tbuckley/cabot-search huggingface dataset:
Abstract 4266: Proteomics for precision oncology: Profiling the proteome of matching tumor and adjacent normal tissue using data-independent acquisition
Authors: Jakob Vowinckel, Karel Novy, Thomas Corwin, Tobias Treiber, Roland Bruderer, Lukas Reiter, Eike von Leitner, Oliver Rinner, Claudia Escher
Journal: Cancer Research (2020)

Abstract Precision oncology requires a deep understanding of the molecular mechanism in cancer biology. The predominant approach today focuses on genome structure and gene expression data, which have become available with the rise of next-gen sequencing technology. On a phenotypic level, however, protein expression and activation are arguably more directly related to cellular function. The availability of combined genome and proteome level data from the same tumor is therefore expected to provide a much more complete picture of a tumor in a particular state. Until recently, proteomics technology could not match the scale of next-gen sequencing and consequently, precision medicine research has almost exclusively been based on gene-level data. Here we show the first truly large-scale data set for protein expression and protein phosphorylation for a large collection of biospecimens derived from the IndivuType cohort of Indivumed, Germany. Matching fresh-frozen tumor and adjacent normal tissue samples from thousands of patients including various cancer entities were obtained from Indivumed's network of partner hospitals Enabled by the novel data-independent acquisition (DIA) workflow, a mass spectrometric method that obtains peptide fragmentation data in a highly parallelized way with high reproducibility and sensitivity, more than 7,000 proteins in the whole proteome (WP) and 20,000 phospho-peptides in the phospho-proteome (PP) workflow were analyzed. Sample processing from 5 mg of tissue per sample was performed on 96-well plates with the help of a liquid handling robot. Phospho-peptide enrichment was carried out using a Kingfisher Flex device and MagReSyn Ti-IMAC magnetic beads (ReSyn Biosciences). Data-independent acquisition (DIA) LC-MS/MS was performed on multiple platforms consisting of a Thermo Scientific Q Exactive HF-X mass spectrometer coupled to a Waters M-Class LC. Chromatography was operating at 5 µL/min, and separation was achieved using 45 min (WP) and 60 min (PP) gradients. With a throughput of 850 WP and 650 PP samples per month, thousands of samples were analyzed to date. The resulting proteome data is integrated into Indivumed's IndivuType multi-omics database, supporting the identification and validation of new molecular cancer drug targets and biomarkers. Citation Format: Jakob Vowinckel, Karel Novy, Thomas Corwin, Tobias Treiber, Roland Bruderer, Lukas Reiter, Eike von Leitner, Oliver Rinner, Claudia Escher. Proteomics for precision oncology: Profiling the proteome of matching tumor and adjacent normal tissue using data-independent acquisition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4266.
Abstract 4501: RNA seq analysis reveals altered immune specific gene signature in African American bladder cancer
Authors: Karthik reddy kami reddy, Balasubramanyam Karanam, Cristian Coarfa, Yair Lotan, Roni J. Bollag, Martha K. Terris, Nagireddy Putluri
Journal: Cancer Research (2020)

Abstract Understanding specific functional gene signature among bladder cancer (BLCA) patients of diverse race/ethnicities remain largely unexplored. Even though the incidence rate of BLCA in African Americans (AA) is nearly half as that of European Americans (EA), but AA have the worst survival. This survival difference can be attributed to unequal access to health care, and social economic status, which in turn delays the treatment in AA patients. Here, we analyzed RNA-seq data from AA and EA patient cohort compare with adjacent benign tissues and identified a set of signature genes which are significantly altered in AA patients. Gene Set Enrichment Analysis (GSEA) reveals that these genes are significantly enriched in immune pathways. Several known cytokines, cell differentiated markers and transcription factors including, growth differentiation marker 2 (GDF2), Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) were downregulated and fibroblast growth factor 1 (FGF1), Caudal type homeobox 1 (CDX1) were upregulated in AA compare to EA. To interrogate the function of specific genes in tumor, we have used an integrated repository portal for tumor-immune system interactions (TISIDB). Using this disease association analysis, we identified a common relationship of these genes with immune response, cytokine signaling and regulation of lymphocyte activation. Our findings indicate that an altered tumor-immune interplay could be a factor for AA BLCA progression and provide the rationale to examine immune specific checkpoint inhibitors to target BLCA on subset of patients from the AA community. Key words: Racial disparity, Immune system, Bladder cancer. Citation Format: Karthik reddy kami reddy, Balasubramanyam Karanam, Cristian Coarfa, Yair Lotan, Roni J. Bollag, Martha K. Terris, Nagireddy Putluri. RNA seq analysis reveals altered immune specific gene signature in African American bladder cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4501.
Abstract 4986: Utilizing image analysis to characterize an 8-plex immunofluorescence immune checkpoint biomarker panel within the tumor tissue microenvironment
Authors: Alison L. Bigley, Lorcan A. Sherry, Nicole Stillie, Douglas Wood, Sean Downing
Journal: Cancer Research (2020)

Abstract Multiplex staining and image analysis are being increasingly deployed for immuno-oncology (I/O) evaluations to investigate and understand the complexity of immune cell / tumor cell interactions in the tumor microenvironment (TME) and in discovering novel predictive biomarkers for targeted immunotherapy. Immune checkpoint inhibitor treatment, guided by immunohistochemically labelled tissue expression of PD-L1 and PD-1, have already been shown to improve outcomes, in the metastatic setting, for non-small cell lung carcinoma (NSCLC) and colorectal cancer (CRC) patients. The purpose of the current study was to phenotype and compare checkpoint and immune cell interactions within NSCLC and CRC tumor types. The study included samples from NSCLC, CRC, and normal tonsil tissues. Sections were stained using InSituPlex® multiplex immunofluorescence (mIF), for studying PD-L1/PD-1 checkpoint expression including immune cell markers for CD3, CD4, CD8, CD68, FoxP3, and pan-CK as an epithelial tumor indicator. Slides were scanned at 20X magnification on the ZEISS Axio Scan.Z1 platform, with individual .tiff format files being generated per marker. Image analysis was performed using the Visiopharm® Oncotopix® platform. Individual marker image layers were aligned, tumor/stroma regions of interest (ROI) classified, and cell formations detected. Quantification of markers was determined across the image layers to evaluate positive cell staining within both cancer indications. Quantitative image analysis data generated included total positive and negative cell counts per marker, per mm2 ROI. Co-localization analysis provided relevant immune cell phenotypes (T-cytotoxic, T-helper, T-regs, and macrophages) and immune cell functional status. Cell spatial analysis relationships were generated, including CD8+/PD-1− and CD8+/PD-1+ to CK+/PD-L1+ tumor cells. This study highlighted the benefits of utilizing an 8-plex staining protocol and detailed image analysis approach for the comprehensive assessment of the immune cell types and interactions within the TME. The ability to carry out multiparameter cellular analysis facilitates the delivery of key phenotypic data, thereby leading to greater understanding of tumor biology. Citation Format: Alison L. Bigley, Lorcan A. Sherry, Nicole Stillie, Douglas Wood, Sean Downing. Utilizing image analysis to characterize an 8-plex immunofluorescence immune checkpoint biomarker panel within the tumor tissue microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4986.
Erratum : Endoscopic management of gastrointestinal motility disorders - Part 1: European Society of Gastrointestinal Endoscopy (ESGE) Guideline (Endoscopy (2020) 52 (498-515) DOI: 10.1055/a-1160-5549)
Authors: Bas L. A. M. Weusten, Maximilien Barret, Albert J. Bredenoord, Pietro Familiari, Jan-Michel Gonzalez, Jeanin E. van Hooft, Sauid Ishaq, Vicente Lorenzo-Zúñiga, Hubert Louis, Suzanne van Meer, Helmut Neumann, Daniel Pohl, Frederic Prat, Daniel von Renteln, Edoardo Savarino, Rami Sweis, Jan Tack, Radu Tutuian, Jan Martinek
Journal: Endoscopy (2020)

In the above-mentioned article, the institution of Daniel Pohl has been corrected. This was corrected in the online version on June 19, 2020.
Melatonin Induction of APP Intracellular Domain 50 SUMOylation Alleviates AD through Enhanced Transcriptional Activation and Aβ Degradation
Authors: Yen-Chen Liu, Wei-Lun Hsu, Yun-Li Ma, Eminy H.Y. Lee
Journal: Molecular Therapy (2020)

The amyloid precursor protein (APP) intracellular domain (AICD) is implicated in the pathogenesis of Alzheimer's disease (AD), but post-translational modification of AICD has rarely been studied and its role in AD is unknown. In this study, we examined the role and molecular mechanism of AICD SUMOylation in the pathogenesis of AD. We found that AICD is SUMO-modified by the SUMO E3 ligase protein inhibitor of activated STAT1 (PIAS1) in the hippocampus at Lys-43 predominantly, and that knockdown of PIAS1 decreases endogenous AICD SUMOylation. AICD SUMOylation increases AICD association with its binding protein Fe65 and increases AICD nuclear translocation. Furthermore, AICD SUMOylation increases AICD association with cyclic AMP-responsive element binding protein (CREB) and p65 and their DNA binding for transcriptional activation of neprilysin (NEP) and transthyretin (TTR), two major Aβ-degrading enzymes, respectively. Consequently, AICD SUMOylation decreases the Aβ level, Aβ oligomerization, and amyloid plaque deposits. It also rescues spatial memory deficits in APP/PS1 mice. Conversely, blockade of AICD SUMOylation at Lys-43 produces the opposite effects. Melatonin is identified as an endogenous stimulus that induces AICD SUMOylation. It also decreases the Aβ level and rescues reduction of PIAS1, NEP, and TTR expression in APP/PS1 mice. In this study, we demonstrate that AICD SUMOylation functions as a novel endogenous defense mechanism to combat AD. The amyloid precursor protein (APP) intracellular domain (AICD) is implicated in the pathogenesis of Alzheimer's disease (AD), but post-translational modification of AICD has rarely been studied and its role in AD is unknown. In this study, we examined the role and molecular mechanism of AICD SUMOylation in the pathogenesis of AD. We found that AICD is SUMO-modified by the SUMO E3 ligase protein inhibitor of activated STAT1 (PIAS1) in the hippocampus at Lys-43 predominantly, and that knockdown of PIAS1 decreases endogenous AICD SUMOylation. AICD SUMOylation increases AICD association with its binding protein Fe65 and increases AICD nuclear translocation. Furthermore, AICD SUMOylation increases AICD association with cyclic AMP-responsive element binding protein (CREB) and p65 and their DNA binding for transcriptional activation of neprilysin (NEP) and transthyretin (TTR), two major Aβ-degrading enzymes, respectively. Consequently, AICD SUMOylation decreases the Aβ level, Aβ oligomerization, and amyloid plaque deposits. It also rescues spatial memory deficits in APP/PS1 mice. Conversely, blockade of AICD SUMOylation at Lys-43 produces the opposite effects. Melatonin is identified as an endogenous stimulus that induces AICD SUMOylation. It also decreases the Aβ level and rescues reduction of PIAS1, NEP, and TTR expression in APP/PS1 mice. In this study, we demonstrate that AICD SUMOylation functions as a novel endogenous defense mechanism to combat AD.
Abstract 2531: The mechanism of HPV oncogenes in the regulation of upstream microRNA pathway in cervical cancer
Authors: Yi Song, Yan Deng, Tao Tang, Chi Chiu Wang
Journal: Cancer Research (2020)

Abstract High risk Human Papillomavirus (HPVs) is a very important etiological agent in cervical cancer. HPV types have been subdivided into low-risk types and high-risk types, which are frequently associated with invasive cervical cancer. HPV16 and HPV18 count for 70% of cervical cancer. The E6, E7 genes in the early region of HPV genome are proved to have a significant impact on progression of cervical cancer. miRNA is a kind of short non-coding RNA which regulates the gene expression on post-transcriptional and translational level, and it has been proved to have a significant impact on tumor development. Our group previously investigated the correlation of miRNAs and HPV oncogenes, and identified several differentially expressed miRNAs in cervical cancer cell lines and clinical specimens. The expression level of miR-145, miR-195 and miR-142-3p were down-regulated in cervical cancer patients. However, whether the HPV oncogenes regulate miRNAs is still unknown. In order to determine the relationship between HPV oncogenes and miRNAs. We did several experiments. We found that up/down-regulate HPV 16/18 E6 and E7 caused an decrease/increase of BRCA1, miR-145 and miR-195, and BRCA1 could increase the expression of miR-145 and miR-195 in different cell lines transfected with HPV 16/18 E6 and E7 by using qRT-PCR and Western-blot. We also found the binding activity of E2F1 and MYC to the promoter region of BRCA1, which validated by ChIP-PCR and Luciferase assay. These pathways were also validated in tumor xenograft nude mice. We also tried to find the target genes of miR-145 and miR-195, and investigated how they affect tumorigenesis in cervical cancer. These findings provided a solid foundation that HPV 16/18 E6 and E7 regulated miR-145 and miR-195 via BRCA1 in cervical cancer. It can be an important pathway for the pathogenesis of cervical cancer induced by high risk HPV. These findings could provide new ways in diagnosis and treatment for cervical cancer. They also give a new insight to investigate molecular pathways for HPV-associated cancers. We believe that further investigation will be done for the mechanisms in the future. Citation Format: Yi Song, Yan Deng, Tao Tang, Chi Chiu Wang. The mechanism of HPV oncogenes in the regulation of upstream microRNA pathway in cervical cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2531.
Abstract 867: Prostate cancer: AI-markers for detecting, grading, and prognosticating 5-year survival post-biopsy
Authors: Daphna Laifenfeld, Cobi Reouven, Inbal Gross, Ronen Heled, Varda Shalev, Judith Sandbank, Chaim Linhart
Journal: Cancer Research (2020)

Abstract Adenocarcinoma of the prostate is a diverse disease with multiple treatment options and inconsistent outcomes, and is the second most common cancer diagnosed in men, with approximately one in nine men diagnosed in their lifetime. The recent development and regulatory approval of whole slide image (WSI) scanning systems, together with the advent of robust computational approaches such as artificial-intelligence (AI) and machine learning, enable the development of new AI-based algorithmic markers (“AI markers”) that can be used to support the pathologist in their diagnostic process, as well as to better predict outcome and thus disease management in prostate cancer patients. Through a collaboration with Maccabi Healthcare Services, we have developed AI-based diagnostic tools that can correctly identify multiple features within prostate core needle biopsies (PCNBs), including adenocarcinoma, Gleason grade, inflammation, high grade prostatic intraepithelial neoplasia, and others. Combining these features with clinical and molecular data, we have developed multi-feature AI markers that prognosticate 5-year survival post-biopsy using thousands of slides from over 500 patients. In addition, we identify explanatory features associated with pre-biopsy PSA levels that together may help guide treatment decisions. Using AI on a combination of multiple data types, including lab tests, clinical outcome, and tissue biopsy, we demonstrate a powerful approach for the development of novel prognostic algorithms. These algorithms constitute low-cost accessible AI markers that are tissue-sparing and can be easily applied in clinical settings for optimal patient stratification for prospective clinical trials, as well as for different treatment options in prostate cancer. Further, this approach can be extended to additional cancer tissues, with the potential to revolutionize the field of precision medicine in oncology. Citation Format: Daphna Laifenfeld, Cobi Reouven, Inbal Gross, Ronen Heled, Varda Shalev, Judith Sandbank, Chaim Linhart. Prostate cancer: AI-markers for detecting, grading, and prognosticating 5-year survival post-biopsy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 867.
Abstract 3678: The role of SCAMP3 in EGFR trafficking and breast cancer cell response
Authors: Ariana C. Acevedo Diaz, Jael Reyes- Chea, Michelle M. Martinez-Montemayor, Ivette J. Suárez-Arroyo
Journal: Cancer Research (2020)

Abstract Breast cancer (BC) affects approximately 1 in 8 women and is the second leading cause of cancer among women in the United States. BC tumors frequently overexpress Epidermal Growth Factor Receptor (EGFR) which contributes to BC progression and poor clinical outcomes. Studies associate the endocytosis related protein, Secretory Carrier Membrane Protein 3 (SCAMP3), with the regulation of EGFR recycling and degradation. Recently, we published that SCAMP3 is overexpressed in BC cells and tumors. Others have identified SCAMP3 as an indicator of poor prognosis in hepatocellular carcinoma. Therefore, we hypothesize that SCAMP3 promotes the trafficking of EGFR, induces EGFR signaling and BC progression. To evaluate whether SCAMP3 has a direct interaction with EGFR, we treated SUM-149 (EGFR+) and MDA-MB-468 (EGFR+++) BC cells with 100ng/mL EGF at different time points, then we evaluated the localization of both proteins by immunofluorescence. Results showed that SCAMP3 co-localizes with EGFR at the cytoplasm at early stimulation times and the perinuclear area after 30 mins in both cell lines. To evaluate if SCAMP3 has a role in BC progression, we knocked down SCAMP3 in SUM-149 cells using the CRISPR/Cas9 technique, and we assessed the effects in cell viability, colony, and sphere formation capacity and EGFR signaling. Knockdown (KO) and wild type (WT) cells were treated with the ligand at the same concentration described above for 30 min. Our results showed that SCAMP3 knockdown decreased cell viability, colony number and the area of formed spheres. The activation of ERK1/2 was also reduced in SCAMP3 KO cells. Taken together, SCAMP3 is involved in the internalization of EGFR, cell viability, proliferation, and tumor sphere formation. We conclude that SCAMP3 has an essential role in EGFR trafficking and BC progression through EGFR downstream signaling modulation. Citation Format: Ariana C. Acevedo Diaz, Jael Reyes- Chea, Michelle M. Martinez-Montemayor, Ivette J. Suárez-Arroyo. The role of SCAMP3 in EGFR trafficking and breast cancer cell response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3678.
Abstract 6244: Turning poorly vascularized tumors into highly vascularized tumors with nanoparticles: Proof of concept and pharmacometric analysis
Authors: Guillaume Sicard, Anne Rodallec, Florian Correard, Cristina Vaghi, Clair Poignard, Joseph Ciccolini, Sébastien Benzekry, Arnauld Sergé, Raphaelle Fanciullino
Journal: Cancer Research (2020)

Abstract Combinatorial regimen are a mainstay in oncology. Taxanes and trastuzumab are both gold standards for HER2 positive breast cancer. To what extent they could reshape tumor micro-environment remains to be elucidated. The aim of this study was to compare in breast cancer mice models the antiproliferative efficacy and impact on tumor neo-angiogenesis of trastuzumab stealth immunoliposomes encapsulating docetaxel and stealth liposomal docetaxel associated with free trastuzumab. Nude mice bearing human MDA-MB-231 breast cancer tumors were treated by saline (control), docetaxel liposome (5mg/kg) associated with free trastuzumab (1.9 mg/kg) or trastuzumab immunoliposome (eq. 5 mg/kg docetaxel and 1.9 mg/kg trastuzumab) QW for 4 consecutive weeks. Tumor growth was monitored twice a week by volumetric measurement using a caliper. Blodd vessels density was evaluated in vivo by fluorescence imaging using Angiosense as a vascular probe plus ex-vivo using anti-CD31 antibodies and electronic microscopy at 2, 4 and 6 weeks. A specific algorithm was developed on MatLab for imaging analysis. No treatment-induced toxicities was observed. After 4 weeks of dosing, no difference in efficacy was seen between treatments (p=0.798) and Angiosense imaging did not show differences either (p=0.628). However electronic microscopy showed that both immunoliposomes and liposomes increased tumor vascular density as compared with control. In addition, a difference between treatments was evidenced because a marked increase in vascularization of central tumors VS. peripheral tumors was observed with trastuzumab immunoliposome as compared with standard docetaxel liposome (p=0.00023). A numerical model based on porous medium theory combined with multi-scale approaches has been derived to describe the spatial distribution of the drugs within tissues. Overall our data suggest that trastuzumab stealth immunoliposomes induce a normalization of tumor vessels with an increase in blood vessels density in central tumors. This could pave the way for sequencing combinatorial strategies so as to improve drug delivery into tumors of the associated treatments. Citation Format: Guillaume Sicard, Anne Rodallec, Florian Correard, Cristina Vaghi, Clair Poignard, Joseph Ciccolini, Sébastien Benzekry, Arnauld Sergé, Raphaelle Fanciullino. Turning poorly vascularized tumors into highly vascularized tumors with nanoparticles: Proof of concept and pharmacometric analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6244.
High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study
Authors: Albert Prats-Uribe, Sergi Sayols-Baixeras, Alba Fernández-Sanlés, Isaac Subirana, Robert Carreras-Torres, Gemma Vilahur, Fernando Civeira, Jaume Marrugat, Montserrat Fitó, Álvaro Hernáez, Roberto Elosua
Journal: Metabolism (2020)