bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A33: Population and evolutionary genomics of prostate cancer-associated variants: implications for health disparities in men of African descent
Authors: Lachance Joseph , Berens Ali , Hansen Matthew , Teng Andrew , Tishkoff Sarah , Rebbeck Timothy 
Published: December 2017

Abstract
To determine why African men are more likely to suffer from prostate cancer (CaP), we integrated GWAS results and scans of selection with allele frequency data from 64 global populations. Despite substantial overlap in genetic risk scores across populations, we find that predicted CaP risk is highest in West Africans and that a small number of loci drive these differences in risk. There is a strong concordance between genetic risk scores and clinical estimates of CaP mortality. Although most CaP-associated loci are evolving neutrally, we find multiple instances where alleles have hitchhiked to high frequencies with linked locally adaptive alleles.
Citation Format: Joseph Lachance, Ali Berens, Matthew Hansen, Andrew Teng, Sarah Tishkoff, Timothy Rebbeck. Population and evolutionary genomics of prostate cancer-associated variants: implications for health disparities in men of African descent [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 A33.
Abstract B18: MAGEC1 and BAGE2 mRNA expression can be used to monitor chemotherapy treatment responses in multiple myeloma patients and pre-empt clinical relapse
Authors: Shires Karen , Wienand Kirsty 
Published: December 2017

Abstract
Being able to monitor the levels of malignant progenitor cells in Multiple Myeloma, as opposed to the plasma cell burden or clinical symptoms alone, will be an important move forward in the management of this disease. The expression of cancer testis antigen MAGE C1 has been previously linked to the malignant stem cell at all stages of this disease, while BAGE2 expression has been clearly associated with the progression to a more advanced disease stage and thus clonal evolution. We investigated the use of a multiplex QRTPCR approach to monitor the co-expression of these transcripts in the peripheral blood as an alternative monitoring methodology. We compared the levels of MAGEC1 and BAGE2 mRNA in the PBMC population to serum M protein and serum beta 2 microglobulin levels at 3-monthly intervals over a 2-year period for 12 patients on chemotherapy regimens. The analysis indicated that the novel QRTPCR analysis of MAGE C1 expression in the less invasive peripheral blood sample type was extremely relevant as a potential minimal residual disease-monitoring tool. Expression of this cancer testis antigen was detectable in all patients throughout treatment, with comparable increases and decreases to serum M protein and/or serum beta 2 microglobulin, but with the advantage of being able to detect disease at a lower level and potentially signal relapse prior to a full clinical relapse. Expression of BAGE2 was only observed in a few patients, but its expression was clearly associated with a worsening clinical profile. As with MAGEC1, the detection of this transcript occurred at least 3 months prior to clinical changes in some patients, indicating its potential use in early medical intervention.
Citation Format: Karen Shires, Kirsty Wienand. MAGEC1 and BAGE2 mRNA expression can be used to monitor chemotherapy treatment responses in multiple myeloma patients and pre-empt clinical relapse [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 B18.
Abstract B27: Unusual presentations of prostate cancer
Authors: Mante Sunny Doodu , Adusei Benjamin , Snyper Nana Yaa 
Published: December 2017

Abstract
Unusual presentations of prostate cancer can usually mislead the Surgeon in the management of his patient. Prostate cancer may presents in such a way that it mimics other conditions such as generalized lymphadenopathy, Supraclavicular lymphadenopathy, dyspnoea, chronic constipation, and ureteric obstruction. Most of these cases have no lower urinary tract symptoms and the main clue is to do a digital rectal examination which is abnormal, an elevated PSA and a TRUS biopsy to make the diagnosis. Treatment is usually with Bicalutamide and LHRH analogues. This leads to resolution of the condition.
Citation Format: Sunny Doodu Mante, Benjamin Adusei, Nana Yaa Snyper. Unusual presentations of prostate 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 B27.
Abstract B31: The role of HIV protein Nef in the development of HIV/AIDS-associated lymphomas
Authors: Mowla Shaheen , Mdletshe Nontlantla 
Published: December 2017

Abstract
Introduction: The pathogenesis HIV-associated lymphomas involve a complex interplay of biological factors, including the immerging role of HIV encoded proteins. These proteins have been shown to have oncogenic potential and to enhance the pathogenesis of HIV-associated malignancies. However, very little is known about the molecular mechanisms involved in this interaction. Here, we investigate the effect of HIV protein Negative Factor (Nef) on the expression of c-MYC and activation-induced cytidine deaminase (AID) in lymphoblasts and lymphoma cells.
Methods: Native histidine-tagged HIV Nef was produced in a bacterial system and used to treat (1) an EBV-immortalized B lymphoblastoid cell line (L1439A) and (2) the established lymphoma cell line Ramos, at various concentrations and for various time points. Changes in the expressions of c-MYC and AID were measured at both the mRNA and proteins levels using qPCR and western blotting respectively. The ability of Nef to regulate the promoter of these two genes was determined using luciferase reporter assays. Furthermore, confocal microscopy was used to investigate the downstream effects of Nef exposure.
Results: In L1439A cells, a general decrease in the expression of c-MYC and AID was observed. After 1 and 3 hours of exposure to HIV-Nef both c-MYC and AID mRNA levels reduced by approximately 0.5-fold. In contrast, the expressions of both genes increased significantly upon these treatments in the lymphoma cell line Ramos. After 3 hours of exposure, c-MYC expression increased by ~1.9-fold, while AID expression increased up to 4.6-fold. The protein expression followed a similar pattern, as indicated by western blotting. Furthermore, luciferase reporter assays showed that the effect on c-MYC expression is likely to be direct since the activity of the c-MYC promoter increased in a dose-dependent manner in the presence of Nef. c-MYC translocated to the nucleus, which is indicative of an active protein. Furthermore, an increase in gamma H2AX foci on DNA, indicative of double strand breaks, shows that the increase in AID lead to genomic instability.
Conclusion: This study demonstrates a differential effect of HIV Nef on normal immortalized lymphoblasts versus lymphoma cells. More importantly, it shows for the first time that HIV Nef may enhance the pathogenesis of lymphomas by triggering pathways and mechanisms which increase the expression of c-MYC and AID.
Citation Format: Shaheen Mowla, Nontlantla Mdletshe. The role of HIV protein Nef in the development of HIV/AIDS-associated lymphomas [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 B31.
Abstract IA22: Emerging signaling pathways in prostate cancer therapy
Authors: Zerbini Luiz F. 
Published: December 2017

Abstract
One major prerequisite to develop targeted therapies is the identification of relevant cellular targets and the identification of the relevant patient population in which to test these therapies. Although androgen ablation therapy, surgery and radiation therapy are effective for the treatment of local prostate cancer (PCa), there is no effective treatment available for patients with metastatic disease. The receptor tyrosine kinase Axl has been implicated in the pathology of many cancers. Increased Axl expression correlates with metastasis, aggressive behavior, and poor survival and have been linked with resistance to chemotherapeutic regimens in tumors. Interestingly, in these reports inhibition of Axl leads to restoration of sensitivity to drug therapy, indicating that Axl may represent a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to some drugs.
We have shown that Axl is overexpressed in PCa and is an essential regulator of PCa proliferation and tumor growth. Axl expression is elevated in hormone-refractory PCa cell lines and Axl knockdown reduces migration and invasion and tumor formation in vivo. The Axl ligand, GAS6, acts as a growth and/or survival factor and its binding to Axl activates PI3K and its downstream targets S6K and Akt. Activation of these pathways has been reported to induce nuclear translocation of the transcription factor nuclear factor kappa B (NF-κB), IL-6 production and STAT3 activation.
The molecule named R428 (now renamed BGB324) inhibits in a dose-dependent manner Gas6 stimulated Axl autophosphorylation and activity with high specificity, selectivity, and affinity and blocks Axl-dependent signaling events, such as Akt phosphorylation, cell invasion, and pro-inflammatory cytokine production. R428/BGB324 effectively prevents or reverses acquired resistance to several cancer therapies in preclinical models. Most importantly, as a result of these and other encouraging preclinical findings of therapeutic value this first-in-class, highly selective Axl inhibitor has entered the clinical trial phase.
Docetaxel, the main chemotherapeutic drug used in aggressive prostate cancer treatment, has shown limited efficacy against metastatic PCa, primarily due to invariable development of drug resistance, necessitating a thorough investigation of the mechanisms underlying this drug resistance and the development of novel, more efficacious therapies to prevent or overcome resistance. Preliminary data from our laboratory provide strong evidence for the notion that Axl plays a pivotal role in resistance to docetaxel and possibly cabazitaxel treatment. Importantly, Axl inhibitor R428 enhances docetaxel efficacy.
Citation Format: Luiz F. Zerbini. Emerging signaling pathways in prostate cancer therapy [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 IA22.
Abstract IA3: The impact of premature death of women from preventable cancers, such as cervical cancer
Authors: Denny Lynette 
Published: December 2017

Abstract
Cervical cancer is the second most common cancer among women living in sub-Saharan Africa, yet more women die from cervical cancer than women with breast cancer. Despite cervical cancer being preventable, services for prevention, early detection and treatment are rare in most poorer countries, and most women die in the 4th-5th decade, a time when their children are particularly vulnerable, especially the girl child. The global adult mortality rate per 1000 population by WHO region in 2011 was 160, with the highest rate being in Lesotho at 541/1000. The under 5 mortality rate per 1000 live births in the African WHO region was 95/1000 in 2012 and 12 in Europe. The Gender Inequality Index (GII) is a composite index that reflects women's relative social disadvantage in three dimensions - reproductive health, empowerment and the labour market. Using the GII, among a number of other indices, it was found that overall women in developing countries had two-fold higher cervical cancer incidence rates and three-fold higher mortality rates than their counterparts from developed countries. Deprivation levels or poverty rates were a strong predictor of cross-national variations in cervical cancer incidence and mortality. Losing a parent, especially a mother for young girls may be catastrophic as her health and care is likely to deteriorate significantly. This paper will explore the range of effects of premature deaths of mothers on children in poor countries.
Citation Format: Lynette Denny. The impact of premature death of women from preventable cancers, such as cervical 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 IA3.
Abstract IA31: Precision prevention: Leveraging genomics to improve cancer control
Authors: Rebbeck Timothy R. 
Published: December 2017

Abstract
Most tumors are incurable once they reach an advanced (e.g., metastatic) stage. Even for those cancers with effective treatment options, prevention has the greatest potential to reduce the burden of cancer in the general population. Prevention has great potential to reduce the burden of cancer before it can cause illness and death. However, not all individuals respond to prevention strategies in the same way: an individual's unique genetic makeup and unique set of biological events that lead to cancer mean that each individual may require a personalized approach to prevention. Precision prevention can be defined as the use of biological, behavioral, socioeconomic, and epidemiological data to devise and implement strategies tailored to reducing cancer incidence and mortality in a specific individual or group of individuals.
In order to develop a precision prevention approach, it is critical that we understand: 1) basic biology of early carcinogenesis (e.g., genomic susceptibility, drivers of cancer, timing of carcinogenic events, reversibility of biological events); 2) heterogeneity (e.g., Inter-individual differences in susceptibility and tumor phenotype, intra-tumor differences in terms of clonality and propensity to metastasize, and response to preventive interventions); 3) unintended Effects of preventive strategies; and 4) implementation and health economics of preventive interventions.
The principles of precision prevention strategies include a focus on those individuals who are at highest risk of suffering or death from cancer (e.g., genetically high-risk individuals and individuals with pre-neoplasia), focus on interventions that are motivated by fundamental biological knowledge, have a favorable cost-benefit ratio, and benefit all populations, including underserved and minority groups.
In order for precision prevention to be successful, research is required to generate fundamental knowledge about cancer etiology and mechanism through scientific discovery; develop novel prevention strategies based on these fundamental discoveries; improve existing prevention strategies by incorporating biological information, biomarkers, risk profiling, and molecular subtyping to optimize prevention efficacy; and understand and implement cost-effective prevention strategies in targeted populations who are most likely to benefit.
Citation Format: Timothy R. Rebbeck. Precision prevention: Leveraging genomics to improve cancer control [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 IA31.
Abstract A10: CRISPR-AnalyzeR (caR): Web-based, interactive and exploratory analysis and documentation of pooled CRISPR/Cas9 screens
Authors: Winter Jan , Schwering Marc , Rauscher Benedikt , Heigwer Florian , Boutros Michael 
Published: December 2017

Abstract
Since the availability of the CRISPR/Cas9 gene editing technique, pooled CRISPR/Cas9 screens have become a powerful and versatile tool for the investigation of functional genomics in a variety of organisms. Pooled CRISPR/Cas9 screens are cost-effective and do not require lab automation, which allows even small labs to perform genome-wide genetic perturbation screens. The analysis of such screens so far requires in-depth knowledge in either bioinformatics or data analysis as there is a limited availability of end-to-end data analysis pipelines (Li et al., 2014; Winter et al., 2015). Moreover, the explorative analysis of screening data using end-to-end analysis tools often comes with certain limitations. Either these pipelines require sufficient computing power on the user machine or have to be run in command-line mode on dedicated machines, which constrains the usability.
A special need for wet-lab scientists is the availability of analysis pipelines which allow them to analyze the screening data on their own, knowing best about potential candidates and the biological background. Here we describe the CRISPR-AnalyzeR (caR), which is a web-based and fully-interactive tool to analyze pooled CRISPR/Cas9 screens meant for wet-lab scientists. caR combines both, end-to-end data analysis and explorative screen analysis that can be accessed via a regular web-browser such as Google Chrome or Firefox from any device - allowing the user to analyze the data in a comfortable, convenient and exploratory way. Moreover, caR uses latest visualization technologies to provide interactive plots and tables, allowing even novice users to analyze their own screens in an exploratory way. caR performs hit-calling using six different analysis methods, which gives the user the power and flexibility to select appropriate follow-up candidates. caR provides an easy-to-follow workflow and guides the user through the whole analysis process, which includes quality control, hit calling, in-depth gene information, data annotation enrichment and downloadable interactive reports to provide a comprehensive documentation.
Since caR is a web-based tool, it can be used via a provided web-server at http://crispr-analyzer.dkfz.de or can be downloaded for a local network installation.
Citation Format: Jan Winter, Marc Schwering, Benedikt Rauscher, Florian Heigwer, Michael Boutros. CRISPR-AnalyzeR (caR): Web-based, interactive and exploratory analysis and documentation of pooled CRISPR/Cas9 screens [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A10.
Abstract A15: Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status
Authors: Carey Jason PW , Vjayaraghavan Smruthi , Hunt Kelly , Keyomarsi Khandan 
Published: December 2017

Abstract
PARP inhibitors represent a novel class of cancer therapeutics that exploit a synthetic lethal mechanism specific to cancer cells with a defect within the Homologous Recombination (HR) DNA repair pathway. Patients with a BRCA1/2 germ-line mutation have the highest response rate to PARP inhibitors. However, early clinical trial data has indicated that only ~30-40% BRCA mutant patients respond to PARP inhibitors. Coincidentally, the oncogene c-myc is the most frequently amplified gene in BRCA mutant tumors (~40-60%) which typically present as Triple Negative Breast Cancer (TNBC). The oncogene c-myc transcriptionally regulates several DNA repair genes, and correlates with poor survival among breast cancer patients. Therefore we hypothesized that dual combination therapy targeting c-myc and PARP is an effective therapeutic strategy in BRCA mutant tumors. C-myc siRNA induced increased sensitivity to PARP inhibitors in BRCA wild-type (MB231) & BRCA mutant (SUM149) TNBC cell lines and down regulated HR repair. Pan CDK inhibitor Dinaciclib demonstrated significant MYC inhibition across several TNBC cell lines. Additionally, Dinaciclib demonstrated synergistic growth inhibition in combination with PARP inhibitor Niraparib in both BRCA wild-type and mutant c-myc expressing TNBC cell lines. Combination therapy also leads to an increase in DNA damage (via γH2AX) with a decrease in HR repair (BRCA1/RAD51). TNBC cell line mouse xenografts demonstrated down regulation of c-myc and RAD51 in Dinaciclib + Niraparib treated tumors. Dual Dinaciclib + Niraparib therapy also induced synergistic growth inhibition in PARP inhibitor acquired resistant cell lines while demonstrating significant growth inhibition across a panel of c-myc overexpressing cancer cell lines (Ovarian, Prostate, Pancreatic, Colon & Lung). In conclusion, we demonstrated that dual CDK + PARP inhibition is synthetic lethal in both BRCA wild-type and mutant TNBC cell lines and is dependent upon down regulation of c-myc. This study supports c-myc as predictor of response to PARP inhibitor therapy and may also serve as a biomarker of response to Dinaciclib + PARPi therapy in high MYC expressing tumors.
Citation Format: Jason PW Carey, Smruthi Vjayaraghavan, Kelly Hunt, Khandan Keyomarsi. Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A15.
Abstract A18: Predicting synergistic drug combinations from genomic features and single-agent response profiles
Authors: Rees Matthew G. , Brenan Lisa , Walker Amanda , Johannessen Cory M. 
Published: December 2017

Abstract
Drug combinations promise to improve clinical responses and/or forestall drug resistance. To capitalize on this promise, we need to know which drugs to combine, and whom to give them to based on the genetic or pathological features of their disease. However, accomplishing this goal has been precluded by the infeasibility of performing comprehensive drug-combination studies across thousands of cellular contexts. We hypothesized that the basal gene-transcription state of cancer cell lines, in concert with the response profiles of hundreds of single-agent small molecules, might be leveraged to nominate synergistic drug combinations, eliminating the need to test all possible drug/drug combinations across cellular models. Specifically, we predicted that inhibiting the protein product of transcripts associated with drug resistance to a given small molecule might induce drug synergy. To test this notion, we analyzed public cell-line drug-sensitivity data to identify candidate compound-gene pairs. We identified 7 examples in which outlier expression of a druggable candidate protein was associated with lack of single-agent response. Inhibition of 6/7 candidate co-targets resulted in cell-line-specific synergistic cell killing across multiple cell line models, validating the overall approach. For example, consistent with clinical findings, we found that high expression of the MGMT gene, encoding O-6-methylguanine-DNA methyltransferase, was uniquely associated with response to alkylating agents such as temozolomide, and that combination of the MGMT inhibitor O-6-benzylguanine with temozolomide resulted in synergistic killing. These initial studies highlight the potential of integrating basal gene expression features with small-molecule response to nominate rational candidates for drug combinations. As public repositories of single-agent response data from diverse cellular contexts continue to expand, so too will our repertoire of therapeutic combinations. Moreover, this approach permits the parallel identification of genomic features that indicate which patient populations are most likely to benefit from such combinations.
Citation Format: Matthew G. Rees, Lisa Brenan, Amanda Walker, Cory M. Johannessen. Predicting synergistic drug combinations from genomic features and single-agent response profiles [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A18.