tbuckley/cabot-search huggingface dataset:
Abstract 4748: Novel predictive biomarker for monitoring adverse reactions to radiation therapy
Authors: Paul OKunieff, Steven Swarts, Elena Peletskya, Anne Vallerga, Rachel Chuang, Michael J. Powell, Aiguo Zhang
Journal: Cancer Research (2017)

Abstract Introduction: Radiation treatment is required by 70% of cancer patients, however there is currently no clinical method for determining the therapeutic response or radiation induced toxicity that can be used during a course of radiation therapy to personalize the dose for individual patients. The only standard method is CT/PET and/or MRI. This is a major clinical concern for radiation oncologists with so many new agents being approved in combination with radiation therapy. Methodology: Herein we describe a highly sensitive clinically validated assay that measures the extent of normal tissue damage induced by radiation by quantitation of circulating free DNA (cfDNA) derived from cellular apoptosis detected in plasma of patients undergoing radiation therapy. The assay employs DNA capture probes and SuperbDNATM signal amplification technology with alkaline phosphatase labelled signaling probes coupled with dioxetane phosphate chemiluminescence detection. The assay can be performed directly on patient plasma samples and can be readily automated. Conclusion: RadTox TM can be used both for research and clinical testing of plasma samples for patients undergoing radiation therapy for optimization and personalization of treatment. Citation Format: Paul OKunieff, Steven Swarts, Elena Peletskya, Anne Vallerga, Rachel Chuang, Michael J. Powell, Aiguo Zhang. Novel predictive biomarker for monitoring adverse reactions to radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4748. doi:10.1158/1538-7445.AM2017-4748
Abstract LB-091: CpG island DNA methylation regulates alternative cleavage and polyadenylation
Authors: Thomas Sweet, Lihua Jin, Josephine Dermawan, Angela H. Ting
Journal: Cancer Research (2017)

Abstract Abnormal DNA methylation pattern is a hallmark of human cancer, and our work in genomic profiling of DNA methylation patterns in prostate and colon cancers have identified the majority of unique DNA hypermethylation to occur outside of gene promoters. While promoter hypermethylation causes transcriptional silencing, the functions of non-promoter DNA methylation are poorly defined. Thus, we began investigating the impact of non-promoter DNA methylation on the transcriptome and specifically focused on studying the functions of DNA methylation near gene 3' ends. Using a pair of isogenic cancer cells (HCT116 and DKO cells) that differ specifically in their ability to maintain DNA methylation, we discovered an intriguing association between gene 3' end differential DNA methylation and alternative cleavage and polyadenylation (APA) events. Briefly, pre-mRNAs undergo cleavage and polyadenylation as part of normal mRNA 3' end formation, and alternative sites of cleavage and polyadenylation can be utilized to produce transcripts with varying regulatory sequences in the 3' untranslated regions (3' UTRs) or protein isoforms via APA within coding sequences. Previous studies have demonstrated that cancer cells can hijack the APA pathway to skew expression of short 3' UTRs in oncogenes to evade negative regulation, highlighting APA as an important process involved in cancer initiation and progression. By using pharmacologic inhibition of DNA methylation and reporter constructs, we demonstrated that CpG island DNA methylation near polyadenylation sites is necessary and sufficient for determining relative usage, most likely by modulating RNA polymerase II elongation rate. By leveraging the Cancer Genome Atlas (TCGA) and the Roadmap Epigenomics data, we could observe the correlation between gene 3' DNA methylation and APA at select loci in vivo. The results of our study will improve overall functional understanding of non-promoter DNA methylation, provide a novel mechanism for APA regulation, and ultimately accelerate discovery of novel targets for cancer management. Note: This abstract was not presented at the meeting. Citation Format: Thomas Sweet, Lihua Jin, Josephine Dermawan, Angela H. Ting. CpG island DNA methylation regulates alternative cleavage and polyadenylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-091. doi:10.1158/1538-7445.AM2017-LB-091
Abstract 4773: Dysregulated expression of pentraxin-3 in glioblastoma (GBM) stem cells: Implications for GBM invasion and progression
Authors: Umadevi V. Wesley, Paul Clark, John S. Kuo, Robert J. Dempsey
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) is highly invasive and resistant to current therapies. The aggressiveness of brain tumor is attributed to GBM stem cells (GSC) that release inflammatory cytokines, and exacerbate inflammation in tumor microenvironment, critically affecting GBM survival and invasiveness. The glycoprotein pentraxin-3 (PTX3), a modulator of tumor-associated inflammation, is known to be correlated with tumor grade and severity of malignancies of some cancers. However, little is known about the role of PTX3 in GBM growth and invasion. In this study, we examined the role of PTX3 in GSCs exhibiting various degree of invasiveness. From patient brain tumors, our team has isolated the small subsets of glioblastoma stem cells (GSCs) and are validated for their self-renewal and multi-lineage potential. Our studies have shown that these GSCs efficiently form orthotopic brain tumors in immune-deficient mice. Our results show that conditioned media from GSCs promote pro-angiogenic tube formation from endothelial cells. GSCs that are grown in the absence of growth factors EGF and bFGF, formed efficient xenografts in immune-deficient mice and showed increased dispersal in the mice brain. Interestingly, polymerase chain reaction (RT-PCR) and immunofluorescence staining showed upregulated expression of PTX3 in these GSCs, and correlated with the degree of invasiveness. Differentiation of GSC into astrocytes in vitro, lead to decreased expression of PTX3. In support of this, recent histochemical study has shown that PTX3 levels correlate with GBM grade and is a candidate biomarker for cancer progression. Thus, PTX3 may represent a new target and marker of inflammation for glioma malignancy. Citation Format: Umadevi V. Wesley, Paul Clark, John S. Kuo, Robert J. Dempsey. Dysregulated expression of pentraxin-3 in glioblastoma (GBM) stem cells: Implications for GBM invasion and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4773. doi:10.1158/1538-7445.AM2017-4773
Abstract 1919: Twist1 modulates paclitaxel-induced cancer stem cell enrichment in triple-negative breast cancer
Authors: Aimin Yang, Xiaoyuan He, Bradley A. Schulte, Steven L. Carroll, Stephen P. Ethier, Gavin Y. Wang
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancers, is highly refractory to chemotherapy and has a high incidence of metastasis and tumor relapse. Targeted therapies for TNBC do not exist because this subtype lacks druggable hormone receptors and HER2 amplification or overexpression. Although Taxane-based chemotherapy is a standard of care for TNBC treatment, paclitaxel (Taxol)-induced cancer stem cell (CSC) enrichment presents a significant challenge to the success of breast cancer treatment. Thus, there is a critical need to understand the mechanisms by which chemotherapy induces CSC enrichment in residual tumors following anticancer therapies. Here we report that Taxol-induced enrichment for CSCs correlates well with a marked upregulation of Twist1 expression in human TNBC cells. Knockdown of Twist1 inhibits the clonogenic capacity of TNBC cells in vitro and TNBC tumorigenesis in vivo. Mammosphere formation assays indicate that silencing of Twist1 greatly diminishes the tumor sphere-forming potential of breast CSCs. Furthermore, limited dilution assays and stem cell xenotransplantation reveal that knockdown of Twist1 expression decreases the frequency of CSCs by 72-fold in human TNBC cells. More importantly, we show that silencing of Twist1 blocks Taxol-induced CSC enrichment in residual tumor cells that have survived drug treatment. Together, these results demonstrate a previously unrecognized role for Twist1 in mediating Taxol-induced CSC enrichment in residual tumors of human TNBC and suggest that targeted inhibition of the Twist1 signaling pathway may represent a novel therapeutic strategy to tackle therapy-induced CSC enrichment in breast cancer treatment. Citation Format: Aimin Yang, Xiaoyuan He, Bradley A. Schulte, Steven L. Carroll, Stephen P. Ethier, Gavin Y. Wang. Twist1 modulates paclitaxel-induced cancer stem cell enrichment in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1919. doi:10.1158/1538-7445.AM2017-1919
Abstract 974: Automating deconvolution of heterogeneous bulk tumor genomic data
Authors: Theodore Roman, Brenda Xiao, Russell Schwartz
Journal: Cancer Research (2017)

Abstract Tumor heterogeneity has been linked to many measures of poor patient outcome. Despite numerous recent methodological advances, though, reliable estimates of clonal and subclonal architecture remain elusive. We present advances in computational deconvolution of tumor heterogeneity, aimed at better handling complex substructure, more automated inference, and increased flexibility to heterogeneous genomic data sources. Our methods make use of geometric models of mixture substructure, a specialized form of a strategy called manifold learning, to better resolve clonal substructure shared across genomic samples. We validate the methods on breast tumor dataset from the Cancer Genome Atlas (TCGA). We find statistically significant Spearman correlation between inferred mixture models and independently derived clinical subtype across DNA, RNA, and combined datasets. DAVID tissue term enrichment, applied to inferred amplified gene sets, further yields significant correlation (p&amp;lt; 0.01) with various ontological terms expected for breast tumors, for example, "Breast Carcinoma". We further verified the ability of the mixture modeling to classify tumors by progression state, showing cross-validated k-fold loss of 0.2538 in separating tumors by early (Stage I - II) vs. late (Stages III-IV) stage, corresponding to significant (p&amp;lt;0.001) separation by chi-squared test. The results demonstrate the effectiveness of our improved geometric deconvolution approach in resolving clonal structure to separate tumors by biologically relevant pathways and degrees of progression. Citation Format: Theodore Roman, Brenda Xiao, Russell Schwartz. Automating deconvolution of heterogeneous bulk tumor genomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 974. doi:10.1158/1538-7445.AM2017-974
Abstract 5559: Using cancer dependency data to discover tumor suppressive and oncogenic functional modules
Authors: Joshua Pan, Robin M. Meyers, Brittany C. Michel, Ann E. Sizemore, Francisca Vazquez, Barbara A. Weir, William C. Hahn, Aviad Tsherniak, Cigall Kadoch
Journal: Cancer Research (2017)

Abstract Efforts to define protein complexes and their functional networks are critical for systems-level understanding of the pathways involved in human cancer. Current methods to catalog human protein complexes via physical interaction are often unable to resolve functional differences between complex members or infer relationships governed by sub-stoichiometric interactions. While functional wiring maps in yeast have been generated by measuring epistatic interactions between pairs of genes, efforts to scale this concept in individual human cell lines have been met with challenges and have only been able to characterize limited numbers of genes at a time. We have developed a scalable approach that can measure functional similarity without the constraints of pairwise genetic interaction experiments. Using data from genome-wide RNAi and CRISPR dropout screens performed in hundreds of cancer cell lines, we leveraged the heterogeneity of gene dependencies across cancer types to measure functional similarity between thousands of genes at once, which in turn allowed us to recreate known inter- and intra-complex functional relationships and to uncover tumor suppressive and oncogenic functional modules in cancer-relevant pathways such as proteolysis, metabolism and transcription. Applying these approaches to the mammalian SWI/SNF (BAF) chromatin remodeling complex, which is mutated in over 20% of human cancer, revealed three functional modules that arose separately during metazoan evolution, one of which is entirely novel and uncharacterized. We then performed biochemical experiments that fully support three specialized complex configurations, each with distinct size, subunit composition, and function. These data reorganize the BAF complex into previously unrecognized modules that better explain mutational burden in human cancer. Notably, we observe that that all known BAF-driven, highly penetrant rare cancers and neurodevelopmental disorders involve disruption within a single functional module we defined, underscoring the value of evaluating disease genomics through the lens of functional modularity. Citation Format: Joshua Pan, Robin M. Meyers, Brittany C. Michel, Ann E. Sizemore, Francisca Vazquez, Barbara A. Weir, William C. Hahn, Aviad Tsherniak, Cigall Kadoch. Using cancer dependency data to discover tumor suppressive and oncogenic functional modules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5559. doi:10.1158/1538-7445.AM2017-5559
Abstract 5170: HDAC inhibitors and the mechanism of resistance in colorectal cancer: RAS and MYC - the partners in crime
Authors: Sylvia S. Ispasanie, Lena Boehme, Martin Eilers, Tilman Brummer, Kathleen Klotz-Noack, Natalia Kuhn, Bastian Gastl, Christine Sers
Journal: Cancer Research (2017)

Abstract Although histone deacetylase inhibitors (HDACi) are considered a promising novel therapeutic approach in the light of their potent tumour-selective effects, the use of these inhibitors for treatment of colorectal cancer (CRC) have thus far demonstrated limited success as a monotherapy. What this eventually boils down to is our incomplete understanding of the molecular mechanisms, the impact of oncogenes, and thus the key pathways through which HDACi affect tumour cell growth. To shed further light on this, the involvement of oncogenic RAS - a key driver of CRC, in determining the responsiveness to HDACi has been explored. By using cell line model systems harbouring conditional oncogenic NRAS, KRAS and HRAS, we uncovered an oncogenic RAS-dependent “safeguard” mechanism imposed in order to evade the cytotoxic effect of HDACi and therefore apoptosis. Characteristically, cells harbouring oncogenic RAS were observed to undergo a reversible senescence-like growth arrest in G2, allowing for re-entry into cell cycle following the withdrawal of HDACi. This mechanism is implemented as a consequence of the direct targeting of RAS by HDAC inhibition, which resulted in a further amplified GTP-binding activity and subsequent signalling through the MAPK pathway. The observed outcome was an increase in the priming of MYC for ubiquitin-mediated proteasomal degradation, thereby enabling the cells to exit the cell cycle and enter the protective state of G2 arrest. This process was functionally reversed with a conditional non-degradable MYC (T58A/S62A), which in turn rendered the cells more susceptible to undergo apoptosis. Conclusively, in the context of a constitutively activating RAS mutation, the prospect of HDACi treatment was effectively improved using current MAPK-targeted therapy by preventing the observed pro-oncogenic effect of the HDACi treatment alone. Note: This abstract was not presented at the meeting. Citation Format: Sylvia S. Ispasanie, Lena Boehme, Martin Eilers, Tilman Brummer, Kathleen Klotz-Noack, Natalia Kuhn, Bastian Gastl, Christine Sers. HDAC inhibitors and the mechanism of resistance in colorectal cancer: RAS and MYC - the partners in crime [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5170. doi:10.1158/1538-7445.AM2017-5170
Ankylosing spondylitis in west Africans---evidence for a non-HLA-B*27 protective effect
Authors: W P MAKSYMOWYCH, G S JHANGRI;, M. BROWN, P. WORDSWORTH
Journal: Annals of the Rheumatic Diseases (1997)

Objective - 

To determine the prevalence of ankylosing spondylitis in the Fula ethnic group in The Gambia, and relate the disease prevalence to the B27 frequency and subtype distribution of that population. 


Methods - 

215 first degree relatives of 48 B27 positive Fula twin pairs, and 900 adult Fula males were screened for ankylosing spondylitis by clinical and, where appropriate, radiographic means. The B27 prevalence was determined by PCR/sequence specific oligonucleotides on finger prick samples from 100 unrelated Fula, and B27 subtype distribution by SSCP on unrelated B27 positive individuals. This data were then compared with the prevalence of ankylosing spondylitis among B27 positive Caucasians. 


Results - 

No case of ankylosing spondylitis was seen. Six per cent of Fula are B27 positive, of which 32% are B*2703 and 68% B*2705. Assuming the penetrance of ankylosing spondylitis in B27 positive Fula is the same as in B27 positive Caucasians, the probability of not observing any cases of ankylosing spondylitis among the Fula examined is remote (P = 6.7 x 10-6). Similarly, the chance of not seeing any cases among those expected to be either B*2705 or B*2703 was small (P = 3.2 x 10-4 for B*2705, and P = 0.02 for B*2703). 


Conclusions - 

The risk of developing ankylosing spondylitis in B27 positive Fula is lower than in B27 positive Caucasians. This is not explained by the B27 subtype distribution among Fula, and suggests the presence of some non-B27 protective factor reducing the prevalence of ankylosing spondylitis in this population.
Abstract 4091: AKT can modulate the in vitro response of HNSCC cell to irreversible EGFR inhibitors
Authors: Renato José Silva-Oliveira, Matias Melendez, Olga Martinho, Maicon Fernando Zanon, Luciano de Souza Viana, André Lopes Carvalho, Rui Manuel Reis
Journal: Cancer Research (2017)

Abstract Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the treatment of patients with locally advanced HNSCC. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib represents a significant therapeutic promise in HNSCC treatment. In this study, we intend to compare the potential cytotoxicity of two irreversible anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in hotspot regions of EGFR, KRAS, NRAS, PIK3CA and PTEN in the eight HNSCC cell lines revealed an EGFR mutation (p.H773Y) and gene amplification in the HN13 cells, and KRAS mutation in the JHU-28 cell line. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The HN13 cell line exhibited a less responsive behavior to all drugs assessed, and interestingly, also displayed the higher levels of AKT phosphorylation. Therefore, we further performed drug combinations and found that with anti-AKT agent (MK2206), afatinib and allitinib, but not cetuximab, sensitivity was restored. Additionally, AKT1gene editing in afatinib and allitinib-treated cell lines showed that AKT1 silencing-induced cell line decreased viability and increased cytotoxicity through caspases 3/7activation.Additionally, in silico analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab, and the AKT pathway constitutes a predictive marker of allitinib response. Importantly, in allitinib and afatinib-resistant cases, the pharmacological combination with AKT inhibitors could restore response and increase treatment success. Citation Format: Renato José Silva-Oliveira, Matias Melendez, Olga Martinho, Maicon Fernando Zanon, Luciano de Souza Viana, André Lopes Carvalho, Rui Manuel Reis. AKT can modulate the in vitro response of HNSCC cell to irreversible EGFR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4091. doi:10.1158/1538-7445.AM2017-4091