tbuckley/cabot-search huggingface dataset:
Abstract 720: Systematic discovery and evaluation of tumor-associated antigens (TAAs) as biomarkers in cancer immunodiagnosis
Authors: Jianxiang Shi, Lu Zhang, Peng Wang, Hua Ye, Liping Dai, Pei Li, Chenglin Luo, Chuhua Song, Kaijuan Wang, Xiao Wang, Jun Ouyang, Zhenyu Ji, Jianying Zhang
Journal: Cancer Research (2017)

Abstract Proteins aberrantly over-expressed in tissues from nineteen types of cancers have been identified from the Human Protein Atlas (HPA) database. Among these proteins, some were overexpressed in several types of cancers while certain proteins were found only overexpressed in certain type of cancers. It is demonstrated that aberrantly overexpressed proteins might shed into the blood and trigger the immune system to produce autoantibodies during the process of oncogenesis. Autoantibodies are more stable and often have higher titer compared to autoantigens. Therefore, we hypothesize that autoantibodies against these aberrantly overexpressed proteins may have the potential to serve as diagnostic biomarkers in certain type of cancers. In current study, we have selected 11 proteins, including EDNRB, KRT4, PLAT, MSLN, WFDC2, F5, FOXA1, AURKC, STC1, CAB39L, and SFTPA1, to further evaluate the diagnostic values of their corresponding serum autoantibodies in five types of cancers, including hepatocellular carcinoma, lung cancer, gastric cancer, breast cancer and ovarian cancer. Sera from 470 patients (94 per cancer type), 94 hepatitis patients and 192 age- and gender-matched normal controls were used in current study. Serum autoantibodies were detected by ELISA. Receiver operating curve (ROC) analysis was used to evaluate the diagnostic value of serum autoantibodies against these potential TAAs. The data indicates that several anti-TAA autoantibodies can be found to have diagnostic value for certain types of cancers. Autoantibodies against PLAT can distinguish breast and ovarian cancer while autoantibodies against SFTPA1 and CAB39L can distinguish cancers both in male and female. However, none of these serum anti-TAAs was found to be specific to a single type of cancer. In summary, HPA database has made systematic discovery of cancer biomarkers possible. Whether these in silicon biomarkers can be used to distinguish normal and cancer still needs to be evaluated in more serum samples from normal controls and cancer patients. Note: This abstract was not presented at the meeting. Citation Format: Jianxiang Shi, Lu Zhang, Peng Wang, Hua Ye, Liping Dai, Pei Li, Chenglin Luo, Chuhua Song, Kaijuan Wang, Xiao Wang, Jun Ouyang, Zhenyu Ji, Jianying Zhang. Systematic discovery and evaluation of tumor-associated antigens (TAAs) as biomarkers in cancer immunodiagnosis [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 720. doi:10.1158/1538-7445.AM2017-720
Abstract 2156: NSC59984 induces mutant p53 degradation via activating ERK2 pathway-MDM2 axis
Authors: Shengliang Zhang, Lanlan Zhou, David Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2017)

Abstract Mutant p53 protein is highly expressed in most cancer cells due to its protein stabilization. Mutant p53 loses wild-type p53 function but gains new oncogenic functions in driving tumor growth and drug resistance. Depletion of mutant p53 is an attractive strategy for cancer therapy. We reported a small-molecule NSC59984 destabilizes mutant p53 protein via protein degradation (Zhang et al., Cancer Research, 2015). In this study, we demonstrate that the ERK2 pathway plays a specific role in NSC59984-induced mutant p53 degradation via MDM2-mediated ubiquitination. We observe a sustained-phosphorylation of ERK1/2 in cancer cells treated with NSC59984. ERK1/2 pathway is negatively regulated by MKP-1. We find that MKP-1 activity is partially inhibited by NSC59984 in a dose dependent manner in vitro. These results suggest that NSC5998 sustains ERK1/2 phosphorylation partially via disruption of the feedback-loop between MKP-1 and ERK2 pathway. Knockdown of ERK2 rescues mutant p53 from NSC59984-mediated degradation, and inhibits NSC59984-restoration of p53 signaling in mutant p53-expressing cells. On the contrary, the effect of NSC59984 on the mutant p53 is not inhibited by the blockage of JNK and P38, two pathways negatively regulated by MKP-1. These results suggest that the ERK2 phosphorylation is specifically required for NSC59984-mediated mutant p53 degradation. We further find that NSC59984 induces ERK2-dependent MDM2 phosphorylation. The effect of NSC59984 on MDM2 phosphoryation is partially inhibited by the blockage of ERK2 signaling (via U0126 treatment or Knockdown of ERK2), not by the attenuation of the JNK pathway. Furthermore, NSC59984-mediated mutant p53 protein degradation is inhibited by MDM2 knockdown, and enhanced by MDM2 overexpression in cancer cells. NSC59984-increased ubiquitination of mutant p53 is attenuated by U0126. Our results suggest that the ERK2 signaling pathway-MDM2 axis is a major determinant of NSC59984-mediated mutant p53 degradation. We further demonstrate that NSC59984 induces cell death via apoptosis, and NSC59984-induced cell death is mainly rescued by inhibition of the ERK2 pathway in p53 mutant cancer cells. Taken together, our results suggest that phosphorylated-ERK2 is an important factor required for NSC59984-mediated mutant p53 degradation which may further contribute to NSC59984-induced cell death in cancer cells. Citation Format: Shengliang Zhang, Lanlan Zhou, David Dicker, Wafik S. El-Deiry. NSC59984 induces mutant p53 degradation via activating ERK2 pathway-MDM2 axis [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 2156. doi:10.1158/1538-7445.AM2017-2156
Plasma Mannose Levels Are Associated with Incident Type 2 Diabetes and Cardiovascular Disease
Authors: Adil Mardinoglu, Alena Stančáková, Luca A. Lotta, Johanna Kuusisto, Jan Boren, Matthias Blüher, Nicholas J. Wareham, Ele Ferrannini, Per Henrik Groop, Markku Laakso, Claudia Langenberg, Ulf Smith
Journal: Cell Metabolism (2017)
Gauging the response of circulating epithelial tumor cells (CETC) and tumor stem cell subpopulations to therapy of early-stage cancer in the individual patient
Authors: K. Pachmann, O. Camara, I. B. Runnebaum, K. Hoeffken
Journal: Journal of Clinical Oncology (2009)

11026 Background: Cells released from the primary tumor persisting and recirculating in the host can lead to the formation of distant metastases. It was claimed that such cells are detectable only in a minor fraction of early-stage cancer patients but we can show that CETC are detectable and can be quantified in the peripheral blood of almost all cancer patients including early-stage solid malignancies. Methods: Using anticoagulated peripheral blood, red blood cell lysis as the only enrichment step, one centrifugation step, staining live cells with fluorochrome labelled anti-epithelial antigen as a search antibody, automated image analysis for detection of positive events and evaluation of exclusively surface located epithelial antigen on vital unfixed cells, CETC were detected in most patients with early stage cancer. Subsequently cells could be stained with anti-ALDH-antibody and in situ hybridized for HER2/neu amplification and quantified repeatedly during neo/adjuvant chemotherapy and during maintenance therapy with hormones or trastuzumab. Results: We here report the results from 497 breast cancer patients analyzed more than three times during the course of disease, 248 during neoadjuvant/adjuvant chemotherapy, 249 during trastuzumab and or hormone therapy. Different pattern of therapy response were obtained with rapidly responding CETC changes over several logs in response to chemotherapy and slow and long-lasting changes extending over several years in response to hormone therapy and trastuzumab. Stem cell like staining was seen in a minor fraction of cells (1%) in about 10% of patients. An increase in cell numbers and in the fraction of HER2/neu amplified cells was under all treatment conditions unequivocally significantly correlated to highly increased risk of relapse. Conclusions: CETC and subpopulation monitoring provides an invaluable tool for prompt gauging of systemic therapy in early stage solid tumors as a tool for therapy guidance and optimal personalized therapies to improve therapy results and spare unnecessary treatments. No significant financial relationships to disclose.
Correlation of Toll-like Receptor (TLR) and PD-1 Pathways in Central Nervous System Lymphoma: A Clinicopathological Study on Outcomes
Authors: Tarsheen Sethi, Alexandra E. Kovach, Samuel M Rubinstein, Laura Lee, Yang Wang, David S. Morgan, John P Greer, Cindy Vnencak-Jones, Nishitha Reddy
Journal: Blood (2016)
Abstract 2021: Ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis through upregulation of keratin-17
Authors: Mee-Hyun Lee, Do Young Lim, Sung Young Lee, Jung Hyun Shim, Xuejiao Liu, Ran Zhao, Hai Huang, G.Timothy Bowden, Young-Joon Surh, Yong-Yeon Cho, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2017)

Abstract Solar UV irradiation is an environmental carcinogen that causes skin cancer. Caspase-7 is expressed at reduced levels in many cancers. The present study was designed to examine the role of caspase-7 in solar-simulated light (SSL)-induced skin cancerr and to elucidate its underlying molecular mechanisms. Our study revealed that mice with genetic ablation of caspase-7 are significantly susceptible to SSL-induced skin carcinogenesis. Epidermal hyperplasia, tumor volume and tumor numbers were increased in caspase-7 knockout (KO) mice compared with SKH1 wild-type mice irradiated with SSL. The expression of cell proliferation biomarkers, such as survivin and Ki-67, was elevated in SSL-irradiated skin of caspase-7 KO mice compared with those observed in SSL-exposed wild-type SKH1 mouse skin. Moreover, SSL-induced apoptosis was abolished in skin from caspase-7 KO mice. 2-DE gel electrophoresis, followed by matrix-assisted laser desorption/ionization-time-of-flight analysis of skin tissue lysates from SSL-irradiated SKH1 wild-type and caspase-7 KO mice revealed an aberrant induction of keratin-17 in caspase-7 KO mice. Immunohistochemical analysis of skin tumors also showed an increase of keratin-17 expression in caspase-7 KO mice compared with SKH1 wild-type mice. Furthermore the expression of keratin-17 was also elevated in SSL-irradiated caspase-7 KO keratinocytes as well as in human basal cell carcinomas. The in vitro caspase activity assay showed keratin-17 as a substrate of caspase-7, but not caspase-3. Overall, our study suggests that genetic loss of caspase-7 promotes SSL-induced skin carcinogenesis by blocking caspase-7-mediated cleavage of keratin-17. Citation Format: Mee-Hyun Lee, Do Young Lim, Sung Young Lee, Jung Hyun Shim, Xuejiao Liu, Ran Zhao, Hai Huang, G.Timothy Bowden, Young-Joon Surh, Yong-Yeon Cho, Ann M. Bode, Zigang Dong. Ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis through upregulation of keratin-17 [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 2021. doi:10.1158/1538-7445.AM2017-2021
Abstract 3207: Targetting proteasome function by inhibition of the proteasome deubiquitinase USP14
Authors: Stig T. Linder, Padraig D'Arcy, Xiaonan Zhang
Journal: Cancer Research (2017)

Abstract The 20S proteasome core particle has evolved as an important target for anti-cancer drug development. We previously identified the small molecule b-AP15 as a novel class of proteasome inhibitors that function by abrogating the deubiquitinating (DUB) activity of the 19S regulatory particle. An optimised lead of b-AP15 (VLX1570) has been approved by the FDA for clinical studies and is currently in clinical trials for relapsed multiple myeloma. VLX1570 has also shown promising activity in Ewings sarcoma and paediatric leukemias. b-AP15 and VLX1570 bind to the proteasome DUB ubiquitin-specific protease-14 (USP14) in vitro and in exposed cells (CETSA). Binding and inhibition of enzymatic activity is believed to be due to targeting Cys114 in the active site. The cell death response to b-AP15/VLX1570 is distinct from that of 20S proteasome inhibitors. Thus, the sensitivity to these compounds is unaffected by overexpression of BCL2-family proteins and unaffected by p53 status. We here show that b-AP15 induces direct effects on mitochondria, possible explaining this phenomenon. We also provide additional understanding of drug-target interactions using a series of compounds identified by screening. Our findings demonstrate promising antiproliferative activities of USP14 inhibitors in vitro and in vivo. Citation Format: Stig T. Linder, Padraig D'Arcy, Xiaonan Zhang. Targetting proteasome function by inhibition of the proteasome deubiquitinase USP14 [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 3207. doi:10.1158/1538-7445.AM2017-3207
Impact of age and sex on the incidence and prevalence of psoriatic arthritis
Authors: Alexander Egeberg, Lars Erik Kristensen
Journal: Annals of the Rheumatic Diseases (2017)

We thank Sewerin and colleagues1 for the interest in our paper regarding the incidence and prevalence of psoriatic arthritis (PsA).2 The questions that were raised are relevant and important. Our paper included only a limited amount of age-stratified and sex-stratified estimates. The sex distribution among patients with (rheumatologist-diagnosed) incident PsA based on the population described in our initial publication2 is presented in figure 1. However, we emphasise that interpretation …
Abstract 667: Immunoprofiling circulating blood as a means to early detection of solid tumors
Authors: Amit Kumar, Dimitry Gabrilovich, Frank J. Rauscher, George Dominguez, Cyrus Sholevar, John Roop, Anthony Campisi, Alexander Polo
Journal: Cancer Research (2017)

Abstract Our goal was to evaluate whether profiling Myeloid Derived Suppressor Cells (MDSCs) in circulation correlated with the existence and stage of multiple, biopsy-verified solid tumor types and to evaluate whether such analyses could enable early detection. The tumor micro-environment (TME) is replete with numerous immune cells, and the type and concentration of such cells can provide prognostic information. The link between high concentrations of MDSCs and poor prognosis is most likely due to the immuno-suppressive effects of such cells. Some fraction of these cells spill into the blood stream. We utilized flow cytometry to phenotypically quantify subsets of MDSCs and other leukocytes in the circulation of biopsy-verified cancer patients, as well as in age and sex matched healthy donors. Our results indicate a marked increase in MDSC levels in the circulation of tumor patients relative to healthy donors. We have analyzed patients presenting over a dozen solid tumor types (lung, breast, ovarian, colon, melanoma, liver, thyroid, pancreatic, uterine, osteosarcoma, appendiceal, leiomyosarcoma, liposarcoma, and vulvar) and found notable differences in the immune-profiles of circulating blood in these patients. It appears that the immune response, as measured by our flow cytometry technique, is general for most tumor types. We will present correlations and inter-relations between different cell types and evidence of tumors. While our studies to date have been performed in an unblinded manner, we will present performance data (specificity and sensitivity) for our approach. Citation Format: Amit Kumar, Dimitry Gabrilovich, Frank J. Rauscher, George Dominguez, Cyrus Sholevar, John Roop, Anthony Campisi, Alexander Polo. Immunoprofiling circulating blood as a means to early detection of solid tumors [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 667. doi:10.1158/1538-7445.AM2017-667
Abstract 5660: Tumor cell death caused by INT230-6 induces protective T cell immunity
Authors: Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Katharine T. Clark, Masaki Terabe, Jay A. Berzofsky
Journal: Cancer Research (2017)

Abstract Standard care for many types of cancer involves systemic administration of cytotoxic agents. This may result in low drug concentration at tumor sites, which limits cell killing. More recently it has been shown that cytotoxic formulations designed for intratumoral delivery improve drug efficacy presumably by increasing drug concentration at the tumor site. Furthermore, it has been discovered that the mechanisms of anticancer agents extend beyond direct tumor cell lysis. One major aspect is that cell death often induces an immune response. Different types of cell death such as necrosis, apoptosis and autophagic cell death induced by cytotoxic agents trigger immune responses with varying degrees of inflammation and involving different types of immune cells. The ideal immune responses that may give maximum benefit to patients would be strong and long lasting anti-tumor T cell responses. In this study, a novel, tissue and cell diffusive cytotoxic formulation, INT230-6, was administered intratumorally over 5 sequential days into subcutaneous 300mm3 murine Colon26 tumors. Treatment resulted in regression from baseline of 100% of the tumors and up to 80% complete response (CR). We then analyzed the T cell responses in the protection induced by INT230-6. No animals achieved a CR after CD8 or CD8/CD4 double depletion at treatment onset, indicating a critical T-cell role in tumor regression. Mice with CRs were protected from re-challenge by either subcutaneous or intravenous re-inoculation of the Colon26. The protection was abrogated by CD4/CD8 double depletion prior to the re-challenge, indicating that immunological T cell memory was induced and was necessary for protection. Hence, INT230-6 given locally to treat tumors induces tumor-specific protective T cell immunity. Colon26 tumors express the endogenous retroviral protein gp70 containing the AH-1 CTL epitope. AH-1-specific CD8 T cells were detected in tumors of mice without treatment. However, these highly expressed PD-1. This was consistent with the observation that the PD-1 blockade enhanced the efficacy of INT230-6. Conversely, INT230-6 enhances the efficacy of checkpoint inhibitors. Citation Format: Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Katharine T. Clark, Masaki Terabe, Jay A. Berzofsky. Tumor cell death caused by INT230-6 induces protective T cell immunity [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 5660. doi:10.1158/1538-7445.AM2017-5660
Abstract 5863: Identifying the radiosensitizing effects of PARP inhibitor in ovarian cancer
Authors: Yue Bi, Ioannis Verginadis, Souvik Dey, linlang Guo, Lilie Lin, Yanfang Zheng, Constantinos Koumenis
Journal: Cancer Research (2017)

Abstract Ovarian cancer is the seventh-most common cancer with a high mortality rate among women. Radiation therapy (RT) is used in ovarian cancer for local relapse, but doses are limited due to concern for small bowel obstruction in patients who have had multiple surgeries and chemotherapeutic regimens. Therefore, it’s an ideal setting to improve the therapeutic window by combining RT and a radiosensitizer. Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in the recognition of DNA damage and the facilitation of DNA repair by recognizing DNA single-strand breaks (SSB). Inhibition of PARP1, especially in tumors driven by BRCA1 or 2 mutations, has been shown to potentiate the DNA-damaging effects of radiation in vitro and in vivo and to increase tumor vasculature perfusion and oxygenation. Approximately half of ovarian cancers have germline or somatic BRCA gene mutation, epigenetic silencing or other mutations that affect homologous recombination (HR) competency resulting in DNA repair defects, making this tumor particularly susceptible to the radiation-sensitizing effects of PARP inhibitors. Here, we investigated the therapeutic effects of the PARP inhibitor olaparib in preclinical models of ovarian cancer. Basic BRCA1 and PARP1 protein and mRNA levels were characterized in a panel of ovarian cancer cell lines. The radiosensitizing effects of olaparib were tested on both HR-proficient and HR-deficient ovarian cancer cells by evaluating the colony formation, DNA damage, apoptosis, and PARP1 activity. Survival benefit of olaparib was also examined in xenograft models of ovarian cancer. Our results demonstrate that combination of olaparib with IR decreased colony formation, inhibited DNA damage (γH2AX) repair, and induced more apoptosis compared to olaparib or IR alone. In addition, HR-deficient cells were more sensitive to IR than HR-proficient cells in the presence of olaparib. Furthermore, olaparib inhibited PARP1 activity in vivo, significantly decreased tumor growth and increased overall survival when combined with IR in mice bearing subcutaneous xenografts of HR-deficient OVCAR8 cells while producing a relative modest effect on overall survival of mice bearing xenografts of HR-proficient SKOV3 cells. These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in ovarian cancer, particularly in tumors with HR-deficiencies. Citation Format: Yue Bi, Ioannis Verginadis, Souvik Dey, linlang Guo, Lilie Lin, Yanfang Zheng, Constantinos Koumenis. Identifying the radiosensitizing effects of PARP inhibitor in ovarian 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 5863. doi:10.1158/1538-7445.AM2017-5863