bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B26: iNOS expression and lethal prostate cancer in patients with localized disease
Authors: Rider Jennifer R. , Erlandsson Ann , Vyas Chirag , Davidsson Sabina , Carlsson Jessica , Andersson Swen-Olof , Andren Ove 
Published: December 2017

Abstract
Inducible nitric oxide synthase (iNOS) has demonstrated both tumor-promoting and tumor-inhibiting effects in prostate cancer. However, the relationship between iNOS protein expression and long-term prostate cancer outcomes is unclear. We evaluated iNOS expression in tumor epithelia and stroma in 300 men with localized tumors diagnosed incidentally by transurethral resection of the prostate (TURP) in Sweden. In this extreme case-control design, cases (N=132) died of prostate cancer and controls (N=168) survived at least 8 years following diagnosis without death from prostate cancer or a competing cause. Immunohistochemistry was undertaken with a polyclonal rabbit anti-human NOS2 antibody (Abcam) and the Ventana (Roche) semi-automated staining system. Two observers individually scored the staining according to intensity and number of positive cells from 0-3. The median value across cores in each patient were then categorized as &lt;1, &gt;1-&lt;2, and &gt;2, separately for epithelial and stromal compartments. Odds ratios for lethal prostate cancer were estimated with logistic regression controlling for the matching factors (age, calendar year of diagnosis), as well as tumor stage, Gleason score, and percent tumor. iNOS was expressed by stromal-associated M1 macrophages and fibroblasts, as well as tumor cells. Gleason score was positively associated with both stromal and epithelial iNOS staining. In the stroma, there was no statistically significant association between iNOS expression and lethal prostate cancer after adjustment for clinical covariates. However, the odds of lethal prostate cancer increased with tumor expression of iNOS in the fully adjusted model. Compared to patients with the lowest category of iNOS expression, the odds ratios for lethal prostate cancer were 2.96 (95% CI: 1.26-6.96) for patients in the second category and 3.80 (95% CI: 1.45-9.97) for patients in the top category. These results suggest that iNOS may help to identify patients with aggressive prostate cancer at the time of diagnosis, or may be a therapeutic target. Given previously reported in vitro data suggesting that iNOS promotes proliferation of androgen-independent prostate tumors, future analyses will investigate association between iNOS expression and time to castration-resistant prostate cancer in this patient population.
Citation Format: Jennifer R. Rider, Ann Erlandsson, Chirag Vyas, Sabina Davidsson, Jessica Carlsson, Swen-Olof Andersson, Ove Andren. iNOS expression and lethal prostate cancer in patients with localized disease [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B26.
Abstract B30: Development of robust in vitro 3D models of human tumors for the identification and evaluation of anti-cancer drugs
Authors: Harvey Amanda Carys , Place Graham , Baggott Kathryn , Samra Satinder , Freathy Caroline , Cross Neil 
Published: December 2017

Abstract
Currently in vivo testing of animals is still the gold standard for drug development and testing of cytotoxic compounds. With the demand for non-animal alternatives raising here we compared the development and functionality of two 3D culture models for tumor spheroids.
Firstly 3D tumor spheroids were generated from lung cancer cell lines (NCI-H1650, NCI-H2170, NCI-H1975 and HCC-827) with known EGFR pathway mutations, and also primary isolated lung cancer epithelial cells, by encapsulation within an Alginate matrix to produced isogenic cell populations. Additionally, spheroids were co-cultured alongside primary Cancer-Associated Fibroblasts (CAFs). Following generation (7 days), spheroids (up to 500µm diameter) were treated with cytotoxic agents. The presence of CAFs attenuated the growth of smaller tumor spheroids (&lt;100μm) although drug responses were not markedly changed in larger spheroids. Secondly, 3D tumor spheroids were generated using the OrganDot system (Asterand Biosciences) for the same lung and primary cell lines. Consistent responses were achieved between OrganDOT cultures and 3D alginate spheroids. Both systems allowed long-term viability of cultures allowing sequential or chronic compound testing.
Both systems produced responses consistent with known genotypes for those cell lines. Ongoing studies using these models are focused at assessing whether anti-EGFR responses may predict the presence or absence of EGFR-pathway mutations in freshly isolated primary lung tumor cultures mutations.
Citation Format: Amanda Carys Harvey, Graham Place, Kathryn Baggott, Satinder Samra, Caroline Freathy, Neil Cross. Development of robust in vitro 3D models of human tumors for the identification and evaluation of anti-cancer drugs [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B30.
Abstract B34: Investigating disruptions in the circadian clock in cancer cells
Authors: Lexow Waldo , Silva Sian-Ailin Da , Leaner Virna D. , Watt Pauline J. van der 
Published: December 2017

Abstract
The circadian clock is man's internal time-keeping mechanism; it synchronizes human physiology with the external cycle of day and night. At the molecular level, all cells display a circadian clock driven by core clock proteins that constitute transcription-translation feedback loops, generating oscillating patterns of circadian clock gene expression over time. It is becoming increasingly apparent that disruptions in the circadian clock may contribute to cancer development. This study aimed to investigate the molecular components of the circadian clock in two cancer types prevalent in South Africa: cervical and oesophageal cancer. To our knowledge the circadian clock has not previously been investigated in these cancer types. Microarray and real-time RT-PCR analyses revealed significantly decreased expression of Period 2 (Per2) mRNA in cervical and oesophageal cancer patient tissue compared to normal tissue. Cervical and oesophageal cancer cell lines similarly displayed significantly reduced mRNA and protein levels of certain circadian clock genes, including positive and negative regulators of the circadian clock. Nuclear transport of circadian clock proteins was investigated, since cancer cells display increased nuclear transport rates and circadian clock proteins rely on nucleocytoplasmic shuttling to maintain the correct pace of the circadian clock. Fluorescence recovery after photobleaching (FRAP) analysis was performed and revealed increased nuclear import rates of Bmal1 in cancer compared to normal cells. Altered expression and nuclear import rates of circadian clock proteins in cancer cells suggest these cells might harbor an impaired circadian clock. Luminescence assays are thus currently being employed to determine whether cancer cells display rhythmic expression of core clock genes, as an indication of a functioning circadian clock. A real-time bioluminescence imager is being used to measure Bmal1 and Per2 promoter-luciferase activities in cancer cells over time, after synchronization of circadian oscillators with the glucocorticoid analogue, Dexamethasone. This type of study is relevant to the field of chronotherapy, where elucidating differences in circadian clock functioning in normal and cancer cells could yield better insights into the timing of administration of chemotherapy, ultimately ensuring a better patient response.
Citation Format: Waldo Lexow, Sian-Ailin Da Silva, Virna D. Leaner, Pauline J. van der Watt. Investigating disruptions in the circadian clock in cancer cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B34.
Abstract B35: Runx3 contributes for the defense against endogenous level of oncogenic K-Ras-induced tumorigenesis
Authors: Chi Xin-Zi , Lee You-Soub , Bae Suk-Chul 
Published: December 2017

Abstract
Recent studies demonstrated that p53 affects only adenocarcinomas in K-RasG12V knockin mice leaving untouched adenomas which are likely to progress into adenocarcinomas (1, 2). These observations raised a fundamental question regarding whether cells can defend against endogenous level of oncogenic signal (3). Runx3, which plays pivotal roles in lineage determination and functions as a tumor suppressor, is frequently inactivated by promoter hypermethylation in various types of human tumors (4). Previously, we showed that deletion of Runx3 markedly enhanced K-Ras-G12V-induced lung tumorigenesis and led to early death (5). In this study, we found that immortalized Runx3-/- mouse embryonic fibroblast cells (MEFs) were tumorigenic. In addition, Runx3 was silenced by promoter hypermethylation in K-Ras-G12V-knockin MEFs. Expression of Runx3 in the K-Ras-G12V MEFs abolished their tumorigenesity. In mice, knockin of K-Ras-G12V in limited number of cells failed to induce tumor, but combination of K-Ras-G12V-knockin and Runx3-knockout by the same targeting method rapidly induced severe lung adenocarcinomas, lymphomas and skin carcinomas (median survival, 48 days). RUNX3 was silenced in all cases of K-Ras-activated human non-small cell lung cancers (n=20). Our results demonstrate that mammalian cells can defend against endogenous oncogenic K-Ras and Runx3 plays a key role in the defense mechanism.
References
1. Feldser et al. (2010). Nature 468, 572-575.
2. Junttila et al. (2010). Nature 468, 567-571.
3. Berns A. (2010). Nature 468:519-20
4. Ito Y, Bae S-C, Chuang LS. (2015). Nat Rev Cancer. 15:81-95.
5. Lee et al., (2013). Cancer Cell. 24(5):603-16.
Citation Format: Xin-Zi Chi, You-Soub Lee, Suk-Chul Bae. Runx3 contributes for the defense against endogenous level of oncogenic K-Ras-induced tumorigenesis [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B35.
Abstract B37: Value of penetrated NIR spectroscopy in the diagnostic process of lung cancer
Authors: Bruha Tomas , Votruba Jiri , Cech Vladimír , Skvarek Josef 
Published: December 2017

Abstract
Background: Recently due to advances in biological therapy and immunotherapy there is an increased need for precise morphological and mutational verification of lung cancer. We have been testing the possibilities of NIR (near infrared) n spectroscopy in the process lung cancer detection.
Methods: For the analyses, we used a custom-made endoscopic lensed microprobe consisting of one excitation and one collection optical fibers that were coupled to a NIR spectrometer. In 55 patients with lung cancer diagnosis undergoing bronchoscopy we carried on 110 measurements of NIR penetrated spectra from both normal and malignant lung tissues. Detected spectral curves of absolute transmittance for normal tissue and pathological tissue were further analyzed utilizing two chosen parameters which are corresponding to important characteristics of the curves. First parameter was statical moment of area under spectral curve referenced to vertical axis of maximal wavelength whose value reflected average intensity of detected signal as well as rate of shifting higher intensities to shorter wavelengths of spectral band (that means how much is investigated tissue permeable on shortest possible wavelengths). As the second parameter serve horizontal coordinates of the centrum of gravity of the area under spectral curve referenced to vertical axis of maximal wavelength whose value reflected just the rate of shifting signal to shorter wavelengths of spectral band regardless absolute intensity (this parameter compared shifting to shorter wavelengths for spectral curves as if were normalized to its maximal intensity value). Finally ratio of pathological to normal value for both parameters was calculated.
Results: Resulting values of these ratios for both above mentioned parameters were higher than 1 for all types of pathologies. Moreover ratio for second parameter is significantly higher for adenocarcinoma than for any type of pathologies.
Conclusion: NIR spectroscopy showed a potential for a reliable discrimination between normal and pathological lung tissue. We observed spectral differences between adenocarcinoma and all other types of lung pathologies.
Acknowledgement:
PROGRAM MPO-TRIO
PROJECT: FV 10657, OPROX, a.s.
Research and development of technologies and methods for optical penetrating spectroscopy of atypical lung tissue nodules.
Note: This abstract was not presented at the conference.
Citation Format: Tomas Bruha, Jiri Votruba, Vladimír Cech, Josef Skvarek. Value of penetrated NIR spectroscopy in the diagnostic process of lung cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B37.
Abstract B40: A novel activating I1171T ALK mutation in neuroblastoma responds better to ceritinib compare to the first generation inhibitor crizotinib
Authors: Siaw Joachim T. , Guan Jikui , Martinsson Tommy , Hansson Magnus , Kogner Per , Palmer Ruth 
Published: December 2017

Abstract
Mutations in the kinase domain of Anaplastic Lymphoma Kinase (ALK) have been suggested to be important players in the genetics and progression of the childhood tumor neuroblastoma. Here we report the appearance of a novel ALK mutation in neuroblastoma together with other chromosomal aberrations that mediate neuroblastoma initiation and progression. Analyses of genomic tumor DNA from biopsy samples initially showed an 11q minus, 17q gain with a mutation of the ALK gene at protein position 1171, which mediate an amino acid change from isoleucine to threonine. We show that mutation of I1171 to threonine generates a potent gain-of-function mutant, as observed in two independent systems. Firstly, in PC12 cell lines expressing ALKI1171T display ligand independent activation of ALK, neurite outgrowth and further downstream signaling activation. Secondly, ALKI1171T meditate foci formation in a NIH3T3 transformation analysis. Finally, pharmacological inhibition of ALKI1171T employing ceritinib, an FDA approved ALK inhibitor show 14-fold better ability to abrogate ALKI1171T compared with crizotinib.
Citation Format: Joachim T. Siaw, Jikui Guan, Tommy Martinsson, Magnus Hansson, Per Kogner, Ruth Palmer. A novel activating I1171T ALK mutation in neuroblastoma responds better to ceritinib compare to the first generation inhibitor crizotinib [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B40.
Abstract IA11: Oxidized 5-methylcytosine: At the interface of epigenetics and DNA repair
Authors: Pfeifer Gerd Peter 
Published: December 2017

Abstract
5-methylcytosine (5mC) is an epigenetic DNA modification that represses transcription when placed into CpG-rich promoter sequences. The removal of 5mC from DNA occurs through stepwise oxidation of the methyl group by 5mC oxidases, the so-called Ten-Eleven-Translocation (TET) enzymes. These oxidases sequentially produce 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Whereas 5hmC occurs at substantial levels in several mammalian cell and tissue types, the other two oxidation products are often described as intermediates in the DNA demethylation pathway, which is completed by base excision repair following excision of 5fC and 5caC by thymine DNA glycosylase (TDG). 5caC is a block to polymerases and may elicit a DNA damage response. Mammalian genomes encode three TET enzymes, TET1, TET2, and TET3. TET3 exists as three major isoforms including an oocyte-specific form, likely responsible for the preferential oxidation of 5mC in the paternal genome of fertilized oocytes, as well as two somatic isoform that differ with regards to presence or absence of an N-terminal zinc finger-type CXXC domain. We recently characterized the full-length TET3 isoform containing the CXXC domain (TET3FL). This CXXC domain binds to unmethylated CpG sequences but, unexpectedly, its highest affinity is towards 5-carboxylcytosine (5caC). We determined the crystal structure of the CXXC domain - 5caC-DNA complex revealing the structural basis of the binding specificity of this domain as a reader of 5CcaCG sequences. We propose that binding of TET3 to its reaction product 5caC through its CXXC domain enforces the genomic specificity of this protein. Mapping of TET3FL in neuronal cell populations showed that Tet3FL is localized at the transcription start sites (TSS) of genes involved in lysosome function, mRNA processing and key genes of the base excision repair pathway. Thus, Tet3FL may function as a regulator of 5caC removal by base excision repair. TET3FL peaks coincided with binding sites for the master regulator of the lysosome and autophagy pathways, TFEB. Active removal of accumulating 5mC from the TSS of genes coding for essential proteins by TET3FL may be important for preventing age-associated diseases including neurodegeneration and cancer.
Citation Format: Gerd Peter Pfeifer. Oxidized 5-methylcytosine: At the interface of epigenetics and DNA repair [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA11.
Abstract IA18: Moving towards precision medicine for melanoma
Authors: Marais Richard 
Published: December 2017

Abstract
Cutaneous melanoma is a potentially deadly skin cancer that is linked to exposure to ultraviolet radiation (UVR). Rapid advances in genome sequencing approaches have provided enormous insight into the genetics of melanoma, revealing that about half of human melanomas carry activating mutations in the protein kinase BRAF. Drugs that target BRAF, or its downstream signaling component MEK, can extend both progression free and overall survival in BRAF mutant melanoma patients. In parallel, drugs that stimulate the immune system to attack melanomas are effective in 20-50% of patients, and in some cases can even lead to cure. Thus, in the last 6-7 years there has been a paradigm shift in the clinical management of melanoma, but nevertheless, the majority of patients still die of their disease, because despite initial excellent responses to BRAF/MEK drugs, most patients will eventually develop resistance and relapse, and we currently do not have effective biomarkers to stratify patients for the large number of immunotherapies that are being developed.
New approaches are therefore needed to stratify melanoma patients to improve clinical outcomes, and to that end we have developed a platform of technologies to guide selection of treatments for individual patients. Next generation sequencing is used to investigate the genetics of tumours with the eventual aim of using selecting the most appropriate drugs for an individual patient. Patient-derived xenografts have been developed from over 100 patients and are used to investigate melanoma biology and the response of individual tumours to hypothesis-driven therapeutic approaches. In cases where tumours are inaccessible, xenografts can sometimes be developed from circulating tumour cells (CDX), allowing the biology of late-stage disease to be investigated. Finally, cell-free tumour DNA (ctDNA) in the blood is used to monitor patient responses to treatments and clinical trials are being designed to use this approach to provide insight into the molecular mechanisms underlying tumour growth, to guide clinical decisions about which drugs to administer and also to guide when to switch treatment from one modality to another.
Citation Format: Richard Marais. Moving towards precision medicine for melanoma [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA18.
Abstract IA28: Deciphering immune regulation and recognition at the tumour site
Authors: Quezada Sergio A. 
Published: December 2017

Abstract
My laboratory is interested in defining and targeting the key pathways regulating immune recognition and destruction of cancerous cells within tumours. In recent years, a number of publications have demonstrated the essential role of the tumour microenvironment in the in vivo activity of checkpoint targeting antibodies. In this talk I will discuss novel developments in this area relating to the mechanism of action and the development of immune modulatory antibodies that promote maximal modulatory activity in different tumour microenvironments. In addition to immune regulation, another key area of research in the field of cancer immunology relates to the recognition of tumour cells by T lymphocytes. Whilst recent studies highlight the potential importance of T cell reactivity towards patient-specific mutant epitopes in the successful outcome of immune modulatory therapies, little is known about the impact of intra-tumour heterogeneity (ITH) on this relation. In the second part of this talk I will describe recent data using multi tumour region sampling to characterise the interplay between ITH, immune-reactivity and immune-regulation in non-small cell lung cancer patients.
Citation Format: Sergio A. Quezada. Deciphering immune regulation and recognition at the tumour site [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA28.