tbuckley/cabot-search huggingface dataset:
Abstract 4347: Differentially expressed genes and molecular pathways in an autochthonous mouse prostate cancer model
Authors: Shiv Verma, Sanjeev Shukla, Mitali Pandey, Gregory T. MacLennan, Sanjay Gupta
Journal: Cancer Research (2019)

Abstract Prostate cancer remains a major public health problem and second leading cause of cancer-related deaths in men in the United States. Despite widespread screening efforts and advancement in therapeutic regimens, incidence of prostate cancer remains steady in the past two decades. Although serum prostate-specific antigen (PSA) has been used as a screening test for prostate cancer for over two decades, the practice remains controversial. As a screening test for prostate cancer, PSA lacks sensitivity and specificity as early detection marker. Furthermore, screening may lead to unnecessary biopsies, over-detection, and overtreatment. There is a need for specific and sensitive biomarker(s) which can differentiate between cancer and non-cancer utilized for screening and early detection. The present study aims to comprehend the molecular pathways of prostate cancer which is essential for early detection and treatment. Dorso-lateral prostate from 20 week transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which spontaneously develops prostate cancer and recapitulates human disease and age-matched non-transgenic littermates were utilized for microarray analysis. Network and pathway analyses were mapped using the Ingenuity Pathway Analysis (IPA), and the database for annotation, visualization and integrated discovery. In total, 136 differentially expressed genes, including 32 downregulated genes and 104 upregulated genes were identified in the dorso-lateral prostate of TRAMP mice, compared to non-transgenic. A subset of differentially expressed genes were validated by QRT-PCR. Among these genes, 36% genes were connected to the nucleic acid binding especially ribosomal proteins which play important roles in protein synthesis, and is the most enriched pathway in the development of prostate cancer. Moreover, the results also suggest deregulation of the metabolic process and an imbalance between extracellular matrix components and adherens junction proteins could induce cancer progression. Taken together, the present study evaluated the underlying pathways and its connection to human cancer, which may further help to assess the risk of prostate cancer detection and its progression to identify potential targets of adjuvant treatment. Citation Format: Shiv Verma, Sanjeev Shukla, Mitali Pandey, Gregory T. MacLennan, Sanjay Gupta. Differentially expressed genes and molecular pathways in an autochthonous mouse prostate cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4347.
Abstract 1461: mRNA therapeutics against cancers and infectious diseases
Authors: Smriti Arya, Qiubin Lin, Nan Zhou, Jiandong Huang
Journal: Cancer Research (2019)

Abstract In vitro transcribed (IVT) mRNA is forming a new basis of drug delivery as it can be synthetically engineered to express the desired protein in lesser time and be more specific than the other 2 types of antigens. Using DNA (coding for proto-oncogenes) for immunization poses a risk for host cell transformation into a malignant one and hence proto-oncogenes would express for a longer time. Therefore, mRNA was considered for cancer immunotherapy as it does not integrate into the host cell's genome, so no question of insertional mutagenesis arises. Our main aim is to develop a stable mRNA system working both in vitro and in vivo and then use this system to develop mRNA vaccines. The stability of IVT mRNA can be increased by changing the 3' and 5' UTRs, adding a 5'cap and 3' poly-A tail which could even increase their half-life to a few days. For creating a stable mRNA working system in vitro, EGFP-2A gene was cloned along with the AdsA (Staphylococcus aureusgene important for infection) in a vector backbone with TMV 3’UTR and 5’UTR. The mRNA created in vitro was with modified uridine and cap 1 structure and transfected to the mammalian cell lines. This transfection was further enhanced by using liposome created in the lab (using some cationic and helper lipids in different ratios) by film rehydration method. The expression of luciferase mRNA was then detected in mice by live imaging indicating that the mRNA system is stable in vivo. Further, to direct the mRNA encoded antigens to MHC1 and MHC2 pathways they were tagged with a htPA secretion tag and MHC1 targeting signal along with a 3XFLAG tag. We tried various mode of injections with AdsA mRNA to have a profile of ELISPOT with differently exposed mRNA (in vivo in mice). Now we are focussing on some neo antigens for tumor to be used as. Avaccine in the form of mRNA. Citation Format: Smriti Arya, Qiubin Lin, Nan Zhou, Jiandong Huang. mRNA therapeutics against cancers and infectious diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1461.
Abstract 15268: Difference in the Prognostic Powers of Brain Natriuretic Peptide and N-Terminal Pro Brain Natriuretic Peptide for Cardiovascular Outcomes in Japanese General Practice Patients With and Without Chronic Kidney Disease; The Japan Morning Surge Home Blood Pressure Study
Authors: Yusuke Ishiyama, Satoshi Hoshide, Ken Kono, Kazuomi Kario
Journal: Circulation (2017)

Introduction: Brain natriuretic peptide (BNP) and N-terminal proBNP (NTproBNP) are well recognized as prognostic biomarkers in general, hypertensive, and cardiovascular populations. The NTproBNP le...
Abstract 1507: Transcriptional profiles of CD14+ cells in situ in melanoma tumors reveal plasticity and localization dependent function
Authors: Jan Martinek, Kyung In Kim, Te-Chia Wu, Victor Wang, Hannah M. Brookes, Lili Sun, Ananya Gulati, Joshy George, Philipp Henrich, Florentina Marches, Anthony Rongvaux, Michael Chiorazzi, Jeff Chuang, Paul Robson, Richard Flavell, Jacques Banchereau, Karolina Palucka
Journal: Cancer Research (2019)

Abstract Mechanisms contributing to immunotherapy resistance in patients are the object of intense studies. Myeloid cells play a major role in tumors and include cells with different functions that can be grossly summarized as: (1) Antigen capture for presentation (dendritic cells, DCs) or for degradation (macrophages); (2) Tissue repair (macrophages) and (3) Effector function (mast cells, monocytes, granulocytes). However, the functional states of myeloid cells in human tumors are not completely understood. To study intact tumor microenvironments we have established a comprehensive approach for cellular and molecular analysis. Modular analysis of bulk RNAseq data of whole melanoma tissue sections stratified patient samples based on lymphocytic infiltrate but revealed inflammation and myeloid modules spread across samples. Polychromatic immunofluorescence and histocytometry showed that CD14+ cells represent the majority of the total tumor immune infiltrate. Furthermore, the majority of T cells present in melanoma tissue are in direct contact with CD14+ cells rather than melanoma cells. The distribution of CD14+ cells shows two distinct patterns: CD14+ cells within cancer nests (intratumoral) which are in close proximity to melanoma cells and are loaded with melanoma protein; CD14+ cells in the tissue surrounding cancer nests (stromal) which do not contain melanoma protein cargo and are organized in dense infiltrates. Using customized immunofluorescence-guided laser capture micro-dissection, we harvested CD14+ cells based on their tissue location and melanoma protein load for downstream analysis. We find that unsupervised clustering of transcriptomes groups cells by their tissue localization, i.e., intratumoral vs. stromal. Computational analysis, revealed distinct and replicable gene signatures associated with different pathways, in intratumoral and stromal CD14+ cells. Thus, the transcriptome differentiates the functional status of CD14+ cells related to their localization within tumor. Citation Format: Jan Martinek, Kyung In Kim, Te-Chia Wu, Victor Wang, Hannah M. Brookes, Lili Sun, Ananya Gulati, Joshy George, Philipp Henrich, Florentina Marches, Anthony Rongvaux, Michael Chiorazzi, Jeff Chuang, Paul Robson, Richard Flavell, Jacques Banchereau, Karolina Palucka. Transcriptional profiles of CD14+ cells in situ in melanoma tumors reveal plasticity and localization dependent function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1507.
Transcriptomic Differences between Primary Colorectal Adenocarcinomas and Distant Metastases Reveal Metastatic Colorectal Cancer Subtypes
Authors: Yasmin Kamal, Stephanie L. Schmit, Hannah J. Hoehn, Christopher I. Amos, H. Robert Frost
Journal: Cancer Research (2019)

Approximately 20% of colorectal cancer patients with colorectal adenocarcinomas present with metastases at the time of diagnosis, and therapies that specially target these metastases are lacking. We present a novel approach for investigating transcriptomic differences between primary colorectal adenocarcinoma and distant metastases, which may help to identify primary tumors with high risk for future dissemination and to inform the development of metastasis-targeted therapies. To effectively compare the transcriptomes of primary colorectal adenocarcinoma and metastatic lesions at both the gene and pathway levels, we eliminated tissue specificity of the "host" organs where tumors are located and adjusted for confounders such as exposure to chemotherapy and radiation, and identified that metastases were characterized by reduced epithelial-mesenchymal transition (EMT) but increased MYC target and DNA-repair pathway activities. FBN2 and MMP3 were the most differentially expressed genes between primary tumors and metastases. The two subtypes of colorectal adenocarcinoma metastases that were identified, EMT inflammatory and proliferative, were distinct from the consensus molecular subtype (CMS) 3, suggesting subtype exclusivity. In summary, this study highlights transcriptomic differences between primary tumors and colorectal adenocarcinoma metastases and delineates pathways that are activated in metastases that could be targeted in colorectal adenocarcinoma patients with metastatic disease. SIGNIFICANCE: These findings identify a colorectal adenocarcinoma metastasis-specific gene-expression signature that is free from potentially confounding background signals coming from treatment exposure and the normal host tissue that the metastasis is now situated within.
Abstract 537: Antibody drug conjugate to treat triple negative breast cancer
Authors: Yingnan Si, Nghi Dang, Seulhee Kim, Lufang Zhou, Xiaosi Han, Runhua Liu, Xiaoguang (Margaret) Liu
Journal: Cancer Research (2019)

Abstract Triple negative breast cancer (TNBC) is characterized by rapid growth, metastasis, and high recurrence. The severe adverse effects and drug resistance associated with standard cytotoxic chemotherapies minimize their clinical benefits. The anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) had been developed and tested to treat TNBC, but no significant efficiency was demonstrated in clinical trials. The goal of this study was to develop a novel antibody-drug conjugate (ADC) to treat TNBC. Specifically, we established a platform to conjugate anti EGFR mAb with mertansine, which inhibits cell division by blocking tubulin polymerization, and also improved the conjugation efficiency by optimizing the linker and drug-to-antibody ratio. Flow cytometry and live cell confocal laser scanning microscopy analysis confirmed that the anti-EGFR ADC can specifically bind to multiple TNBC subtypes, is effectively internalized, and release potent drug intracellularly within 1 hour after mixing. The IC50 study showed that the anti-EGFR ADC killed &amp;gt;90% TNBC cells with dose of 5 nM. The TNBC xenograft mouse model also showed that the constructed ADC had high anticancer efficacy and successfully inhibited tumor growth. Moreover, the live-animal imaging using In Vivo Imaging System and the tissue microarray samples with immunohistochemical analysis of TNBC and organs indicated that our ADC specifically target TNBC in vivo. Further evaluations, such as maximal tolerated dose (MTD), pharmacokinetics (PK), and biodistribution, are needed. To summarize, we developed an EGFR-targeted ADC, which could provide an effective targeted therapy to treat TNBC and improve the life quality and survival rate of patients with TNBC. Note: This abstract was not presented at the meeting. Citation Format: Yingnan Si, Nghi Dang, Seulhee Kim, Lufang Zhou, Xiaosi Han, Runhua Liu, Xiaoguang (Margaret) Liu. Antibody drug conjugate to treat triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 537.
Abstract 4545: Quantitative profiling of Cytochrome P450 2S1 in colorectal cancer by PRM assay
Authors: Sadr ul Shaheed, Laurence H. Patterson, Klaus Pors, Chris W. Sutton
Journal: Cancer Research (2019)

Abstract Introduction: Cytochromes P450s (CYPs) constitute a superfamily of xenobiotic metabolising enzymes responsible for metabolism of many pharmaceuticals in the liver. Elevated mRNA levels of specific isoforms, such as CYP2S1, are associated with poor prognosis in colorectal cancer (CRC), and represent novel therapeutic targets for biotransformation of prodrugs to potent cytotoxics at the cancer site. In order to understand the expression of CYP2S1 protein, we have developed a parallel reaction monitoring mass spectrometry (PRM MS) assay to screen CRC samples. Method: Peptides (n=3) uniquely associated with CYP2S1 were synthesized and used as standards to optimise analytical performance (fragmentation conditions, LC retention time, LOQ, LOD, dynamic range) in an Orbitrap Fusion-based PRM MS assay. Levels of CYP2S1 were then determined in protein extracts of CRC, relative to the standards. Results: The PRM MS assay yielded quantitative data over 3 orders of magnitude. CYP2S1 was detected in C106, CaCO2, HCC2998, HT55 and DLD1 cell lines (0.05-1.08pg) and HT55 and DLD1 xenografts (0.29-0.41pg). CYP2S1 was also detected in patient-specific CRC tissues, with elevated levels in Stage III tumours. Conclusions: The PRM MS assay provides a specific, sensitive, high throughput method for identifying CYP2S1 compared to established enzyme and immunoassays. CYP2S1 levels vary considerably across CRC sources highlighting the importance of screening to identify the correct models for new drug development and the right patients for subsequent treatment. Citation Format: Sadr ul Shaheed, Laurence H. Patterson, Klaus Pors, Chris W. Sutton. Quantitative profiling of Cytochrome P450 2S1 in colorectal cancer by PRM assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4545.
The influence of prognostic factors on metastatic breast cancer survival over time.
Authors: Margaret Quinn Rosenzweig, Su Yon Jung, Adam Brufsky
Journal: Journal of Clinical Oncology (2012)

1589 Background: Recent evidence suggests that survival in metastatic breast cancer is slowly improving associated with the use of better adjuvant and metastatic chemotherapeutic and targeted agents. Patient and clinical factors such as age, estrogen status, non-white race, Her 2 status, disease free interval and sites of metastatic breast cancer involvement indicate worse clinical outcome after recurrence. This analysis focused on the influence of these factors on metastatic breast cancer survival over time. Methods: Subjects were women with metastatic breast cancer from one large urban practice, of the University of Pittsburgh Cancer Institute Breast Cancer Program followed from 1999 through December, 2008. Patients were dichotomized into two time categories: A) 1999 through 2004 and B) 2005 through 2008. Outliers of long term survivors (n =72) with survival extending beyond 6 years were excluded. Log rank tests were conducted for assessing the relationship between prognostic factors and survival. Results: Cohorts included patients diagnosed with metastatic breast cancer in 1999 through 2004, (n=284) and 2005 through 2008, (n=332). They were followed up to December, 2011. Median survival improved over time (p=0.053). Estrogen negativity remained significant for worse survival across both time periods (p&lt;0.0001). Age, presence of brain metastasis and Her 2 status were not significant for influence on survival at either time interval. Shorter disease free interval (p= 0.02), higher number of metastatic sites (p=.001) and presence of visceral metastasis at diagnosis (p=0.003) became significant for worse survival in the 2005-2008 intervals but had not been in the earlier time period. African American race was highly significant (&lt;0.001) for worse survival in 1999-2004 but lost significance in 2005 through 2008 with dramatic survival increase (median survival - 12.5 months to 35 months). Conclusions: It is important for clinicians to clarify the prognostic features associated with worse outcomes in metastatic breast cancer. With newly emergent therapies and sensitivity toward specific patient factors these features evolve over time.
Gemcitabine plus cisplatin therapy, a safety regimen in advanced bladder cancer
Authors: J. Song, H. Chung
Journal: Journal of Clinical Oncology (2005)

4799 Background: We evaluated the efficacy and toxicity of gemcitabine plus cisplatin (GC) therapy compared with methotrexate, vinblastin, doxorubicin puls cisplastin (MVAC) therapy in patients with advanced bladder cancer. Methods: Thirty-eight patients with measurable bladder cancer who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,000mg/m2 intravenously over 30 minutes on days 1, 8, and 15 and cisplatin 75mg/m2 over 1 hour on day 2 of a 28-day cycle. Patients were treated with six cycles, unless disease progression or severe toxicity. Primary end point was overall survival. All toxicities were compared with previous our MVAC therapy results. Thirty-five patients were scheduled to receive MVAC therapy (methotrexate 30mg/m2, vinblastin 3mg/m2, doxorubicin 30mg/m2 puls cisplastin 70mg/m2). Results: There were six complete responses and 17 partial responses in 38 assessable patients, for an overall response rate of 23 of 38 (60.5%). The median survival was similar on both threatment group and 26 patients who had received GC therapy still alive at this time. Toxicity was primarily hematologic, with 3 of 38 patients (7.9%) having grade 3 anemia, with 6 of 38 patients (15.7%) having grade 3 granulocytopenia and 2 of 38 (5.2%) having grade 3 thrombocytopenia. Three patients had severe gastro-intestinal symptom and one patient had severe low performance status. More GC than MVAC had high grade granulocytopenia(15.7% v 33.3%, p<0.05). All patients required a dose modification of gemcitabine at some point in their therapy; the primary reason was thrombocytopenia and/or neutropenia. Conclusions: Gemcitabine plus cisplatin therapy is an active regimen for the treatment of advanced bladder cancer and better safety profile and tolerability than MVAC therapy. No significant financial relationships to disclose.
Abstract 4658: Cigarette smoke extract and benzo(a)pyrene induce osteopontin expression in lung cancer and promote mesenchymal stem cell recruitment
Authors: Ya-Jing Jiang, An-Chen Chang, Po-Chun Chen, Chih-Hsin Tang
Journal: Cancer Research (2019)

Abstract Cigarette smoking produces many organic compounds, including the carcinogenic polycyclic aromatic hydrocarbon benzo(a)pyrene, (BAP), which is linked to lung cancer. Tumor tissue recruits mesenchymal stem cells (MSCs; undifferentiated multipotent adult stem cells) to increase cancer cell proliferation, invasion and metastasis. We sought to determine the effects of cigarette smoke extract (CSE) and BAP stimulation on lung cancer cells and MSCs. We found that CSE and BAP increased mRNA and protein expression of osteopontin (OPN), a member of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs) family, but had no such effects on any other SIBLINGs proteins. A National Center for Biotechnology Information (NCBI) analysis of data from the Gene Expression Omnibus (GEO) database (GSE31210) identified much higher OPN expression in current and ex-cigarette smokers with lung cancer than in lung cancer patients who were nonsmokers. Our analysis found that stimulating lung cancer cells with CSE and BAP led to the recruitment of MSCs, which adhered to lung cancer cells via OPN production. Next, we used a gene set from the BioCarta database to investigate signaling pathways associated with lung cancer. We found that the MAPK, JAK/STAT and RAS signaling pathways had the highest repeatability in lung cancer patients who were cigarette smokers. We discovered that CSE and BAP only activated the JAK2/STAT3 pathway and that transfection of lung cancer cells with JAK2 and STAT3 small interfering RNAs interrupted CSE- and BAP-induced OPN expression, inhibiting MSC recruitment and adhesion. We are now investigating whether MSCs link back to lung cancer cells and further induce migration and invasion. In summary, our data indicate that CSE and BAP increase OPN expression in lung cancer cells through the JAK2/STAT3 signaling pathway and thereby recruit MSCs and their adhesion to cancer cells. Citation Format: Ya-Jing Jiang, An-Chen Chang, Po-Chun Chen, Chih-Hsin Tang. Cigarette smoke extract and benzo(a)pyrene induce osteopontin expression in lung cancer and promote mesenchymal stem cell recruitment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4658.
A dual-systems perspective on temporal cognition: Implications for the role of emotion
Authors: Filip M. Nuyens, Mark D. Griffiths
Journal: Behavioral and Brain Sciences (2019)

Abstract This commentary explores how emotion fits in the dual-systems model of temporal cognition proposed by Hoerl &amp; McCormack. The updating system would be affected by emotion via the attentional/arousal effect according to the attentional gate model. The reasoning system would be disrupted by emotion, especially for traumatic events. Time discrepancies described in the dual-systems model are also explained.