)-mimetic birinapant in high-grade serous ovarian cancer cell lines identifies synergism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-254. doi:10.1158/1538-7445.AM2015-LB-254
Abstract LB-268: Black rapsberries induced protection in pancreatic cancer mouse models
Authors: Pan Pan , Skaer Chad , Wang Hsin Tzu , Tsai Susan , Oshima Kiyoko , Huang Yi-Wen , Stoner Gary , Lechner John , Wang Li-Shu
Published: August 2015

Backgrounds and objectives Pancreatic ductal adenocarcinoma (PDAC) is the 12th most common cancer worldwide with 338,000 new cases diagnosed in 2012. The estimated 5-year survival rate of diagnosed PDAC patients is less than 4%, making it the 7th leading cause of cancer death. Over-expression of epidermal growth factor (EGF) receptors and ErbB2 receptors has been associated with the development and progression of human PDAC. Diets rich in fruits and vegetables have been reported to reduce the risk of PDAC incidence and its recurrence. Our current study aimed to investigate the effects of dietary black raspberries (BRBs) on pancreatic carcinogenesis..

Methods 4-5 weeks old pancreas-specific (Pdx-1-cre) mutant mice that carry constitutively-activated oncogene K-ras (G12D) and loss-of-function tumor-suppressor gene Trp53 (R172H), hereafter refers to KPC mice, were fed with control (n = 26) or 5% BRB (n = 29) diet. In addition, orthotopic pancreatic cancer xenografts were injected with luciferase transfected human Panc-1 cells. Four weeks after Panc-1 cells were injected, these mice were given control (n = 8) or 5% BRB (n = 19) diet for 6 weeks.

Results Kaplan-Meier survival analysis showed that BRBs prolonged survival of KPC mice with a medium survival of 124 days in comparison to 79 days from mice fed with control diet (p = 0.03). Molecular studies suggest that BRBs decreased the activation of EGF receptor and ErbB2 receptor signaling pathways. Further, BRBs significantly suppressed growth of Panc-1 tumors and it was associated with decreased EGF receptor activation.

Conclusion These results suggest that BRBs might protect against carcinogenesis of PDAC through regulating EGF receptor and ErbB2 receptor signaling pathways. Further investigation of the downstream pathways of EGF receptor and ErbB2 receptor activation is warranted.

Citation Format: Pan Pan, Chad Skaer, Hsin Tzu Wang, Susan Tsai, Kiyoko Oshima, Yi-Wen Huang, Gary Stoner, John Lechner, Li-Shu Wang. Black rapsberries induced protection in pancreatic cancer mouse models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-268. doi:10.1158/1538-7445.AM2015-LB-268
Abstract LB-275: Beneficial regulation of metabolic profiles by black raspberries in human colorectal cancer patients
Authors: Pan Pan , Skaer Chad , Stirdivant Steven , Young Matthew R. , Stoner Gary , Lechner John , Huang Yi-Wen , Wang Li-Shu
Published: August 2015

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 Skaer, Steven Stirdivant, Matthew R. Young, Gary Stoner, John 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 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-275. doi:10.1158/1538-7445.AM2015-LB-275
Abstract LB-295: Analysis of miR-21 isomiRs in lung cancer
Authors: Leikin Jennie D. , Zingone Adriana , Brown Derek , Mitchell Khadijah , Khan Mohammed , Vidal Oscar , Ryan Brid
Published: August 2015

microRNAs (miRNA) are small non-coding RNAs that target mRNA transcripts. Primarily, they bind to the 3′UTR of mRNA sequences and repress protein translation. They are involved in the regulation of over 60% of human genes. miRNAs are deregulated in cancer and expression signatures have been correlated with cancer diagnosis, progression and prognosis. Thus, they are being pursued for clinical application. isomiRs, or miRNA variants that are generated post-transcriptionally, were originally classified as experimental error in cloning and next generation sequencing studies. However, over the past five years it has become increasingly clear that isomiRs are evolutionarily conserved, prevalent and functional. miR-21 is overexpressed and associated with poor prognosis in multiple malignancies and as such it is currently under development as a therapeutic target. Thus, we examined the isomiR landscape of miR-21 in lung cancer using data from The Cancer Genome Atlas (lung adenocarcinoma n = 420 and squamous cell carcinoma n = 296). Raw sequence files were extracted from TCGA, cleaned and analyzed using STATA 13. We observed that there are significantly more isomiRs of miR-21 in both lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) compared to non-involved adjacent lung tissue. Specifically, LUAD had total of 244 5p variants and LUSC had 232 5p variants, compared with 74 and 105 in non-involved tissue, respectively. The most prevalent isomiR of miR-21 was not the canonical ‘miRBase’ isomiR and the most common edit was a 5′ deletion with 3′ addition. There were 15 miR-21-5p isomiRs in LUAD and 12 in LUSC that were prevalent (defined as detected in more than 50% of patients) and were expressed at a significantly higher level defined as detected with a FPKM value greater than 50) in tumor versus non-involved tissue samples. The average fold change was 5.7 in LUAD (range 2.8-21.1) and 2.7 in LUSC (range 1.7-5.6). Of the prevalent miR-21-5p isomiRs, 6 in LUAD and 4 in LUSC had a change in the canonical miR-21 seed sequence. An analysis of the targets of these isomiRs using the target prediction algorithms Targetscan and Diana revealed limited overlap in gene targets (0% to 54%) compared with canonical miR-21-5p targets. Our work highlights a high complexity of miRNA sequence heterogeneity in lung cancer. Combining the characterization of miR-21 isomiRs and pursuing translational laboratory studies will allow us to determine the functionality of these isomiRs and their relevance for human cancer diagnosis and treatment.

Citation Format: Jennie D. Leikin, Adriana Zingone, Derek Brown, Khadijah Mitchell, Mohammed Khan, Oscar Vidal, Brid Ryan. Analysis of miR-21 isomiRs in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-295. doi:10.1158/1538-7445.AM2015-LB-295
Abstract PL02-03: Early detection and prevention of liver cancer: Leveraging lessons learned from liver repair
Authors: Diehl Anna Mae E.
Published: August 2015

Liver cancer is currently among the top causes of cancer mortality worldwide and is increasing in both incidence and prevalence.The fact that cirrhosis is the strongest known risk factor for primary liver cancer suggests that injured liver is carcinogenic. The presentation will summarize evidence indicating that liver injury is carcinogenic because it stimulates regenerative responses (e.g., activation of developmental morphogenic signaling pathways) that relax forces which normally constrain the inherent multi-potency of adult liver cells. There are two main take-home messages. First, cirrhosis reflects defective regulation of these normal regenerative responses and thus, sustained tissue enrichment with permissive signals for multi-potency. Second, this cirrhotic microenvironment is particularly advantageous for liver cells with epistatic genetic/epigenetic events which enable escape from counter-regulatory signals that antagonize multi-potency.

Citation Format: Anna Mae E. Diehl. Early detection and prevention of liver cancer: Leveraging lessons learned from liver repair. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr PL02-03. doi:10.1158/1538-7445.AM2015-PL02-03
Abstract SY15-04: Angiogenesis revisited: Endothelial cell metabolism as a target
Authors: Carmeliet Peter
Published: August 2015

Angiogenesis, the growth of new blood vessels, plays a crucial role in numerous diseases, including cancer. Anti-angiogenesis therapies have been developed to starve cancer cells from nutrients. Clinically approved anti-angiogenic drugs prolong the survival of cancer patients, but their success is limited by intrinsic refractoriness and acquired resistance. New strategies are thus needed to block tumor angiogenesis via alternative mechanisms. We recently reported that PFKFB3-driven glycolysis regulates the endothelial cell function and identity during vessel sprouting, even capable of overruling the potent activity of Notch, and that its loss in endothelial cells causes vascular hypobranching defects. Moreover, partial and transient reduction of glycolysis by blocking PFKFB3 reduced pathological angiogenesis in several disease models. Ongoing studies explore the role of lipid and amino acid metabolism in vessel sprouting, and assess the therapeutic potential of targeting these metabolic pathways for anti-angiogenic therapy.

Citation Format: Peter Carmeliet. Angiogenesis revisited: Endothelial cell metabolism as a target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY15-04. doi:10.1158/1538-7445.AM2015-SY15-04
Abstract SY16-02: Clinical whole exome interpretation for precision cancer medicine
Authors: Van Allen Eliezer M.
Published: August 2015

Translating whole exome sequencing (WES) for prospective clinical use may impact the care of cancer patients. However, since this approach greatly expands the quantity of genomic data generated for an individual patient, multiple innovations are necessary for clinical implementation. These include clinical analysis and interpretation of large scale WES data, effective representation of WES data in a clinical environment for physician consumption, and development of knowledge-sharing platforms to ensure effective curation of clinically relevant variants. Here, we describe heuristic methods for the clinical interpretation of WES data. We also discuss approaches that may facilitate physician understanding of WES data in a clinical setting. Finally, we review existing knowledge bases and emerging mechanisms for crowdsourcing variant curation that may enable prospective WES-scale genomic profiling. Overall, this methodology may inform the widespread implementation of precision cancer medicine.

Citation Format: Eliezer M. Van Allen. Clinical whole exome interpretation for precision cancer medicine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY16-02. doi:10.1158/1538-7445.AM2015-SY16-02
Abstract SY36-03: Intraoperative molecular imaging with protease-activated fluorescent imaging agents
Authors: Whitley Melodi J. , Cardona Diana M. , Blazer Dan G. , Hwang Shelley , Greenup Rachel A. , Mosca Paul J. , Cahill Joan , Mito Jeffrey K. , Cuneo Kyle C. , Larrier Nicole , O'Reilly Erin , Spasojevic Ivan , Riedel Richard F. , Eward William C. , Griffith Linda G. , Bawendi Moungi G. , Ferrer Jorge , Strasfeld David B. , Lee W. David , Brigman Brian , Kirsch David G.
Published: August 2015

Intra-operative detection of residual cancer in the tumor bed can be used to decrease the risk of a positive surgical margin, reduce the rate of re-excision, and tailor adjuvant therapy. LUM015 is a pegylated protease-activated imaging agent containing a near infrared fluorophore and quencher attached by a polypeptide linker. Using mouse models of soft tissue sarcoma (STS), we showed that LUM015 selectively localizes to the tumor and upon cleavage of the linker by proteases in the tissue, the quencher is released, allowing fluorescence to be detected.

We recently completed a phase I clinical trial to test the safety of LUM015 in human patients with cancer. This open-label nonrandomized trial compared 3 dose cohorts (0.5, 1.0, and 1.5 mg/kg) of LUM015 in order to determine a safe dose of LUM015 that labels tumors in humans. A total of 15 subjects, 12 with STS and 3 with breast cancer, received IV LUM015 prior to surgical resection without any adverse pharmacological activity (APA). Quantitative fluorescence imaging of the resected tissues revealed that tumor fluorescence was significantly higher than corresponding normal tissue from the same patient (p<0.0001) with a mean tumor to normal fluorescence ratio of 5.4. Furthermore, within the study population, the distribution of tumor fluorescence values was significantly higher than those recorded for fat or muscle (p<0.009).

We conducted comparative analyses of LUM015 pharmacodynamics in mouse and human subjects showing that biodistribution into tumors and activation by proteases is conserved across species. These studies revealed the presence of a novel, small molecule metabolite that correlates strongly with tissue fluorescence. Additional in vivo studies in mice and in vitro studies with mouse and human tissues showed that LUM015 is selectively distributed to and accumulates in tumors to result in increased fluorescence when compared to normal tissues.

Citation Format: Melodi J. Whitley, Diana M. Cardona, Dan G. Blazer, Shelley Hwang, Rachel A. Greenup, Paul J. Mosca, Joan Cahill, Jeffrey K. Mito, Kyle C. Cuneo, Nicole Larrier, Erin O'Reilly, Ivan Spasojevic, Richard F. Riedel, William C. Eward, Linda G. Griffith, Moungi G. Bawendi, Jorge Ferrer, David B. Strasfeld, W. David Lee, Brian Brigman, David G. Kirsch. Intraoperative molecular imaging with protease-activated fluorescent imaging agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY36-03. doi:10.1158/1538-7445.AM2015-SY36-03
Abstract SY42-03: One carbon metabolism and cancer
Authors: Maddocks Oliver , Labuschagne Christiaan , Vousden Karen H.
Published: August 2015

Cancer cells adapt their metabolism to allow for growth and proliferation, while maintaining survival under conditions of fluctuating nutrient availability. Recent studies have shown that cancer cells are highly dependent on the non-essential amino acid serine. We have found a key requirement for serine is to maintain the one carbon cycle needed for nucleotide synthesis. Serine depletion impedes nucleotide synthesis and inhibits proliferation, a response that can be rescued by providing glycine and one-carbon units in the form of formate. More recently, we have been examining the fate of serine and the effect of serine depletion on other pathways that require one-carbon metabolism, such as NADPH production and the methionine cycle. We found that the adaptation to serine starvation involves diversion of glycolytic intermediates into the de novo SSP, resulting in a greater dependence on OXPHOS to provide energy. Interestingly, the serine produced during this period of adaptation is channeled into antioxidant defense through generation of both glutathione and NADPH, to help buffer the ROS produced from this increase in OXPHOS. Defects in the ability to make this adaptation and limit ROS, as seen in cells lacking p53, impedes the ability of cells to cope with a loss of exogenous serine.

Serine is also required to support the S-adenosyl methionine (SAM) cycle, although surprisingly we have found that this reflected a requirement for ATP rather than one-carbon units. As a consequence, serine depletion caused a decrease in the conversion of methionine to SAM and a rapid remodeling of DNA methylation. We are currently examining the consequences on gene specific methylation and expression.

Funded by CR-UK and ERC

Citation Format: Oliver Maddocks, Christiaan Labuschagne, Karen H. Vousden. One carbon metabolism and cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY42-03. doi:10.1158/1538-7445.AM2015-SY42-03
Abstract SY43-02: Mismatch repair, gut microbiota, and the etiology of colon cancer
Authors: Martin Alberto
Published: August 2015

The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APC(Min/+)Msh2-/- and APC(Min/+)Mlh1-/- mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuels hyperproliferation of Msh2-/- and Mlh1-/- colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and potentially modulating the differentiation of transit-amplifying cells in the colon. These data show that mismatch repair deficiency sensitizes colon epithelial cells to transformation by gut microbiota, and thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction.

Citation Format: Alberto Martin. Mismatch repair, gut microbiota, and the etiology of colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY43-02. doi:10.1158/1538-7445.AM2015-SY43-02
Association Between Use of Statins and Mortality in Patients With Heart Failure and Ejection Fraction of ≥50%
Authors: Alehagen Urban , Benson Lina , Edner Magnus , Dahlström Ulf , Lund Lars H.
Published: August 2015

Background—

The pathophysiology of heart failure with preserved ejection fraction is poorly understood, but may involve a systemic proinflammatory state. Therefore, statins might improve outcomes in patients with heart failure with preserved ejection fraction defined as ≥50%.

Methods and Results—

Of 46 959 unique patients in the prospective Swedish Heart Failure Registry, 9140 patients had heart failure and ejection fraction ≥50% (age 77±11 years, 54.0% women), and of these, 3427 (37.5%) were treated with statins. Propensity scores for statin treatment were derived from 40 baseline variables. The association between statin use and primary (all-cause mortality) and secondary (separately, cardiovascular mortality, and combined all-cause mortality or cardiovascular hospitalization) end points was assessed with Cox regressions in a population matched 1:1 based on age and propensity score. In the matched population, 1-year survival was 85.1% for statin-treated versus 80.9% for untreated patients (hazard ratio, 0.80; 95% confidence interval, 0.72–0.89;
P
<0.001). Statins were also associated with reduced cardiovascular death (hazard ratio, 0.86; 95% confidence interval, 0.75–0.98;
P
=0.026) and composite all-cause mortality or cardiovascular hospitalization (hazard ratio, 0.89; 95% confidence interval, 0.82–0.96;
P
=0.003).

Conclusions—

In heart failure with ejection fraction ≥50%, the use of statins was associated with improved outcomes. The mechanisms should be evaluated and the effects tested in a randomized trial.
Effects of Postconditioning on Neurogenesis and Angiogenesis During the Recovery Phase After Focal Cerebral Ischemia
Authors: Esposito Elga , Hayakawa Kazuhide , Maki Takakuni , Arai Ken , Lo Eng H.
Published: August 2015

Background and Purpose—

Postconditioning may be a clinically feasible way to protect the brain after a stroke. However, its effects during the recovery phase post stroke remain to be fully elucidated. Here, we examine the hypothesis that ischemic postconditioning amplifies neurogenesis and angiogenesis during stroke recovery.

Methods—

Male Sprague–Dawley rats were subjected to 100-minute transient middle cerebral artery occlusion (MCAO) or postconditioning (100-minute middle cerebral artery occlusion plus 10-minute reperfusion plus 10-minute reocclusion). After 2 weeks, infarct volumes, behavioral outcomes, and immunohistochemical markers of neurogenesis and angiogenesis were quantified.

Results—

Postconditioning significantly reduced infarction and improved neurological outcomes. Concomitantly, brains subjected to postconditioning showed an increase in doublecortin/BrdU and collagen-IV/Ki67-positive cells.

Conclusions—

These results suggest that therapeutic effects of postconditioning may involve the promotion of neurogenesis and angiogenic remodeling during the recovery phase after focal cerebral ischemia.
Text Critical Notes on 4QJoba
Authors: Seow C. L.
Published: August 2015

Several commentaries on the book of Job have appeared since the publication of 4QJoba in 2000. Yet none has taken its readings into consideration in the exegesis of the passages represented therein. It is the purpose of this study, therefore, to reexamine the variants in 4QJoba, assess their value for the textual criticism and exegesis of the book, and consider the relationship of the ms to the mt and other Vrss. This article contends that 4QJoba does not strictly belong to the text tradition represented by the mt and that in several cases it preserves readings that are at least viable if not even superior to what one finds in the mt, including at 31:15; 36:23, 24; 37:1, and 37:2.
Several additions to the moss flora of Pakistan
Authors: Sollman Philip
Published: August 2015

Sixteen species and a variety of the Pottiaceae are newly reported for Pakistan. Barbula longicostata X.J. Li and Barbula funalis Dixon and Badhw. are synonymised with Didymodon acutus var. icmadophilus (Schimp. ex Müll. Hal.) R.H. Zander. and Pseudocrossidium hornschuchianum (Schultz) R.H. Zander respectively. A note on Syntrichia montana Nees is given.
Uktena riparia n. gen., n. sp. (Annelida, Clitellata, Lumbriculidae), a new spermatophore-producing oligochaete
Authors: FEND STEVEN V. , RODRIGUEZ PILAR , LENAT DAVID R.
Published: August 2015

Uktena riparia n. gen., n. sp. has been collected in hyporheic habitats at several sites in North Carolina, southeastern USA. The genus is defined by unusual characters related to reproductive structures, including the formation of encapsulated spermatophores for sperm transfer and large bundles of genital chaetae, both previously unknown in the Lumbriculidae. The simultaneous occurrence of both spermatophores and spermathecae is rare in the microdrile oligochaetes. Uktena spermatophores appear more similar to those reported in leeches than to those in other microdrile oligochaete families. Possible synapomorphies associating Uktena with the genera Kincaidiana and Guestphalinus include a filiform, ringed proboscis, a forward shift of reproductive organs relative to the usual position in the family, and spermathecae in the atrial segment. The new species adds to the already diverse, endemic lumbriculid fauna of the North Carolina Sandhills ecoregion.
Karyosystematics of Triatoma rubrofasciata (De Geer, 1773) (Hemiptera: Reduviidae: Triatominae)
Authors: ALEVI KAIO CESAR CHABOLI , BORSATTO KELLY CRISTINE , MOREIRA FELIPE FERRAZ FIGUEIREDO , JURBERG JOSÉ , AZEREDO-OLIVEIR MARIA TERCÍLIA VILELA DE
Published: August 2015

Triatoma rubrofasciata (De Geer) is the first species of triatomine described, and little is known on its vector biology. Studies are restricted to starvation resistance, interspecific morphometric variability, morphometry of testis follicles, coloration of the testicular peritoneal sheath, ultrastructure of the male accessory glands, phylogeny and cytogenetics. Thus, this study aims to address the karyosystematics of T. rubrofasciata and the possible events related to karyotype evolution of this species. Four adult males were analyzed cytogenetically. The analysis of meiotic metaphases of T. rubrofasciata allowed to confirm the karyotype of species, out more, 2n = 25 (22A + X1X2Y). This number is very important for taxonomic and evolutionary inferences on the species, because of the 88 triatomine species with described karyotype, only T. rubrofasciata exhibits 25 chromosomes. Based on the hypothesis of the karyotype 2n = 22 (20A + XY) as ancestral for triatomines, we propose three evolutionary hypotheses for the emergence of the karyotype of T rubrofasciata, all supported by agmatoploidy events (fission). Basically the hypotheses are 1) fission for a pair of autosomes, resulting in 22 autosomes and later fission of sex chromosome X; 2) fission of pair of autosomes and the sex chromosome X concomitantly; 3) fission of sex chromosome X and subsequently fission of pair of autosomes. Thus, this study highlights for the first time the importance of the number of chromosomes of T. rubrofasciata as characteristic diagnosis in Triatominae subfamily and describes three evolutionary hypotheses that possibly led the emergence of karyotype of this insect of global importance.
A revision of the genus Paracallisoma Chevreux, 1903 (Crustacea: Amphipoda: Scopelocheiridae: Paracallisominae) with a redescription of the type species of the genus Paracallisoma and the description of two new genera and two new species from the Atlantic Ocean
Authors: HORTON TAMMY , THURSTON MICHAEL H.
Published: August 2015

The genus Paracallisoma (Crustacea: Amphipoda) is revised and the type species, Paracallisoma alberti is redescribed based on holotype material supplemented with new material from the region of the type locality. This revision results in the establishment of two new genera, Pseudocallisoma gen. nov. and Haptocallisoma gen. nov., and the description of a new species of Haptocallisoma and a new species of Paracallisoma from the North Atlantic Ocean. An account of all known species within the three genera is given and updated keys to the genera and species are provided.
Platycuma bamberconfabulor sp. nov. (Crustacea: Cumacea: Nannastacidae) from Antarctica, with a note on the gut of Platycuma
Authors: GERKEN SARAH , WATLING LES
Published: August 2015

Platycuma bamberconfabulor sp. nov. is based on a specimen from the Ross Sea. The species can be distinguished from the other species in the genus through the combination of a laterally expanded and somewhat dorsoventrally flattened carapace, anterior margin of the carapace excavate in dorsal view, uropod peduncles less than twice as long as pleonite 6, and subequal pleonites 4 and 5.
Indoapseudes bamberi sp. nov. (Crustacea: Tanaidacea: Pagurapseudidae: Hodometricinae) from Iriomote Island, Ryukyu Islands, southwestern Japan
Authors: KAKUI KEIICHI , NARUSE TOHRU
Published: August 2015

We describe Indoapseudes bamberi sp. nov., based on a specimen from Funaura Bay, Iriomote Island, Japan. This species can be distinguished from its five congeners by having the combination of the antenna with a squama and pereopods 1 and 2 with one dorsal spine on the basis. We also determined part of the nucleotide sequence for the cytochrome c oxidase subunit I (COI) gene in I. bamberi, and present a key to Indoapseudes species.
Variability of Hawaiian Winter Rainfall during La Niña Events since 1956
Authors: O’Connor Christopher F. , Chu Pao-Shin , Hsu Pang-Chi , Kodama Kevin
Published: August 2015

Rainfall in Hawaii during La Niña years has undergone abnormal variability since the early 1980s. Traditionally, Hawaii receives greater-than-normal precipitation during the La Niña wet seasons. Recently, La Niña years have experienced less-than-normal rainfall. A drying trend in Hawaiian precipitation during La Niña years is evident. A changepoint analysis determined that the shift in precipitation occurred in 1983, forming the two epochs used for comparison in this study. The first epoch (E1) runs from 1956 to 1982 and the second epoch (E2) from 1983 to 2010. Location-specific changes in rainfall anomalies from E1 to E2 throughout the Hawaiian Islands are examined, illustrating that the greatest difference in rainfall between epochs is found on the climatologically drier sides (i.e., south and west) of the islands. Variations in tropical sea surface temperatures and circulation features in the northern Pacific Ocean have changed during La Niña wet seasons, thus changing La Niña–year rainfall.

The strengthening, broadening, and westward shifting of the eastern North Pacific subtropical high, coupled with an eastward elongation and intensification of the subtropical jet stream, are two main influences when considering the lack of precipitation during the recent La Niña wet seasons. Moisture transport analysis shows that variations in circulation structures play a dominant role in the reduction of moisture flux convergence in the Hawaiian region during the second epoch. Additionally, a storm-track analysis reveals that the changes found in the aforementioned circulation features are creating a less favorable environment for the development of Kona lows and midlatitude fronts in the vicinity of Hawaii.