tbuckley/cabot-search huggingface dataset:
Abstract 871: Development of a smartphone-based electrochemiluminescence biosensor for dopamine detection in advanced breast cancer
Authors: Hyun J. Kwon, Padma P. Tadi Uppala, Elmer C. Rivera, Mabio R. Neto, Daniel Marsh, Jonathan J. Swerdlow, Rodney L. Summerscales
Journal: Cancer Research (2020)

Abstract Introduction: Studies conducted in our laboratory on proteomic profiling of breast cancer serum among women by shotgun LC-MS methodology have identified several biomarkers for early detection of breast cancer. However, not all of the identified biomarkers have been validated due to costs involved with validation tests. The development of a reliable, cost-effective highly sensitive portable system, the Electrochemiluminescence (ECL) biosensor will enable us to validate identified biomarkers that have valuable diagnostic applications. The purpose of this study was to detect dopamine, which has been identified as a biomarker in advanced breast cancer. Dopamine and its receptors act as novel therapeutic agents in advanced breast cancer. Dopamine significantly enhances the efficacy of commonly used anticancer drugs through its antiangiogenic action. Methods: In this work, a compact, mobile phone-based ECL sensor apparatus was developed using the phone cameras, screen-printed electrodes (SPE), and mobile app for dopamine detection. Methods of DC voltage application for ECL reaction were comprehensively studied from the mobile phone itself or external power. Under optimized sensing conditions, with disposable carbon SPE and 20 mM coreactant tri-n-propylamine (TPrA), acceptable repeatability and reproducibility were achieved in terms of relative standard deviation (RSD) of intra- and interassays, which were 6.7 and 5.5 %, respectively. The biochemical compound dopamine was measured due to its ECL quenching characteristics and its clinical significance in breast cancer detection and therapeutic properties. The quenching mechanism of Ru(bpy)32+/TPrA by dopamine was investigated based on the estimation of the constants of the Stern-Volmer equations. Results: The linear range for detectable dopamine concentration was from 1.0 to 50 µM (R2 = 0.982). As the developed mobile phone-based ECL sensor is simple, small and assembled from low-cost components, it offers new opportunities for the development of inexpensive analytical methods and compact sensors. Conclusion: The ECL sensor demonstrated that a new instrumentation with mobile technology in the point-of-care diagnostics of breast cancer could provide reliability and sensitivity of a high-end equipment. This project is funded by the NSF CBET division. Citation Format: Hyun J. Kwon, Padma P. Tadi Uppala, Elmer C. Rivera, Mabio R. Neto, Daniel Marsh, Jonathan J. Swerdlow, Rodney L. Summerscales. Development of a smartphone-based electrochemiluminescence biosensor for dopamine detection in advanced breast 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 871.
Abstract 6159: Blocking neuropeptide Y Y5 receptor prevents hypoxia-induced Ewing sarcoma metastasis
Authors: Mina T. Adnani, Susana Galli, Sung Hyeok Hong, Jason U. Tilan, Joanna Kitlinska
Journal: Cancer Research (2020)

Abstract Ewing sarcoma (ES) is the second most prevalent malignant bone tumor after osteosarcoma in children and adolescents. While survival of patients with localized ES has improved, patients with metastatic ES still lack adequate therapies, which results in poor survival rates. Thus, there is an important need for new therapies targeting ES metastases and preventing its dissemnation. Previously, we have shown that ES cells constitutively express high levels of NPY and its receptors - Y1R and Y5R. However, tumor hypoxia changes expression pattern and functions of NPY system, leading to the activation of its Y2R and Y5R, which stimulate ES cell motility and invasiveness under these conditions. Hence, the goal of this study was to determine the role of NPY in hypoxia-induced ES metastases. Here, we focused on Y5R, since our data from other malignancies implicated this receptor as the major mediator of NPY's pro-metastatic effects. To this end, we used doxycycline (DOX)-inducible CRIPSR/Cas9 system to create an SK-ES1/Y5R knockout (KO) cell line. The Y5R KO significantly decreased motility of SK-ES1 cells. To determine the impact of this phenomenon on ES metastases, SK-ES1/Cas9/Y5RsgRNA cells were injected into gastrocnemius muscles of SCID/bg mice and the animals were fed with DOX+ or control diet. The Y5R KO did not affect primary tumor growth. Once the xenografts reached a volume of 0.25cm3, a femoral artery ligation (FAL) was performed in the tumor-bearing limbs to induce hypoxic conditions. Both primary tumors and their corresponding metastases were sequenced to confirm the efficiency of gene editing. Notably, majority of metastases arising in mice bearing SKES-1/Y5RsgRNA+DOX xenografts were initiated by the clones without Y5R gene modification, confirming the role of Y5R in ES dissemination. The frequency of metastases with efficient Y5R KO originating from hypoxic tumors was markedly decreased, as compared to the control group (-DOX). Moreover, Y5R KO prevented hypoxia-induced increase in osseous metastases previously reported by our group. Collectively, these data validate NPY/Y5R axis as a crucial mediator of the hypoxia-induced ES metastasis and implicate Y5R receptor as a novel target for therapies preventing ES dissemination. Importantly, the Y5R antagonist is already available and used in clinical trials. Citation Format: Mina T. Adnani, Susana Galli, Sung Hyeok Hong, Jason U. Tilan, Joanna Kitlinska. Blocking neuropeptide Y Y5 receptor prevents hypoxia-induced Ewing sarcoma metastasis [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 6159.
Abstract 684: Gastrointestinal/liver-targeted TLR7 agonist for treatment of colorectal and liver cancers
Authors: Andrew T. Miller, Evelyn Rodrigo, Manny Corpuz, David Plouffe, Tom Y.-H. Wu
Journal: Cancer Research (2020)

Abstract Anti-PD1/L1 has become the backbone of immune therapy for many cancer types. However, the majority of patients do not respond due to a myriad of mechanisms affecting the tumor microenvironment, including low tumor mutational burden and low immune cell infiltrate. Innate immune agonists can potentially address both issues by increasing tumor antigen presentation and tumor microenvironment inflammation, thereby turning cold tumors hot. As clinical proof-of-concept, many intratumoral TLR/STING agonists have shown promising anti-tumor responses as single agents and in combination with checkpoint inhibitors; however, successful clinical applications have been limited to cutaneous-accessible tumor types. APR003 is an orally-administered GI/liver-targeted small molecule TLR7 agonist designed for the treatment of visceral colorectal and liver cancers. Studies in mice and monkeys demonstrate robust Type-1 Interferon pathway activation with good tolerability. APR003 is efficacious in several syngeneic orthotopic models of liver and colon cancer, both as single agent and in combination with anti-PDL1. Mechanistic studies show enhancement of CD103+ dendritic cells in tumor draining lymph nodes and tumor antigen-specific T cells in the tumor microenvironment. Pre-clinical pharmacology data will be presented. Citation Format: Andrew T. Miller, Evelyn Rodrigo, Manny Corpuz, David Plouffe, Tom Y.-H. Wu. Gastrointestinal/liver-targeted TLR7 agonist for treatment of colorectal and liver cancers [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 684.
Benefits and harms of exercise therapy in people with multimorbidity: A systematic review and meta-analysis of randomised controlled trials
Authors: Alessio Bricca, Lasse K. Harris, Madalina Jäger, Susan M. Smith, Carsten B. Juhl, Søren T. Skou
Journal: Ageing Research Reviews (2020)

To investigate the benefits and harms of exercise therapy on physical and psychosocial health in people with multimorbidity.Systematic review of randomised controlled trials (RCTs). Data sources MEDLINE, EMBASE, CENTRAL and CINAHL from 1990 to April 20th, 2020 and Cochrane reviews on the effect of exercise therapy for each of the aforementioned conditions, reference lists of the included studies, the WHO registry and citation tracking on included studies in Web of Science.RCTs investigating the benefit of exercise therapy in people with multimorbidity, defined as two or more of the following conditions: osteoarthritis (of the knee or hip), hypertension, type 2 diabetes, depression, heart failure, ischemic heart disease, and chronic obstructive pulmonary disease on at least one of the following outcomes: Health-related quality of life (HRQoL), physical function, depression or anxiety.Meta-analyses using a random-effects model to assess the benefit of exercise therapy and the risk of non-serious and serious adverse events according to the Food and Drug Administration definition. Meta-regression analyses to investigate the impact of pre-specified mediators of effect estimates. Cochrane 'Risk of Bias Tool' 2.0 and the GRADE assessment to evaluate the overall quality of evidence.Twenty-three RCTs with 3363 people, testing an exercise therapy intervention (mean duration 13.0 weeks, SD 4.0) showed that exercise therapy improved HRQoL (standardised mean difference (SMD) 0.37, 95 % CI 0.14 to 0.61) and objectively measured physical function (SMD 0.33, 95 % CI 0.17 to 0.49), and reduced depression symptoms (SMD -0.80, 95 % CI -1.21 to -0.40) and anxiety symptoms (SMD -0.49, 95 % CI -0.99 to 0.01). Exercise therapy was not associated with an increased risk of non-serious adverse events (risk ratio 0.96, 95 % CI 0.53-1.76). By contrast, exercise therapy was associated with a reduced risk of serious adverse events (risk ratio 0.62, 95 % CI 0.49 to 0.78). Meta-regression showed that increasing age was associated with lower effect sizes for HRQoL and greater baseline depression severity was associated with greater reduction of depression symptoms. The overall quality of evidence for all the outcomes was downgraded to low, mainly due to risk of bias, inconsistency and indirectness.Exercise therapy appears to be safe and to have a beneficial effect on physical and psychosocial health in people with multimorbidity. Although the evidence supporting this was of low quality, it highlights the potential of exercise therapy in the management and care of this population.
Abstract 2478: Assessing regulatory network rewiring in cancer patients using chromatin accessibility profiles
Authors: Andre Forbes, Duo Xu, Ekta K. Khurana
Journal: Cancer Research (2020)

Abstract The regulation of gene expression in humans is the result of a complex interplay between DNA, small RNA molecules and a multitude of proteins, particularly histones and transcription factors (TFs). To identify the key TFs regulating gene expression in cancer we are integrating ATAC-Seq data from 371 TCGA patients in conjunction with matching expression data and DNA-binding motifs for 780 TFs and TF families. We infer the regulatory networks in these patients by detecting true TF binding events in individual patients and the regulatory elements that said TFs are bound to using the Protein Interaction Quantification algorithm (PIQ). The inferred networks were then clustered by the similarity of inferred TF binding activity followed by identification of the TFs most likely driving the identity of each cluster. We observe robust clustering by site of origin of disease with canonical TFs such as FOXA1 and ESR1 being putative key TFs in ER+ breast cancer, PAX8 in renal cancer as well as TP63 and SOX2 in multiple squamous cell cancers. To validate these putative super-TFs, we used gene essentiality data from CRISPR-mediated knockout experiments of 18K genes in 625 well characterized cell lines performed by the Broad Institute. We observe statistically significant differences in the essentiality of putative super-TFs in cell lines matching the disease types of clusters. Citation Format: Andre Forbes, Duo Xu, Ekta K. Khurana. Assessing regulatory network rewiring in cancer patients using chromatin accessibility profiles [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 2478.
Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction
Authors: Kieran F. Docherty, Pardeep S. Jhund, Inder Anand, Olof Bengtsson, Michael Böhm, Rudolf A. de Boer, David L. DeMets, Akshay S. Desai, Jaroslaw Drozdz, Jonathan Howlett, Silvio E. Inzucchi, Per Johanson, Tzvetana Katova, Lars Køber, Mikhail N. Kosiborod, Anna Maria Langkilde, Daniel Lindholm, Felipe A. Martinez, Béla Merkely, Jose C. Nicolau, Eileen O’Meara, Piotr Ponikowski, Marc S. Sabatine, Mikaela Sjöstrand, Scott D. Solomon, Sergey Tereshchenko, Subodh Verma, John J.V. McMurray
Journal: Circulation (2020)

In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events.
Abstract 6349: A subgroup of potent CB002 xanthine derivatives define a novel class of anti-cancer drugs that restore the p53 pathway in tumors with mutated p53 and target an S-phase checkpoint
Authors: Liz Janice Hernandez Borrero, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2020)

Abstract Tumor suppressor TP53 is a transcription factor found to be mutated in over 50% of human tumors. Unique to other tumor suppressors, mutations in TP53 result in a stable protein that acquires a gain-of-function activity leading to an aggressive tumor with more metastatic potential and resistance to chemotherapy. The TP53 gene codes for the p53 protein which controls cell survival fate depending on the type of cellular stress signals. A well-known DNA damage stress response signaling pathway involves the activation of ATR/ATM and phosphorylation of Chk1/Chk2 leading to p53 activation and cell cycle arrest. As of now, there are no FDA approved drugs that restore the p53-pathway in any tumors. We previously discovered the parental compound CB002 along with its analogs that are capable of restoring the p53-pathway in tumors with mutated p53. These compounds are xanthine analogs but unlike known xanthines such as caffeine, pentoxifylline and theophylline, they restore the p53 pathway, including upregulation of Noxa, but do not deregulate the G2 checkpoint. Rather, 24 hr treatment in DLD-1 and SW480 cells, shows that our analogs induce p53 transcriptional targets whereas caffeine, pentoxifylline and theophylline do not. In addition, our cell cycle analysis data in synchronized SW480 cells treated with etoposide suggests that CB002 and its analogs perturb the S-phase of the cell cycle and do not deregulate the G2 checkpoint. This is also evidenced by increased p-RPA/RPA2 and cyclin E, and decreased p-histone 3 protein expression. Our microarray data indicates that our p53-pathway restoring xanthine analogs downregulate essential proteins of the DNA synthesis and repair machinery. We are currently investigating the involvement of key kinases and transcriptional factors regulated in S-phase following treatment with CB002 and its more potent analogs. Our data also suggests the activation of ATR in response to CB002 analog treatment in SW480 cells at 24 hrs. We are evaluating the benefit of synthetic lethality of these analogs in BRCA-deficient cell lines, focusing on target identification, determining the proteomic changes and in vivo efficacy of our p53-pathway restoring CB002 xanthine analogs. Taken together, our data suggests that CB002 and its potent xanthine analogs may provide a unique therapeutic strategy that can be clinically translated. Citation Format: Liz Janice Hernandez Borrero, David T. Dicker, Wafik S. El-Deiry. A subgroup of potent CB002 xanthine derivatives define a novel class of anti-cancer drugs that restore the p53 pathway in tumors with mutated p53 and target an S-phase checkpoint [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 6349.
Author Correction: Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes
Authors: Pier Vitale Nuzzo, Jacob E. Berchuck, Keegan Korthauer, Sandor Spisak, Amin H. Nassar, Sarah Abou Alaiwi, Ankur Chakravarthy, Shu Yi Shen, Ziad Bakouny, Francesco Boccardo, John Steinharter, Gabrielle Bouchard, Catherine R. Curran, Wenting Pan, Sylvan C. Baca, Ji-Heui Seo, Gwo-Shu Mary Lee, M. Dror Michaelson, Steven L. Chang, Sushrut S. Waikar, Guru Sonpavde, Rafael A. Irizarry, Mark Pomerantz, Daniel D. De Carvalho, Toni K. Choueiri, Matthew L. Freedman
Journal: Nature Medicine (2020)
Abstract 1511: A highly plastic cell state emerges during lung adenocarcinoma evolution
Authors: Jason Earl Chan, Nemanja Despot Marjanovic, Matan Hofree, David Canner, Katherine Wu, Griffin Hartmann, Olivia C. Smith, Jonathan Kim, Anna Hudson, Ayshwarya Subramanian, Kenneth Pitter, Natasha Rekhtman, Pierre P. Massion, John T. Poirier, Charles M. Rudin, Tyler Jacks, Aviv Regev, Tuomas Tammela
Journal: Cancer Research (2020)

Abstract The role of tumor heterogeneity in the progression of lung adenocarcinoma remains poorly understood. In order to understand how tumor heterogeneity impacts tumor evolution, we profiled single cell transcriptomes from genetically engineered mouse lung tumors at various stages. We observed a set of reproducible transcriptional states whose diversity increased over time. Additionally, we identified a highly plastic cell state that arose in every tumor we obtained. We profiled this cell state and identified a robust potential for phenotypic switching, an increased potential for spheroid formation in tumor sphere cultures, and an enrichment of the highly plastic cell state after chemotherapeutic stress in vivo. Our work suggests that the highly plastic cell state plays a significant role, and perhaps even drives, tumor progression and resistance to therapy in lung adenocarcinoma. Citation Format: Jason Earl Chan, Nemanja Despot Marjanovic, Matan Hofree, David Canner, Katherine Wu, Griffin Hartmann, Olivia C. Smith, Jonathan Kim, Anna Hudson, Ayshwarya Subramanian, Kenneth Pitter, Natasha Rekhtman, Pierre P. Massion, John T. Poirier, Charles M. Rudin, Tyler Jacks, Aviv Regev, Tuomas Tammela. A highly plastic cell state emerges during lung adenocarcinoma evolution [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 1511.
Abstract 4112: OTULIN promotes Wnt/β-Catenin activation by genotoxic treatments and enhances drug-resistance in breast cancer
Authors: Wei Wang, Li Mingqi, Yayun Chi, Jingyan Xue, Beshoy Fahmy, Jiong Wu, Zhaohui Wu
Journal: Cancer Research (2020)

Abstract Patients with basal-like breast cancer and triple-negative breast cancer (TNBC) generally have a worse prognosis than other breast cancer subtypes due to rapid-arising therapeutic resistance accompanied by aggressive metastasis. The drug-resistant tumor cells, including cancer stem-like cells with intrinsic resistance or tumor cells acquired resistance during treatments, could adopt a drug-tolerant state and serve as seeds for recurrent metastatic lesions. However, the molecular events orchestrating the innate and adaptive therapeutic resistance are not completely understood. We found that a linear ubiquitin-specific deubiquitinase OTULIN is overexpressed in breast tumors, especially in the basal-like subtype. Increased OTULIN levels were also observed in PDX samples from chemo-refractory TNBC patients compared to those were responsive to chemotherapy. OTULIN overexpression significantly increased TNBC cell resistance to chemotherapy and is associated with shorter OS and DFS in breast cancer patients. Mechanistically, we found genotoxic treatments induce OTULIN phosphorylation, which is required for the activation of Wnt/β-Catenin signaling in TNBC cells. Inhibiting Wnt/β-Catenin signaling or OTULIN sensitized TNBC xenografts to Doxorubicin treatment in vivo. In TNBC patients, increased OTULIN levels are higher in subtypes enriched with Wnt/β-catenin signaling signature. Our findings suggest that OTULIN may increase TNBC therapeutic resistance and aggressiveness by promoting Wnt/β-Catenin activation in response to chemotherapy. Targeting OTULIN and the chemotherapy-induced Wnt/β-Catenin activation may serve as a promising strategy to mitigate drug resistance and reduce metastasis in TNBC patients. Citation Format: Wei Wang, Li Mingqi, Yayun Chi, Jingyan Xue, Beshoy Fahmy, Jiong Wu, Zhaohui Wu. OTULIN promotes Wnt/β-Catenin activation by genotoxic treatments and enhances drug-resistance in breast 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 4112.