tbuckley/cabot-search huggingface dataset:
Abstract 3658: Dendritic cells dictate the responsiveness of PD-L1 blockade in cancer
Authors: Maud Mayoux, Marieke F. Fransen, Andreas Roller, Ines Matos, Vesna Pulko, Vaios Karanikas, Pablo Umana, Christian Klein, Ferry A. Ossendorp, Wei Xu
Journal: Cancer Research (2017)

Abstract Recent advances in cancer immunotherapies with PD-1/PD-L1 pathway blockade have transformed the way that cancer is being treated, leading to durable responses and prolonged overall survival. The general thinking is that PD-1/PD-L1 blockade reinvigorates tumor-infiltrating PD-1+ T cells with exhausted phenotypes. However, a mechanistic understanding on why only a subset of patients (10-30%) responds to checkpoint inhibition remains largely unknown, as does the exact immune mechanism of PD-1/PD-L1 blockade. Here, we discovered that PD-L1 blockade mediates anti-tumor immunity via dendritic cells. In human blood, in vitro and ex vivo dendritic cells (DCs) express both PD-1 and PD-L1, and an activation signal via TLR agonists triggers downregulation of PD-1 to empower the T cell stimulatory capability of DCs. In contrast, tolerogenic DCs remain PD-1 positive, correlating to T cell-unresponsiveness. Anti-PD-L1 Ab directly induces maturation of DCs and renders them capable of stimulating T cell proliferation. Similarly, anti-PD-L1 Ab treatment in tumor-bearing mice induces massive infiltration and activation of CD11c+ DCs in the spleen and draining lymph node, indicating that PD-1 is a negative regulator in DCs. Furthermore, ablation of DCs prior to anti-PD-L1 Ab treatment in an established MC38 tumor model in CD11c-DTR mice suggests a crucial role of DCs in mediating response to PD-L1 treatment. In support of the preclinical evidence that DCs are the primary target of anti-PD-L1 Ab, we analyzed RNA-seq data from tumor biopsies at baseline in patients with renal cell carcinoma prior to treatment with atezolizumab and found that the abundance of genes related to cross-presenting DC subsets (such as XCR1) correlates with a survival advantage in response to atezolizumab (HR=0.13, median OS is 16.2 months in patients with DC gene score &amp;lt;50% versus NR (not reached) in those &amp;gt;50%). In conclusion, we discovered abundance of tumor-infiltrating DCs as a novel biomarker that can predict the clinical response of PD-L1 blockade. We postulate that checkpoint inhibition directly on tumor-infiltrating DCs likely contributes to amplification of Ag-specific priming of tumor-specific T cells. Citation Format: Maud Mayoux, Marieke F. Fransen, Andreas Roller, Ines Matos, Vesna Pulko, Vaios Karanikas, Pablo Umana, Christian Klein, Ferry A. Ossendorp, Wei Xu. Dendritic cells dictate the responsiveness of PD-L1 blockade in 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 3658. doi:10.1158/1538-7445.AM2017-3658
Abstract 482: miRNAs involved in LY6K and estrogen receptor-α contribute to tamoxifen susceptibility in breast cancer
Authors: Yesol Kim, Dasom Son, Kyung Hyun Yoo, Jong Hoon Park
Journal: Cancer Research (2017)

Abstract Estrogen receptor-alpha is a clinically important therapeutic target for breast cancer. However, tumors that lose ERα are less responsive to anti-estrogens such as tamoxifen. MicroRNAs are small RNAs that regulate expression of their target gene and dysregulations of miRNA has been identified in many diseases including human cancer. However, only a few miRNAs associated with tamoxifen resistance has been reported. In this study, we found that lymphocyte antigen 6 complex, which is a member of the Ly-6/μPAR superfamily and related to breast cancer progression and metastasis, is inversely correlated with ERα expression. We, for the first time, found miRNAs involved in the regulatory molecular mechanism between ERα and LY6K and related to tamoxifen susceptibility in breast cancer. miR-192-5p, induced by LY6K, downregulates ERα directly and induced tamoxifen resistance in ERα-positive breast cancer cells. In addition, re-expression of ERα in ERα-negative breast cancer cells increased miR-500a-3p expression and directly inhibits LY6K expression. Ectopic expression of miR-500a-3p sensitized ERα-negative cells to tamoxifen by increasing apoptosis. Finally, we observed an inverse correlation between LY6K and ERα in primary breast cancer samples. We found that patients with recurrence showed high expression of miR-192-5p after tamoxifen treatments. In addition, expression of miR-500a-3p was significantly correlated to survival outcome. As miRNAs involved in the regulatory mechanism between LY6K and ERα can affect tamoxifen resistance, downregulating miR-192-5p or re-expressing miR-500a-3p could be a potential therapeutic approach for treating tamoxifen resistant patients. Citation Format: Yesol Kim, Dasom Son, Kyung Hyun Yoo, Jong Hoon Park. miRNAs involved in LY6K and estrogen receptor-α contribute to tamoxifen susceptibility in 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 482. doi:10.1158/1538-7445.AM2017-482
Abstract 3773: Tapping CD4 T cells for cancer immunotherapy
Authors: Sébastien Wälchli, Marit R. Myhre, Nadia Mensali, Anne Fåne, Kari Lislerud, Gunnar Kvalheim, Gustav Gaudernack, Else M. Inderberg
Journal: Cancer Research (2017)

Abstract T-cell based immunotherapy represents an attractive strategy for the treatment of cancer. Whereas cellular anti-tumor immune responses have typically been attributed to CD8 T cells, CD4 T cells play a critical role in tumor elimination and the priming and maintenance of CD8 T-cell responses. Recent findings have highlighted new opportunities for CD4 T cells in cancer immunotherapy. We have isolated CD4+ T cells reactive against tumor antigens from patients who experienced clinical benefit from treatment with cancer vaccines targeting antigens such as hTERT, survivin and frequent neoantigens such as frameshift mutated TGFβRII. Strong T-cell responses against the vaccine or unrelated cancer antigens suggesting epitope spreading correlated with enhanced survival and tumor regression in late stage cancer patients. These HLA class II restricted T-cell clones recognised target cells loaded with long peptides or protein and for some CD4+ T cell clones we could also show direct tumor recognition. TCRs were expressed in expanded third-party T cells by mRNA electroporation or retroviral transduction and tested for functionality. Both CD8+ and CD4+ T cells expressing the TCRs produced TNF-α, IFN-γ and redirected T cells had the capacity to kill following co-incubation with their targets. Selecting highly functional CD4+ T-cell clones reactive against tumor-associated or -specific antigens from patients with clinical responses after treatment with immunotherapy is a successful method for identifying highly functional HLA class II restricted TCRs for adoptive immunotherapy. These HLA class II-restricted TCRs may be of therapeutic value both in haematopoietic malignancies and in melanoma where tumor cells frequently express HLA class II. Furthermore, combining HLA class I- and class II-restricted TCRs for T-cell redirection may provide a more potent therapeutic effect in adoptive T cell therapy. Citation Format: Sébastien Wälchli, Marit R. Myhre, Nadia Mensali, Anne Fåne, Kari Lislerud, Gunnar Kvalheim, Gustav Gaudernack, Else M. Inderberg. Tapping CD4 T cells for cancer immunotherapy [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 3773. doi:10.1158/1538-7445.AM2017-3773
Abstract 14785: Mean Platelet Volume is an Independent Predictor of Left Ventricular Systolic Dysfunction and is Associated with Adverse Cardiovascular Outcomes
Authors: Ravi Prasad Avati Nanjundappa, Danny Eapen, Gautam Kumar, Pankaj Manocha, Riyaz Patel, Salman Sher, Hatem A Kassem, Muhammad Hammadah, Ayman S Tahhan, Nima Ghasemzadeh, Naureen Farook, Mohammad S Qadir, Veledar Emir, Laurence Sperling, Maziar A Zafari, Habib Samady, Arshed A Quyyumi
Journal: Circulation (2012)

Background: Mean Platelet Volume (MPV) is a readily available estimate of platelet size in circulating blood and may be a marker of cardiovascular (CV) risk. We hypothesized that an elevated MPV is...
Abstract 3585: Determination of gene amplifications with a next-generation sequencing cancer panel
Authors: Ina L. Deras, Aaron Wise, Chen Zhao, Christine Glidewell-Kenney, Phillip Le, Elizabeth Upsall Aderhold, Karen Gutekunst
Journal: Cancer Research (2017)

Abstract TruSight® Tumor 15* (TST15) uses next-generation sequencing technology to detect somatic point mutations, insertions, and deletions in 15 genes that are commonly mutated in solid tumors. It accurately detects low-frequency mutations with low DNA input and is optimized for formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The test is a multiplexed PCR panel that includes primers to support amplification detection in the EGFR, ERBB2, and MET genes. Here we describe development of a bioinformatics analysis method to enable detection of these gene amplifications. DNA extracted from 31 FFPE samples with amplifications in EGFR, ERBB2, or MET—some with dual amplifications—were diluted with DNA extracted from 18 normal FFPE samples to create a total of 67 unique samples at low-level amplification. Undiluted and diluted samples were assessed for quality based on amplifiability (ΔCq or library yield) and tested with TST15. For comparison, the samples were also tested with droplet digital PCR (ddPCR) to determine the copy ratio of target to wild type. For amplifiable samples, the TST15 algorithm was able to detect amplifications in EGFR and ERBB2 at ddPCR ratios of 1.4 and 1.6, respectively. ddPCR was unable to accurately quantify low MET amplifications; therefore, expected ddPCR ratios were used for comparison. The TST15 algorithm was able to detect amplifications in MET samples at an expected ddPCR ratio of 1.3. Poor sample quality (i.e., high ΔCq or low library yield) impaired amplification detection. In some samples, the presence of multiple amplifications also impaired detection. The addition of this algorithm to the TST15 workflow will allow researchers to more accurately characterize tumor samples by detecting somatic mutations and amplifications simultaneously. *For Research Use Only. Not for use in diagnostic procedures. Citation Format: Ina L. Deras, Aaron Wise, Chen Zhao, Christine Glidewell-Kenney, Phillip Le, Elizabeth Upsall Aderhold, Karen Gutekunst. Determination of gene amplifications with a next-generation sequencing cancer panel [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 3585. doi:10.1158/1538-7445.AM2017-3585
The impact of preoperative bacteriuria on the risk of periprosthetic joint infection after primary knee or hip replacement: a retrospective study with a 1-year follow up
Authors: M. Honkanen, E. Jämsen, M. Karppelin, R. Huttunen, H. Huhtala, A. Eskelinen, J. Syrjänen
Journal: Clinical Microbiology and Infection (2017)
Abstract 5339: Molecular phylogenetic classification of human papillomaviruses and cancer associated genes: In correlation with cervical cancer manifestation
Authors: John Idoko, Mohammed Faruk, Jigo Yaro, James Enemari, Peter Akpulu
Journal: Cancer Research (2017)

Abstract Human papillomaviruses (HPVs) are a diverse group of small double stranded Deoxyribonucleic acid viruses implicated in many malignancies including cervical cancer. The viruses are also attributed to premalignant epithelial lesions in this disease. Cervical cancer is a leading course of morbidity and mortality in African women and beyond. We aimed to study the molecular phylogenetic classification of HPVs and cervical cancer associated genes in relation with tumour manifestation. Phylogenetic tree was constructed based on nucleotide sequence alignments using ClustalX 2.1 algorithms to classify 31 different HPV DNA virus types and 10 cervical cancer associated genes. Study of immunohistochemistry markers associated with cervical cancer pathology was performed. The nucleotide sequences used include HPV- 1 (V01116), HPV-14 (D90261), HPV-20 (D90262), HPV-21 (D90263), HPV-25 (D90264), HPV-5 (M22961), HPV-47 (M32305), HPV-8 (M12737), HPV-2 (X55964), HPV-57 (X55965), HPV-6: X00203), HPV-11 (M14119), HPV-13 (X62843), HPV-43 (HE962420.1 E6 gene), HPV-44 (U31788.1), HPV-42 (HE820226.1 E6 gene for E6 protein), HPV-16 (K02718), HPV 16 (KJ869425.1 E6 and E7 variants), HPV-35 (M74117), HPV-31 (J04353), HPV-52 (KJ869430.1), HPV-33 (M12732), HPV-58 (D90400), HPV-51 (M62877), HPV-18 (X05015), HPV-45 (M27363), HPV-39 (M38185), (ME180, M73258), HPV 16 (KJ869425.1 E6 and E7 variants), Ki-67 (NM_002417.4), p53 (AB082923.1), EGFR (NM_005228.3), MYC (M25803.1), KRAS (EF471957.1), TGF-B (AF254794.1) and RB (AH002963.2) genes. The resulting phylogenetic tree provides a conventional classification of the HPVs and the cancer genes into groups encompassing the known tissue tropism and oncogenic potential of each gene type associated with the disease. The implications of a phylogenetic taxonomy on the diagnostic detection of HPVs as they relate to cervical cancer associate genes are shown to be important in disease management. Citation Format: John Idoko, Mohammed Faruk, Jigo Yaro, James Enemari, Peter Akpulu. Molecular phylogenetic classification of human papillomaviruses and cancer associated genes: In correlation with cervical cancer manifestation [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 5339. doi:10.1158/1538-7445.AM2017-5339
Abstract 4766: Translation from unconventional 5' start sites drives tumor initiation
Authors: Ataman Sendoel, Joshua G. Dunn, Edwin H. Rodriguez, Shruti Naik, Nicholas C. Gomez, Brian Hurwitz, John Levorse, Brian D. Dill, Daniel Schramek, Henrik Molina, Jonathan S. Weissman, Elaine Fuchs
Journal: Cancer Research (2017)

Abstract How translational control impacts tumor-initiation and malignancy is just beginning to unfold. Here, we devise an epidermis-specific, in vivo ribosome profiling strategy to interrogate the translational landscape during the transition from normal homeostasis to malignancy. Inducing SOX2, broadly expressed in oncogenic RAS-associated cancers, we find that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. Seeking mechanism, we find that during tumor-initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing translational efficiency of oncogenic mRNAs. An in vivo RNAi screen of translational regulators revealed that dampening conventional EIF2 complexes has dire consequences for normal but not oncogenic growth. Conversely, we identify alternative initiation factors essential for cancer progression, where they mediate initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a hitherto unappreciated role of 5’UTR translation in cancer, and expose new targets for therapeutic intervention. Citation Format: Ataman Sendoel, Joshua G. Dunn, Edwin H. Rodriguez, Shruti Naik, Nicholas C. Gomez, Brian Hurwitz, John Levorse, Brian D. Dill, Daniel Schramek, Henrik Molina, Jonathan S. Weissman, Elaine Fuchs. Translation from unconventional 5' start sites drives tumor initiation [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 4766. doi:10.1158/1538-7445.AM2017-4766
Circulating tumor cells and risk of venous thromboembolism in metastatic breast cancer patients
Authors: M. Mego, U. De Giorgi, L. Hsu, E. Andreopoulou, V. Valero, S. Dawood, B. Handy, J. M. Reuben, M. Cristofanilli
Journal: Journal of Clinical Oncology (2009)

1060 Background: Cancer is well-recognized risk factor for venous thromboembolism (VTE), and VTE is associated with a higher risk of death in cancer patients. Coagulation activation by tissue factor (TF) is associated with cancer growth and disease progression. Circulating tumor cells (CTCs) are an independent predictor of survival in metastatic breast cancer (MBC) patients. The aim of this study was to test the hypothesis that CTCs are associated with the risk of VTE in MBC patients. Methods: This retrospective study included 362 MBC patients treated in M. D. Anderson Cancer Center between January 2004 and December 2007. CTCs were detected and enumerated using the CellSearch system. Patients were assigned to cohorts based on the highest CTC counts during the course of the disease. All venous thrombosis and/or pulmonary embolism in the presence of unequivocal medical documentation were classified as events. Results: At a median follow up of 11.1 months (range 0–38 months) 30 patients (8.3%) experienced VTE. Median survival was 16.3 months vs. 37.2 months (p = 0.003) in patients with and without VTE, respectively. Patients with ≥ 3 CTCs had an elevated risk of VTE in comparison to patients with &lt; 3 CTCs (12.1% vs 3.7%; p = 0.003). In multivariate analysis, the presence of visceral metastasis, increased number of metastatic sites and ≥ 3 CTCs were associated with the risk of VTE. Conclusions: This retrospective study showed that CTCs are associated with increased risk of VTE in MBC. Prospective assessment of coagulation status and its correlation to CTC counts and clinical outcome are warranted. No significant financial relationships to disclose.
Abstract 4956: Transcriptome-wide association study identifies new prostate cancer susceptibility genes in the OncoArray data
Authors: Nicholas Mancuso, Wei Zheng, Kathryn Penney, Zsofia Kote-Jarai, Christopher Haiman, Simon Gayther, Matthew Freedman, Bogdan Pasaniuc
Journal: Cancer Research (2017)

Abstract Genome-wide association studies (GWAS) have identified over 150 genomic regions harboring risk variants for prostate cancer which explain one third of all familial risk. However, with some notable exceptions, the causal variants and target susceptibility genes at these risk loci have yet to be identified. Recent work has shown a strong overlap between loci associated with gene expression levels (eQTLs) in prostate tissue and GWAS loci, which suggests that the causal mechanism at a significant proportion of risk loci includes causal alleles that regulate expression levels of nearby susceptibility genes. While overlapping eQTLs with GWAS is a powerful method to prioritize susceptibility genes, it is often the case that multiple eQTLs co-localize at the GWAS risk region (due to linkage disequilibrium (LD) and correlations across transcript levels). This prohibits the identification of the true susceptibility gene as opposed to spurious co-localization at the same locus. We recently leveraged gene expression imputation to perform transcriptome-wide association studies (TWAS) as a principled approach to measure the strength of association between gene expression and disease status. Here, we use imputed expression to identify new susceptibility genes for prostate cancer in the OncoArray GWAS data. We integrate gene expression data from more than 44 tissues across ~4,000 individuals with GWAS of prostate cancer from the OncoArray in ~140,000 individuals. Our approach identified 118 susceptibility genes for prostate cancer that reside in 90 independent loci across the genome. Of these, we report 7 genes located more than 0.5 Megabases away from any previously reported GWAS loci for prostate cancer, thus providing new risk loci. Second, we use TWAS to investigate genes previously reported as susceptibility genes for prostate cancer through overlaps of eQTL and GWAS. We find 36 (out of 86 previously reported genes) to be significant in TWAS. Overall, our findings highlight the power of integrating gene expression data with GWAS and provide testable hypotheses for future functional validation of prostate cancer risk. Citation Format: Nicholas Mancuso, Wei Zheng, Kathryn Penney, The PRACTICAL Consortium, Zsofia Kote-Jarai, Christopher Haiman, Simon Gayther, Matthew Freedman, Bogdan Pasaniuc. Transcriptome-wide association study identifies new prostate cancer susceptibility genes in the OncoArray 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 4956. doi:10.1158/1538-7445.AM2017-4956
Abstract 2414: Fibromodulin expression in human prostate cancer tissue: Implications for prostate cancer progression
Authors: Estebana Ines Benedetti Padron, Angelo De Marzo, Javier Baena Del Valle, Jan Geliebter, Niradiz Reyes
Journal: Cancer Research (2017)

Abstract Background: Fibromodulin is a small leucine-rich proteoglycan important for extracellular matrix organization and essential for tissue repair in multiple organs. Recently, differential expression of fibromodulin has been shown in human prostate cancer cell lines with different cancer phenotypes and in human prostate cancer tissue compared to normal/benign tissue. Methods: The protein expression level of fibromodulin was analyzed by immunohistochemistry using a prostate tissue microarray (TMA), constructed from archival radical prostatectomy and trans-urethral prostatectomy tissue specimens, from patients with localized prostate cancer (PCa). Stained sections from the donor blocks were evaluated, and a representative area from PCa, high grade prostatic intraepithelial neoplasia (HGPIN), proliferative inflammatory atrophy (PIA), and benign prostate tissue (BPT) was included into the TMA. Staining for each lesion was scored, using H-score, by microscopic assessment of the percentage of epithelial cells with positive staining. H-score values were compared between groups by ANOVA test, and p &amp;lt; 0.05 was considered statistically significant. The Ethical Review Board of the academic institution approved this study. Results: Fibromodulin expression at protein level was evaluated in 378 cores representing PCa (143 cores), HGPIN (58), PIA (102), and BPT (78). Mean fibromodulin expression in cores with PCa, HGPIN, and PIA was significantly higher than mean of fibromodulin expression in normal glands (p&amp;lt;0.0001). There was a higher mean staining score in PCa (156, 95% CI:144–167), compared to HGPIN (131.4, 95% CI:109-153), PIA (128, 95% CI:117-138), and BPT (33.3, 95% CI:27-38). Thus, fibromodulin expression increased across the PCa progression model. Conclusions: The expression pattern of fibromodulin showed a significant increase from benign prostate tissue through pre-cancerous lesions to PCa. These findings suggest that this proteoglycan may be involved in the process of prostate cancer progression, with low levels in pre-cancerous lesions and higher levels in cancer tissue. Additional studies are required to determine the biological role and potential clinical implications of fibromodulin in prostate cancer. Citation Format: Estebana Ines Benedetti Padron, Angelo De Marzo, Javier Baena Del Valle, Jan Geliebter, Niradiz Reyes. Fibromodulin expression in human prostate cancer tissue: Implications for prostate cancer 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 2414. doi:10.1158/1538-7445.AM2017-2414